Neurogastroenterology & Motility Neurogastroenterol Motil (2014) 26, 1215–1221
doi: 10.1111/nmo.12416
MINI-REVIEW
Management strategies for achalasia M. F. VELA
Division of Gastroenterology and Hepatology, Mayo Clinic Arizona, Scottsdale, AZ, USA
Key Messages
• Pneumatic dilation and surgical myotomy have similar effectiveness in randomized controlled trials, and they are currently considered the most effective treatments for achalasia. botulinum toxin injection, a safe treatment with good short-term effectiveness, is reserved for patients who are not candidates for more definitive therapies. Treatment of patients who fail or relapse after initial therapy is challenging and the effectiveness of pneumatic dilation and surgical myotomy is lower in this group. Peroral endoscopic myotomy (POEM) appears promising in early uncontrolled studies, but this technique should not be adopted widely until high-quality randomized trials confirm its efficacy and safety.
• Endoscopic • •
Abstract Treatment options for achalasia include oral pharmacologic therapy, endoscopic injection of botulinum toxin, pneumatic dilation, and myotomy (conventionally by laparoscopy, but more recently by an endoscopic approach). Oral pharmacologic agents have fallen out of use because of insufficient efficacy and frequent side effects. Endoscopic injection of botulinum toxin is safe and has good short-term effectiveness, but as the effect invariably wears off after a few months, this treatment is reserved for patients who are not candidates for more definitive treatments. Pneumatic dilation and surgical myotomy are currently considered the most effective treatments, with similar effectiveness in randomized controlled trials with follow-up of up to 2 years. The risk/benefit ratio and choice of therapy depend on patient characteristics (age, comorbidities, disease stage, prior treatments), patient’s preference, and locally available expertise.
Treatment of patients who fail or relapse after initial therapy is challenging and the success rate of pneumatic dilation or myotomy in this group is lower compared with previously untreated patients. The recently developed peroral endoscopic approach to myotomy has achieved excellent results in early uncontrolled studies, but high-quality randomized trials are needed to ensure widespread adoption is reasonable. Finally, retrospective data suggest that achalasia subtypes as defined by high-resolution esophageal pressure topography may guide treatment choice, but confirmation in prospective outcome studies is awaited. Keywords achalasia, botulinum toxin injection, Heller myotomy, peroral endoscopic myotomy, pneumatic dilation.
INTRODUCTION Achalasia is a primary esophageal motor disorder characterized by neuronal degeneration of the myenteric plexus leading to impaired relaxation of the lower esophageal sphincter (LES) and absent esophageal peristalsis. Although fairly uncommon, achalasia stands out among the esophageal motor disorders as
Address for Correspondence Marcelo F. Vela, MD, MSCR, Division of Gastroenterology and Hepatology, Mayo Clinic Arizona, Scottsdale, AZ, USA. Tel: 480-301-4461; fax: 480-301-8679; e-mail: [email protected] Received: 21 July 2014 Accepted for publication: 22 July 2014
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tion of undigested food and saliva in 75%, weight loss in 60%, chest pain in 40–50%, and heartburn in 40%.6 In the current era of frequent use and sometimes overuse of proton pump inhibitors (PPI), we are seeing an increasing number of patients with heartburn and other esophageal symptoms, who fail to respond to these medications. It is important to remember that in some patients, PPI-refractory heartburn may in fact be explained by achalasia. For this reason, recent guidelines for gastro-esophageal reflux disease mandate esophageal manometry prior to antireflux surgery, with the main purpose of ruling out achalasia masquerading as GERD.7 The gold standard for diagnosing achalasia is esophageal manometry; radiographic and endoscopic evaluation provides additional useful information. In a patient with symptoms suggestive of achalasia, a barium esophagram showing a dilated esophagus that tapers into a ‘bird-beak’ at the gastro-esophageal junction supports the diagnosis. However, these classic radiographic findings are not always present, especially in early stages of the disease when esophageal dilation is not prominent. Achalasia cannot be diagnosed by endoscopy. Although patients may present with esophageal dilation, retention of food particles and secretions, and a ‘puckered’ esophago-gastric junction (EGJ), endoscopy is often normal. Nonetheless, endoscopy is recommended in all patients with suspected achalasia with the main purpose of ruling out mechanical obstruction or pseudoachalasia.5 The hallmark findings of achalasia on manometry are impaired LES relaxation and esophageal aperistalsis.8 Basal LES pressure may be elevated as may be the resting esophageal body pressure, but these features are not uniformly present. Based upon conventional manometry with analysis of line tracings, variants such as vigorous achalasia (i.e., high-amplitude, nonpropagating peristaltic contractions) were previously described.9 More recently, analysis of HREPT plots obtained during high-resolution manometry has led to the description of three subtypes of achalasia: type I or classic achalasia with low intraesophageal pressure, type II with panesophageal pressurization, and type III with high-amplitude spastic contractions (Fig. 1). In the original retrospective cohort study, it was noted that response to therapy was best in type II achalasia and somewhat lower in type I; patients with type III achalasia had poor response to all forms of therapy.10 Two other retrospective studies11,12 and post hoc analysis of data from a randomized trial comparing pneumatic dilation and surgical myotomy13 have come to similar conclusions: response is best for type II and worse for type III achalasia. Thus, while
the most clearly defined in terms of clinical, manometric, and radiographic presentation. Furthermore, in contrast to other esophageal motility disorders, an ample body of literature is available to support treatment decisions. The last decade has brought us significant progress in achalasia diagnosis, with the development of high-resolution esophageal topography (HREPT) as a more sensitive diagnostic modality, leading to a new classification of achalasia subtypes that may help direct management. Treatment options have also advanced with the introduction of incisionless, endoscopic myotomy as a promising new therapy. Despite these advances, the management of patients that fail primary therapy remains challenging, which is highlighted in the article by Legros et al. in the current issue of Neurogastroenterology and Motility.1 This review discusses the epidemiology, etiology, clinical presentation, and diagnosis of achalasia, with greater emphasis on the treatment of this disease.
