Review Article United European Gastroenterology Journal 2020, Vol. 8(1) 13–34 European Guideline on Achalasia – UEG and ! Author(s) 2020 ESNM recommendations Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/2050640620903213 journals.sagepub.com/home/ueg RAB Oude Nijhuis1, G Zaninotto2, S Roman3, GE Boeckxstaens4, P Fockens1, MW Langendam5, AA Plumb6, AJPM Smout1, EM Targarona7, AS Trukhmanov8 , BLAM Weusten9 and AJ Bredenoord1 Abstract Introduction: Achalasia is a primary motor disorder of the oesophagus characterised by absence of peristalsis and insuf- ficient lower oesophageal sphincter relaxation. With new advances and developments in achalasia management, there is an increasing demand for comprehensive evidence-based guidelines to assist clinicians in achalasia patient care. Methods: Guidelines were established by a working group of representatives from United European Gastroenterology, European Society of Neurogastroenterology and Motility, European Society of Gastrointestinal and Abdominal Radiology, and the European Association of Endoscopic Surgery in accordance with the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. A systematic review of the literature was performed and the certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. Recommendations were voted upon using a nominal group technique. Results: These guidelines focus on the definition of achalasia, treatment aims, diagnostic tests, medical, endoscopic and surgical therapy, management of treatment failure, follow-up and oesophageal cancer risk. Conclusion: These multidisciplinary guidelines provide a comprehensive evidence-based framework with recommendations on the diagnosis, treatment and follow-up of adult achalasia patients. Keywords Dysphagia, oesophagus, manometry, myotomy, motility Received: 25 October 2019; accepted: 25 December 2019 1 Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology & Metabolism, Amsterdam University Medical Centers, Abbreviations University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands 2 Department of Surgery and Cancer, Imperial College, London, UK AGREE, Appraisal of Guidelines for Research and Evaluation; 3 Digestive Physiology, Hôpital Edouard Herriot, Lyon, France 4 BMI, body mass index; BTX, botulinum toxin; EA, oesopha- Department of Chronic Diseases, Metabolism and Ageing, Translational geal adenocarcinoma; EAES, European Association of Research Center for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium 5 Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Endoscopic Surgery; ESGAR, European Society of Amsterdam UMC, University of Amsterdam, Amsterdam Public Health Gastrointestinal and Abdominal Radiology; ESNM, Research Institute, Amsterdam, The Netherlands European Society of Neurogastroenterology and Motility; 6 Centre for Medical Imaging, University College London, London, UK 7 GORD, gastro-oesophageal reflux disease; GRADE, Grading Department of General and Digestive Surgery, Hospital De La Santa Creu I of Recommendations Assessment, Development, and Sant Pau, Autonomous University of Barcelona, Barcelona, Spain 8 I.M. Sechenov First Moscow State Medical University, Ministry of Health of Evaluation; HRM, high-resolution manometry; IP, imped- the Russian Federation (Sechenov University), Moscow, Russia ance planimetry; IRP, integrated relaxation pressure; LOS, 9 Department of Gastroenterology and Hepatology, St Antonius Hospital, lower oesophageal sphincter; LHM, laparoscopic heller Nieuwegein, the Netherlands; Department of Gastroenterology and myotomy; OGJ, oesophago-gastric junction PD, pneumatic Hepatology, University Medical Center Utrecht, Utrecht University, Utrecht, dilation; PICO, patient, intervention, control, outcome; the Netherlands POEM, peroral endoscopic myotomy; PPI, proton pump Corresponding author: Albert J. Bredenoord, Department of Gastroenterology & Hepatology, inhibitor; RCT, randomised controlled trial; SSC, squamous Academic Medical Center, Amsterdam, PO Box 22660, 1100 DD cell carcinoma; TBE, timed barium oesophagram; UEG, Amsterdam, the Netherlands. United European Gastroenterology. Email: a.j.bredenoord@amsterdamumc.nl 14 United European Gastroenterology Journal 8(1) Introduction behalf of United European Gastroenterology (UEG), Achalasia is a primary motility disorder in which insuf- European Society of Neurogastroenterology and Motility ficient relaxation of the lower oesophageal sphincter (ESNM), the European Society of Gastrointestinal and (LOS) and absent peristalsis result in stasis of ingested Abdominal Radiology (ESGAR), and The European foods and subsequently, lead to oesophageal symptoms Association of Endoscopic Surgery (EAES) to form a of dysphagia, regurgitation, chest pain or weight loss.1 guideline expert working group. All concerned societies Achalasia occurs as an effect of destruction of enteric were contacted and asked to support the guideline by neurons controlling the LOS and oesophageal body appointing one or two representatives for the guideline musculature by an unknown cause, most likely inflam- committee. First, the guideline development team (RON, matory. Idiopathic achalasia is a rare disease and AB, and ML) drafted the guideline protocol and the pre- affects individuals of both sexes and all ages. The liminary list of clinical topics to be covered by the guide- annual incidence is estimated between 1.07–2.2 cases lines. This list was circulated to a panel of achalasia per 100,000 individuals with prevalence rates estimated patients. Based upon patients’ interests, the final list of between 10–15.7 per 100,000 individuals.2–4 research questions was formatted into the PICO (patient, A diagnosis of achalasia should be considered when intervention, control, outcome) framework, and presented patients present with dysphagia in combination with to all members of the guideline working group at an initial other oesophageal symptoms and when upper endos- meeting which occurred on 23rd of October at UEG week copy ruled out other disorders. Barium esophagogram 2018. All working group members were assigned to one of may reveal a classic ‘‘bird’s beak’’ sign, oesophageal the subgroups (diagnosis, treatment or follow-up) and dilation, or a corkscrew appearance. Oesophageal were responsible for the elaboration of one or multiple manometry is the golden standard for the diagnosis research questions. Results of the search strategies and of achalasia; incomplete relaxation of the LOS, GRADE assessments were first discussed in conference reflected by an increased integrative relaxation pres- calls by each group and checked again for completeness, sure, in absence of normal peristalsis, are the diagnostic after which these documents were updated and subse- hallmarks. The use of high-resolution manometry quently sent to the entire group in advance of a face-to- (HRM) has led to the subclassification of achalasia face consensus meeting. into three clinically relevant groups based on oesopha- geal contractility patterns, as seen in Table 1. From assessment of evidence to recommendation The clinical care of patients with achalasia has chan- ged significantly in the past decade under influence of An electronic literature search was performed on the new developments such as high-resolution manometry, 18th of October 2018 using MEDLINE, EMBASE per-oral endoscopic myotomy and studies providing (accessed via Ovid), The Cochrane Database of new insights regarding achalasia subtypes, cancer risk Systematic Reviews (The Cochrane Library), and the and follow-up. Given the substantial growth of know- Cochrane Central Register of Controlled Trials ledge in the past years, there is need for a comprehen- (CENTRAL) without restrictions of language or pub- sive, evidence-based European guideline covering all lication year. The search strategy and the process of aspects of the disease. This multidisciplinary guideline study selection categorised per research question can aims to provide an evidence-based framework with rec- be found in appendix A. Risk of bias was assessed ommendations on the diagnosis, treatment and follow- using the appropriate study-design specific tools up of adult achalasia patients. Chagas disease and (appendix B). The certainty of evidence was