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Current Problems in Surgery

Current Problems in Surgery 55 (2018) 10–37

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Modern management of esophagealachalasia: From pathophysiologyto treatment

Francisco Schlottmann, MDa, Fernando Herbella, MDb,Marco E. Allaix, MDc, Marco G. Patti, MDd,*

Epidemiology

Achalasia is a rare disease with an incidence of approximately 1 per 100,000 individuals. It occurswith equal frequency in men and women and in Caucasian and non-Caucasian individuals, and theincidence increases with age. In most studies, the mean age at diagnosis is more than 50 years.1 Theprevalence of the disease is, however, variable worldwide (Fig 1). In countries where Chagas´ diseaseis endemic, the prevalence may reach up to 840 per 100,000 individuals, as it is the case in Brazil.2 Inthis country, Chagas´ disease currently affects between 5 and 18 million people, and an estimated15%-20% will develop Chagasic esophagopathy.3

Interestingly, the prevalence of achalasia seems to be increasing,4 probably because of a higherawareness of the disease and improved ability to establish the diagnosis. For instance, achalasia has oftenbeen mistaken as gastroesophageal reflux disease (GERD),5 and traditionally up to 45%-50% of patientsreferred to a motility laboratory are taking proton pump inhibitors on the assumption that the symptomsare caused by GERD.6 In addition, when experts use state of the art technology and diagnostic criteria, theincidence and prevalence of achalasia is at least 2- to 3-fold greater than previous estimates.7

Pathophysiology

In physiologic conditions, the lower esophageal sphincter (LES) has a myogenic tone to preventreflux of gastric contents, and it relaxes in response to swallowing, esophageal distension, or gastric

oi.org/10.1067/j.cpsurg.2018.01.00140/& 2018 Elsevier Inc. All rights reserved.

e aHospital Alemán of Buenos Aires, University of Buenos Aires, Buenos Aires, Argentina; bEscola Paulista dee, Federal University of São Paulo, São Paulo, Brazil; cDepartment of Surgical Sciences, University of Torino,Italy; and dCenter of Esophageal Diseases and Swallowing, University of North Carolina School of Medicine,ill, NC

ess reprint requests to Marco G. Patti, MD, Center of Esophageal Diseases and Swallowing, University of NorthSchool of Medicine, Chapel Hill, NC.ail address: [email protected] (M.G. Patti).

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Fig. 1. Worldwide prevalence of achalasia (cases/100,000 inhabitants) based on studies from the last 10 years(2007-2017).

F. Schlottmann et al. / Current Problems in Surgery 55 (2018) 10–37 11

distension. The LES is under neurogenic control through the myenteric plexus, which contains bothexcitatory (acetylcholine) and inhibitor (nitric oxide [NO] and vasoactive intestinal polypeptide)neurons. Contrary to the LES, the esophageal body does not have a resting tone, and primaryperistalsis is initiated by nonsequential simultaneous central activation, and is believed to bepropagated mostly by peripheral mechanisms to produce deglutive inhibition followed byexcitation.8,9

The pathophysiology of achalasia involves the selective degeneration of inhibitory neurons of theesophageal myenteric plexus, which are needed for peristalsis of the smooth muscle of theesophageal body, as well as relaxation of the tonic LES.10 The etiology of this degenerative process,however, remains largely unknown. Detailed examination of resection specimens has showninfiltration of cytotoxic lymphocytes expressing activation markers.11 Some viruses such as varicella-zoster, human papilloma, and herpes have been implicated in initiating an inflammatoryreaction.12,13 The involvement of the esophagus only, with sparing of the remaining gastrointestinaltract, could be explained by the affinity of the herpes virus for the squamous rather than thecolumnar epithelium. However, previous investigators have failed to detect such viruses in myotomyspecimens from achalasia patients.14,15 Thus, the inciting antigen remains unknown. Overall, the

Fig. 2. Carlos Justiniano Ribeiro Chagas (center, black suit) receiving Albert Einstein in 1925.

F. Schlottmann et al. / Current Problems in Surgery 55 (2018) 10–3712

neurons producing NO are usually affected, whereas the cholinergic neurons are largely spared. As aconsequence, the LES does not relax properly and it is often hypertensive.

There are other theories for the etiology of idiopathic achalasia. An autoimmune etiology hasbeen suggested, with evidence of antibodies against myenteric neurons in the serum of achalasiapatients.16,17 There are also reported familial cases of achalasia, including a case report of siblingswith coexistent Hirschprung’s disease.18 Albeit extremely rare, such cases raise the possibility of agenetic basis of the disease.