EPIDEMIOLOGY AND ETIOLOGY Achalasia is rare, with an estimated incidence of ~1/ 100 000 and a prevalence of 10/100 000; it occurs equally in males and females, without racial predilection, and across all ages, with a peak incidence between the ages of 30 and 60.2 While it is well established that the motor abnormalities seen in achalasia are due to destruction of the myenteric plexus, the exact etiology of the disease remains unknown, with available studies suggesting infectious, genetic, and autoimmune mechanisms.3 Although proof for a hypothesis that may incorporate all of these factors is lacking, it is possible that an initial insult, possibly a viral infection, may trigger an inflammatory cascade leading to acute myenteric plexus inflammation. Genetically susceptible individuals may go on to develop antimyenteric autoantibodies resulting in chronic inflammation and ultimately destruction of the myenteric plexus.4 Needless to say, further studies are needed to clarify the etiology of achalasia, with the hope of accomplishing gains in the diagnosis and treatment of this disease.
CLINICAL PRESENTATION AND DIAGNOSIS Incomplete LES relaxation and esophageal aperistalsis typically result in dysphagia to solids and liquids without oropharyngeal transfer difficulty, along with regurgitation of bland undigested food and/or saliva.5 Dysphagia is seen in over 90% of patients, regurgita-
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Figure 1 High-resolution esophageal pressure topography plots showing the three achalasia subtypes. Note that lower esophageal sphincter relaxation impairment, a hallmark of achalasia, is present in the three subtypes. In achalasia type I there is no esophageal body pressurization. Type II achalasia is characterized by pan-esophageal pressurization, and type III by highamplitude spastic contractions.
dilated or sigmoid esophagus may require esophagectomy.6 The risk/benefit ratio and choice of therapy depend on patient characteristics (age, comorbidities, disease stage, prior treatments), patient’s preference, and locally available expertise. A proposed algorithm for the treatment of achalasia is depicted in Fig. 2.
prospective outcome data are not yet available, it appears that these achalasia subtypes may predict response to therapy and could help guide management.
TREATMENT Currently, there is no treatment that can reverse the damage to the myenteric plexus and restore normal esophageal motor function. Therefore, the available therapies aim to disrupt the LES and reduce its pressure to allow esophageal emptying by gravity. Reduction of the LES pressure can be achieved through oral pharmacologic therapy, endoscopic injection of botulinum toxin, pneumatic dilation, or myotomy (conventionally by laparoscopy, but more recently by an endoscopic approach). Of these, pneumatic dilation and surgical myotomy are currently considered the most effective treatments.5 ‘Endstage’ cases presenting with a very
Oral pharmacologic therapy Medications that produce smooth muscle relaxation including nitrates, calcium channel blockers, and phosphodiesterase-5 inhibitors can reduce LES pressure and may result in symptom improvement in some patients, but clinical efficacy is overall limited and side effects are frequent. Therefore, these agents have fallen out of use and are employed only rarely, for short-term relief of achalasia symptoms in patients who cannot tolerate more invasive therapies or as a bridge to more definitive treatment.14 Untreated achalasia
Figure 2 Proposed algorithm for the management of achalasia. Patients without prior treatment who are not surgical candidates because of age or comorbidities can be treated by botulinum toxin injection (Botox), with repeat injections as needed. Those who are good surgical candidates can have initial treatment with either graded pneumatic dilation or laparoscopic Heller myotomy. Some studies suggest that young males (i.e., less than 40 years old) may achieve higher success rate with myotomy. Patients who fail initial therapy or relapse following initial success should undergo repeat treatment at a center with achalasia expertise. These patients can be treated with either pneumatic dilation or myotomy; those with end-stage disease may need esophagectomy. Patients who previously failed myotomy or dilation and are no longer good surgical candidates can be treated with botox.
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Surgery precluded
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Endoscopic botulinum toxin injection
matic dilation, excellent/good responses were reported in 90% of patients after 6 months, but response declined to 44% after 6 years of follow-up.23 The perforation rate after pneumatic dilation is ~2% in experienced hands (range 0–16%); gastro-esophageal reflux occurs in 15–33% of patients after this procedure and is rarely severe.24
Endoscopic injection of botulinum toxin into the LES reduces LES pressure by inhibition of acetylcholine release from nerve endings, which counterbalances the effect of the selective loss of inhibitory neurotransmitters (mainly nitrous oxide) in achalasia.15 It is very safe, easy to administer, and provides symptom relief initially in ~85% of patients; however, the effect of a single injection was limited to 6 months or less in over 50% of patients in an early trial.16 Subsequent studies17–19 confirmed that botulinum toxin is initially effective, but the benefit of a single injection lasts less than 1 year in the majority of patients, with eventually a need for repeat injections or other forms of achalasia treatment. Given its favorable safety profile, botulinum toxin injection is a reasonable option for the short-term treatment of achalasia, but it cannot be recommended as a long-term solution for patients who are candidates for more definitive therapies. Thus, this treatment is currently reserved for patients in whom pneumatic dilation or myotomy is precluded by patient-related risks.5
Surgical myotomy Surgical myotomy disrupts the LES fibers through a longitudinal incision. Over the years, the technique evolved from open thoracotomy and laparotomy, to a minimally invasive laparoscopic or thoracoscopic approach. Laparoscopic myotomy has been established as the preferred method for several years, because of decreased morbidity and faster recovery.25 The majority of the literature regarding the effectiveness of myotomy is uncontrolled. In a systematic review of 39 uncontrolled studies of laparoscopic myotomy that included a total of 3086 patients with variable followup of 8–83 months, symptom improvement was achieved in a mean 89% of patients (range 77– 100%).26 A recent, large, multicenter randomized controlled trial that compared graded pneumatic dilation with laparoscopic Heller myotomy found that the success rate for surgery after 2 years was 87%.22 As with pneumatic dilation, the efficacy of Heller myotomy decreases with longer follow-up periods. In a series of 73 patients treated with Heller myotomy, excellent/good responses were reported in 89% and 57% of patients at 6 months’ and 6 years’ follow-up, respectively.23 GERD is a frequent complication after myotomy. Adding a partial fundoplication to the myotomy decreases, but does not eliminate, the risk of GERD, and recent gastroenterology and surgery society guidelines recommend an antireflux procedure along with myotomy.5,27 There is some debate as to the type of partial fundoplication that works best in this setting. A recent multicenter randomized controlled trial that compared an anterior Dor vs a posterior Toupet fundoplication found a non-significant higher percentage of abnormal pH test results after Dor vs Toupet (41% vs 21%), with similar improvement of dysphagia and regurgitation symptoms in both groups.28