assessed achalasia secondary to other disorders, as can be seen using the GRADE methodology (www.gradewor- after fundoplication, bariatric surgery, sarcoid infiltra- kinggroup.org) and for each outcome graded into tion, opiate usage or malignancy, is not covered by this four levels: high, moderate, low, or very low quality guideline. This guideline is intended for clinicians (Table 2). Based on the certainty of evidence and the involved in their management, including gastroenter- balance between desirable and undesirable outcomes, ologists, endoscopists, radiologists, gastrointestinal sur- patient values and preferences, applicability, feasibility, geons, dietitians and primary care practitioners. equity and costs/resources, recommendations were categorised into four final categories (strong or condi- tional recommendations in favour of or against an Methodology intervention), as proposed by GRADE (Table 3). In case of insufficient or limited evidence, research The achalasia guideline working group questions were answered by and classified as ‘expert Ten researchers and clinicians with recognised expertise opinion’. The results of data extraction, the risk of in the field of clinical achalasia management were gath- bias and quality of the evidence assessments are pre- ered (AB, GB, PF, AP, SR, AS, AT, ET, BW, GZ) on sented in appendix C and appendix D. Oude Nijhuis et al. 15 Table 1. Manometric subtypes of achalasia. Type I Classic achalasia  Median IRP > Cutoff*  100% failed peristalsis Type II Achalasia with  Median IRP > Cutoff* oesophageal compression  100% failed peristalsis  20% pan-oesophageal pressurization Type III Spastic achalasia  Median IRP > Cutoff*  No normal peristalsis  20% premature contractions with DCI>450 DCI, Distal Contractile Integral; IRP, Integrated Relaxation Pressure. *note: the cutoff for IRP is catheter-depending, varying between 15 and 28 mmHg. 16 United European Gastroenterology Journal 8(1) Consensus process material). The working group formulated 30 recom- In order to establish consensus-based recommenda- mendations based on these reviews (Table 4). tions, a second physical meeting was organised in Amsterdam, the Netherlands on the 11th of April 1. Achalasia diagnosis 2019. GRADE assessments and recommendations were presented and discussed. Voting was conducted 1.1 What is the current definition of achalasia? according to the nominal group technique and based upon a six-point Likert scale (1: strongly disagree; 2: Recommendation 1.1 mostly disagree; 3: somewhat disagree; 4: somewhat Achalasia is a disorder characterised by insufficient LOS relaxation agree; 5: mostly agree; 6: strongly agree). A recommen- and absent peristalsis. It is usually primary (idiopathic) but can be dation was approved if > 75% of the members agreed secondary to other conditions that affect oesophageal function. In (reflected by a Likert score of 4–6). idiopathic achalasia the enteric neurons controlling the LOS and oesophageal body musculature are affected by an unknown cause, most likely inflammatory. Recommendations Expert opinion recommendation Clinical questions formed the basis of the systematic Consensus: 100% agree [Vote: Aþþ, 100%; Aþ, 0%; A, 0%; D 0%; literature reviews (appendix A in supplementary Dþ, 0%; Dþþ, 0%] Table 2. Grading of Recommendations Assessment, Development, 1.2 What is the value of HRM and conventional and Evaluation Definitions of Quality, and Certainty of the Evidence (GRADE). manometry in achalasia diagnosis? Certainty The diagnosis of achalasia not only requires impaired of evidence Definition OGJ relaxation, but also absent or abnormal peristal- sis. Therefore, oesophageal manometry is considered High We are very confident that the true effect lies close as being the gold standard for the diagnosis of to the estimate of the effect. achalasia, as it evaluates both pressures of the lower Moderate We are moderately confident in the effect estimate. oesophageal sphincter (LOS) and contractility of the The true effect is likely to be close to the estimate oesophageal body. Worldwide, high-resolution mano- of effect, but there is a possibility that it is sub- metry (HRM), usually defined as manometry carried stantially different. out with a catheter with at least 21 pressure sensors Low Our confidence in the estimate is limited. The true spaced at 1-cm intervals,5 is rapidly replacing conven- effect may be substantially different from the esti- tional manometry. The generally perceived advantages mate of effect. of HRM over conventional manometry are that pos- Very low We have very little confidence in the effect esti- itioning of the catheter is less critical and that interpret- mate. The true effect is likely to be substantially different from the estimate of effect. ation of the recorded pressures, displayed in the form of topographical colour-coded plots, is more intuitive. Table 3. Grading of Recommendations Assessment, Development, and Evaluation Definitions on Strength of Recommendation and Guide to Interpretation. Strength of Wording in recommendation the guideline For the patient For the clinician Strong ‘‘We recommend . . .’’ Most individuals in this situ- Most individuals should receive the recommended ation would want the recom- course of action. Formal decision aids are not likely mended course and only a to be needed to help individuals make decisions con- small proportion would not. sistent with their values and preferences. Conditional ‘‘We suggest . . .’’ The majority of individuals in Different choices would be appropriate for different this situation would want the patients. Decision aids may be useful in helping indi- suggested course, but many viduals in making decisions consistent with their would not. values and preferences. Clinicians should expect to spend more time with patients when working towards a decision. Oude Nijhuis et al. 17 Table 4. Summary of recommendations of the United European Gastroenterology Clinical Guidelines Committee for the diagnosis, management and follow-up of Achalasia. Certainty of Recommendations Strength evidence Voting Diagnosis 1.1 Achalasia is a disorder characterised by insufficient LOS relaxation and Expert opinion – 100% absent peristalsis. It is usually primary (idiopathic) but can be secondary to other conditions that affect oesophageal function. In idiopathic achalasia the enteric neurons controlling the LOS and oesophageal body musculature are affected by an unknown cause, most likely inflammatory. 1.2 We recommend using high-resolution manometry (with topographical Strong Moderate 100% pressure presentation) to diagnose achalasia in adult patients with sus- pected achalasia. 1.3 We suggest using a barium esophagram to diagnose achalasia if mano- Conditional Moderate 100% metry is unavailable, although it is less sensitive than oesophageal mano- metry. The working group suggests using timed barium esophagram, if available, over standard barium esophagram. 1.4 We suggest against making the diagnosis of achalasia solely based on Expert opinion – 100% impaired OGJ distensibility as measured with impedance planimetry. 1.5 I. We suggest against making the diagnosis of achalasia solely based on Expert opinion – 100% endoscopy. II. We suggest performing endoscopy in all patients with symptoms sug- Expert opinion – 77.8% gestive of achalasia to exclude other diseases. 1.6 We suggest additional testing using CT or endoscopic ultrasound only Conditional Low 100% in those achalasia patients suspected of malignant pseudo-achalasia. Multiple recognised risk factors for malignant pseudo-achalasia e.g. age > 55 yrs, duration of symptoms < 12 months, weight loss >10 kg, severe difficulty passing LES with scope may prompt further imaging. 1.7 We suggest to provide the patient with the following information on the Expert opinion – 100% disease and the treatment: Information on the disease  normal function of oesophagus  rare condition that affects the neurons, leads to LES dysrelaxation and absent peristalsis, exact cause not known  no increased chance of disease in siblings  what might happen if left untreated  no progression to other organs  small increased risk of cancer Information on treatment options  explanation of all treatment options, choice of treatment is based upon shared-decision making.  