In addition to the idiopathic form of achalasia, there are other types of achalasia that aresecondary to known causes, such as Chagas' disease. The disease was first described by Carlos Chagas(Fig 2) in 1909, and it is caused by the inoculation through a bug bite of a parasite (Trypanosomacruzi) that results in systemic invasion of internal organs such as the heart, the brain, and thegastrointestinal tract.19 Chagas’ disease patients are usually inoculated during childhood, butsymptoms may take several years to develop. The mean age of patients in Chagas series ranges from33-50 years, whereas idiopathic achalasia seems to have a bimodal distribution of incidence by age,with peaks at around age 30 and 60 years.20 The parasite leads to an immunological reaction withdestruction of the esophageal plexus, causing a disease undistinguishable from idiopathicachalasia.21

A secondary form of achalasia—pseudoachalasia—is caused by malignancy. Cancer of theesophagus can cause an achalasia type picture, and it should be carefully excluded in patients olderthan 60 years, who have been symptomatic for a short time, and have lost a considerable amount ofweight.22 In addition to locally invasive cancers, cancer of the breast and small cell lung cancer havebeen known to cause a paraneoplastic syndrome with disordered esophageal motility, probablysecondary to humoral factors, neuronal degeneration, or abnormal neurotransmission.23,24 Finally,achalasia is part of the Allgrove’s (triple A) syndrome, characterized by achalasia, alacrima, andadrenal insufficiency. Sometimes mental retardation and peripheral and autonomic neuropathy canalso be present.25

Regardless of the cause, the lack of peristalsis and the nonrelaxing LES affect the emptying offood from the esophagus into the stomach, and eventually cause dilatation and tortuosity of theesophageal body. Additionally, an increased risk of squamous cell esophageal cancer has beenidentified, albeit very low.26 Treated patients who develop GERD have also an increased risk ofdeveloping Barrett’s esophagus and adenocarcinoma.27

Clinical presentation

The diagnosis of achalasia can be challenging, as it is a rare disease and symptoms arenonspecific; dysphagia, regurgitation, chest pain, heartburn, and aspiration can be caused bydiseases other than achalasia. As a consequence, there is often a long delay between the onset ofsymptoms and the diagnosis.28

Dysphagia

Dysphagia, both for solids and liquids, is the most frequently reported symptom, being present inapproximately 95% of patients. Some patients adapt to this symptom by changing their diet, and areable to maintain a stable weight, whereas others experience a progressive increase in dysphagia thateventually leads to weight loss.29

Regurgitation and aspiration

Regurgitation of undigested food is the second most common symptom, and it is present inapproximately 70% of patients. Regurgitation occurs more frequently in the supine position and cancause aspiration with cough, hoarseness, wheezing, and episodes of pneumonia.


Heartburn

Heartburn is experienced by 40%-50% of patients. In the untreated patient it is not due toabnormal gastroesophageal reflux, but rather to stasis and fermentation of undigested food in theesophagus. Unfortunately, this symptom is often attributed to gastroesophageal reflux and patientsare treated with proton pump inhibitors with a consequent delay in diagnosis.30

Chest pain

Chest discomfort or pain is experienced by 40%-50% of patients, and it is often exacerbated byeating. The cause of chest pain is still unknown, but it has been suggested that esophageal distensionor esophageal contractions of abnormally high amplitude or long duration maybe responsible.31

Perretta and colleagues32 analyzed 211 achalasia patients, of whom 117 experienced chest pain(55%). The pain was felt mostly in the retrosternal area, particularly during the day. At a medianfollow-up of 2 years, chest pain resolved in 84% of patients and improved in 11% after a successfullaparoscopic Heller myotomy (LHM), suggesting that the effect was due to improved esophagealemptying.

Eckardt score

The Eckardt score is the grading systemmost frequently used for the evaluation of symptoms andefficacy of achalasia treatment.33 It attributes points (0-3 points) to 4 symptoms of the disease(dysphagia, regurgitation, chest pain, and weight loss), and its total ranges from 0-12 (Table 1).Treatment is usually considered successful if it brings the Eckardt score to equal or less than 3.

Diagnostic evaluation

Since a diagnosis based on symptoms only is uncertain, a thorough evaluation should beperformed in all patients with symptoms suggestive of achalasia. The diagnostic evaluation includesesophagogastroduodenoscopy (EGD), barium swallow, esophageal manometry, and sometimesambulatory 24-hour pH monitoring.

Esophagogastroduodenoscopy

This is the first test usually performed in patients with dysphagia to rule out a mechanical causesuch as a peptic stricture or cancer. An infiltrating tumor of the gastroesophageal junction can mimicthe clinical, radiological, and manometric findings of achalasia, resulting in impaired LES relaxationand absence of peristalsis. This condition, “secondary achalasia” or “pseudoachalasia,” should besuspected in patients older than 60 years, with rapidly progressing dysphagia and severe weightloss.34

Table 1Clinical scoring system for achalasia (Eckardt score)

Score Weight loss (kg) Dysphagia Retrosternal Pain Regurgitation

0 None None None None1 o5 Occasional Occasional Occasional2 5-10 Daily Daily Daily3 410 Each meal Each meal Each meal


In approximately 30%-40% of patients the EGD can be normal.35 In the remaining patients,retained food can be found, and the esophagus can be dilated or tortuous. The esophageal mucosacan be normal or show signs of esophagitis usually secondary to food stasis or candida infection36

(Fig 3).

