Management of treatment-naïve achalasia: choosing the right therapeutic option

Introduction

Achalasia is a chronic and progressive motility disorder of the esophagus characterized by failure of the lower esophageal sphincter (LES) to relax after swallowing (1). This is associated with aperistalsis and intraluminal pressurization along the esophageal body (2). Together they impair the transit of food from the mouth into the stomach, resulting in gradual onset dysphagia to both solids and liquids. Other symptoms may include regurgitation, chest pain, coughing and weight loss (1). Additionally, patients are at risk of aspiration pneumonia, malnutrition, and esophageal squamous cell carcinoma (3).

Achalasia is an uncommon disease. In the era of high-resolution manometry (HRM), the estimated incidence is 2–3/100,000 persons/year with a prevalence of 1/10,000 Jeny(4-6). Although the incidence increases with age, it does not discriminate between gender or race (7-9).

The etiology of achalasia is not well understood, but is likely multifactorial with infection, autoimmunity and neurodegeneration as contributing factors (10,11). The most common form of achalasia is idiopathic, where there is selective loss of nitric oxide and vasoactive intestinal peptide producing inhibitory neurons within the myenteric plexus of Auerbark (10-12). This leads to unopposed vagal acetylcholine stimulation of the LES and esophageal smooth muscles, resulting in aperistalsis, intraluminal pressurization, and impaired esophageal emptying (13). A similar clinical picture can be seen in patients with proximal gastric cancers (pseudo-achalasia) or Chagas disease, whereby the myenteric plexus is destroyed by tumor infiltration or Trypanosoma cruzi infection, respectively (14,15).

The diagnosis of achalasia is based on a combination of radiologic, manometric, and endoscopic findings. The timed barium esophagram, although operator dependent, is diagnostic in over 80% of cases (16). Pathognomonic findings on barium swallow include the “bird’s beak” appearance at the gastro-esophageal junction (GEJ), dilated esophageal body, aperistalsis, and a barium height of >2 cm at five minutes (17). HRM demonstrates impaired LES relaxation (18), classifies achalasia into three distinct subtypes, and excludes other functional disorders of the esophagus (19). Importantly, upper gastrointestinal endoscopy is required to rule out pseudo-achalasia (20).

This review will focus on the management of idiopathic achalasia. Here, we will discuss the aims of treatment, therapeutic options, their mechanisms of action and clinical outcomes, as well as some pertinent factors to consider when selecting the right treatment modality for patients with treatment-naïve disease.

Treatment objectives in achalasia

There is currently no cure for achalasia. Treatment options are aimed at symptomatic palliation, particularly of dysphagia and regurgitation, to improve quality-of-life (21).

Treatment options and their therapeutic mechanisms

Current therapies for achalasia are aimed at reducing LES pressure (22). This can be accomplished pharmacologically using muscle relaxants or mechanically by dividing muscle fibers. Therapeutic strategies can also be categorized into medical, endoscopic, and surgical modalities.

Medicinal agents include nitric oxide donors (sildenafil and nitrates) and the calcium channel blocker, nifedipine. Glyceryl trinitrate or isosorbide dinitrate are prodrugs which undergo enzymatic metabolism to produce nitric oxide. This metabolite, via intracellular signaling, relaxes smooth muscles (23). Sildenafil potentiates the same pathway by inhibiting phosphodiesterase-mediated degradation of nitric oxide (24). Contrastingly, nifedipine interferes with calcium influx into smooth muscle cells by blocking transmembrane calcium channels, thereby preventing muscle contraction (25). Through these mechanisms, nitrates, sildenafil and nifedipine relaxes the LES. However, as these agents act systemically, they have dose-limiting adverse effects (26).

Endoscopic therapies for achalasia include botulinum toxin (botox) injection, pneumatic balloon dilatation, peroral endoscopic myotomy (POEM), and placement of a self-expanding metallic stent (SEMS). For botox injection, approximately 80–100 units of botulinum toxin is injected into four quadrants of the LES (27). Botox acts by binding presynaptically to high-affinity recognition sites on vagal nerve terminals to decrease acetylcholine release. This causes a neuromuscular blockade leading to relaxation of the LES (28). The effect of botox typically last for 3–12 months (27). Pneumatic balloon dilatation involves stretching and subsequently breaking the LES muscle fibers through the use of a 10 cm long and 30–40 mm diameter high pressure balloon (21). Dilatation can be once-off or undertaken in a graded fashion titrated to the patient’s symptoms. POEM is an advanced endoscopic technique involving division of the inner circular muscle fibers of the distal oesophagus, LES, and gastric cardia through an endoscopically created submucosal tunnel (29). Stenting has been recently proposed as another therapeutic strategy for achalasia. This technique aims to deploy a retrievable 5–10 cm long and 20–30 mm wide, partially or fully covered SEMS across the GEJ to maintain its patency (30).

Surgery for achalasia is an esophago-cardiomyotomy or Heller’s myotomy, whereby the serosal and muscular layers of the distal oesophagus, GEJ, and gastric cardia are divided. The myotomy usually extends 6-8 cm along the anterior surface of the esophagus and 2–3 cm along the lesser curve of the stomach (31-34). This operation is commonly laparoscopic, and incorporates a partial fundoplication to minimize postoperative gastroesophageal reflux (35).

Whilst the plethora of options listed above have all been described, the mainstay of treatment is by and large limited to surgical myotomy, balloon dilation and in palliative cases, botox injection. POEM is increasingly finding favor as an alternative to surgical myotomy but is early in evolution of long-term results.

Treatment considerations

Given the range of treatment options available for achalasia, the choice of intervention should take into account patient, disease, procedural, and surgeon factors. Patient factors include their age, frailty, active co-morbidities, symptomatology, previous esophago-gastric and hiatal surgery, as well as personal preferences. Disease factors include objective measurements of disease severity, underlying esophageal anatomy, achalasia subtype, and whether the patient has presented with treatment-naïve, recurrent or end-stage disease. Procedural factors include the likelihood of achieving technical success and long-term symptomatic remission. This needs to be balanced against the potential adverse outcomes of each intervention. Finally, surgeon expertise and institutional resources may also influence clinical decision making. In the literature, the definition of therapeutic success is variably reported. Outcomes may be assessed using symptoms scores (e.g., Eckardt score) and quality-of-life questionnaires (e.g., SF-36), or determined using radiologic and manometric investigations. Not infrequently however, motility parameters fail to correlate with clinical response to treatment (21).

Therapies for treatment-naïve achalasia

Medical therapy

Muscle relaxants reduce LES pressure and increase esophageal emptying (36-43). However, their symptomatic control is rather disappointing (44), and does not correlate with objective testing (37,45,46). Additionally, common side-effects such as headaches, postural hypotension, tachyphylaxis, and peripheral edema result in poor compliance. Critically, the quality of evidence supporting their use is poor. Existing trials are improperly designed, lack power, and have no long-term follow-up. In a Cochrane review by Wen et al., only two randomized controlled trials (RCT) of nitrates for achalasia were identified. The authors concluded that these studies were inappropriately designed and therefore had no implications on practice (47). Similarly, a systematic review by Bassotti et al. found that there were limited data to demonstrate the effectiveness of nifedipine, nitrates, and sildenafil for patients with achalasia (48). Therefore, in light of poor-quality evidence, limited clinical efficacy, and dose-limiting adverse outcomes, muscle relaxants are currently not recommended for the treatment of achalasia (21).