treatment is not curative, but does improve symptoms  risk of complications  risk of reflux  efficacy of treatments Treatment 2.1 I. We suggest that in the treatment of achalasia symptom relief should be Expert opinion – 100% regarded as the primary treatment aim. II. We suggest that improvement of objectively measured oesophageal Expert opinion – 100% emptying on barium esophagram should be regarded as an important additional treatment aim. 2.2 We suggest against the use of calcium blockers, phosphodiesterase inhibi- Expert opinion – 100% tors or nitrates for the treatment of achalasia. (continued) 18 United European Gastroenterology Journal 8(1) Table 4. Continued. Certainty of Recommendations Strength evidence Voting 2.3 Botulinum toxin therapy can be considered an effective and safe Conditional Moderate 88.9% therapy for short-term symptom relief in oesophageal achalasia. 2.4 Graded pneumatic dilatation is an effective and relatively safe treatment Strong High 100% for oesophageal achalasia. 2.5 POEM is an effective and relatively safe treatment for Achalasia. Strong High 100% 2.6 Laparoscopic Heller myotomy combined with an anti-reflux procedure is an Strong High 100% effective and relatively safe therapy for achalasia. 2.7 We suggest taking age and manometric subtype into account when select- Conditional Moderate 100% ing a therapeutic strategy. 2.8 I. Treatment decisions in achalasia should be made based on patient- Strong Moderate 100% specific characteristics, patient preference, possible side effects and/or complications and a center’s expertise. Overall, graded repetitive PD, LHM and POEM have comparable efficacy. II. Botulinum toxin should be reserved for patients that are unfit for more Conditional Moderate 100% invasive treatments, or in whom a more definite treatment needs to be deferred. 2.9 We suggest treating recurrent or persistent dysphagia after laparoscopic Conditional Very low 100% Heller myotomy with PD, POEM or redo surgery. 2.10 We suggest treating recurrent or persistent dysphagia after POEM with Conditional Very low 100% either re-POEM, laparoscopic Heller myotomy or pneumatic dilation. 2.11 Oesophagectomy should be considered the last resort to treat achalasia, Expert opinion – 100% after all other treatments have been considered. 2.12 We suggest against oesophageal stents and intrasphincteric injection of Expert opinion – 100% sclerosing agents in the treatment of achalasia. Follow-up 3.1 I. Patients with recurrent or persistent dysphagia after initial treatment Expert opinion – 100% should undergo repeat evaluation with timed barium esophagram with or without oesophageal manometry. II. Repeat endoscopy should be considered in patients with recurrent Expert opinion – 100% dysphagia. 3.2 I. In patients with persistent or recurrent chest pain, inappropriate emp- Expert opinion – 100% tying due to ineffective initial treatment or recurrent disease should be excluded by TBE with or without oesophageal manometry. For type III achalasia, we suggest a repeat HRM to exclude or confirm persistent spas- tic contractions. II. If there is no evidence of impaired oesophageal emptying, empirical Expert opinion – 100% treatment with PPI, endoscopy and/or 24 hr pH-(impedance)metry can be considered. 3.3 I. We suggest follow-up endoscopy to screen for GERD in patients treated Expert opinion – 100% with myotomy without anti-reflux procedure. II. In case of reflux symptoms in absence of reflux esophagitis, TBE, Expert opinion – 100% empiric PPI therapy, and/or 24-h oesophageal pH-(impedance)monitoring can be considered. III. Proton pump inhibitors are the first line treatment of GORD after Expert opinion – 100% achalasia treatment. We recommend lifelong PPI therapy in patients with oesophagitis > grade A (LA classification). 3.4 We suggest against performing systematic screening for dysplasia and car- Conditional Low 100% cinoma. However, the threshold of upper GI endoscopy should be low in patients with recurrent symptoms and longstanding achalasia. Oude Nijhuis et al. 19 In 4 of the 5 included studies, the diagnosis of acha- suspension, to measure height and width of the barium lasia was made more often with HRM than with con- column in order to assess oesophageal emptying more ventional manometry.6–9 However, one may argue that objectively (Figure 1).15 Because of this advantage, TBE a higher rate of achalasia diagnosis with HRM does not is generally preferred over a standard barium esopha- prove that HRM is better than conventional manome- gram. One study compared TBE with HRM, and try; HRM might also lead to more false-positive find- found a sensitivity of 85% and specificity of 86%.15 ings. The only prospective randomised trial that compared HRM and conventional manometry9 had Recommendation 1.3 the additional advantage of defining the clinical out- We suggest using a barium esophagram to diagnose achalasia if come after 6 months as the gold standard, and found manometry is unavailable, although it is less sensitive than a superior sensitivity of HRM for the diagnosis of acha- oesophageal manometry. The working group suggests using lasia to that of conventional manometry (93 vs 78%). timed barium esophagram, if available, over standard barium The specificities of both tests were equal (100%).9 esophagram. In two studies the diagnostic values of imaging tech- conditional recommendation, moderate certainty of evidence niques were compared with manometry.10,11 The results Consensus: 100% agree [Vote: Aþþ, 88.9%; Aþ, 11.1%; A, 0%; D of these two studies lend some support to the notion 0%; Dþ, 0%; Dþþ, 0%] that manometry rather than imaging is the gold stand- ard for the diagnosis of achalasia. 1.4 What is the value of impedance planimetry in Recommendation 1.2 the diagnosis of achalasia? We recommend using high-resolution manometry (with topo- graphical pressure presentation) to diagnose achalasia in adult Oesophageal impedance planimetry is a technique in patients with suspected achalasia. which the cross-sectional area of the oesophagus is sim- ultaneously measured at multiple levels using a saline- Strong recommendation, moderate certainty of evidence filled cylindrical bag containing an array of impedance Consensus: 100% agree [Vote: Aþþ, 66.7%; Aþ, 33.3%; A, 0%; D 0%; Dþ, 0%; Dþþ, 0%] electrodes.6 The commercially-available device for endo- luminal impedance planimetry is known as EndoflipÕ . Studies using impedance planimetry have consistently 1.3 What is the value of (timed) barium swallow demonstrated that the distensibility of the oesophago- gastric junction (OGJ) is reduced in untreated achalasia studies in achalasia diagnosis? compared to healthy controls.16–19 A systematic review The barium esophagram is generally seen as a valuable identified 6 studies with data on oesophago-gastric junc- and complementary, but relatively insensitive, diagnos- tion (OGJ) distensibility in untreated achalasia patients tic test. One study evaluated the diagnostic value of (n ¼ 154) and 5 studies with data in healthy subjects barium esophagraphy in comparison with HRM and (n ¼ 98) and found that at 40-mL distension there found a high sensitivity, but poor specificity for detect- was a clear difference between the two groups (point ing dysmotility. The authors conclude that barium swal- estimates < 1.6 mm2/mmHg and > 2.7 mm2/mmHg in low studies accurately rule out achalasia-related patients and controls respectively).20 dysmotility but are not very helpful in diagnosing However, in order to distinguish achalasia from other causes of dysmotility.12 Two studies comparing OGJ outflow obstruction, information about the motil- barium esophagraphy with conventional manometry ity of the tubular oesophagus is required, which is not found sensitivities for achalasia diagnosis between 58 – provided by impedance planimetry measurement. 