Barium swallow

This test provides valuable information about the anatomy of the esophagus (diameter and axis).Typical radiologic findings are narrowing at the level of the gastroesophageal junction (so called“bird beak”), slow emptying of the contrast from the esophagus into the stomach with an air-fluidlevel, and tertiary contractions of the esophageal wall (Fig 4). A chest radiograph may also showmediastinal enlargement, air-fluid level in the mediastinum, and lung changes suggestive of chronicaspiration (Fig 5). In more advanced cases, severe dilatation with stasis of food and a sigmoid-likeappearance can occur (Fig 6). In addition, it is possible to identify associated pathology such as anepiphrenic diverticulum (Fig 7).

A timed barium swallow can be also performed to assess emptying of the esophagus, bymeasuring the height of the barium column 5 minutes after ingestion of diluted barium.37 Thebarium swallow, however, fails to show abnormalities in approximately 30% of patients, particularlyin the early stage of the disease. Considering the rarity of this disease, the familiarity of theradiologist with achalasia is very important for a proper interpretation.

Esophageal manometry

Esophageal manometry is the gold standard for the diagnosis of achalasia. Lack of peristalsis andpartial or absent relaxation of the LES in response to swallowing are the key criteria for thediagnosis. Although in the past it was thought that the LES was hypertensive in all patients, today itis known that an elevated LES pressure is present in only approximately 50% of patients.38

The introduction of high-resolution manometry (HRM) has improved the ability to diagnoseachalasia and identify new variants. As compared to conventional manometry, HRM allows morecomfort and speediness to the test, easiness to teach, interobserver and intraobserver reproduci-bility, and compensation of movement artefacts.39 The test is performed after an overnight fast usinga solid-state catheter with 36 circumferential sensors located at 1-cm intervals. The probe is insertedtransnasally, and is positioned to record from the pharynx to the stomach. Pressure, length, andrelaxation of the lower and upper esophageal sphincters are recorded. Esophageal body motility isassessed by 10 swallows of 5 mL of water, given at 30 second intervals. When the esophagus is

Fig. 3. Endoscopic findings in a patient with achalasia: dilated esophagus with retention of food. (Color version of thefigure available online.)

Fig. 4. Barium esophagram in a case of achalasia shows esophageal dilatation and a smooth tapering of the distalesophagus (bird’s beak sign—arrow).

Fig. 5. Chest radiography in a case of achalasia. Note a mediastinal enlargement (arrow) and air-fluid level in themediastinum (*).


Fig. 6. End-stage achalasia with an esophageal diameter 410 cm.


dilated and sigmoid, it might be difficult to pass the catheter through the gastroesophageal junction,and fluoroscopic or endoscopic guidance may be necessary.

In 2008, Pandolfino and colleagues40 proposed a new classification according to the HRMmanometric patterns of esophageal body contractions—the so called Chicago classification. Thisclassification, now in version 3.0,41 divides achalasia into 3 subtypes (Fig 8): type I, incomplete LESrelaxation, aperistalsis, and absence of esophageal pressurization; type II, incomplete LES relaxation,aperistalsis, and panesophageal pressurization in at least 20% of swallows; and type III, incompleteLES relaxation and premature “spastic” contractions (distal latency o 4.5 seconds) in at least 20% ofswallows.

Fig. 7. Epiphrenic diverticulum in a patient with achalasia.

Fig. 8. Chicago classification of esophageal achalasia. Type I: absence of esophageal pressurization; type II:panesophageal pressurization; and type III: premature contractions. (Color version of the figure available online.)


It is unclear whether this classification represents different entities or part of a diseaseprogression. A recent study showed that patients with type III achalasia had shorter history ofsymptoms, a higher incidence of chest pain, and a less dilated esophagus. In addition, all patientswith a sigmoid-shaped esophagus had pattern I achalasia.42 This study supports the theory that theChicago classification represents different stages in the evolution of the disease, with type III beingthe earliest stage, type II an intermediate stage, and type I the final stage.

Different from conventional manometry, the Chicago classification has prognostic value. Pandolfinoand colleagues43 found that type II achalasia patients were significantly more likely to respond to LHMor pneumatic dilatation (PD), as compared to type I and type III. Concordantly, Salvador andcolleagues44 evaluated patients who underwent LHM and found that treatment failure rates weresignificantly different among the subtypes of achalasia: type I, 14.6%; type II, 4.7%; and type III, 30.4%(P o 0.001). A recent meta-analysis encompassing 9 studies and 727 patients also showed that type IIachalasia was associated with the best prognosis after PD and LHM, whereas type III achalasia had theworst prognosis.45 In addition, although in types I and II achalasia PD and LHM appear to be the bestoptimal treatment, type III achalasia seems to be better managed with per-oral endoscopic myotomy(POEM), probably due to the ability to perform a longer myotomy of the thoracic esophagus.46,47

Ambulatory pH monitoring

This test is recommended in selected patients when the diagnosis is uncertain, to distinguishbetween GERD (real reflux) and achalasia (false reflux). Unfortunately, many patients are treatedwith acid reducing medications, or even with a fundoplication, on the assumption that theheartburn and the regurgitation are secondary to abnormal reflux. A recent study examined therecords of 524 patients whose final diagnosis was achalasia, and found that 152 patients (29%) hadbeen treated for an average of 29 months with proton pump inhibitors with poor response(classified as having “refractory GERD”), and had been referred for antireflux surgery.48