Pneumatic dilation The LES fibers can be disrupted by forceful dilation using pneumatic balloons. The present-day technique consists of outpatient, sedated endoscopy to determine landmarks, immediately followed by placement of a balloon across the LES, usually under fluoroscopic but sometimes under direct endoscopic guidance. The dilation protocol varies somewhat across different centers, but the balloon is inflated to sufficient pressure (usually 7–12 psi) for 15–60 s to break the LES muscle fibers. Postdilation esophagram is mandatory to rule out perforation. A review of the numerous uncontrolled studies of pneumatic dilation is beyond the scope of this review, but a brief examination of the controlled trials is worthwhile. There are no studies comparing pneumatic dilation with sham dilation. In earlier randomized controlled trials that compared pneumatic dilation with botulinum toxin injection, symptom improvement rates for dilation at 12 months ranged between 53% and 70%.17,20,21 In a more recent randomized controlled trial that compared graded pneumatic dilation (allowing for repeat dilation) with laparoscopic Heller myotomy, the success rate for dilation after 2 years was 92%.22 Data regarding longterm effectiveness of pneumatic dilation are limited, but available studies reveal a decline in the proportion of patients in remission as time goes on. For instance, in a series of 106 patients treated with graded pneu-
Comparative effectiveness of pneumatic dilation vs Heller myotomy There is a paucity of high-quality, randomized controlled trials comparing pneumatic dilation and Heller
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myotomy. In an early trial that randomized 25 patients to laparoscopic Heller myotomy and 26 to pneumatic dilation, treatment failure was significantly less common after surgery in the per-protocol analysis (4% vs 23%), but significance was lost in the intention-to-treat analysis.29 More recently, a highquality, large, multicenter randomized controlled trial was carried out in five European centers. In this study, 200 patients with achalasia were randomly assigned to graded pneumatic dilation or laparoscopic Heller myotomy; after 2 years of follow-up, there was no significant difference in treatment success rates for dilation compared with myotomy (92% vs 87%).22 A subsequent meta-analysis concluded that short- and long-term treatment success is higher for myotomy compared with dilation, but only two randomized controlled trials directly comparing these modalities were included (these are the two studies summarized above); the other 14 studies in the analysis include 5 randomized trials comparing dilation or surgery with other modalities, and 9 uncontrolled studies.30 Furthermore, definition of treatment success varied and in some of the studies, lack of improvement after a single dilation rather than a series of treatments in a graded approach was considered failure. Thus, based upon the highest-quality data that are available, it appears that Heller myotomy and pneumatic dilation have similar effectiveness on a 1- to 2-year horizon. That said, earlier studies and the multicenter European randomized trial found that young age (less than 40 years) increases the risk of failure for pneumatic dilation in males,22,23 and myotomy may therefore be a better option in this specific group. It is important to note that the success rates for both dilation and myotomy decline over time, and repeat intervention may be required. To date, whether response to dilation or surgery varies in the different achalasia subtypes as defined by HREPT has not been studied in randomized controlled trials.
In 2010, the first human series was published, demonstrating statistically significant reduction in both resting LES pressure and dysphagia symptom score in all patients (mean follow-up of 5 months), without any serious complications.33 Subsequent studies achieved similar results with a very low rate of serious complications. In a recent review that includes nine uncontrolled studies of POEM for achalasia, success rates after a mean 1–12 months ranged from 89% to 100%.32 GERD is frequent after POEM, but appears to respond to acid suppression with PPIs in the available studies. Not surprisingly, there is a lot of enthusiasm for this technique. However, it is important to bear in mind that all the available studies are uncontrolled and follow-up data are limited to 12 months at best. Adequately powered, randomized controlled trials comparing POEM with surgical myotomy and pneumatic dilation are needed to discern where this modality may fit in the treatment of achalasia patients. For now, POEM should be performed only within trials aiming to elucidate whether POEM is a suitable alternative to other treatments and which patients may benefit from this approach, possibly using achalasia subtypes as defined by HREPT.
Management of treatment failures As mentioned earlier, the proportion of patients who remain in remission after successful pneumatic dilation or surgical myotomy declines over time, and repeat intervention may be required. In two studies of patients who were followed up for a mean 5–7 years after successful graded pneumatic dilation, additional treatment (mostly repeat dilation but also surgery in some) was required in 23–33%.34,35 Likewise, in two reports of patients who were followed up for a mean 5– 6 years after laparoscopic Heller myotomy, additional therapy (mostly pneumatic dilation, but re-do myotomy and botulinum toxin injection were also used) was needed in 18–21%.36,37 Treatment of patients who fail to respond to or relapse after initial improvement following myotomy represents a clinical challenge and data regarding their management are very limited. These patients should be treated in a center with expertise in multiple treatment modalities for achalasia (Fig. 2). In a report of 48 patients who presented at a tertiary center having failed myotomy, rates of symptom improvement after pneumatic dilation and repeat myotomy were 67% and 57%; eight of these patients ended up requiring esophagectomy.6 Of note, a preexisting myotomy does not appear to increase the risk of perforation during pneumatic dilation, although data
Peroral endoscopic myotomy (POEM): an emerging option for achalasia A peroral approach that allows endoscopic myotomy without a surgical incision was initially described in a porcine model in 2007.31 The procedure consists of four consecutive steps: (i) mucosal incision 10–15 cm above the EGJ to allow entry into the submucosa, (ii) creation of a submucosal tunnel through a combination of blunt dissection and electrocautery until the LES is reached, (iii) myotomy of the circular muscle layer with an electrocautery device, and (iv) closure of the mucosal entry with multiple endoscopic clips.32
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about this issue are limited.38 The most recent data regarding the management of patients with recurrence after Heller myotomy are included in the current issue of Neurogastroenterology and Motility. Legros et al. assessed the efficacy and safety of pneumatic dilation in 18 patients with relapsing symptoms after myotomy,1 finding that pneumatic dilation led to remission in 14 (78%) patients, but eight of them required repeat dilations during the follow-up period, highlighting the need for close follow-up and repeated treatments in this challenging group.