SEMS

SEMS have been recently proposed as a potential therapeutic strategy for achalasia. They are typically removed 5–6 days after deployment. Experience with SEMS is predominantly limited to several Chinese groups (49-55), with only three case series totaling 26 patients reported from European investigators (56-58). Overall, technical success as defined by adequate stent deployment and immediate symptomatic control was achieved in all patients. Clinical remission at three years post-intervention ranged from 49–85% (51-53,56,59), with one prospective non-randomized study reporting a durable long-term remission rate of 83% at ten years (54,55). This study also compared SEMS with pneumatic balloon dilatation and found that SEMS had superior long-term dysphagic control (SEMS 78% vs. pneumatic balloon dilatation 17%). Similarly, in an RCT of SEMS versus botox injection, SEMS achieved greater symptomatic response (SEMS 49% vs. botox 4%) and lower sphincteric pressures than botox injection at three years post-intervention (53). Despite these encouraging results, patients who received SEMS experienced significantly higher complications than those who underwent pneumatic balloon dilatation or botox injection (53,55). These included bleeding 12% (50,54), chest pain 25–40% (50,54), gastro-esophageal reflux 20% (50,54) and stent migration 5–10% (54), including one case of colonic obstruction by SEMS migration (56). Importantly, the efficacy of SEMS was inconsistent across different studies. For example, in a retrospective analysis by Zhao et al., SEMS and pneumatic balloon dilatation achieved comparable remission rates (SEMS 47% vs. pneumatic balloon dilatation 53%) at three years (51). Taken together, due to limited global experience and variable efficacy, there is currently insufficient evidence to support the general use of retrievable SEMS for patients with achalasia (60). Certainly, the authors would caution against this strategy.

Botulinum toxin (Botox) injection

Botox was first proposed as a treatment option for achalasia over 20 years ago (61). Despite its modest clinical efficacy, botox injection is still used today owing to a very high safety profile. On the basis of symptomatic, radiologic and manometric assessment, botox injection has an overall technical failure rate of 10–35% due to inadequate dosing and misplaced injections (62-66). In patients who respond to botox therapy, symptomatic control typically lasts for 3–12 months after the first injection (66-68), and 8–16 months after the second injection (66,68,69). Clinical response is associated with a 30–40% reduction in mean sphincteric pressure (70), but it is unclear whether treatments beyond the second injection further extends the clinical remission period. Botox injection is generally well tolerated with commonly described adverse effects including chest discomfort and gastro-esophageal reflux in 5–20% of patients. Rarely, bleeding, mucosal ulceration, mediastinitis, and allergic reactions can occur.

Several RCTs have compared the outcomes of botox injection to pneumatic balloon dilatation and laparoscopic Heller’s myotomy (Table 1) (53,62,63,65,71-74). Compared to pneumatic balloon dilatation, botox injection achieved equivalent symptomatic control at six months post-intervention. However by one year, disease recurrence was significantly higher in the botox injection cohort (63,65,69,71,72,75). A Cochrane meta-analysis of five RCTs found that despite similar clinical and manometric outcomes between pneumatic balloon dilatation and botox injection at one month post-treatment, remissions rates were significantly lower at 6 (Pneumatic balloon dilatation 81% vs. Botox injection 52%, RR: 1.57, 95% CI: 1.19–2.09) and 12 (Pneumatic balloon dilatation 73% vs. Botox injection 38%, RR: 1.88, 95% CI: 1.35–2.61) months in patients who received botox injection. Complication rates were comparable between the two groups, however, three cases of esophageal perforation were identified in the pneumatic balloon dilatation cohort (76). Similarly, whilst symptom control and sphincteric pressures were comparable between botox injection and laparoscopic Heller’s myotomy at six months post-intervention, disease remission was significantly higher in patients who underwent laparoscopic Heller’s myotomy than botox injection at two years (77). The efficacy of combining botox injection with pneumatic balloon dilatation has also been evaluated in three prospective trials (66,73,78). Combination botox injection and pneumatic balloon dilatation achieved greater symptomatic response, lower sphincteric pressures, and longer disease remission than single modality therapy across all studies.

Numerous studies have sought to identify predictors of therapeutic response to botox injection. Amongst the many factors that have been evaluated, older age (>50 years) and a low baseline sphincteric pressure (<40 mmHg) are favorable predictors of response and durability (64,66,79,80). Although not validated across all studies (72,77), younger patients are associated with higher rates of complications from botox injection (81). Based on these findings, botox injection may be recommended as first line therapy for achalasia in patients over 50 years of age, with low baseline sphincter pressures, who are co-morbid and unfit for other more invasive therapies (pneumatic balloon dilatation, laparoscopic Heller’s myotomy, or POEM). Botox injection may also be used in conjunction with pneumatic balloon dilatation to augment treatment response.

Pneumatic balloon dilatation

Pneumatic balloon dilatation was first introduced in the same era as botox injection (82). Overall, technical success as defined by improvement in symptoms scores within the first month post-dilatation, ranges from 75–96% (63,65,67,83-85). Clinical response typically lasts for 10–12 months (78,86) with repeated dilatations lengthening the remission period. In a retrospective analysis by West et al., patients who underwent 3–7 dilatations were found to have a clinical relapse rate of 60% at 15 years (87). Symptomatic response was associated with a 20–30% decrease in mean sphincteric pressure, and a 30% reduction in esophageal diameter (88). Commonly reported adverse events included chest pain 27% (54), bleeding 5% (54), and gastro-esophageal reflux 5–40% (83,84,88-91). Esophageal perforation occurred in 1-8% of dilatations (83,88,91-95), a major complication potentially resulting in significant patient morbidity. Perforation risk was highest in patients over 65 years of age, with high amplitude distal esophageal contractions, undergoing their first dilatation, and/or using a Witzel dilator (as compared with the Rigiflex balloon from Boston Scientific) (94).

Pneumatic balloon dilatation has been compared to laparoscopic Heller’s myotomy in several RCTs (Table 2) (82,85,90,92,95-99). At one year post-intervention, patient who underwent laparoscopic Heller’s myotomy achieved better symptomatic control than those who were dilated (85,100). This difference however, was not appreciable at two years, with most trials demonstrating comparable remission rates, LES pressures, esophageal emptying times and quality-of-life scores at two, five and six years of follow-up (95-97,99,101). Only two studies have reported a higher remission rate in the laparoscopic Heller’s myotomy group at five years post-intervention (82,102). Similarly, two meta-analyses inferred a relative therapeutic equivalence between pneumatic balloon dilatation and laparoscopic Heller’s myotomy in the short to medium term (103,104). Pneumatic balloon dilatation however, is associated with higher rates of gastro-esophageal reflux (82,84,97), and esophageal perforation than laparoscopic Heller’s myotomy (95,103,104).

Pond et al. compared pneumatic balloon dilatation to POEM in a world-first RCT (90). They found that despite dilating with a 40 mm diameter balloon, remission rates at three, twelve and twenty-four months were inferior to the POEM cohort. POEM also resulted in lower sphincteric pressures and improved esophageal emptying but was associated with a significantly higher rate of gastro-esophageal reflux.

The predictors of therapeutic response to pneumatic balloon dilatation are similar to those identified for botox injection. These include older age (>40 years), type 2 achalasia (Chicago classification v3), and a post-dilatation LES pressure <10 mmHg (105-107). Although not confirmed in all studies (88,108), male gender, daily chest pain, age <40 years, type 3 achalasia, severely delayed esophageal emptying (on timed barium swallow), and a pre-treatment esophageal diameter <4 cm are potential predictors of treatment failure (92,95).

In summary, pneumatic balloon dilatation may be recommended as first line therapy for achalasia in patients over 40 years of age with type 2 achalasia who decline laparoscopic Heller’s myotomy or POEM and accept the risk of esophageal perforation associated with pneumatic balloon dilatation.

POEM

POEM is a relatively novel technique introduced in the last decade for the treatment of achalasia. As a result, outcome data is limited with most reporting single center retrospective series with short to medium term follow-up. Overall, the technical success rate for this procedure, as defined by an Eckardt score ≤3 within three months post-intervention, ranged from 90–100% (90,109-111). Symptomatic relapse at three years was approximately 10–15% (111-113), with a projected median symptom-free interval of five years (112,114). Clinical response to POEM was typically associated with a mean LES pressure reduction of 60–70% (109,112), a decrease in mean barium height of 80% (114), and significant improvements in quality-of-life scores at one year post-intervention (115). The learning curve for POEM is estimated to be 7–40 cases (116-119).