75%.11,13 However, as the positive predictive accuracy Recent studies indicate that dynamic impedance plan- was 96%, the authors concluded that the barium eso- imetry can also provide information on peristalsis.21,22 phagram is a useful tool in achalasia diagnosis.11 Similar However, this technique assesses distension-, rather sensitivity and specificity rates were obtained in another than swallow-induced contractions, and requires sed- study comparing barium swallow studies with HRM; ation. Furthermore, high-quality diagnostic studies the diagnostic sensitivity, specificity and accuracy of comparing impedance planimetry with the gold stand- the barium esophagram were 78.3%, 88.0%, and ard HRM are not available yet. In line with this, one 83.0%, respectively.14 Consequently, it may be con- recommendation from a recent AGA clinical practice cluded that diagnosing achalasia by using barium eso- update on functional lumen imaging is that clinicians phagram alone has a limited yield. The technique of should not make a diagnosis of achalasia based on timed barium esophagram (TBE) is similar to the impedance planimetry alone.23 usual barium swallow study but uses set time intervals There is data to suggest that impedance planimetry (1, 2 and 5 minutes) after ingestion of a fixed barium may be used as an additional tool to diagnose achalasia 20 United European Gastroenterology Journal 8(1) Figure 1. Interpretation of timed barium esophagram. Radiographs taken 0, 1, 2 and 5 minutes in left posterior oblique position after ingestion of 100 to 200 mL low-density barium suspension in an achalasia patient. Measurement of height and width of barium column, measured from the OGJ to the barium-foam interface. Barium height of >5 cm at 1 min and >2 cm at 5 min are suggestive of achalasia. in patients who do not meet the manometric criteria advanced stages, a diagnosis of achalasia is supported (Chicago 3.0) for achalasia. In 13 patients with symp- by endoscopic findings such as an oesophageal dilata- toms and signs of achalasia, but with manometrically tion with axis deviation and tortuosity and retained normal integrated relaxation pressure (IRP), OGJ dis- saliva and food in the oesophagus.28–30 tensibility was below the lower limit of normal. Treatment of these patients as if the diagnosis Recommendation 1.5 were achalasia resulted in a decrease of symptoms.24 a. We suggest against making the diagnosis of achalasia solely This observation suggests that impedance planimetry based on endoscopy. may be a useful complimentary diagnostic tool for the diagnosis of achalasia, in a subset of patients with Expert opinion recommendation Consensus: 100% agree [Vote: Aþþ, 100%; Aþ, 0%; A, 0%; D 0%; a low IRP. Dþ, 0%; Dþþ, 0%] b. We suggest performing endoscopy in all patients with symptoms Recommendation 1.4 suggestive of achalasia to exclude other diseases. We suggest against making the diagnosis of achalasia solely based on impaired OGJ distensibility as measured with impedance Expert opinion recommendation planimetry. Consensus: 77.8% agree [Vote: Aþþ, 77.8%; Aþ, 0%; A, 0%; D 0%; Dþ, 22.2%; Dþþ, 0%] Expert opinion recommendation Consensus: 100% agree [Vote: Aþþ, 100%; Aþ, 0%; A, 0%; D 0%; Dþ, 0%; Dþþ, 0%] 1.6 In which patients should additional diagnostic tests be performed in order to 1.5 What is the value of endoscopy in achalasia exclude pseudo-achalasia? diagnosis? Malignant pseudo-achalasia is the condition in which a Thorough endoscopic evaluation of the gastro-oeso- patient is initially diagnosed with achalasia, and some- phageal junction and gastric cardia is recommended times even treated for achalasia, but later found to have in all patients with symptoms suggestive of achalasia an underlying malignancy as the primary cause. This to exclude other diseases, especially to rule out malig- can occur in a submucosally growing adenocarcinoma nancies. However, the value of endoscopy in achalasia of the cardia, locally advanced pancreatic cancer, sub- diagnosis is relatively low. Depending on the stage of mucosal metastases or anti-Hu-producing carcinomas disease, endoscopic evaluation can suggest a diagnosis (typically small cell lung carcinomas).31 Certainly not of achalasia in 30-50% of patients. Achalasia diagnosis all patients diagnosed with achalasia should undergo can easily be missed, as endoscopic abnormalities are additional testing in the form of a CT scan or endo- uncommon in early-stage achalasia.25–27 In more scopic ultrasound to rule out malignancy, however, Oude Nijhuis et al. 21 valuable time is missed if malignancy is not detected in 2. Achalasia treatment an early stage. Only two studies have addressed the 2.1 What should we aim for when treating issue of how to identify patients with malignant achalasia patients? pseudo-achalasia.32,33 Both case-control studies identi- fied the same differences between patients with primary Treatment can be considered for the purpose of reducing achalasia and patients with malignant pseudo-achala- symptoms and consequently, improvement of quality of sia: relatively short duration of symptoms, considerable life. As the evidence for the use of standardized question- weight loss and older age. The study by Ponds et al also naires in the clinical setting is limited, a thorough clinical identified difficulty introducing the endoscope in the assessment of oesophageal symptoms before and after stomach as mentioned by the endoscopist as a risk therapy should be used to evaluate treatment success. factor. A model was produced in which presence of Secondly, treatment might prevent progression to end- less than 2 risk factors did not result in increased risk stage disease and occurrence of late complications, such for malignancy, while risk increased from presence of 2 as aspiration and carcinogenesis. However, data on the risk factors or more. The authors recommend add- natural history of disease to support this is scarce. There itional testing in these patients. are series showing that if patients remain untreated, oesophageal distension progresses over a period of many Recommendation 1.6 years.34,35 There is some indirect evidence that treatment We suggest additional testing using CT or endoscopic ultrasound can prevent progression of the disease; in a study evaluat- only in those achalasia patients suspected of malignant pseudo- ing patients treated with pneumatic dilation (PD), the per- achalasia. Multiple recognised risk factors for malignant pseudo- sistence of oesophageal stasis on timed barium achalasia e.g. age > 55 yrs, duration of symptoms < 12 months, esophagraphy was associated with progressive oesopha- weight loss > 10 kg, severe difficulty passing LES with scope may geal dilatation of 0.5 cm in a 2-year period, whereas suc- prompt further imaging. cessful PD (no stasis on TBE) was not.36 Additionally, Conditional recommendation, low certainty of evidence several surgical studies showed that treatment directed Consensus: 100% agree [Vote: Aþþ, 66.7%; A22.2%; A, 11.1%; D to LOS pressure is less effective in patients with late- 0%; Dþ, 0%; Dþþ, 0%] stage disease and decompensated oesophagus.37–39 In summary, there is some indirect evidence that adequate treatment might reduce the risk of progressive oesopha- 1.7 What information should the newly geal dilation in patients with achalasia, potentially pre- venting a state of gross oesophageal dilation, which in diagnosed patient receive? turn is associated with poor outcome. In addition to ameli- We recommend to provide the patient with information oration of symptoms, improvement of objectively mea- on the disease and the treatment stated in Table 1.7.1. sured oesophageal emptying should therefore be regarded as an important additional treatment aim. Table 1.7.1. Information the newly diagnosed achalasia patient should receive. Recommendation 2.1 a. We suggest that in the treatment of achalasia symptom relief Information on the disease should be regarded as the primary treatment aim.  normal function of oesophagus Expert opinion recommendation  rare condition that affects the neurons, leads to LOS dysre- Consensus: 100% agree [Vote: Aþþ, 100%; Aþ, 0%; A, 0%; D 0%; laxation and absent peristalsis, exact cause not known Dþ, 0%; Dþþ, 0%]  no increased chance of disease in siblings  what might happen if left untreated b. We suggest that improvement of objectively measured oesopha-  no progression to other organs geal emptying on barium esophagram should be regarded as  small increased risk of cancer an important additional treatment aim. Information on treatment options Expert opinion recommendation  explanation of all treatment options, choice of treatment is Consensus: 100% agree [Vote: Aþþ, 66.7%; A22.2%; A, 11.1%; D based upon shared-decision making. 