The test is performed after discontinuing acid-suppression medications 7 days (proton pumpinhibitors) or 3 days (histamine-2 receptor antagonists) before the study. A dual-channel pHcatheter with 2 sensors located 15 cm apart is placed transnasally so that the distal and the proximalsensors are positioned 5 and 20 cm above the upper border of the manometrically determined LES.Gastroesophageal reflux is evaluated in terms of number of reflux episodes and amount of acidexposure (pH o 4). It is very important not only to consider the reflux score, but to examinecarefully the tracing to distinguish between GERD (real reflux) and achalasia (false reflux). In bothGERD and achalasia this score can be abnormal, but the tracings are very different. Whereas in GERDthe tracing is characterized by intermittent drops of the pH below 3 with subsequent return of the

Fig. 9. pH monitoring tracings of real reflux (GERD) and false reflux (achalasia).


values above 5, in achalasia there is a slow and progressive drift of the pH below 4 with no or veryslow return to higher values (Fig 9).

The pH monitoring should also be performed whenever possible after treatment—PD, POEM, orLHM—as some patients develop postprocedural abnormal reflux, which is often asymptomatic.49

This is particularly important when treating young patients.Overall, the American College of Gastroenterology guidelines for the diagnosis of achalasia

recommend endoscopy to rule out pseudoachalasia, barium swallow to delineate the esophagealemptying and anatomy, and esophageal manometry to confirm the diagnosis.50

Treatment of esophageal achalasia

Themain goal of the treatment of achalasia patients is to decrease the LES pressure, thus improving theemptying of the esophagus into the stomach. The management of patients with esophageal achalasia ismultidisciplinary, and includes surgical and nonsurgical options. Among the nonsurgical treatmentmodalities, there are 3 well-established options: pharmacologic therapy, endoscopic botulinum toxininjection (EBTI), and endoscopic PD. As pharmacologic therapy and EBTI are less effective than LHM in therelief of symptoms, they are mostly considered in those patients who are unfit for surgery.50,51

Pharmacologic treatment

Pharmacologic agents include smooth muscle relaxants, such as long-lasting nitrates and calciumchannel blockers, and 5′-phosphodiesterase inhibitors. As achalasia is a disease characterized byimpaired release of NO from inhibitory neurons, the rationale for the use of these agents lies in theenhancement of the residual neural inhibitory function in the esophageal wall.

Smooth muscle relaxants

These drugs decrease transiently the LES pressure, thus leading to temporary relief of dysphagia.The use of nitroglycerin for the treatment of achalasia was first described in the early 1940s.52,53


Nitrates act by increasing the concentration of NO in the smooth muscle cells that in turns activatesthe guanylate cyclase with a subsequent increase in the synthesis of cyclic GMP (guanosine 3′, 5′monophosphate). The cyclic GMP interferes with the phosphorylation process, resulting indephosphorylation of the light chain of myosin and therefore in inhibition of the normal contractileprocess of smooth muscle. As a consequence, NO acts as an inhibitory nonadrenergic noncholinergicneurotransmitter mediated by cyclic GMP.54

On the other side, calcium channel blockers act by blocking the action of the calcium that isnecessary for the contraction of the esophageal smooth muscle cells. However, both types of drugsdo not improve LES relaxation or esophageal motility.55

The delayed esophageal emptying and the stasis of the esophageal contents alter the kinetics ofabsorption of these drugs; as a consequence, they are usually administered sublingually (eg,nifedipine 10-30 mg sublingually 30-45 minute before meals; isosorbide dinitrate 5 mg sublingually10-15 minute before a meal).56,57

Most studies that have analyzed the efficacy of smooth muscle relaxants were not controlled, andincluded a very limited number of patients. Only a few of them are single- or double-blind, placebo-controlled studies.58-62 Unfortunately, these studies were not properly designed and did not have anobjective measure of both short- and long-term effects. With these methodological limitations, long-acting nitrates show a shorter time to achieve the maximum effect (3-27 minute vs 30-120 minute)and a higher rate of symptom improvement in the short term than calcium channel blockers (53%-87% vs 0%-75%). However, their use is associated with several side effects that make patientsfrequently shift to calcium channel blockers.55 For instance, Gelfond and colleagues63 tested theeffects of sublingual isosorbide dinitrate (5 mg) and nifedipine (20 mg) in 15 achalasia patients. Thefollowing variables were evaluated: the manometric LES pressure, the esophageal emptying, and theclinical response. The mean basal LES pressure was significantly decreased in both groups, with amaximum reduction of 63.5% 10 minutes after receiving isosorbide dinitrate, but by only 46.7%, 30minutes after nifedipine. The esophageal radionuclide test meal retention was significantly reducedonly after receiving isosorbide dinitrate. A total of 8 patients cleared their test meal within 10minutes after isosorbide dinitrate administration compared to only 2 in the nifedipine group. A totalof 13 patients reported symptom relief by isosorbide dinitrate and 8 by nifedipine. However, thisrelief was not confirmed in 4 patients by the esophageal empting study. More prominent side effectswere observed after administration of nitrates.