Based on two large systematic reviews, the POEM procedure has a major complication rate of 2.7–3.3% and an overall mortality rate of less than 0.1% (114,120). The potentially life-threatening complications include esophageal perforation and bleeding (109,121) and, although not life-threatening, POEM results in the highest rate of gastro-esophageal reflux amongst all therapies for achalasia (21). As evidenced by pH monitoring, the risk of abnormal esophageal acid exposure has been reported to be as high as 88% after POEM (122). Despite a relatively poor correlation between objective testing and clinical disease (122,123), 10-65% of patients experience symptomatic reflux within one year of POEM (90,109,113,114,121,124,125). The risk of developing gastro-esophageal reflux disease (GERD), along with the severity of reflux, also increases with time (112). Hiatus hernia and obesity have been found to be predictors of GERD development (116), and although most patients responded to proton pump inhibitors, they became dependent on this therapy (122).

Comparative studies between POEM and laparoscopic Heller’s myotomy have uniformly demonstrated equivalence in most intraoperative and postoperative domains (110,114,126-132), including operative time, analgesic requirements and complication rates. Functional outcomes such as Eckardt scores, LES pressures, esophageal emptying times, and quality-of-life measures were also comparable between the two modalities. In some studies, POEM was associated with a slightly shorter (<24 h) length of stay (130,133). The risk of GERD however, was markedly higher in the POEM cohort than those who underwent laparoscopic Heller’s myotomy (132,134-136). These findings are quantified by a large meta-analysis, which demonstrated that POEM and laparoscopic Heller’s myotomy have similar remission rates at one (94% vs. 91%) and two (93% vs. 90%) years of follow-up. The risk of abnormal esophageal acid exposure (OR 4.3, 95% CI: 2.96–6.27), erosive esophagitis (OR 9.31, 95% CI: 4.71–19.85), and GERD (OR 1.69, 95% CI: 1.33–2.14) were significantly higher in the POEM cohort (137).

Several studies have analyzed potential predictors of therapeutic outcome for POEM. Similar to botox injection and pneumatic balloon dilatation, younger age and type 3 achalasia have been associated with early disease relapse (110,113). These factors however, have not been validated in other studies (109).

In summary, POEM has been validated as a treatment option for achalasia. It achieves excellent outcomes in the short to medium term whilst being less invasive than laparoscopic Heller’s myotomy. Given the lack of long-term outcome data, and a relatively higher risk of postoperative GERD, POEM may be most appropriate for older patients, and those with greater co-morbidities (133).

Heller’s myotomy

Heller’s cardiomyotomy is regarded as the gold standard treatment for achalasia (21). This procedure was initially performed via an open trans-thoracic or trans-hiatal approach (138,139). With advances in minimally invasive technology over the last 30 years, most surgeons have elected to myotomize the esophagus via a laparoscopic trans-hiatal route (139). Overall, this technique has excellent efficacy with a technical success rate, as defined by a decrease in symptoms score within the first three months post laparoscopic Hellers myotomy, ranging from 80–100% in contemporary series (67,84). This is associated with a mean LES pressure reduction of 40–80% (140). Prospective trials have reported a five-year recurrence rate post laparoscopic Heller’s myotomy of approximately 5–15% (82,95). Retrospective studies have demonstrated durable disease control from laparoscopic Heller’s myotomy with 20–30% of patients experiencing clinical relapse (141,142). The failure to alleviate dysphagia is partly attributed to inadequate myotomy length (31,33,142). The learning curve for laparoscopic Heller’s myotomy is relatively short and is estimated to be 16–20 cases (143,144).

Laparoscopic Heller’s myotomy has a high safety profile. In a single center series of 400 patients by Zaninotto et al., their reported morbidity and mortality rates were 2% and 0% respectively (33). Causes of postoperative complications include mucosal perforation, splenic injury, pneumothorax and wound bleeding (33). GERD is the most common long-term adverse outcome following laparoscopic Heller’s myotomy (145) and its incidence increases with time (141). In those who have undergone a concurrent fundoplication, 7–15% of patients have abnormal acid exposure on pH monitoring (85,141,146-149). This is associated with a 5–11% risk of erosive esophagitis (149), and 2–7% risk of symptomatic reflux (149-151). Without fundoplication, the rate of symptomatic reflux, as reported by Jara et al., increases from 24% at one year to 48% at ten years post laparoscopic Heller’s myotomy (141). Data from RCTs have shown that a partial fundoplication procedure (either anterior 180 or posterior 270 degrees) significantly reduced the risk of GERD post laparoscopic Heller’s myotomy (35,152), without compromising the swallowing function of a myotomy (153). There appeared to be no difference in reflux control between a Dor or Toupet fundoplication (154,155). In contrast, Rebecchi et al. demonstrated in their RCT that a 360-degree Nissen fundoplication generated more dysphagia without additional reflux control at five years of follow-up (151).

Based on trials highlighted above, laparoscopic Heller’s myotomy with fundoplication achieves superior achalasia-related symptomatic control than botox injection, but has similar medium-term efficacy when compared with pneumatic balloon dilatation and POEM. Importantly, in comparison to pneumatic balloon dilatation and POEM, laparoscopic Heller’s myotomy with fundoplication has the lowest rate of post-interventional GERD.

The factors that predict therapeutic success post-LHM include: age >40 years, pre-treatment LES pressures >30 mmHg, and post-treatment LES pressures <18 mmHg or a >50% decrease in LES pressures (33,97,156). Conversely, the factors that predict treatment failure include male gender, daily chest pain, severe preoperative dysphagia, sigmoid esophagus, and type 3 achalasia (33, 150).

Taken together, laparoscopic Heller’s myotomy with fundoplication is the current standard of care for patients with achalasia. This procedure should be recommended to patients who are young, fit for surgery, with high baseline LES pressures, and who are not prepared to accept the higher risk of GERD that is associated with pneumatic balloon dilatation and POEM.

Therapies for different subtypes of achalasia

The advent of HRM has enabled the reclassification of achalasia into three distinct subtypes (19). As detailed in the Chicago Classification version 3.0 (157), type 1 achalasia is characterized by aperistalsis without abnormal esophageal pressures, type 2 features aperistalsis with intermittent periods of pan-esophageal pressurization, and type 3 is defined as aperistalsis with distal esophageal spastic contractions (27). Type 2 is the most prevalent, accounting for 65% of all presentations. Types 1 and 3 constitutes the remaining 25% and 10%, respectively (158). Importantly, these subtypes predict therapeutic outcomes (159). Type 2 achalasia exhibit the greatest response to botox injection, pneumatic balloon dilatation, laparoscopic Heller’s myotomy and POEM (96–100%). This is followed by types 1 (56–81%) and 3 (29–66%) (19,116). A meta-analysis of non-randomized studies supports these findings (160). Furthermore, disease recurrence is lowest in type 2 and highest in type 3 achalasia (27,158). In a series of 246 consecutive patients, Salvador et al. found that clinical relapse at six months post laparoscopic Heller’s myotomy was 5%, 15% and 30% for subtypes 2, 1 and 3, respectively (161).

Currently, there is insufficient evidence to enable personalized therapy based on HRM alone. There are no trials that specifically compare the efficacy of botox injection across different achalasia subtypes. In a post-hoc analysis of a multicenter European trial which randomized patients to pneumatic balloon dilatation or laparoscopic Heller’s myotomy, Rohof et al. found that at two years post-treatment, pneumatic balloon dilatation achieved greater symptomatic control than laparoscopic Heller’s myotomy in those with type 2 achalasia (158). This difference, despite being statistically significant, was small in effect (pneumatic balloon dilatation 100% vs. laparoscopic Heller’s myotomy 93%). In the same analysis, laparoscopic Heller’s myotomy had a higher success rate than pneumatic balloon dilatation for patients with type 3 achalasia (laparoscopic Heller’s myotomy 86% vs. pneumatic balloon dilatation 40%). However, this comparison failed to reach statistical significance due to low patient numbers (158).