and choice of therapy depend on patient characteristics (age, comorbidities, disease stage, prior treatments), patient’s preference, and locally available expertise. The proportion of patients who remain in remission after successful pneumatic dilation or surgical myotomy declines over time and repeat intervention is required in some patients. Treatment of patients who fail or relapse after initial therapy is challenging and the success rate of pneumatic dilation or myotomy in these patients is lower compared with previously untreated patients. POEM represents an innovative way to perform myotomy with excellent results in early uncontrolled studies, but high-quality randomized trials are needed to ensure widespread adoption is reasonable. Finally, retrospective data suggest that achalasia subtypes as defined by HREPT may guide treatment choice, but prospective outcome studies will be needed to solidify this concept.
SUMMARY Several options are available for the treatment of achalasia. Oral pharmacologic agents have a very limited role because of insufficient efficacy and frequent side effects. Endoscopic injection of botulinum toxin is safe and effective in the short term, but the effect wears off usually after a few months and this treatment is thus reserved for patients who are not candidates for more definitive treatments. Pneumatic dilation and laparoscopic Heller myotomy provide the greatest opportunity for treatment success; both show similar effectiveness in randomized controlled trials with follow-up of up to 2 years. The risk/benefit ratio
REFERENCES 1 Legros L, Ropert A, Brochard C, Bouguen G, Pagenault M, Siproudhis L, Bretagne JF. Long-term results of pneumatic dilation for relapsing symptoms of achalasia after Heller myotomy. Neurogastroenterol Motil 2014; 26: 1248–55. 2 Francis DL, Katzka DA. Achalasia: an update on the disease and its treatment. Gastroenterology 2010; 139: 369–74. 3 Petersen RP, Martin AV, Pellegrini CA, Oelschlager BK. Synopsis of investigations into proposed theories on the etiology of achalasia. Dis Esophagus 2012; 25: 305–10. 4 Park W, Vaezi MF. Etiology and pathogenesis of achalasia: the current understanding. Am J Gastroenterol 2005; 100: 1404–14. 5 Vaezi MF, Pandolfino JE, Vela MF. ACG clinical guideline: diagnosis and management of achalasia. Am J Gastroenterol 2013; 108: 1238–49. 6 Vela MF, Richter JE. Management of achalasia at a tertiary center - a
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FUNDING No funding declared.
CONFLICTS OF INTEREST The author has no competing interests.
complicated disease. Gastroenterology 2003; 124: A236. Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol 2013; 108: 308–28. Bredenoord AJ, Fox M, Kahrilas PJ, Pandolfino JE, Schwizer W, Smout AJ. Chicago classification of esophageal motility disorders defined in high resolution esophageal pressure topography. Neurogastroenterol Motil 2012; 24(Suppl. 1): 57–65. Spechler SJ, Castell DO. Classification of oesophageal motility abnormalities. Gut 2001; 19: 145–51. Pandolfino JE, Kwiatek MA, Nealis T, Bulsiewicz W, Post J, Kahrilas PJ. Achalasia, a new clinically relevant classification by high-resolution manometry. Gastroenterology 2008; 135: 1526–33. Salvador R, Costantini M, Zaninotto G, Morbin T, Rizzetto C, Zanatta L, Ceolin M, Finotti E et al. The preoperative manometric pattern predicts the outcome of surgical treatment for
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esophageal achalasia. J Gastrointest Surg 2010; 14: 1632–45. Pratap N, Kalapala R, Darisetty S, Joshi N, Ramchandani M, Banerjee R, Lakhtakia S, Gupta R et al. Achalasia cardia subtyping by high-resolution manometry predicts the therapeutic outcome of pneumatic balloon dilatation. J Neurogastroenterol Motil 2011; 17: 48–53. Rohof WO, Salvador R, Annese V, Bruley des Varannes S, Chaussade S, Costantini M, Elizalde JI, Gaudric M et al. Outcomes of treatment for achalasia depend on manometric subtype. Gastroenterology 2013; 144: 718–25. Eckardt AJ, Eckardt V. Treatment and surveillance strategies in achalasia: an update. Nat Rev Gastroenterol Hepatol 2011; 8: 311–9. Hoogerwerf WA, Pasricha PJ. Pharmacologic therapy in treating achalasia. Gastrointest Endosc Clin N Am 2001; 11: 311–24. Pasricha PJ, Rai R, Ravich WJ, Hendrix TR, Kalloo AN. Botulinum toxin for achalasia: long-term outcome and
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predictors of response. Gastroenterology 1996; 110: 1410–5. Vaezi MF, Richter JE, Wilcox CM, Schroeder PL, Birgisson S, Slaughter RL, Koehler RE, Baker ME. Botulinum toxin versus pneumatic dilation in the treatment of achalasia: a randomized trial. Gut 1999; 44: 231–9. Annese V, Bassotti G, Coccia G, Dinelli M, D’Onofrio V, Gatto G, Leandro G, Repici A et al. A multicenter randomized study of intrasphincteric botulinum toxin in patients with oesophageal achalasia. Gut 2000; 46: 597–600. Neubrand M, Scheurlen C, Schepke M, Sauerbach T. Long-term results and prognostic factors in the treatment of achalasia with botulinum toxin. Endoscopy 2002; 34: 519–23. Muehldorfer SM, Schneider TH, Hochberger J, Martus P, Hahn EG, Ell C. Esophageal achalasia: intrasphincteric injection of botulinum toxin versus balloon dilation. Endoscopy 1999; 31: 517–21. Allescher HD, Storr M, Seige M, Gonzales-Donoso R, Ott R, Born P, Frimberger E, Weigert N et al. Treatment of achalasia: botulinum toxin injection vs pneumatic balloon dilation. A prospective study with longterm follow-up. Endoscopy 2001; 33: 1007–17. Boeckxstaens GE, Annese V, des Varannes SB, Chaussade S, Costantini M, Cuttitta A, Elizalde JI, Fumagalli U et al. Pneumatic dilation versus laparoscopic Heller’s myotomy for idiopathic achalasia. N Engl J Med 2011; 364: 1807–16. Vela MF, Richter JE, Khandwala F, Blackstone EH, Wachsberger D, Baker ME, Rice TW. The long-term efficacy of pneumatic dilatation and heller