Among the calcium channel blockers, nifedipine is the most tested and effective agent. Forinstance, Triadafilopoulos and colleagues62 reported the results of a placebo-controlled, double-blind, crossover study aiming at evaluating the effects of oral nifedipine and verapamil on LESpressure, amplitude of esophageal body contraction, and symptoms in 8 achalasia patients. Patientswere randomized to receive up to 20 mg nifedipine, 160 mg verapamil, or placebo. Esophagealmanometry was obtained before and after 4 weeks on each drug. Diary cards were kept to recordand grade symptoms and drug plasma level determinations were correlated with manometric andclinical findings. Both drugs led to a statistically significant reduction in mean LES pressure.However, only nifedipine caused a significant reduction in the amplitude of contractions of thesmooth muscle portion of the esophagus. The authors observed no significant improvement ofsymptoms with any of the drugs.

5′-Phosphodiesterase inhibitors

More recently, the use of sildenafil, a 5′-phosphodiesterase inhibitor, has been proposed. Thisagent has an inhibitory action on the 5′-phosphodiesterase that inactivates the NO-stimulated cGMP,thus increasing the intracellular levels of cGMP and therefore promoting the relaxation of thesmooth muscular cells.64,65 Experimental studies have shown that the use of sildenafil is associatedwith reduction in the esophageal contractions amplitude and with a delay in the propagation of theperistaltic waves in the transitional zone between the esophageal striated and smooth musclesegments. This agent reduces the LES pressure by 50%, with no effects on the LES relaxation inducedby swallowing. Bortolotti and colleagues66 investigated the effects of sildenafil in 14 patients with


esophageal achalasia. After a basal period of 30 minutes, a 50-mg tablet of sildenafil dissolved inwater was infused in the stomach in 7 patients and one of placebo in the other 7 patients, randomlyand in double-blind manner. Esophageal motility and LES pressure were measured every minute for60 minutes. The authors compared the values of the entire postinfusion period, the nadir values, andthe values of the last 5-minute period with the basal value in each group and between the 2 groupsof patients. They found that LES tone, residual pressure, and wave amplitude were significantlydecreased after sildenafil compared with both the basal period and the placebo group, with amarked interpatient variability. The maximum inhibitory effect (approximately 50%) was obtained10-15 minutes after the infusion and lasted less than 60 minutes. Sildenafil did not appear to modifythe wave propagation. The authors concluded that this agent might be used in patients with earlydisease in whom the inhibitory neuronal function is not completely destroyed.

Eherer and colleagues67 investigated the effects of sildenafil on esophageal motor function inboth healthy subjects and patients with esophageal motility disorders. Six healthy male volunteersparticipated in a randomized double-blind study on 2 separate days before and 1 hour after oralintake of either sildenafil 50 mg or placebo. Esophageal manometry was performed to assess thevector volume of the LES and pressure amplitude of the esophageal body. Four of the volunteersunderwent 12-hour ambulatory esophageal manometry on 2 separate days, once with sildenafil50 mg and once with placebo. A total of 11 patients with hypercontractile esophageal motilitydisorders were recruited in an open study of the effect of 50 mg sildenafil on manometric featuresand symptoms. The authors found that sildenafil significantly decreased the LES pressure and theamplitude of peristaltic waves without influencing the propagation in the distal esophageal body inhealthy subjects. The effect of sildenafil lasted at least 8 hours in 75% of subjects. Among the 11patients with hypercontractile esophageal motility disorders, manometric improvement aftersildenafil was observed in 9 patients, but these changes led to symptom improvement in only4 patients. However, 2 of these patients reported side effects (sleep disturbance and feeling oftightness in the chest) that prevented them to continue the pharmacologic treatment. Side effects(dizziness and headache) were experienced also by 3 of 5 patients who did not have symptom relief.Only 2 female patients had marked clinical benefit with minimal or no side effects.

Overall, several factors significantly limit the use of these agents for the treatment of achalasiapatients. The duration of action is short, the symptom improvement is very limited, and theirefficacy decreases overtime. In addition, patients can experience severe side effects such ashypotension, headache, dizziness, and peripheral edema.68

Endoscopic management

Endoscopic botulinum toxin injection

Botulinum toxin inhibits acetylcholine release at the level of the cholinergic synapses, thusdecreasing LES pressure. The standard protocol for EBTI into the LES consists of the injection of 100units of toxin with a sclerotherapy needle in 4 quadrants, approximately 1 cm above theesophagogastric junction. The complication rate associated with this procedure is very low, andimmediate symptom relief or improvement is achieved in approximately 80% of patients.69 Mainpredictors of poor response to this endoscopic treatment are lack of an initial symptomatic responseto EBTI and residual LES pressure of 18 mmHg or greater after EBTI. The effect of EBTI progressivelydiminishes overtime, with more than 60% of patients experiencing recurrent symptoms after1 year.70 EBTI must be repeated in most patients to achieve some benefits that, however, have ashort duration due to the regeneration of the axons and the development of antibodies.71-73

A systematic review and meta-analysis of the literature published in 200969 reported the resultsof EBTI as primary treatment modality, showing relief or improvement of symptoms inapproximately 80% of patients within 1 month after the procedure. Nevertheless, symptom reliefdecreased at 3 months (70%), 6 months (53%), and 12 months (40%). At least a second EBTI was donein 47% of patients.