0%; Dþ, 0%; Dþþ, 0%]  treatment is not curative, but does improve symptoms  risk of complications  risk of reflux 2.2 What is the role of oral pharmacological  efficacy of treatments therapy in achalasia? Expert opinion recommendation There is no convincing evidence that treatment with Consensus: 100% agree [Vote: Aþþ, 100%; Aþ, 0%; A, 0%; D 0%; Dþ, 0%; Dþþ, 0%] smooth muscle relaxants (calcium blockers, phospho- diesterase inhibitors or nitrates) provides symptomatic 22 United European Gastroenterology Journal 8(1) relief in adults with achalasia. The table presented in treatment regimens with multiple dilations performed appendix C summarises the available literature. None in case of recurrent symptoms, increase the efficacy. A of the studies is of sufficiently high quality, has suffi- single series of PDs is less efficacious than LHM or cient sample size and measured adequate endpoints to POEM, while there is no difference in safety between answer this question.40–46 Treatment with smooth the two treatment groups.50–53 In studies in which muscle relaxants can cause side-effects, and is therefore repeated dilation was allowed upon symptom recur- not recommended. It should certainly not delay an rence, the efficacy of PD generally approached that of effective endoscopic or surgical treatment. Whether LHM at a similar safety profile.54–58 Given the risk of chest pain that is presumed to be due to spastic con- perforation, it is always advised to start with a 30-mm tractions can be relieved with medical therapy will be balloon in an untreated achalasia patient. A second discussed in question 3.2. dilation with 35 mm will prolong the time to recurrence.54,59 Recommendation 2.2 We suggest against the use of calcium blockers, phosphodiesterase Recommendation 2.4 inhibitors or nitrates for the treatment of achalasia. Graded pneumatic dilatation is an effective and relatively safe treatment for oesophageal achalasia. Expert opinion recommendation Consensus: 100% agree [Vote: Aþþ, 66.7%; Aþ, 33.3%; A, 0%; D Strong recommendation, high certainty of evidence 0%; Dþ, 0%; Dþþ, 0%] Consensus: 100% agree [Vote: Aþþ, 100%; Aþ, 0%; A, 0%; D 0%; Dþ, 0%; Dþþ, 0%] 2.3 What is the comparative therapeutic efficacy and safety of endoscopic botulinum toxin 2.5 What is the comparative therapeutic efficacy injection in the treatment of achalasia? and safety of per-oral endoscopic myotomy? Endoscopic injection of botulinum toxin (BTX) in the POEM appears to be a safe treatment option with a low LOS has been compared with laparoscopic Heller rate of serious adverse events.50,60 Although no long- myotomy (LHM) or endoscopic pneumatic dilation term (beyond 2 years) follow-up data are available yet, (PD) in several RCTs.47–49 The results of these studies POEM appears to be equally effective to LHM. In a all point in the same direction; BTX injections result in recently published multicentre RCT, treatment success a reduction in LOS pressure, stasis and symptoms in rate, defined as a reduction in Eckardt score <3 and the the short term, but generally the disease symptoms and absence of severe complications or need for re-treat- signs recur with time. PD and BTX treatment are ment, after 2 years of follow-up was significantly equally effective at the short term, while PD is the higher in patients treated with POEM compared to more effective endoscopic treatment in the long term patients treated with PD.50 In this study, patients (greater than six months). Heller and BTX treatment assigned to the PD arm were treated with a single are equally effective at the short term; Heller is the more 30-mm dilation, and received a second dilation with a effective treatment in the long term (greater than six 35-mm balloon if still symptomatic (which was the case months). in 50 of 66 (76%) patients). GORD occurs more fre- quently after POEM than after LMH or PD, but high Recommendation 2.3 grades of oesophagitis are uncommon.61,62 However, Botulinum toxin therapy can be considered an effective and safe one should note that it is very challenging to objectify therapy for short-term symptom relief in oesophageal achalasia. GORD in achalasia patients, as gastro-oesophageal acid reflux is hard to differentiate from fermentation Conditional recommendation, moderate certainty of evidence due to stasis. Nevertheless, in patients with a high Consensus: 88.9% agree [Vote: Aþþ, 88.9%; Aþ, 0%; A, 0%; D, risk of post-procedure GORD who are unwilling to 11.1%; Dþ, 0%; Dþþ, 0%] use proton pump inhibitor (PPI) therapy, LHM or PD might be preferred over POEM. 2.4 What is the comparative therapeutic efficacy and safety of endoscopic dilation? Recommendation 2.5 Per-oral endoscopic myotomy is an effective and relatively safe Pneumatic dilation (PD) has been compared to endo- treatment for oesophageal achalasia. scopic botulinum toxin injections in the LOS, POEM and Heller myotomy. A factor of importance when Strong recommendation, high certainty of evidence Consensus: 100% agree [Vote: Aþþ, 100%; Aþ, 0%; A, 0%; D 0%; comparing the different studies is the PD regimen fol- Dþ, 0%; Dþþ, 0%] lowed, which varies widely. Broadly speaking, Oude Nijhuis et al. 23 2.6 What is the comparative therapeutic efficacy treatment than younger individuals. Manometric sub- and safety of surgical myotomy? type 3 was associated with poor treatment outcome in During a surgical cardiomyotomy, the spastic LOS is general. Interestingly, of the 49 included studies that disrupted by cleaving the muscle layers of both the LOS evaluated sex as potential predictor, 90% did not find and cardia, allowing passage of foods. Nowadays, the an association between sex and treatment outcome, procedure is typically performed laparoscopically and indicating that sex most likely is not of predictive combined with a partial anti-reflux procedure (fundo- value in clinical decision making. The predictive value plication). A complete 360-degree wrap should be of some of the studied factors, such as chest pain and avoided in achalasia patients to prevent worsening, symptom severity remains unclear, as the total body of rather than relieving, the dysphagia.63 Six RCTs com- evidence was inconclusive or insufficient to draw firm pared the efficacy of LHM versus PD (two of them conclusions. It is suggested that age and manometric reporting long-term results) and multiple meta-analyses subtype should be taken into account when selecting a were performed.51–58,64,65 These studies report a similar therapeutic strategy, in conjunction with information outcome for LHM and PD when multiple sessions of on efficacy and safety of the individual procedures, graded dilations were allowed (sequential dilations). patient preference, and local expertise. However, LHM performed better than two sessions of PD. The meta-analysis (where PD outcome was Recommendation 2.7 assessed independently of the number of PD sessions) We suggest taking age and manometric subtype into account when was in favour of LHM. LHM was more effective than selecting a therapeutic strategy. PD in type III achalasia in a sub-group analysis of the European Achalasia Trial. One RCT compared LHM Conditional recommendation, moderate certainty of evidence Consensus: 100% agree [Vote: Aþþ, 100%; Aþ, 0%; A, 0%; D, to botulinum toxin injection and showed a better out- 0%; Dþ, 0%; Dþþ, 0%] come for LHM after 6 months of follow-up, after an initial similar response.49 There is only one RCT, com- paring LHM and POEM, showing a similar symptom- 2.8 Overall recommendations on treatment atic outcome for the two treatments after a follow-up of up to 2 years.60 A meta-analysis focusing on risk of (comparative effectiveness and safety) iatrogenic reflux after POEM versus LHM suggested Based on the systematic reviews and GRADE assess- the increased risk of GORD after POEM.61 ments of research question 2.3 – 2.7 combined, the working group proposes the following overall recom- Recommendation 2.6 mendations with regard to achalasia therapy: Laparoscopic Heller myotomy combined with an anti-reflux pro- cedure is an effective and relatively safe therapy for achalasia. Recommendation 2.8 Strong recommendation, high certainty of evidence a. Treatment decisions in achalasia should be made based on Consensus: 100% agree [Vote: Aþþ, 100%; Aþ, 0%; A, 0%; D, patient-specific characteristics, the patient’s preference, pos- 0%; Dþ, 0%; Dþþ, 0%] sible side effects and/or complications and a center’s expertise. Overall, graded repetitive PD, LHM and POEM have comparable efficacy. 