Laparoscopic Heller’s myotomy is the current gold standard for the treatment of type 3 achalasia. However, POEM is conceivably superior as it allows for a longer myotomy. Despite a paucity of studies in this area, available data suggests that POEM is effective for patients with type 3 achalasia. Reported disease remission rates at 19, 27 and 40 months post-POEM are 90% (116), 89% (126), and 87% (113) respectively. In a retrospective study comparing POEM to laparoscopic Heller’s myotomy in patients with type 3 achalasia, POEM achieved significantly higher clinical response (POEM 98% vs. laparoscopic Heller’s myotomy 81%), shorter operative time (median, POEM: 102 min vs. laparoscopic Heller’s myotomy 264 min), longer myotomy length (median, POEM 16 cm vs. laparoscopic Heller’s myotomy 8 cm), and lower perioperative adverse events (162).

In summary, manometric subtypes of achalasia have prognostic value. Type 2 predicts favorable response and type 3 is associated with disease recurrence for all treatment modalities. Laparoscopic Heller’s myotomy, pneumatic balloon dilatation and POEM have similar efficacy for types 1 and 2. In type 3 achalasia, laparoscopic Heller’s myotomy is potentially more efficacious than pneumatic balloon dilatation, whilst POEM may be an overall superior alternative. Despite these findings, treatment decisions should be holistic and not based solely on HRM classification.