There are several reports that show more complications and less predictable outcomes inpatients undergoing LHM after repeated endoscopic treatments, mainly due to transmuralinflammation and fibrosis occurring after EBTI.74,75 For instance, Patti and colleagues74 comparedthe outcomes after LHM and partial anterior fundoplication in 44 achalasia patients who had beenpreviously treated with medications (group A—16 patients), PD (group B—18 patients), or EBTI(group C—10 patients). The EBTI treatment group was further subdivided according to theirresponse to the endoscopic treatment: no response (C1) or response (C2). The correct anatomicplanes were identified intraoperatively in 100% of patients with no previous endoscopic treatment,in 89% of PD patients, in 100% of patients who did not respond to EBTI, but in only 25% of patientswith a response to EBTI. Esophageal perforation occurred in 5% of PD patients and in 50% of patientswith a response to previous EBTI. As a consequence, mean length of hospital stay was 26 ± 8 hoursfor group A, 38 ± 25 hours for PD patients, 26 ± 11 hours for patients without response to EBTI, and72 ± 65 hours for patients with response to EBTI. At follow-up, good to excellent results wereobtained in 87% of group A patients, 95% of PD patients, 100% patients with no response to EBTI, butin only 50% of patients who did report a response to EBTI. The results of this study showed that inthe group of patients who did respond to EBTI, the myotomy was more technically challenging andthe outcomes less predictable as compared to the other groups. Smith and colleagues75 analyzed theresults of 209 patients undergoing Heller myotomy for achalasia; 98% of cases were completed bylaparoscopy. A total of 154 patients were treated before surgery with either EBTI or PD (100 PD only,33 EBTI only, and 21 both). The group of patients who received preoperative endoscopic treatmentsexperienced a higher rate of intraoperative complications; gastroesophageal perforation occurred in9.7% and 3.6% of patients, respectively, whereas no cases of esophageal perforations occurred inpatients who underwent Heller myotomy without prior treatment. Postoperative severe dysphagiaand pulmonary complications were more frequently observed among those patients who hadprevious endoscopic treatment (10.4% vs 5.4%). The long-term myotomy failure rate was also higherin the endoscopically treated group (19.5% vs 10.1%).

Similar results were reported by Horgan and colleagues.76 In a retrospective analysis of 57achalasia patients, 15 patients underwent LHM after 1 or more EBTIs, whereas 42 patientsunderwent LHM alone. Challenges in identifying and dissecting the submucosal plane wereencountered in 53.3% of patients with previous EBTI and in 7% of patients who had surgeryalone. Esophageal perforation occurred in 2 patients (13.3%) who had been previously treatedendoscopically, but in only 1 patient (2.4%) who had LHM alone. All mucosal perforations wererecognized intraoperatively and repaired laparoscopically, with no adverse effect on the clinicaloutcome.

Recently, a Cochrane review77 of 7 randomized controlled trials (RCTs) comparing EBTI and PDincluded 178 achalasia patients (Table 2).78-83 Clinical and manometric evaluations were performedbetween 1 and 4 weeks after the initial treatment in all studies. Symptom scores at 1-year follow-upwere available in all studies, whereas LES pressure values at 12 months were assessed in only 3 RCTs.Five RCTs reported the response to the initial endoscopic treatment modality at 6 and 12 months.

Table 2Endoscopic botulinum toxin injection (EBTI) vs pneumatic dilatation (PD): the evidence

Study EBTI vs PD Initialremission

Mean esophagealpressure withinfirst weeks

Remission at6 months

Remission at12 months

Vaezi and colleagues78 22 vs 20 EBTI ¼ PDMuehldorfer and colleagues79 12 vs 12 EBTI ¼ PD PD 4 EBTIGhoshal and colleagues80 7 vs 10 EBTI ¼ PD EBTI ¼ PD EBTI ¼ PD EBTI ¼ PDMikaeli and colleagues81 20 vs 19 EBTI ¼ PD EBTI ¼ PD PD 4 EBTI PD 4 EBTIBansal and colleagues82 16 vs 18 EBTI ¼ PD EBTI ¼ PD PD 4 EBTIZhu and colleagues83 29 vs 28 EBTI ¼ PD EBTI ¼ PD EBTI ¼ PD EBTI ¼ PD


Overall, there were no significant differences in symptom remission and LES pressure within1 month of the endoscopic treatment between EBTI and PD. At 6 months and 12 months, symptomremission rates were lower after EBTI than PD (52% vs 81%, P ¼ 0.0015 and 37.5% vs 73%, P ¼ 0.0002,respectively). Serious complications were observed after EBTI, whereas esophageal perforationoccurred in 3 (1.6%) patients after PD.