2.7 What are predictors of treatment outcome? Strong recommendation, moderate certainty of evidence How to choose initial treatment? Consensus: 100% agree [Vote: Aþþ, 55.6%; Aþ, 44.4%; A, 0%; D 0%; Dþ, 0%; Dþþ, 0%] In order to guide therapeutic decisions, it is useful to distinguish patient types that are likely to respond b. Botulinum toxin therapy should be reserved for patients who are too unfit for more invasive treatments, or in whom a more favourably to a certain therapy. Patient-specific factors definite treatment needs to be deferred. such as age, sex, and manometric type are commonly believed to be predictive of treatment outcome, with the Conditional recommendation, moderate certainty of evidence unfavourable effect of young age undoubtedly being the Consensus: 100% agree [Vote: Aþþ, 100%; Aþ, 0%; A, 0%; D 0%; most frequently described example.66–69 A recently pub- Dþ, 0%; Dþþ, 0%] lished review systematically assessed 75 studies that investigated potential patient-specific predictors.70 A total of 34 predictors were identified, but of all pre-ther- 2.9 How to treat post-Heller recurrence? apeutic factors, only age and manometric subtype were Minimally invasive surgical therapy in achalasia is identified as important predictors with a strong level of effective in the majority of patients, however symptom cumulative evidence. A meta-analysis confirmed that relapse occurs in 10-20% of patients at the long term.55 older patients (>45 years) responded better to PD No adequate prospective controlled trials have been 24 United European Gastroenterology Journal 8(1) conducted on management of failed Heller myotomy 2.11 What are indications for oesophagectomy? due to low patient numbers. Current options for treat- Oesophagectomy for achalasia is associated with a high ment of Heller recurrence include endoscopic dilation, risk of complications and mortality.87,88 A systematic POEM, or redo surgery. When no gross anatomic review of 8 studies and 1307 patients that underwent abnormalities are present, PD or POEM can be con- oesophagectomy, reported a complication rate of 19%- sidered. Both procedures show equally modest efficacy 50% and a mortality rate 0-3.8%.87 In a large series of rates, but PD is often regarded a less-invasive first over 500 patients, oesophagectomy was initially per- step.71–79 In the event of recurrence due to a too tight formed in less than 1% of the entire population, but or twisted fundoplication, or a more complex anatomy ultimately 17% of patients required oesophageal resec- with oesophageal distortion, fibrosis or a post-myot- tion. Particularly those who failed surgical treatment or omy diverticulum, redo surgery may be considered. those with end-stage achalasia, which is often asso- However, this is associated with a substantial risk of ciated with massive oesophageal dilatation and tortu- post-operative complications.74,80–82 osity.82 In a report on 53 patients with end-stage achalasia that underwent oesophageal resection, the Recommendation 2.9 indications were tortuous mega-oesophagus (64%) or We suggest treating recurrent or persistent dysphagia after lap- oesophageal stricture formation due to reflux (7%).89 aroscopic Heller myotomy with PD, POEM or redo surgery. Other indications for oesophageal resection are pres- ence of high-grade dysplasia or cancer. Although the Conditional recommendation, very low certainty of evidence in-hospital mortality after esophagectomy is lower in Consensus: 100% agree [Vote: Aþþ, 22.2%; Aþ, 77.8%; A, 0%; D patients with achalasia than in patients with cancer 0%; Dþ, 0%; Dþþ, 0%] (2.8% vs. 7.7%, respectively), it is still a substantial risk, especially as the indication for resection is not as strong as for malignant disease. Moreover, the overall 2.10 How to treat post-POEM recurrence post-operative complication rate is similar in both Although POEM has good-to-excellent efficacy rates, patient groups.90 Hence, oesophagectomy should be treatment failure with recurrent or persistent symptoms considered the last resort in end-stage achalasia, does occur.50,62,83 In a recently published randomised where disabling symptoms reoccur despite aggressive controlled trial comparing endoscopic myotomy with treatment.91,92 On the other hand, as the risk and com- PD, the authors reported clinical failure in 8% of plexity of oesophageal resection increases with the patients treated with POEM after two years of follow- deterioration of a patient’s condition and nutritional up.50 Data on the best therapeutic approach after status, end-stage achalasia should be carefully fol- POEM failure is limited. Two case series reported suc- lowed-up to promptly identify when oesophagectomy cess rates of 80-100% after three months of follow-up in is necessary. patients treated with re-POEM after initial failure.84,85 Another study evaluating retreatment after POEM fail- Recommendation 2.11 ure in 43 patients, showed that retreatment with either Oesophagectomy should be considered the last resort to treat LHM or re-POEM gives modest efficacy rates of 45% achalasia, after all other treatments have been considered. and 63%, respectively, whereas PD showed a poor effi- cacy of only 20%.86 These results may indicate superior- Expert opinion recommendation Consensus: 100% agree [Vote: Aþþ, 77.8%; Aþ, 22.2%; A, 0%; D ity of both POEM and LHM compared to PD in the 0%; Dþ, 0%; Dþþ, 0%] management of POEM failure. However, it must be noted, that the data to support this is weak and based on case series only. Moreover, PD is feasible and avail- 2.12 What is the role of alternative therapies in able in many centres, and is considered to be less invasive the treatment of achalasia? than re-myotomy and can therefore not completely be omitted in the management of this patient group. Several studies have investigated the use of alternative therapies such as oesophageal stents93–101 and Recommendation 2.10 intrasphincteric injection with ethanolamine oleate in We suggest treating recurrent or persistent dysphagia after POEM achalasia treatment.102–105 Overall, there is no high- with either re-POEM, laparoscopic Heller myotomy or pneumatic quality evidence to support that either of these thera- dilation. pies are effective for symptom relief in achalasia patients. Moreover, as occurrence of complications Conditional recommendation, very low certainty of evidence such as bleeding, stent migration, or strictures are Consensus: 100% agree [Vote: Aþþ, 77.8%; Aþ, 22.2%; A, 0%; D 0%; Dþ, 0%; Dþþ, 0%] fairly common, use of these therapies is not recommended. Oude Nijhuis et al. 25 where the diagnosis of achalasia is beyond doubt, it Recommendation 2.12 may be appropriate to proceed immediately to further We suggest against oesophageal stents and intrasphincteric injec- treatment without repeat testing (for example, POEM tion of sclerosing agents in the treatment of achalasia. after failure to improve with PD). Expert opinion recommendation Since the commonest causes of recurrent dysphagia Consensus: 100% agree [Vote: Aþþ, 100%; Aþ, 0%; A, 0%; D 0%; are incomplete myotomy, post-treatment scarring, and Dþ, 0%; Dþþ, 0%] oesophageal stasis due to aperistalsis and functional dysphagia, objective testing should be targeted at these conditions. Timed barium esophagram helps 3. Achalasia follow-up determine if there is persistent delay to oesophageal 3.1 How to diagnose and manage recurrent or emptying, but reports regarding its usefulness as a pre- dictor of long-term treatment success are conflict- persistent dysphagia after treatment? ing.36,55,108 High-resolution manometry provides Despite treatment, a proportion of patients will experi- additional information on LOS pressure. Impedance ence ongoing or recurrent symptoms that significantly planimetry might be a useful complementary tool to impair quality of life.86,106 In some cases, treatment assess OGJ distensibility and determine treatment effi- does not lead to meaningful improvement in the first cacy.16,110 In patients with a suspicion of severe place (persistent symptoms). In others, a period of ini- oesophagitis, possible candida oesophagitis or ana- tial improvement is followed by subsequent recurrence. tomic abnormalities endoscopy should be considered. In general terms, the former suggests that initial treat- ment was incomplete, whereas the latter can be due to a Recommendation 3.1 variety of causes. There is no universal definition of a. Patients with recurrent or persistent dysphagia after initial what constitutes persistence or recurrence of symptoms. treatment should undergo repeat evaluation with timed In most trials an Eckardt score above 3 or a less than barium esophagram with or without oesophageal manometry. 