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myotomy for the treatment of achalasia. Clin Gastroenterol Hepatol 2006; 4: 580–7. Richter JE. Update on the management of achalasia: balloons, surgery and drugs. Expert Rev Gastroenterol Hepatol 2008; 2: 435–45. Ali A, Pellegrini CA. Laparoscopic myotomy: technique and efficacy in treating achalasia. Gastrointest Endosc Clin N Am 2001; 11: 347–58. Campos GM, Vittinghoff E, Rabl C, Takata M, Gadenst€atter M, Lin F, Ciovica R. Endoscopic and surgical treatments for achalasia: a systematic review and meta-analysis. Ann Surg 2009; 249: 45–57. Stefanidis D, Richardson W, Farrell TM, Kohn GP, Augenstein V, Fanelli RD. SAGES guidelines for the surgical treatment of esophageal achalasia. Surg Endsoc 2012; 26: 296–311. Rawlings A, Soper NJ, Oelschlager B, Swanstrom L, Matthews BD, Pellegrini C, Pierce RA, Pryor A et al. Laparoscopic Dor versus Toupet fundoplication following Heller myotomy for achalasia: results of a multicenter, prospective, randomizedcontrolled trial. Surg Endosc 2012; 26: 18–26. Kostic S, Kjellin A, Ruth M, L€ onroth H, Johnsson E, Andersson M, Lundell L. Pneumatic dilation or laparoscopic cardiomyotomy in the management of newly diagnosed idiopathic achalasia. World J Surg 2007; 31: 470–8. Schoenberg MB, Marx S, Kersten JF, R€ osch T, Belle S, K€ahler G, Vassiliou MC, L€ uth S et al. Laparoscopic Heller myotomy versus endoscopic balloon dilatation for the treatment of achalasia: a network meta-analysis. Ann Surg 2013; 258: 943–52. Pasricha PJ, Hawari R, Ahmed I, Chen J, Cotton PB, Hawes RH, Kalloo AN, Kantsevoy SV et al. Submucosal
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endoscopic esophageal myotomy: a novel experimental approach for the treatment of achalasia. Endoscopy 2007; 39: 761–4. Bredenoord AJ, Roxch T, Fockens P. Peroral endoscopic myotomy for achalasia. Neurogastroenterol Motil 2014; 26: 3–12. Inoue H, Minami H, Kobayashi Y, Sato Y, Kaga M, Suzuki M, Satodate H, Odaka N et al. Peroral endoscopic myotomy (POEM) for esophageal achalasia. Endoscopy 2010; 42: 265–71. Zerbib F, Thetiot V, Richy F, Benajah DA, Message L, Lamouliatte H. Repeated pneumatic dilations as long-term maintenance therapy for esophageal achalasia. Am J Gastroenterol 2006; 101: 692–7. Hulselmans M, Vanuytsel T, Degreef T, Sifrim D, Coosemans W, Lerut T, Tack J. Long-term outcome of pneumatic dilation in the treatment of achalasia. Clin Gastroenterol Hepatol 2010; 8: 30–5. Bonatti H, Hinder RA, Klocker J, Neuhauser B, Klaus A, Achem SR, de Vault K. Long-term results of laparoscopic Heller myotomy with partial fundoplication for the treatment of achalasia. Am J Surg 2005; 19: 345–51. Costantini M, Zaninotto G, Guirroli E, Rizzetto C, Portale G, Ruol A, Nicoletti L, Ancona E. The laparoscopic Heller-Dor operation remains an effective treatment for esophageal achalasia at a minimum 6-year follow-up. Surg Endosc 2005; 19: 345–51. Guardino JM, Vela MF, Connor JT, Richter JE. Pneumatic dilation for the treatment of achalasia in untreated patients and patients with failed Heller myotomy. J Clin Gastroenterol 2004; 38: 855.
doi: 10.1111/nmo.12416
MINI-REVIEW
Management strategies for achalasia M. F. VELA
Division of Gastroenterology and Hepatology, Mayo Clinic Arizona, Scottsdale, AZ, USA
Key Messages
• Pneumatic dilation and surgical myotomy have similar effectiveness in randomized controlled trials, and they are currently considered the most effective treatments for achalasia. botulinum toxin injection, a safe treatment with good short-term effectiveness, is reserved for patients who are not candidates for more definitive therapies. Treatment of patients who fail or relapse after initial therapy is challenging and the effectiveness of pneumatic dilation and surgical myotomy is lower in this group. Peroral endoscopic myotomy (POEM) appears promising in early uncontrolled studies, but this technique should not be adopted widely until high-quality randomized trials confirm its efficacy and safety.
• Endoscopic • •
Abstract Treatment options for achalasia include oral pharmacologic therapy, endoscopic injection of botulinum toxin, pneumatic dilation, and myotomy (conventionally by laparoscopy, but more recently by an endoscopic approach). Oral pharmacologic agents have fallen out of use because of insufficient efficacy and frequent side effects. Endoscopic injection of botulinum toxin is safe and has good short-term effectiveness, but as the effect invariably wears off after a few months, this treatment is reserved for patients who are not candidates for more definitive treatments. Pneumatic dilation and surgical myotomy are currently considered the most effective treatments, with similar effectiveness in randomized controlled trials with follow-up of up to 2 years. The risk/benefit ratio and choice of therapy depend on patient characteristics (age, comorbidities, disease stage, prior treatments), patient’s preference, and locally available expertise.