Based on these data, EBTI seems to be associated with worse clinical mid- and long-termoutcomes than PD. Similarly, the outcomes reported after EBTI are much poorer than those obtainedwith LHM. Zaninotto and colleagues84 randomly assigned to EBTI or LHM 100 patients with a newdiagnosis of esophageal achalasia. The study protocol included symptom scores, manometricassessment of LES pressures, and radiologic evaluation of the esophageal diameter before and afterthe treatment. EBTI consisted of double injection, a month apart, of 100 units of botulinum toxin atthe level of the esophagogastric junction. Forty patients were randomized to ETBI and 40 patients toLHM. There was no mortality. Postoperative morbidity in the surgical group included 1 patient withbleeding at the trocar site. Median hospital stay after LHM was 6 days, while all ETBIs wereperformed in an outpatient setting. Six months after the index procedure, there was no significantdifference in LES pressure between the 2 groups, but symptom scores improved more after LHMthan EBTI, and a greater reduction in the esophageal diameter was also observed after surgery. At2-year follow-up, the percentage of asymptomatic patients was significantly lower in the EBTI group(35% vs 87.5%; P o 0.05).

Pneumatic dilatation

PD, using a Rigiflex balloon (Boston Scientific Corporation, MA) is an effective endoscopic optionfor the treatment of esophageal achalasia. A graded approach should be used in every achalasiapatient. The first PD session should be performed by using a 30 mm Rigiflex balloon, and largerballoons (35 and 40 mm in diameter) should be used 2-4 weeks later in the presence of persistentsymptoms secondary to inadequate dilatation. However, patients should be advised that whendysphagia rapidly recurs after a PD with a 40-mm balloon, the response to further PDs is unlikely.85

From a technical point of view, some basic principles should be followed to achieve the bestoutcomes and to minimize the risk of complications. First, appropriate dietary instructions should begiven to patients before PD, aiming at having minimal or no residual contents in the esophagusduring the procedure. Second, the appropriate positioning of the balloon under fluoroscopicguidance over a guide-wire should be performed. When the correct position of the balloon at thelevel of the gastroesophageal junction is confirmed, the balloon is progressively inflated, aiming atobtaining a progressive and controlled tearing of the muscle fibers. The endpoint is the completeopening of the LES, which is usually obtained with distention pressures of 8-15 psi. The balloondilator is then completely deflated in order to minimize the risk of injury to the oropharynx.85

After the procedure, the patient’s pain should be strictly monitored for at least 2 hours and anupper gastrointestinal radiologic study with gastrografin should be obtained if an esophagealperforation is suspected. Once discharged, the patient should be instructed to go to the emergencyroom in case of occurrence of thoracic pain, fever, shortness of breath, or subcutaneousemphysema.85

Long-term studies have reported different rates of relief of dysphagia at 5 years (40%-78%) orbeyond (12%-58% at 15 years) after PD. These wide ranges depend on the definition of success, on themethods used to evaluate patient’s symptoms, and on the number of PDs. Even in the seriesreporting the best long-term outcomes, repeated PD sessions are needed in up to one-third ofpatients. Well-recognized predictors of poor response are failure after the first or second PD, age lessthan 40 years, male sex, large esophageal diameter, type I and III achalasia according to the ChicagoClassification, pulmonary symptoms, and postprocedural reduction in LES pressure less than50%.86-89 Those patients who undergo additional PDs have worse outcomes than those whosuccessfully respond to the first PD, and than those who undergo LHM. For instance, Gockel andcolleagues87 compared the outcomes of 19 patients who had never reached clinical remission afterrepeated PDs and underwent Heller myotomy, with 34 patients who had relief of dysphagia after a


single PD and with 14 patients who reported symptom remission after several PDs. With a medianfollow-up of 10 years in the surgical group, 10.6 years in the group of patients who were treated withonly one PD session, and 6.9 years in patients with several PDs, the 10-year remission rate was 77%in the first group, 72% in the second group, and only 45% in the third group. The authors also foundthat young age was associated with an increased PD failure rate requiring Heller myotomy.

Esophageal perforation is the most frequent and feared complication after PD, with reportedrates in the literature ranging between 0% and 8%.69 However, the use of Rigiflex balloons in a high-volume center has reduced dramatically the incidence of esophageal perforation to less than 1%.90

Postprocedural esophagitis occurs in up to 40% of patients treated with PD, and pathologicgastroesophageal reflux is objectively detected by using ambulatory 24-hour pH monitoring in up to33% of the patients properly evaluated.91-93

During the last 10 years, several RCTs comparing PD and LHM have been published (Table 3).94-101

The pooled analysis of these RCTs shows higher rates of symptom remission after LHM at 3 monthsand 1 year, whereas the outcomes at 2 and 5 years seem to be equivalent. In particular, 81% ofLHM patients are symptom-free at 3 months compared to 69.6% of PD patients. At 1 year,remission rates are 80.6% and 70.4%, respectively. At 2 years, 69.2% of LHM patients reportto be symptom-free compared to 64.8% of PD patients. Lastly, the remission rate at 5 years was85.3% after LHM and 78.2% after PD. Overall, 25% of patients required a re-treatment, morefrequently after PD.