50% improvement in symptoms is regarded as treat- Expert opinion recommendation ment failure.47,50,54,107–109 However, this fails to distin- Consensus: 100% agree [Vote: Aþþ, 100%; Aþ, 0%; A, 0%; D 0%; guish between dysphagia, and alternative troublesome Dþ, 0%; Dþþ, 0%] symptoms such as regurgitation or chest pain. Although dysphagia is the most common ongoing b. Repeat endoscopy should be considered in patients with recur- symptom after achalasia treatment,86 the aetiology rent dysphagia. may be different to that in the treatment-naive setting Expert opinion recommendation (Table 3.1.1). Consensus: 100% agree [Vote: Aþþ, 66.7%; Aþ, 33.3%; A, 0%; D Given the wide variety of potential causes of recur- 0%; Dþ, 0%; Dþþ, 0%] rent dysphagia, it is critical to undertake a comprehen- sive evaluation using objective testing in order to 3.2 How to diagnose and manage recurrent or determine the pathophysiology underpinning the recur- persistent chest pain after treatment? rent symptoms, and thus select appropriate treatment. Conversely, in selected cases of persistent dysphagia, Although chest pain is one of the main presenting symp- toms of achalasia, its response to treatment is less well studied and remarkably underreported, most likely as Table 3.1.1. Potential causes for persistent and recurrent dys- dysphagia is considered the leading and most relevant phagia after initial treatment. symptom. Nevertheless, up to 64% of patients report chest pain, often occurring in the middle of the night Common  Persistent OGJ non-relaxation (e.g. incomplete myotomy) (in 47% of patients with chest pain) and lasting from a  Post-treatment oesophageal fibrosis/scarring few minutes to almost 24 hours.111 In contrast to dys-  Excessively tight fundoplication post-myotomy phagia, chest pain is more challenging to treat and rep-  Gastro-oesophageal reflux (with or without oesophagitis) resents a risk factor for unsatisfactory treatment results  Aperistalsis and oesophageal stasis for both pneumatic dilation (PD) and laparoscopic  Functional dysphagia Heller myotomy (LHM).37,54,112 In approximately 19% Uncommon of patients, chest pain is completely relieved following  Development of malignant stricture LHM, but in the remainder chest pain persists, with an  Wrap migration after fundoplication and myotomy intensity that is less (73%), similar (21%) or even more  Benign stricture (e.g. from reflux) severe (4%) than before surgery.113 Comparable results  Extrinsic compression from hiatal hernia (para-oesophageal) have been reported for PD.111 Of note, chest pain per- or post-treatment collection sists in these patients even though dysphagia was 26 United European Gastroenterology Journal 8(1) successfully treated. In general, achalasia-associated Continued. chest pain seems to decrease with time, but complete manometry. For type III achalasia, we suggest a repeat HRM to disappearance is rather exceptional.111 exclude or confirm persistent spastic contractions. The exact cause underlying (non-cardiac) chest pain Expert opinion recommendation remains unknown, and can be attributed to acid reflux, Consensus: 100% agree [Vote: Aþþ, 88.9%; Aþ, 11.1%; A, 0%; D oesophageal motor abnormalities or visceral hypersen- 0%; Dþ, 0%; Dþþ, 0%] sitivity. However, as chest pain is also considered to result from oesophageal distension as a result of incom- b. If there is no evidence of impaired oesophageal emptying, plete emptying, treatment failure should first be empirical treatment with PPI, endoscopy and/or 24-hour pH excluded in patients with persistent or recurrent chest (impedance) monitoring can be considered. pain by performing oesophageal manometry and timed Expert opinion recommendation barium esophagram (TBE). Consensus: 100% agree [Vote: Aþþ, 100%; Aþ, 0%; A, 0%; D 0%; If manometry (IRP above cut-off; catheter-depend- Dþ, 0%; Dþþ, 0%] ing, varying between 15 and 28 mmHg)114 or TBE are abnormal (barium column height of >5cm after 5 min- 3.3 How to manage reflux disease after utes),115 treatment should aim to normalize oesopha- geal emptying. HRM also serves to exclude spastic treatment? contractions as cause of the pain. If there is no evidence As the aim of achalasia treatment is to alleviate the indicating insufficient treatment, one can consider OGJ obstruction, an expected side effect of treatment investigation for gastro-oesophageal reflux (GER) as is the occurrence of gastro-oesophageal reflux disease trigger of chest pain using 24-hour pH (impedance) (GORD), usually defined in achalasia as the presence of monitoring and treat accordingly.116 Data demonstrat- reflux oesophagitis or pathological acid exposure. ing the effect of PPI on chest pain in achalasia are how- Indeed GORD is frequently observed after treatment ever lacking, and anecdotally the response to PPI is (10 to 31% of cases after pneumatic dila- poor if there is chest pain without heartburn. tion51–53,55,58,121 5 to 35% after Heller’s myot- The management of achalasia patients with chest pain omy52,53,55,121–123 and up to 60% of patients after with no evidence of GER and normal oesophageal emp- POEM)50,60,61,124–126 GORD complications including tying/IRP remains a major challenge, mainly as there are peptic stricture, Barrett’s mucosa, and oesophageal no or only a limited number of randomised clinical trials adenocarcinoma have been reported after achalasia available. Hence, clinical decision making is mostly treatment.124,126–130 Comparative studies demonstrated based on studies performed in patients with non-cardiac that the rate of GORD was similar after PD and LHM chest pain due to oesophageal dysmotility. Potential with fundoplication.121 One study showed that LHM options for medical treatment are smooth muscle relax- without lateral and posterior dissection might also ants (nifedipine, nitrates, diltiazem), botulinum toxin achieve sufficient reflux control.131 However, in other injection or neuromodulators (imipramine, venlafaxine, studies, prevalence of GORD was significantly higher sertraline)116; however, the success rates are rather lim- after POEM or laparoscopic Heller myotomy without ited and/or the effect is short lasting (in case of botulinum fundoplication than after pneumatic dilation or laparo- toxin). Of interest, evidence is accumulating that POEM scopic Heller myotomy with fundoplication.50,60,62,132 might be effective in relieving chest pain, both in patients Therefore, systematic screening for GORD after acha- with achalasia and other primary oesophageal motility lasia treatment should be recommended if the risk for disorders. Several case series evaluating patients with GORD is high. Moreover, due to the different GORD hypercontractile oesophageal motility disorders and rates, the choice of achalasia treatment should take into chest pain that were treated with POEM showed promis- account the risk of iatrogenic reflux disease. In line with ing results.117–120 However, as none of the studies were this, empiric PPI therapy might be considered in sham-controlled, patient numbers were small and patients that underwent myotomy without an anti- lengths of follow-up relatively short, future controlled reflux procedure. data with longer follow-up is needed to investigate the GORD symptoms such as heartburn and regurgita- exact role of POEM for patients with chest pain after tion are not reliable to diagnose