Treatment of patients who fail or relapse after initial therapy is challenging and the success rate of pneumatic dilation or myotomy in this group is lower compared with previously untreated patients. The recently developed peroral endoscopic approach to myotomy has achieved excellent results in early uncontrolled studies, but high-quality randomized trials are needed to ensure widespread adoption is reasonable. Finally, retrospective data suggest that achalasia subtypes as defined by high-resolution esophageal pressure topography may guide treatment choice, but confirmation in prospective outcome studies is awaited. Keywords achalasia, botulinum toxin injection, Heller myotomy, peroral endoscopic myotomy, pneumatic dilation.
INTRODUCTION Achalasia is a primary esophageal motor disorder characterized by neuronal degeneration of the myenteric plexus leading to impaired relaxation of the lower esophageal sphincter (LES) and absent esophageal peristalsis. Although fairly uncommon, achalasia stands out among the esophageal motor disorders as
Address for Correspondence Marcelo F. Vela, MD, MSCR, Division of Gastroenterology and Hepatology, Mayo Clinic Arizona, Scottsdale, AZ, USA. Tel: 480-301-4461; fax: 480-301-8679; e-mail: [email protected] Received: 21 July 2014 Accepted for publication: 22 July 2014
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tion of undigested food and saliva in 75%, weight loss in 60%, chest pain in 40–50%, and heartburn in 40%.6 In the current era of frequent use and sometimes overuse of proton pump inhibitors (PPI), we are seeing an increasing number of patients with heartburn and other esophageal symptoms, who fail to respond to these medications. It is important to remember that in some patients, PPI-refractory heartburn may in fact be explained by achalasia. For this reason, recent guidelines for gastro-esophageal reflux disease mandate esophageal manometry prior to antireflux surgery, with the main purpose of ruling out achalasia masquerading as GERD.7 The gold standard for diagnosing achalasia is esophageal manometry; radiographic and endoscopic evaluation provides additional useful information. In a patient with symptoms suggestive of achalasia, a barium esophagram showing a dilated esophagus that tapers into a ‘bird-beak’ at the gastro-esophageal junction supports the diagnosis. However, these classic radiographic findings are not always present, especially in early stages of the disease when esophageal dilation is not prominent. Achalasia cannot be diagnosed by endoscopy. Although patients may present with esophageal dilation, retention of food particles and secretions, and a ‘puckered’ esophago-gastric junction (EGJ), endoscopy is often normal. Nonetheless, endoscopy is recommended in all patients with suspected achalasia with the main purpose of ruling out mechanical obstruction or pseudoachalasia.5 The hallmark findings of achalasia on manometry are impaired LES relaxation and esophageal aperistalsis.8 Basal LES pressure may be elevated as may be the resting esophageal body pressure, but these features are not uniformly present. Based upon conventional manometry with analysis of line tracings, variants such as vigorous achalasia (i.e., high-amplitude, nonpropagating peristaltic contractions) were previously described.9 More recently, analysis of HREPT plots obtained during high-resolution manometry has led to the description of three subtypes of achalasia: type I or classic achalasia with low intraesophageal pressure, type II with panesophageal pressurization, and type III with high-amplitude spastic contractions (Fig. 1). In the original retrospective cohort study, it was noted that response to therapy was best in type II achalasia and somewhat lower in type I; patients with type III achalasia had poor response to all forms of therapy.10 Two other retrospective studies11,12 and post hoc analysis of data from a randomized trial comparing pneumatic dilation and surgical myotomy13 have come to similar conclusions: response is best for type II and worse for type III achalasia. Thus, while
the most clearly defined in terms of clinical, manometric, and radiographic presentation. Furthermore, in contrast to other esophageal motility disorders, an ample body of literature is available to support treatment decisions. The last decade has brought us significant progress in achalasia diagnosis, with the development of high-resolution esophageal topography (HREPT) as a more sensitive diagnostic modality, leading to a new classification of achalasia subtypes that may help direct management. Treatment options have also advanced with the introduction of incisionless, endoscopic myotomy as a promising new therapy. Despite these advances, the management of patients that fail primary therapy remains challenging, which is highlighted in the article by Legros et al. in the current issue of Neurogastroenterology and Motility.1 This review discusses the epidemiology, etiology, clinical presentation, and diagnosis of achalasia, with greater emphasis on the treatment of this disease.
EPIDEMIOLOGY AND ETIOLOGY Achalasia is rare, with an estimated incidence of ~1/ 100 000 and a prevalence of 10/100 000; it occurs equally in males and females, without racial predilection, and across all ages, with a peak incidence between the ages of 30 and 60.2 While it is well established that the motor abnormalities seen in achalasia are due to destruction of the myenteric plexus, the exact etiology of the disease remains unknown, with available studies suggesting infectious, genetic, and autoimmune mechanisms.3 Although proof for a hypothesis that may incorporate all of these factors is lacking, it is possible that an initial insult, possibly a viral infection, may trigger an inflammatory cascade leading to acute myenteric plexus inflammation. Genetically susceptible individuals may go on to develop antimyenteric autoantibodies resulting in chronic inflammation and ultimately destruction of the myenteric plexus.4 Needless to say, further studies are needed to clarify the etiology of achalasia, with the hope of accomplishing gains in the diagnosis and treatment of this disease.
CLINICAL PRESENTATION AND DIAGNOSIS Incomplete LES relaxation and esophageal aperistalsis typically result in dysphagia to solids and liquids without oropharyngeal transfer difficulty, along with regurgitation of bland undigested food and/or saliva.5 Dysphagia is seen in over 90% of patients, regurgita-
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Figure 1 High-resolution esophageal pressure topography plots showing the three achalasia subtypes. Note that lower esophageal sphincter relaxation impairment, a hallmark of achalasia, is present in the three subtypes. In achalasia type I there is no esophageal body pressurization. Type II achalasia is characterized by pan-esophageal pressurization, and type III by highamplitude spastic contractions.
dilated or sigmoid esophagus may require esophagectomy.6 The risk/benefit ratio and choice of therapy depend on patient characteristics (age, comorbidities, disease stage, prior treatments), patient’s preference, and locally available expertise. A proposed algorithm for the treatment of achalasia is depicted in Fig. 2.
prospective outcome data are not yet available, it appears that these achalasia subtypes may predict response to therapy and could help guide management.