Conclusions

Although an uncommon disease, achalasia is the most well-defined esophageal motility disorder. Multiple treatment options have been proposed with a wide range of therapeutic efficacies and safety profiles. It is crucial to consider patient, disease, procedural, and surgeon factors (Table 3) when tailoring the right therapeutic approach for patients with treatment-naïve disease.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Sarah K. Thompson) for the series “Achalasia” published in Annals of Esophagus. The article has undergone external peer review.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/aoe.2020.04.03). The series “Achalasia” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Boeckxstaens GE, Zaninotto G, Richter JE. Achalasia. Lancet 2014;383:83-93. [Crossref] [PubMed]
2. Patel DA, Lappas BM, Vaezi MF. An Overview of Achalasia and Its Subtypes. Gastroenterol Hepatol (N Y) 2017;13:411-21. [PubMed]
3. Eckardt VF, Hoischen T, Bernhard G. Life expectancy, complications, and causes of death in patients with achalasia: results of a 33-year follow-up investigation. Eur J Gastroenterol Hepatol 2008;20:956-60. [Crossref] [PubMed]
4. Samo S, Carlson DA, Gregory DL, et al. Incidence and Prevalence of Achalasia in Central Chicago, 2004-2014, Since the Widespread Use of High-Resolution Manometry. Clin Gastroenterol Hepatol 2017;15:366-73. [Crossref] [PubMed]
5. Duffield JA, Hamer PW, Heddle R, et al. Incidence of Achalasia in South Australia Based on Esophageal Manometry Findings. Clin Gastroenterol Hepatol 2017;15:360-5. [Crossref] [PubMed]
6. van Hoeij FB, Ponds FA, Smout AJ, Bredenoord AJ. Incidence and costs of achalasia in The Netherlands. Neurogastroenterol Motil 2018;30. [PubMed]
7. Farrukh A, DeCaestecker J, Mayberry JF. An epidemiological study of achalasia among the South Asian population of Leicester, 1986-2005. Dysphagia 2008;23:161-4. [Crossref] [PubMed]
8. Sadowski DC, Ackah F, Jiang B, et al. Achalasia: incidence, prevalence and survival. A population-based study. Neurogastroenterol Motil 2010;22:e256-61. [Crossref] [PubMed]
9. Birgisson S, Richter JE. Achalasia in Iceland, 1952-2002: an epidemiologic study. Dig Dis Sci 2007;52:1855-60. [Crossref] [PubMed]
10. Park W, Vaezi MF. Etiology and pathogenesis of achalasia: the current understanding. Am J Gastroenterol 2005;100:1404-14. [Crossref] [PubMed]
11. Sodikoff JB, Lo AA, Shetuni BB, et al. Histopathologic patterns among achalasia subtypes. Neurogastroenterol Motil 2016;28:139-45. [Crossref] [PubMed]
12. Mearin F, Mourelle M, Guarner F, et al. Patients with achalasia lack nitric oxide synthase in the gastro-oesophageal junction. Eur J Clin Invest 1993;23:724-8. [Crossref] [PubMed]
13. Clark SB, Rice TW, Tubbs RR, et al. The nature of the myenteric infiltrate in achalasia: an immunohistochemical analysis. Am J Surg Pathol 2000;24:1153-8. [Crossref] [PubMed]
14. Tracey JP, Traube M. Difficulties in the diagnosis of pseudoachalasia. Am J Gastroenterol 1994;89:2014-8. [PubMed]
15. Herbella FA, Aquino JL, Stefani-Nakano S, et al. Treatment of achalasia: lessons learned with Chagas' disease. Dis Esophagus 2008;21:461-7. [Crossref] [PubMed]
16. de Oliveira JM, Birgisson S, Doinoff C, et al. Timed barium swallow: a simple technique for evaluating esophageal emptying in patients with achalasia. AJR Am J Roentgenol 1997;169:473-9. [Crossref] [PubMed]
17. Blonski W, Kumar A, Feldman J, et al. Timed Barium Swallow: Diagnostic Role and Predictive Value in Untreated Achalasia, Esophagogastric Junction Outflow Obstruction, and Non-Achalasia Dysphagia. Am J Gastroenterol 2018;113:196-203. [Crossref] [PubMed]
18. Pandolfino JE, Ghosh SK, Rice J, et al. Classifying esophageal motility by pressure topography characteristics: a study of 400 patients and 75 controls. Am J Gastroenterol 2008;103:27-37. [Crossref] [PubMed]
19. Pandolfino JE, Kwiatek MA, Nealis T, et al. Achalasia: a new clinically relevant classification by high-resolution manometry. Gastroenterology 2008;135:1526-33. [Crossref] [PubMed]
20. Müller M, Eckardt AJ, Wehrmann T. Endoscopic approach to achalasia. World J Gastrointest Endosc 2013;5:379-90. [Crossref] [PubMed]
21. Zaninotto G, Bennett C, Boeckxstaens G, et al. The 2018 ISDE achalasia guidelines. Dis Esophagus 2018;31. [PubMed]
22. Tuason J, Inoue H. Current status of achalasia management: a review on diagnosis and treatment. J Gastroenterol 2017;52:401-6. [Crossref] [PubMed]
23. Torfgård KE, Ahlner J. Mechanisms of action of nitrates. Cardiovasc Drugs Ther 1994;8:701-17. [Crossref] [PubMed]
24. Francis SH, Corbin JD. Sildenafil: efficacy, safety, tolerability and mechanism of action in treating erectile dysfunction. Expert Opin Drug Metab Toxicol 2005;1:283-93. [Crossref] [PubMed]
25. Reid JL, Millar JA, Struthers AD. Nifedipine--studies on its mechanism of action and interaction with other circulatory control mechanisms in man. Postgrad Med J 1983;59:98-103. [PubMed]
26. Nassri A, Ramzan Z. Pharmacotherapy for the management of achalasia: Current status, challenges and future directions. World J Gastrointest Pharmacol Ther 2015;6:145-55. [Crossref] [PubMed]
27. Pandolfino JE, Gawron AJ. Achalasia: a systematic review. JAMA 2015;313:1841-52. [Crossref] [PubMed]
28. Dressler D, Saberi FA, Barbosa ER. Botulinum toxin: mechanisms of action. Arq Neuropsiquiatr 2005;63:180-5. [Crossref] [PubMed]
29. Banks M, Sweis R. POEM and the management of achalasia. Frontline Gastroenterol 2017;8:143-7. [Crossref] [PubMed]
30. Sioulas AD, Malli C, Dimitriadis GD, et al. Self-expandable metal stents for achalasia: Thinking out of the box! World J Gastrointest Endosc 2015;7:45-52. [Crossref] [PubMed]
31. Oelschlager BK, Chang L, Pellegrini CA. Improved outcome after extended gastric myotomy for achalasia. Arch Surg 2003;138:490-5. [Crossref] [PubMed]
32. Wright AS, Williams CW, Pellegrini CA, et al. Long-term outcomes confirm the superior efficacy of extended Heller myotomy with Toupet fundoplication for achalasia. Surg Endosc 2007;21:713-8. [Crossref] [PubMed]
33. Zaninotto G, Costantini M, Rizzetto C, et al. Four hundred laparoscopic myotomies for esophageal achalasia: a single centre experience. Ann Surg 2008;248:986-93. [Crossref] [PubMed]
34. Teitelbaum EN, Soper NJ, Pandolfino JE, et al. An extended proximal esophageal myotomy is necessary to normalize EGJ distensibility during Heller myotomy for achalasia, but not POEM. Surg Endosc 2014;28:2840-7. [Crossref] [PubMed]
35. Campos GM, Vittinghoff E, Rabl C, et al. Endoscopic and surgical treatments for achalasia: a systematic review and meta-analysis. Ann Surg 2009;249:45-57. [Crossref] [PubMed]
36. Gelfond M, Rozen P, Gilat T. Isosorbide dinitrate and nifedipine treatment of achalasia: a clinical, manometric and radionuclide evaluation. Gastroenterology 1982;83:963-9. [Crossref] [PubMed]
37. Triadafilopoulos G, Aaronson M, Sackel S, et al. Medical treatment of esophageal achalasia. Double-blind crossover study with oral nifedipine, verapamil, and placebo. Dig Dis Sci 1991;36:260-7. [Crossref] [PubMed]
38. Bortolotti M, Labo G. Clinical and manometric effects of nifedipine in patients with esophageal achalasia. Gastroenterology 1981;80:39-44. [Crossref] [PubMed]
39. Nasrallah SM, Tommaso CL, Singleton RT, et al. Primary esophageal motor disorders: clinical response to nifedipine. South Med J 1985;78:312-5. [Crossref] [PubMed]
40. Traube M, Dubovik S, Lange RC, et al. The role of nifedipine therapy in achalasia: results of a randomized, double-blind, placebo-controlled study. Am J Gastroenterol 1989;84:1259-62. [PubMed]
41. Coccia G, Bortolotti M, Michetti P, et al. Prospective clinical and manometric study comparing pneumatic dilatation and sublingual nifedipine in the treatment of oesophageal achalasia. Gut 1991;32:604-6. [Crossref] [PubMed]
42. Bortolotti M, Mari C, Lopilato C, et al. Effects of sildenafil on esophageal motility of patients with idiopathic achalasia. Gastroenterology 2000;118:253-7. [Crossref] [PubMed]