GORD in achala- initial achalasia treatment. sia patients, especially as regurgitation is also a hallmark of achalasia and poor oesophageal emptying. Recommendation 3.2 Upper endoscopy can reveal oesophagitis and a. In patients with persistent or recurrent chest pain, inappropriate Barrett’s mucosa as proof of GORD. Another way emptying due to ineffective initial treatment or recurrent disease to diagnose GORD is 24-h oesophageal pH monitor- should be excluded by TBE with or without oesophageal ing. The interpretation of this examination requires a (continued) careful review of pH tracings to eliminate periods of Oude Nijhuis et al. 27 oesophageal fermentation.53 The correlation between (retrospective or prospective, length of Follow-up, oesophageal symptoms and objective diagnosis of number of patients, countries) might explain some of GORD (including oesophagitis and oesophageal acid the observed differences. While the absolute risk of exposure) is poor.62,123,133–135 Upper GI endoscopy, oesophageal cancer is quite low in achalasia, the rela- TBE and 24-h pH monitoring might be tive risk of cancer is higher in achalasia patients than in complementary. the general population (risk ratio to develop EA and So far, no study has clearly evaluated the man- SCC in achalasia patients is 6.63 and 72.65 respect- agement of GORD after achalasia treatment. Post- ively).143,144 Most of the cases of carcinoma are treatment GORD is usually treated successfully with observed more than 10 years after symptom PPI. The percentage of patients on PPI after acha- onset.144,145 The type of treatment does not influence lasia treatment is up to 60%.60,61,136–138 Few other the risk of cancer130,146 but to date there are no long- GORD treatments have been proposed for refractory term data following POEM. Cancer risk might be cases and presented only as case reports higher in males and in patients with Chagas (re-do fundoplication, Roux-en-Y gastric bypass, eso- disease.130,146,147 phagectomy, transoral incisionless Screening practices differ among geographic regions fundoplication).89,139,140 (routine endoscopy versus no endoscopy, screening intervals).92,148 Chromoendoscopy with lugol was pro- Recommendation 3.3 posed to improve the detection rate of dysplastic lesion a. We suggest follow-up endoscopy to screen for GORD in patients but the yield was low and hampered by stratification treated with myotomy without anti-reflux procedure. risk.145 Finally the cost efficacy of the screening has not been Expert opinion recommendation demonstrated; the low absolute risk of cancer and the Consensus: 100% agree [Vote: Aþþ, 44.4%; Aþ, 44.4%; A, 11.1%; difficulty to identify pre-neoplastic lesions might D 0%; Dþ, 0%; Dþþ, 0%] explain the absence of advantage to screen achalasia b. In case of reflux symptoms in absence of reflux oesophagitis, patients for oesophageal cancer. TBE, empiric PPI therapy, and/or 24-h oesophageal pH-(imped- ance)monitoring can be considered. Recommendation 3.4 Expert opinion recommendation We suggest against performing systematic screening for dysplasia Consensus: 100% agree [Vote: Aþþ, 77.8%; Aþ, 22.2%; A, 0%; D and carcinoma. However, the threshold of upper GI endoscopy 0%; Dþ, 0%; Dþþ, 0%] should be low in patients with recurrent symptoms and longstand- c. Proton pump inhibitors are the first line treatment of GORD ing achalasia. after achalasia treatment. We recommend lifelong PPI Conditional recommendation, low certainty of evidence therapy in patients with oesophagitis > grade A (LA Consensus: 100% agree [Vote: Aþþ, 66.7%; Aþ, 33.3%; A, 0%; D classification). 0%; Dþ, 0%; Dþþ, 0%] Expert opinion recommendation Consensus: 100% agree [Vote: Aþþ, 33.3%; Aþ, 55.6%; A, 11.1%; D 0%; Dþ, 0%; Dþþ, 0%] Conclusions and future perspectives The ESNM/UEG guidelines on the management of 3.4 Is surveillance endoscopy for dysplasia achalasia are the result of an evidence-based approach and international and multidisciplinary efforts. These needed? guidelines provide recommendations for key aspects What is the incidence of oesophageal cancer in achalasia of the diagnosis and management of achalasia, com- patients? bined with comments based on the best-available litera- Achalasia is a risk factor for oesophageal cancer. Poor ture and the opinions of leading European achalasia oesophageal clearance increases bacterial growth, chem- experts. The main objective of these guidelines is to ical irritation and mucosal inflammation that can facili- reduce variation in practice and improve patient out- tate dysplastic changes of oesophageal epithelial cells comes across Europe. Consequently, thorough and and result in squamous cell carcinoma (SCC).141 extensive dissemination of these guidelines is needed Furthermore, acid exposure secondary to reduction of to assure high compliance in clinical practice. oesophago-gastric junction pressure as a consequence Promotion of the guideline as well as education play of achalasia treatment may lead to Barrett’s mucosa a key role in this regard. Future well-designed clinical and oesophageal adenocarcinoma (EA).142 trials should address the gaps of knowledge and unmet The exact level of risk for oesophageal cancer (SCC needs that have arisen during the development of this and EA) is controversial. Differences in study design guideline. 28 United European Gastroenterology Journal 8(1) Author contributions 5. Fox MR and Bredenoord AJ. Oesophageal high-resolu- RON and AB were responsible for drafting the guidelines tion manometry: moving from research into clinical prac- protocol, coordinating the development of the guidelines tice. Gut 2008; 57: 405–423. 2007/09/27. DOI: 10.1136/ and the initial list of research questions to be covered by gut.2007.127993. the guidelines. RON and ML conducted the literature 6. Carlson DA, Ravi K, Kahrilas PJ, et al. Diagnosis of search and systematic selection of articles. Working group Esophageal Motility Disorders: Esophageal Pressure expert members (AB, GB, PF, AP, SR, AS, AT, ET, BW, Topography vs. Conventional Line Tracing. The GZ) systematically appraised the literature and assessed the American journal of gastroenterology 2015; 110: 967–977; evidence according to GRADE and drafted the statements. quiz 978. 2015/06/03. DOI: 10.1038/ajg.2015.159. RON and ML provided methodological support. All expert 7. Soudagar AS, Sayuk GS and Gyawali CP. Learners members voted on the recommendations. RON and AB favour high resolution oesophageal manometry with drafted the manuscript, which was reviewed, revised and better diagnostic accuracy over conventional line tra- approved by all authors. cings. Gut 2012; 61: 798–803. 2011/10/15. DOI: 10.1136/ gutjnl-2011-301145. 8. Clouse RE, Staiano A, Alrakawi A, et al. Application of Declaration of conflicting interests topographical methods to clinical esophageal manome- No disclosures or conflicts of interest: GB, ML, RON, AT, ET, try. The American journal of gastroenterology 2000; 95: AS, BW, GZ. Research support: Bayer (AB), Crospon (SR), 2720–2730. 2000/10/29. DOI: 10.1111/j.1572-0241.2000. Diversatek (SR), Laborie (AB), Medtronic (SR) Nutricia (AB), 03178.x. Norgine (AB). Advisory, honoraria or consultation: Calypso 9. Roman S, Huot L, Zerbib F, et al. High-Resolution (AB), Celgene (AB), Cook (PF), Diversatek (AB), EsoCap Manometry Improves the Diagnosis of Esophageal (AB), Ethicon (PF), Falk (AB), Fujifilm (PF), Laborie (AB), Motility Disorders in Patients With Dysphagia: A Medtronic (PF, SR), Olympus (PF), Regeneron (AB). Speaker’s Randomized Multicenter Study. The American journal bureau: Actavis (AP), Falk (AB), Janssen-Cilag (AP), Laborie of gastroenterology 2016; 111: 372–380. 2016/02/03. (AB), Mayoly Spindler (SR), Medtronic (AB), Takeda (AP). DOI: 10.1038/ajg.2016.1. 10. O’Rourke AK, Lazar A, Murphy B, et al. Utility of Funding Esophagram versus High-Resolution Manometry in the These guidelines have been developed and funded within the Detection of Esophageal Dysmotility. Otolaryngology– head and neck surgery: official journal of American United European Gastroenterology. Academy of Otolaryngology-Head and Neck Surgery 2016; 154: 888–891. 2016/02/26. DOI: 10.1177/ ORCID iD 0194599816629379. 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