TREATMENT Currently, there is no treatment that can reverse the damage to the myenteric plexus and restore normal esophageal motor function. Therefore, the available therapies aim to disrupt the LES and reduce its pressure to allow esophageal emptying by gravity. Reduction of the LES pressure can be achieved through oral pharmacologic therapy, endoscopic injection of botulinum toxin, pneumatic dilation, or myotomy (conventionally by laparoscopy, but more recently by an endoscopic approach). Of these, pneumatic dilation and surgical myotomy are currently considered the most effective treatments.5 ‘Endstage’ cases presenting with a very
Oral pharmacologic therapy Medications that produce smooth muscle relaxation including nitrates, calcium channel blockers, and phosphodiesterase-5 inhibitors can reduce LES pressure and may result in symptom improvement in some patients, but clinical efficacy is overall limited and side effects are frequent. Therefore, these agents have fallen out of use and are employed only rarely, for short-term relief of achalasia symptoms in patients who cannot tolerate more invasive therapies or as a bridge to more definitive treatment.14 Untreated achalasia
Figure 2 Proposed algorithm for the management of achalasia. Patients without prior treatment who are not surgical candidates because of age or comorbidities can be treated by botulinum toxin injection (Botox), with repeat injections as needed. Those who are good surgical candidates can have initial treatment with either graded pneumatic dilation or laparoscopic Heller myotomy. Some studies suggest that young males (i.e., less than 40 years old) may achieve higher success rate with myotomy. Patients who fail initial therapy or relapse following initial success should undergo repeat treatment at a center with achalasia expertise. These patients can be treated with either pneumatic dilation or myotomy; those with end-stage disease may need esophagectomy. Patients who previously failed myotomy or dilation and are no longer good surgical candidates can be treated with botox.
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matic dilation, excellent/good responses were reported in 90% of patients after 6 months, but response declined to 44% after 6 years of follow-up.23 The perforation rate after pneumatic dilation is ~2% in experienced hands (range 0–16%); gastro-esophageal reflux occurs in 15–33% of patients after this procedure and is rarely severe.24
Endoscopic injection of botulinum toxin into the LES reduces LES pressure by inhibition of acetylcholine release from nerve endings, which counterbalances the effect of the selective loss of inhibitory neurotransmitters (mainly nitrous oxide) in achalasia.15 It is very safe, easy to administer, and provides symptom relief initially in ~85% of patients; however, the effect of a single injection was limited to 6 months or less in over 50% of patients in an early trial.16 Subsequent studies17–19 confirmed that botulinum toxin is initially effective, but the benefit of a single injection lasts less than 1 year in the majority of patients, with eventually a need for repeat injections or other forms of achalasia treatment. Given its favorable safety profile, botulinum toxin injection is a reasonable option for the short-term treatment of achalasia, but it cannot be recommended as a long-term solution for patients who are candidates for more definitive therapies. Thus, this treatment is currently reserved for patients in whom pneumatic dilation or myotomy is precluded by patient-related risks.5
Surgical myotomy Surgical myotomy disrupts the LES fibers through a longitudinal incision. Over the years, the technique evolved from open thoracotomy and laparotomy, to a minimally invasive laparoscopic or thoracoscopic approach. Laparoscopic myotomy has been established as the preferred method for several years, because of decreased morbidity and faster recovery.25 The majority of the literature regarding the effectiveness of myotomy is uncontrolled. In a systematic review of 39 uncontrolled studies of laparoscopic myotomy that included a total of 3086 patients with variable followup of 8–83 months, symptom improvement was achieved in a mean 89% of patients (range 77– 100%).26 A recent, large, multicenter randomized controlled trial that compared graded pneumatic dilation with laparoscopic Heller myotomy found that the success rate for surgery after 2 years was 87%.22 As with pneumatic dilation, the efficacy of Heller myotomy decreases with longer follow-up periods. In a series of 73 patients treated with Heller myotomy, excellent/good responses were reported in 89% and 57% of patients at 6 months’ and 6 years’ follow-up, respectively.23 GERD is a frequent complication after myotomy. Adding a partial fundoplication to the myotomy decreases, but does not eliminate, the risk of GERD, and recent gastroenterology and surgery society guidelines recommend an antireflux procedure along with myotomy.5,27 There is some debate as to the type of partial fundoplication that works best in this setting. A recent multicenter randomized controlled trial that compared an anterior Dor vs a posterior Toupet fundoplication found a non-significant higher percentage of abnormal pH test results after Dor vs Toupet (41% vs 21%), with similar improvement of dysphagia and regurgitation symptoms in both groups.28
Pneumatic dilation The LES fibers can be disrupted by forceful dilation using pneumatic balloons. The present-day technique consists of outpatient, sedated endoscopy to determine landmarks, immediately followed by placement of a balloon across the LES, usually under fluoroscopic but sometimes under direct endoscopic guidance. The dilation protocol varies somewhat across different centers, but the balloon is inflated to sufficient pressure (usually 7–12 psi) for 15–60 s to break the LES muscle fibers. Postdilation esophagram is mandatory to rule out perforation. A review of the numerous uncontrolled studies of pneumatic dilation is beyond the scope of this review, but a brief examination of the controlled trials is worthwhile. There are no studies comparing pneumatic dilation with sham dilation. In earlier randomized controlled trials that compared pneumatic dilation with botulinum toxin injection, symptom improvement rates for dilation at 12 months ranged between 53% and 70%.17,20,21 In a more recent randomized controlled trial that compared graded pneumatic dilation (allowing for repeat dilation) with laparoscopic Heller myotomy, the success rate for dilation after 2 years was 92%.22 Data regarding longterm effectiveness of pneumatic dilation are limited, but available studies reveal a decline in the proportion of patients in remission as time goes on. For instance, in a series of 106 patients treated with graded pneu-
Comparative effectiveness of pneumatic dilation vs Heller myotomy There is a paucity of high-quality, randomized controlled trials comparing pneumatic dilation and Heller
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myotomy. In an early trial that randomized 25 patients to laparoscopic Heller myotomy and 26 to pneumatic dilation, treatment failure was significantly less common after surgery in the per-protocol analysis (4% vs 23%), but significance was lost in the intention-to-treat analysis.29 More recently, a highquality, large, multicenter randomized controlled trial was carried out in five European centers. In this study, 200 patients with achalasia were randomly assigned to graded pneumatic dilation or laparoscopic Heller myotomy; after 2 years of follow-up, there was no significant difference in treatment success rates for dilation compared with myotomy (92% vs 87%).22 A subsequent meta-analysis concluded that short- and long-term treatment success is higher for myotomy compared with dilation, but only two randomized controlled trials directly comparing these modalities were included (these are the two studies summarized above); the other 14 studies in the analysis include 5 randomized trials comparing dilation or surgery with other modalities, and 9 uncontrolled studies.30 Furthermore, definition of treatment success varied and in some of the studies, lack of improvement after a single dilation rather than a series of treatments in a graded approach was considered failure. Thus, based upon the highest-quality data that are available, it appears that Heller myotomy and pneumatic dilation have similar effectiveness on a 1- to 2-year horizon. That said, earlier studies and the multicenter European randomized trial found that young age (less than 40 years) increases the risk of failure for pneumatic dilation in males,22,23 and myotomy may therefore be a better option in this specific group. It is important to note that the success rates for both dilation and myotomy decline over time, and repeat intervention may be required. To date, whether response to dilation or surgery varies in the different achalasia subtypes as defined by HREPT has not been studied in randomized controlled trials.