43. Eherer AJ, Schwetz I, Hammer HF, et al. Effect of sildenafil on oesophageal motor function in healthy subjects and patients with oesophageal motor disorders. Gut 2002;50:758-64. [Crossref] [PubMed]
44. Storr M, Allescher HD. Esophageal pharmacology and treatment of primary motility disorders. Dis Esophagus 1999;12:241-57. [Crossref] [PubMed]
45. Bassotti G, D'Onofrio V, Battaglia E, et al. Treatment with botulinum toxin of octo-nonagerians with oesophageal achalasia: a two-year follow-up study. Aliment Pharmacol Ther 2006;23:1615-9. [Crossref] [PubMed]
46. Kim CH, Cameron AJ, Hsu JJ, et al. Achalasia: prospective evaluation of relationship between lower esophageal sphincter pressure, esophageal transit, and esophageal diameter and symptoms in response to pneumatic dilation. Mayo Clin Proc 1993;68:1067-73. [Crossref] [PubMed]
47. Wen ZH, Gardener E, Wang YP. Nitrates for achalasia. Cochrane Database Syst Rev 2004;CD002299 [PubMed]
48. Bassotti G, Annese V. Review article: pharmacological options in achalasia. Aliment Pharmacol Ther 1999;13:1391-6. [Crossref] [PubMed]
49. Dai J, Shen Y, Li X, et al. Long-term efficacy of modified retrievable stents for treatment of achalasia cardia. Surg Endosc 2016;30:5295-303. [Crossref] [PubMed]
50. Cheng YS, Li MH, Chen WX, et al. Selection and evaluation of three interventional procedures for achalasia based on long-term follow-up. World J Gastroenterol 2003;9:2370-3. [Crossref] [PubMed]
51. Zhao H, Wan XJ, Yang C. Comparison of endoscopic balloon dilation with metal stentplacement in the treatment of achalasia. J Dig Dis 2015;16:311-8. [Crossref] [PubMed]
52. Zeng Y, Dai YM, Wan XJ. Clinical remission following endoscopic placement of retrievable, fully covered metal stents in patients with esophageal achalasia. Dis Esophagus 2014;27:103-8. [Crossref] [PubMed]
53. Cai XB, Dai YM, Wan XJ, et al. Comparison between botulinum injection and removable covered self-expanding metal stents for the treatment of achalasia. Dig Dis Sci 2013;58:1960-6. [Crossref] [PubMed]
54. Li YD, Cheng YS, Li MH, et al. Temporary self-expanding metallic stents and pneumatic dilation for the treatment of achalasia: a prospective study with a long-term follow-up. Dis Esophagus 2010;23:361-7. [PubMed]
55. Li YD, Tang GY, Cheng YS, et al. 13-year follow-up of a prospective comparison of the long-term clinical efficacy of temporary self-expanding metallic stents and pneumatic dilatation for the treatment of achalasia in 120 patients. AJR Am J Roentgenol 2010;195:1429-37. [Crossref] [PubMed]
56. De Palma GD. Self-expanding metal stents for endoscopic treatment of esophageal achalasia unresponsive to conventional treatments. Long-term results in eight patients. Endoscopy 2001;33:1027-30. [Crossref] [PubMed]
57. Coppola F, Gaia S, Rolle E, et al. Temporary endoscopic metallic stent for idiopathic esophageal achalasia. Surg Innov 2014;21:11-4. [Crossref] [PubMed]
58. Rieder E, Asari R, Paireder M, et al. Endoscopic stent suture fixation for prevention of esophageal stent migration during prolonged dilatation for achalasia treatment. Dis Esophagus 2017;30:1-6. [Crossref] [PubMed]
59. Cheng YS, Ma F, Li YD, et al. Temporary self-expanding metallic stents for achalasia: a prospective study with a long-term follow-up. World J Gastroenterol 2010;16:5111-7. [Crossref] [PubMed]
60. Mukherjee S, Kaplan D, Parasher G, et al. Expandable metal stents in achalasia--is there a role? Am J Gastroenterol 2000;95:2185-8. [PubMed]
61. Pasricha PJ, Ravich WJ, Hendrix TR, et al. Treatment of achalasia with intrasphincteric injection of botulinum toxin. A pilot trial. Ann Intern Med 1994;121:590-1. [Crossref] [PubMed]
62. Bansal R, Nostrant TT, Scheiman JM, et al. Intrasphincteric botulinum toxin versus pneumatic balloon dilation for treatment of primary achalasia. J Clin Gastroenterol 2003;36:209-14. [Crossref] [PubMed]
63. Muehldorfer SM, Schneider TH, Hochberger J, et al. Esophageal achalasia: intrasphincteric injection of botulinum toxin A versus balloon dilation. Endoscopy 1999;31:517-21. [Crossref] [PubMed]
64. Neubrand M, Scheurlen C, Schepke M, et al. Long-term results and prognostic factors in the treatment of achalasia with botulinum toxin. Endoscopy 2002;34:519-23. [Crossref] [PubMed]
65. Ghoshal UC, Chaudhuri S, Pal BB, et al. Randomized controlled trial of intrasphincteric botulinum toxin A injection versus balloon dilatation in treatment of achalasia cardia. Dis Esophagus 2001;14:227-31. [Crossref] [PubMed]
66. Martínek J, Siroky M, Plottova Z, et al. Treatment of patients with achalasia with botulinum toxin: a multicenter prospective cohort study. Dis Esophagus 2003;16:204-9. [Crossref] [PubMed]
67. Vela MF, Richter JE, Wachsberger D, et al. Complexities of managing achalasia at a tertiary referral center: use of pneumatic dilatation, Heller myotomy, and botulinum toxin injection. Am J Gastroenterol 2004;99:1029-36. [Crossref] [PubMed]
68. Martínek J, Spicak J. A modified method of botulinum toxin injection in patients with achalasia: a pilot trial. Endoscopy 2003;35:841-4. [Crossref] [PubMed]
69. Annese V, Basciani M, Perri F, et al. Controlled trial of botulinum toxin injection versus placebo and pneumatic dilation in achalasia. Gastroenterology 1996;111:1418-24. [Crossref] [PubMed]
70. Pasricha PJ, Ravich WJ, Hendrix TR, et al. Intrasphincteric botulinum toxin for the treatment of achalasia. N Engl J Med 1995;332:774-8. [Crossref] [PubMed]
71. Vaezi MF, Richter JE, Wilcox CM, et al. Botulinum toxin versus pneumatic dilatation in the treatment of achalasia: a randomised trial. Gut 1999;44:231-9. [Crossref] [PubMed]
72. Mikaeli J, Fazel A, Montazeri G, et al. Randomized controlled trial comparing botulinum toxin injection to pneumatic dilatation for the treatment of achalasia. Aliment Pharmacol Ther 2001;15:1389-96. [Crossref] [PubMed]
73. Zhu Q, Liu J, Yang C. Clinical study on combined therapy of botulinum toxin injection and small balloon dilation in patients with esophageal achalasia. Dig Surg 2009;26:493-8. [Crossref] [PubMed]
74. Zaninotto G, Marchese Ragona R, Briani C, et al. The role of botulinum toxin injection and upper esophageal sphincter myotomy in treating oropharyngeal dysphagia. J Gastrointest Surg 2004;8:997-1006. [Crossref] [PubMed]
75. Allescher HD, Storr M, Seige M, et al. Treatment of achalasia: botulinum toxin injection vs. pneumatic balloon dilation. A prospective study with long-term follow-Up. Endoscopy 2001;33:1007-17. [Crossref] [PubMed]
76. Leyden JE, Moss AC, MacMathuna P. Endoscopic pneumatic dilation versus botulinum toxin injection in the management of primary achalasia. Cochrane Database Syst Rev 2014;CD005046 [PubMed]
77. Zaninotto G, Annese V, Costantini M, et al. Randomized controlled trial of botulinum toxin versus laparoscopic heller myotomy for esophageal achalasia. Ann Surg 2004;239:364-70. [Crossref] [PubMed]
78. Mikaeli J, Bishehsari F, Montazeri G, et al. Injection of botulinum toxin before pneumatic dilatation in achalasia treatment: a randomized-controlled trial. Aliment Pharmacol Ther 2006;24:983-9. [Crossref] [PubMed]
79. D'Onofrio V, Miletto P, Leandro G, et al. Long-term follow-up of achalasia patients treated with botulinum toxin. Dig Liver Dis 2002;34:105-10. [Crossref] [PubMed]
80. Pasricha PJ, Rai R, Ravich WJ, et al. Botulinum toxin for achalasia: long-term outcome and predictors of response. Gastroenterology 1996;110:1410-5. [Crossref] [PubMed]
81. van Hoeij FB, Tack JF, Pandolfino JE, et al. Complications of botulinum toxin injections for treatment of esophageal motility disordersdagger. Dis Esophagus 2017;30:1-5. [PubMed]
82. Csendes A, Braghetto I, Henriquez A, et al. Late results of a prospective randomised study comparing forceful dilatation and oesophagomyotomy in patients with achalasia. Gut 1989;30:299-304. [Crossref] [PubMed]
83. Zerbib F, Thetiot V, Richy F, et al. Repeated pneumatic dilations as long-term maintenance therapy for esophageal achalasia. Am J Gastroenterol 2006;101:692-7. [Crossref] [PubMed]
84. Novais PA, Lemme EM. 24-h pH monitoring patterns and clinical response after achalasia treatment with pneumatic dilation or laparoscopic Heller myotomy. Aliment Pharmacol Ther 2010;32:1257-65. [Crossref] [PubMed]
85. Hamdy E, El Nakeeb A, El Hanfy E, et al. Comparative Study Between Laparoscopic Heller Myotomy Versus Pneumatic Dilatation for Treatment of Early Achalasia: A Prospective Randomized Study. J Laparoendosc Adv Surg Tech A 2015;25:460-4. [Crossref] [PubMed]
86. Javed AT, Batte K, Khalaf M, et al. Durability of pneumatic dilation monotherapy in treatment-naive achalasia patients. BMC Gastroenterol 2019;19:181. [Crossref] [PubMed]
87. West RL, Hirsch DP, Bartelsman JF, et al. Long term results of pneumatic dilation in achalasia followed for more than 5 years. Am J Gastroenterol 2002;97:1346-51. [Crossref] [PubMed]
88. Bravi I, Nicita MT, Duca P, et al. A pneumatic dilation strategy in achalasia: prospective outcome and effects on oesophageal motor function in the long term. Aliment Pharmacol Ther 2010;31:658-65. [Crossref] [PubMed]
89. Leeuwenburgh I, Van Dekken H, Scholten P, et al. Oesophagitis is common in patients with achalasia after pneumatic dilatation. Aliment Pharmacol Ther 2006;23:1197-203. [Crossref] [PubMed]
90. Ponds FA, Fockens P, Lei A, et al. Effect of Peroral Endoscopic Myotomy vs Pneumatic Dilation on Symptom Severity and Treatment Outcomes Among Treatment-Naive Patients With Achalasia: A Randomized Clinical Trial. JAMA 2019;322:134-44. [Crossref] [PubMed]
91. Dobrucali A, Erzin Y, Tuncer M, et al. Long-term results of graded pneumatic dilatation under endoscopic guidance in patients with primary esophageal achalasia. World J Gastroenterol 2004;10:3322-7. [Crossref] [PubMed]
92. Boeckxstaens GE, Annese V, des Varannes SB, et al. Pneumatic dilation versus laparoscopic Heller's myotomy for idiopathic achalasia. N Engl J Med 2011;364:1807-16. [Crossref] [PubMed]
93. Elliott TR, Wu PI, Fuentealba S, et al. Long-term outcome following pneumatic dilatation as initial therapy for idiopathic achalasia: an 18-year single-centre experience. Aliment Pharmacol Ther 2013;37:1210-9. [Crossref] [PubMed]
94. Borotto E, Gaudric M, Danel B, et al. Risk factors of oesophageal perforation during pneumatic dilatation for achalasia. Gut 1996;39:9-12. [Crossref] [PubMed]
95. Moonen A, Annese V, Belmans A, et al. Long-term results of the European achalasia trial: a multicentre randomised controlled trial comparing pneumatic dilation versus laparoscopic Heller myotomy. Gut 2016;65:732-9. [Crossref] [PubMed]
96. Kostic S, Kjellin A, Ruth M, et al. Pneumatic dilatation or laparoscopic cardiomyotomy in the management of newly diagnosed idiopathic achalasia. Results of a randomized controlled trial. World J Surg 2007;31:470-8. [Crossref] [PubMed]
97. Borges AA, Lemme EM, Abrahao LJ Jr, et al. Pneumatic dilation versus laparoscopic Heller myotomy for the treatment of achalasia: variables related to a good response. Dis Esophagus 2014;27:18-23. [Crossref] [PubMed]
98. Persson J, Johnsson E, Kostic S, et al. Treatment of achalasia with laparoscopic myotomy or pneumatic dilatation: long-term results of a prospective, randomized study. World J Surg 2015;39:713-20. [Crossref] [PubMed]
99. Chrystoja CC, Darling GE, Diamant NE, et al. Achalasia-Specific Quality of Life After Pneumatic Dilation or Laparoscopic Heller Myotomy With Partial Fundoplication: A Multicenter, Randomized Clinical Trial. Am J Gastroenterol 2016;111:1536-45. [Crossref] [PubMed]
100. Schoenberg MB, Marx S, Kersten JF, et al. Laparoscopic Heller myotomy versus endoscopic balloon dilatation for the treatment of achalasia: a network meta-analysis. Ann Surg 2013;258:943-52. [Crossref] [PubMed]
101. Vela MF, Richter JE, Khandwala F, et al. The long-term efficacy of pneumatic dilatation and Heller myotomy for the treatment of achalasia. Clin Gastroenterol Hepatol 2006;4:580-7. [Crossref] [PubMed]
102. Kostic S, Johnsson E, Kjellin A, et al. Health economic evaluation of therapeutic strategies in patients with idiopathic achalasia: results of a randomized trial comparing pneumatic dilatation with laparoscopic cardiomyotomy. Surg Endosc 2007;21:1184-9. [Crossref] [PubMed]
103. Yaghoobi M, Mayrand S, Martel M, et al. Laparoscopic Heller's myotomy versus pneumatic dilation in the treatment of idiopathic achalasia: a meta-analysis of randomized, controlled trials. Gastrointest Endosc 2013;78:468-75. [Crossref] [PubMed]
104. Cheng JW, Li Y, Xing WQ, et al. Laparoscopic Heller myotomy is not superior to pneumatic dilation in the management of primary achalasia: Conclusions of a systematic review and meta-analysis of randomized controlled trials. Medicine (Baltimore) 2017;96:e5525 [Crossref] [PubMed]
105. Hulselmans M, Vanuytsel T, Degreef T, et al. Long-term outcome of pneumatic dilation in the treatment of achalasia. Clin Gastroenterol Hepatol 2010;8:30-5. [Crossref] [PubMed]
106. Di Nardo G, Rossi P, Oliva S, et al. Pneumatic balloon dilation in pediatric achalasia: efficacy and factors predicting outcome at a single tertiary pediatric gastroenterology center. Gastrointest Endosc 2012;76:927-32. [Crossref] [PubMed]
107. Rajput S, Nandwani SK, Phadke AY, et al. Predictors of response to pneumatic dilatation in achalasia cardia. Indian J Gastroenterol 2000;19:126-9. [PubMed]
108. Tanaka Y, Iwakiri K, Kawami N, et al. Predictors of a better outcome of pneumatic dilatation in patients with primary achalasia. J Gastroenterol 2010;45:153-8. [Crossref] [PubMed]
109. Von Renteln D, Fuchs KH, Fockens P, et al. Peroral endoscopic myotomy for the treatment of achalasia: an international prospective multicenter study. Gastroenterology 2013;145:309-11.e1. [Crossref] [PubMed]
110. Kumagai K, Tsai JA, Thorell A, et al. Per-oral endoscopic myotomy for achalasia. Are results comparable to laparoscopic Heller myotomy? Scand J Gastroenterol 2015;50:505-12. [Crossref] [PubMed]
111. Inoue H, Minami H, Kobayashi Y, et al. Peroral endoscopic myotomy (POEM) for esophageal achalasia. Endoscopy 2010;42:265-71. [Crossref] [PubMed]
112. Inoue H, Sato H, Ikeda H, et al. Per-Oral Endoscopic Myotomy: A Series of 500 Patients. J Am Coll Surg 2015;221:256-64. [Crossref] [PubMed]
113. Guo H, Yang H, Zhang X, et al. Long-term outcomes of peroral endoscopic myotomy for patients with achalasia: a retrospective single-center study. Dis Esophagus 2017;30:1-6. [Crossref] [PubMed]
114. Patel K, Abbassi-Ghadi N, Markar S, et al. Peroral endoscopic myotomy for the treatment of esophageal achalasia: systematic review and pooled analysis. Dis Esophagus 2016;29:807-19. [Crossref] [PubMed]
115. Vigneswaran Y, Tanaka R, Gitelis M, et al. Quality of life assessment after peroral endoscopic myotomy. Surg Endosc 2015;29:1198-202. [Crossref] [PubMed]
116. Hungness ES, Sternbach JM, Teitelbaum EN, et al. Per-oral Endoscopic Myotomy (POEM) After the Learning Curve: Durable Long-term Results With a Low Complication Rate. Ann Surg 2016;264:508-17. [Crossref] [PubMed]
117. Kurian AA, Dunst CM, Sharata A, et al. Peroral endoscopic esophageal myotomy: defining the learning curve. Gastrointest Endosc 2013;77:719-25. [Crossref] [PubMed]
118. Teitelbaum EN, Soper NJ, Arafat FO, et al. Analysis of a learning curve and predictors of intraoperative difficulty for peroral esophageal myotomy (POEM). J Gastrointest Surg 2014;18:92-8. [Crossref] [PubMed]
119. Patel KS, Calixte R, Modayil RJ, et al. The light at the end of the tunnel: a single-operator learning curve analysis for per oral endoscopic myotomy. Gastrointest Endosc 2015;81:1181-7. [Crossref] [PubMed]
120. Zhang XC, Li QL, Xu MD, et al. Major perioperative adverse events of peroral endoscopic myotomy: a systematic 5-year analysis. Endoscopy 2016;48:967-78. [Crossref] [PubMed]
121. Swanstrom LL, Kurian A, Dunst CM, et al. Long-term outcomes of an endoscopic myotomy for achalasia: the POEM procedure. Ann Surg 2012;256:659-67. [Crossref] [PubMed]