In 2010, the first human series was published, demonstrating statistically significant reduction in both resting LES pressure and dysphagia symptom score in all patients (mean follow-up of 5 months), without any serious complications.33 Subsequent studies achieved similar results with a very low rate of serious complications. In a recent review that includes nine uncontrolled studies of POEM for achalasia, success rates after a mean 1–12 months ranged from 89% to 100%.32 GERD is frequent after POEM, but appears to respond to acid suppression with PPIs in the available studies. Not surprisingly, there is a lot of enthusiasm for this technique. However, it is important to bear in mind that all the available studies are uncontrolled and follow-up data are limited to 12 months at best. Adequately powered, randomized controlled trials comparing POEM with surgical myotomy and pneumatic dilation are needed to discern where this modality may fit in the treatment of achalasia patients. For now, POEM should be performed only within trials aiming to elucidate whether POEM is a suitable alternative to other treatments and which patients may benefit from this approach, possibly using achalasia subtypes as defined by HREPT.
Management of treatment failures As mentioned earlier, the proportion of patients who remain in remission after successful pneumatic dilation or surgical myotomy declines over time, and repeat intervention may be required. In two studies of patients who were followed up for a mean 5–7 years after successful graded pneumatic dilation, additional treatment (mostly repeat dilation but also surgery in some) was required in 23–33%.34,35 Likewise, in two reports of patients who were followed up for a mean 5– 6 years after laparoscopic Heller myotomy, additional therapy (mostly pneumatic dilation, but re-do myotomy and botulinum toxin injection were also used) was needed in 18–21%.36,37 Treatment of patients who fail to respond to or relapse after initial improvement following myotomy represents a clinical challenge and data regarding their management are very limited. These patients should be treated in a center with expertise in multiple treatment modalities for achalasia (Fig. 2). In a report of 48 patients who presented at a tertiary center having failed myotomy, rates of symptom improvement after pneumatic dilation and repeat myotomy were 67% and 57%; eight of these patients ended up requiring esophagectomy.6 Of note, a preexisting myotomy does not appear to increase the risk of perforation during pneumatic dilation, although data
Peroral endoscopic myotomy (POEM): an emerging option for achalasia A peroral approach that allows endoscopic myotomy without a surgical incision was initially described in a porcine model in 2007.31 The procedure consists of four consecutive steps: (i) mucosal incision 10–15 cm above the EGJ to allow entry into the submucosa, (ii) creation of a submucosal tunnel through a combination of blunt dissection and electrocautery until the LES is reached, (iii) myotomy of the circular muscle layer with an electrocautery device, and (iv) closure of the mucosal entry with multiple endoscopic clips.32
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about this issue are limited.38 The most recent data regarding the management of patients with recurrence after Heller myotomy are included in the current issue of Neurogastroenterology and Motility. Legros et al. assessed the efficacy and safety of pneumatic dilation in 18 patients with relapsing symptoms after myotomy,1 finding that pneumatic dilation led to remission in 14 (78%) patients, but eight of them required repeat dilations during the follow-up period, highlighting the need for close follow-up and repeated treatments in this challenging group.
and choice of therapy depend on patient characteristics (age, comorbidities, disease stage, prior treatments), patient’s preference, and locally available expertise. The proportion of patients who remain in remission after successful pneumatic dilation or surgical myotomy declines over time and repeat intervention is required in some patients. Treatment of patients who fail or relapse after initial therapy is challenging and the success rate of pneumatic dilation or myotomy in these patients is lower compared with previously untreated patients. POEM represents an innovative way to perform myotomy with excellent results in early uncontrolled studies, but high-quality randomized trials are needed to ensure widespread adoption is reasonable. Finally, retrospective data suggest that achalasia subtypes as defined by HREPT may guide treatment choice, but prospective outcome studies will be needed to solidify this concept.
SUMMARY Several options are available for the treatment of achalasia. Oral pharmacologic agents have a very limited role because of insufficient efficacy and frequent side effects. Endoscopic injection of botulinum toxin is safe and effective in the short term, but the effect wears off usually after a few months and this treatment is thus reserved for patients who are not candidates for more definitive treatments. Pneumatic dilation and laparoscopic Heller myotomy provide the greatest opportunity for treatment success; both show similar effectiveness in randomized controlled trials with follow-up of up to 2 years. The risk/benefit ratio
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FUNDING No funding declared.
CONFLICTS OF INTEREST The author has no competing interests.
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