122. Khashab MA, El Zein M, Kumbhari V, et al. Comprehensive analysis of efficacy and safety of peroral endoscopic myotomy performed by a gastroenterologist in the endoscopy unit: a single-center experience. Gastrointest Endosc 2016;83:117-25. [Crossref] [PubMed]
123. Jones EL, Meara MP, Schwartz JS, et al. Gastroesophageal reflux symptoms do not correlate with objective pH testing after peroral endoscopic myotomy. Surg Endosc 2016;30:947-52. [Crossref] [PubMed]
124. Kumbhari V, Khashab MA. Peroral endoscopic myotomy. World J Gastrointest Endosc 2015;7:496-509. [Crossref] [PubMed]
125. Teitelbaum EN, Soper NJ, Santos BF, et al. Symptomatic and physiologic outcomes one year after peroral esophageal myotomy (POEM) for treatment of achalasia. Surg Endosc 2014;28:3359-65. [Crossref] [PubMed]
126. Zhang Y, Wang H, Chen X, et al. Per-Oral Endoscopic Myotomy Versus Laparoscopic Heller Myotomy for Achalasia: A Meta-Analysis of Nonrandomized Comparative Studies. Medicine (Baltimore) 2016;95:e2736 [Crossref] [PubMed]
127. Marano L, Pallabazzer G, Solito B, et al. Surgery or Peroral Esophageal Myotomy for Achalasia: A Systematic Review and Meta-Analysis. Medicine (Baltimore) 2016;95:e3001 [Crossref] [PubMed]
128. Wirsching A, Boshier PR, Klevebro F, et al. Comparison of costs and short-term clinical outcomes of per-oral endoscopic myotomy and laparoscopic Heller myotomy. Am J Surg 2019;218:706-11. [Crossref] [PubMed]
129. Bhayani NH, Kurian AA, Dunst CM, et al. A comparative study on comprehensive, objective outcomes of laparoscopic Heller myotomy with per-oral endoscopic myotomy (POEM) for achalasia. Ann Surg 2014;259:1098-103. [Crossref] [PubMed]
130. Ramirez M, Zubieta C, Ciotola F, et al. Per oral endoscopic myotomy vs. laparoscopic Heller myotomy, does gastric extension length matter? Surg Endosc 2018;32:282-8. [Crossref] [PubMed]
131. Schneider AM, Louie BE, Warren HF, et al. A Matched Comparison of Per Oral Endoscopic Myotomy to Laparoscopic Heller Myotomy in the Treatment of Achalasia. J Gastrointest Surg 2016;20:1789-96. [Crossref] [PubMed]
132. Werner YB, Hakanson B, Martinek J, et al. Endoscopic or Surgical Myotomy in Patients with Idiopathic Achalasia. N Engl J Med 2019;381:2219-29. [Crossref] [PubMed]
133. Docimo S Jr, Mathew A, Shope AJ, et al. Reduced postoperative pain scores and narcotic use favor per-oral endoscopic myotomy over laparoscopic Heller myotomy. Surg Endosc 2017;31:795-800. [Crossref] [PubMed]
134. Stavropoulos SN, Modayil R, Friedel D. Per oral endoscopic myotomy for the treatment of achalasia. Curr Opin Gastroenterol 2015;31:430-40. [Crossref] [PubMed]
135. Stavropoulos SN, Desilets DJ, Fuchs KH, et al. Per-oral endoscopic myotomy white paper summary. Surg Endosc 2014;28:2005-19. [Crossref] [PubMed]
136. Stavropoulos SN, Modayil RJ, Friedel D, et al. The International Per Oral Endoscopic Myotomy Survey (IPOEMS): a snapshot of the global POEM experience. Surg Endosc 2013;27:3322-38. [Crossref] [PubMed]
137. Schlottmann F, Luckett DJ, Fine J, et al. Laparoscopic Heller Myotomy Versus Peroral Endoscopic Myotomy (POEM) for Achalasia: A Systematic Review and Meta-analysis. Ann Surg 2018;267:451-60. [Crossref] [PubMed]
138. Abir F, Modlin I, Kidd M, et al. Surgical treatment of achalasia: current status and controversies. Dig Surg 2004;21:165-76. [Crossref] [PubMed]
139. Allaix ME, Patti MG. Heller myotomy for achalasia. From the open to the laparoscopic approach. World J Surg 2015;39:1603-7. [Crossref] [PubMed]
140. Topart P, Deschamps C, Taillefer R, et al. Long-term effect of total fundoplication on the myotomized esophagus. Ann Thorac Surg 1992;54:1046-51. [Crossref] [PubMed]
141. Jara FM, Toledo-Pereyra LH, Lewis JW, et al. Long-term results of esophagomyotomy for achalasia of esophagus. Arch Surg 1979;114:935-6. [Crossref] [PubMed]
142. Malthaner RA, Tood TR, Miller L, et al. Long-term results in surgically managed esophageal achalasia. Ann Thorac Surg 1994;58:1343-6. [Crossref] [PubMed]
143. Bloomston M, Serafini F, Boyce HW, et al. The "learning curve" in videoscopic Heller myotomy. JSLS 2002;6:41-7. [PubMed]
144. Yano F, Omura N, Tsuboi K, et al. Learning curve for laparoscopic Heller myotomy and Dor fundoplication for achalasia. PLoS One 2017;12:e0180515 [Crossref] [PubMed]
145. Lyass S, Thoman D, Steiner JP, et al. Current status of an antireflux procedure in laparoscopic Heller myotomy. Surg Endosc 2003;17:554-8. [Crossref] [PubMed]
146. Jamieson GG. Gastro-esophageal reflux following myotomy for achalasia. Hepatogastroenterology 1991;38:506-9. [PubMed]
147. Andreollo NA, Earlam RJ. Heller's myotomy for achalasia: is an added anti-reflux procedure necessary? Br J Surg 1987;74:765-9. [Crossref] [PubMed]
148. Falkenback D, Johansson J, Oberg S, et al. Heller's esophagomyotomy with or without a 360 degrees floppy Nissen fundoplication for achalasia. Long-term results from a prospective randomized study. Dis Esophagus 2003;16:284-90. [Crossref] [PubMed]
149. Ortiz A, de Haro LF, Parrilla P, et al. Very long-term objective evaluation of heller myotomy plus posterior partial fundoplication in patients with achalasia of the cardia. Ann Surg 2008;247:258-64. [Crossref] [PubMed]
150. Khajanchee YS, Kanneganti S, Leatherwood AE, et al. Laparoscopic Heller myotomy with Toupet fundoplication: outcomes predictors in 121 consecutive patients. Arch Surg 2005;140:827-33. [Crossref] [PubMed]
151. Rebecchi F, Giaccone C, Farinella E, et al. Randomized controlled trial of laparoscopic Heller myotomy plus Dor fundoplication versus Nissen fundoplication for achalasia: long-term results. Ann Surg 2008;248:1023-30. [Crossref] [PubMed]
152. Aguilar-Paiz LA, Valdovinos-Díaz MA, Flores-Soto C, et al. Prospective evaluation of gastroesophageal reflux in patients with achalasia treated with pneumatic dilatation, thoracic or abdominal myotomy. Rev Invest Clin 1999;51:345-50. [PubMed]
153. Kurian AA, Bhayani N, Sharata A, et al. Partial anterior vs partial posterior fundoplication following transabdominal esophagocardiomyotomy for achalasia of the esophagus: meta-regression of objective postoperative gastroesophageal reflux and dysphagia. JAMA Surg 2013;148:85-90. [Crossref] [PubMed]
154. Rawlings A, Soper NJ, Oelschlager B, et al. Laparoscopic Dor versus Toupet fundoplication following Heller myotomy for achalasia: results of a multicenter, prospective, randomized-controlled trial. Surg Endosc 2012;26:18-26. [Crossref] [PubMed]
155. Wei MT, He YZ, Deng XB, et al. Is Dor fundoplication optimum after laparoscopic Heller myotomy for achalasia? A meta-analysis. World J Gastroenterol 2013;19:7804-12. [Crossref] [PubMed]
156. Sharp KW, Khaitan L, Scholz S, et al. 100 consecutive minimally invasive Heller myotomies: lessons learned. Ann Surg 2002;235:631-8. [Crossref] [PubMed]
157. Kahrilas PJ, Bredenoord AJ, Fox M, et al. The Chicago Classification of esophageal motility disorders, v3.0. Neurogastroenterol Motil 2015;27:160-74. [Crossref] [PubMed]
158. Rohof WO, Salvador R, Annese V, et al. Outcomes of treatment for achalasia depend on manometric subtype. Gastroenterology 2013;144:718-25. [Crossref] [PubMed]
159. Pandolfino JE, Gawron AJ. Msci. JAMA patient patient: Achalasia. JAMA 2015;313:1876. [Crossref] [PubMed]
160. Ou YH, Nie XM, Li LF, et al. High-resolution manometric subtypes as a predictive factor for the treatment of achalasia: A meta-analysis and systematic review. J Dig Dis 2016;17:222-35. [Crossref] [PubMed]
161. Salvador R, Costantini M, Zaninotto G, et al. The preoperative manometric pattern predicts the outcome of surgical treatment for esophageal achalasia. J Gastrointest Surg 2010;14:1635-45. [Crossref] [PubMed]
162. Kumbhari V, Tieu AH, Onimaru M, et al. Peroral endoscopic myotomy (POEM) vs laparoscopic Heller myotomy (LHM) for the treatment of Type III achalasia in 75 patients: a multicenter comparative study. Endosc Int Open 2015;3:E195-201. [Crossref] [PubMed]