Even though these data support the equivalence of both treatment modalities, postoperativecomplications requiring medical care (mainly esophageal perforations) occurred more frequentlyafter PD than LHM (4.9% vs 0.8%). In addition, the interpretation of these results might be biased bysome methodological issues of these RCTs. First, the sample size of most trials97-101 is limited to 50-94 patients. Second, even the large multicenter European trial that included 201 patients hadsignificant limitations. First, the protocol was revised during the study period, changing the PDtechnique after the observation of a 31% esophageal perforation rate with 35-mm balloons. Second,gastroenterologists and surgeons had different experience. In particular, the skills and experiences ofsome surgeons is questionable since surgeons were required to have performed only 5 myotomies inorder to participate in the RCT. In addition, the number of patients undergoing LHM over a 6-year

Table 3Laparoscopic Heller myotomy (LHM) vs pneumatic dilatation (PD): symptom remission (A), adverse event andpostoperative reflux (B) rates

(A)

Study LHM/PD Meanfollow-up

Remission at1 year

Remission at2 years

Remission at5 years

Boeckxstaens and colleagues95 106/95 76 LHM ¼ PD LHM ¼ PD LHM ¼ PDKostic and colleagues97 25/25 12 LHM 4 PDPerson and colleagues98 25/28 81.5 LHM 4 PDBorges and colleagues99 44/48 24 LHM ¼ PD LHM ¼ PDHamdy and colleagues100 25/25 24 LHM 4 PDNovais and Lemme101 47/47 3 LHM ¼ PD

(B)

Study LHM/PD Adverse events Postoperative reflux

Boeckxstaens and colleagues95 106/95 LHM ¼ PD LHM ¼ PDKostic and colleagues97 25/25 LHM ¼ PDBorges and colleagues99 44/48 LHM ¼ PD LHM o PDHamdy and colleagues100 25/25 LHM ¼ PD LHM ¼ PDNovais and colleagues101 47/47 LHM ¼ PD LHM o PD


study period in the 14 involved centers suggest that 1 myotomy per year was performed in eachinstitution, with a perfoaration rate of 11%, very high in untreated achalasia patients. Specifictechnical details of the anterior partial fundoplication, such as the separation of the edges of themyotomy and the number and site of rows of sutures were not reported. Third, no objective dataabout esophageal acid exposure and its correlation with symptoms were reported. Althoughsymptom and quality-of-life evaluation was performed 1 month after treatment and yearlythereafter, 24-hour pH monitoring was performed 1 year after treatment, and every 3 yearsthereafter. Lastly, even though no statistically significant difference in relief of dysphagia after LHMand PD was reported, subgroup analyses demonstrated that patients younger than 40 years hadbetter results after myotomy. Postprocedural LES pressure and the rate of pathologic reflux did notsignificantly differ between the 2 treatment modalities. Similarly, quality-of-life improvementshowed no significant differences between the 2 groups.

There is very limited evidence about costs of both treatment options. Ehlers and colleagues102

recently published the results of a large retrospective cohort population-based study of US patientswith achalasia initially treated with PD or LHM between 2009 and 2014. A total of 1061 achalasiapatients were included: 82% who underwent LHM and 18% who underwent PD. The authors found ahigher 1-year cumulative risk of esophageal perforation after PD (1.6% vs 0.8%); however, thedifference was not statistically significant. No differences were observed in 30-day mortality (0.5% vs0.3%, respectively). During the follow-up, the rate of reintervention was lower after LHM (9.5% vs48%), as was the need for diagnostic tests (73% vs 85%) and readmission (10% vs 23%). Initial meantotal and out-of-pocket costs were significantly higher in the LHM group. However, at 1 year bothtotal and out-of-pocket costs were similar.

Surgical treatment of esophageal achalasia

History

At the beginning of the 20th century, symptoms of achalasia were exclusively attributed to theesophageal dilatation. Therefore, surgeons developed operations to decrease the esophagealdiameter such as esophagoplasties, or performed an esophago-esophageal anastomosis.103 After-wards, the obstacle at the esophagogastric junction was believed to be responsible for thesymptoms, and a cardioplasty became the treatment of choice. In 1910, Wendel reported the firstcardioplasty performed through a vertical incision onto the anterior wall of the cardia and sutured ittransversally.104 In 1914, Ernst Heller105 first described a transabdominal extramucosal cardioplastyperformed onto the anterior and posterior walls of the cardia. The operation devised by Heller wasrapidly accepted and became the operation of choice, although the double (anterior and posterior)myotomy was replaced by a single, anterior cleavage of the tunica muscularis as proposed by DeBruine Groeneveldt in 1918 and by Zaaijer in 1923.106,107 As to the details of the operation, Zaaijerhighlighted: “It does not appear to make any difference relative to the subsequent findings whetherone incision is made on the anterior side and one on the posterior wall as Heller did, or one incisiononly on the anterior side as has been employed by De Bruine Groeneveldt and myself.”107

During the 1940s, the transabdominal approach was preferred, although many still favored atransthoracic approach. Earle B. Kay noted in 1948: “Most opinions have favored the transabdominalapproach, in that this was felt to be associated with less risk.”108 In addition, the laparotomy allowedthe addition of a fundoplication. However, by that time it was still debated whether or not anantireflux procedure should be added to the myotomy. Rudolph Nissen popularized a fundoplicationthat bears his name in 1956, but it was in 1962 that J. Dor from Marseille, France, proposed the“technique de Heller-Nissen modifiee” for the prevention of reflux after a Heller cardiomyotomy.109

This operation was performed through a transabdominal approach, and the left side of the myotomywas sutured to the anterior wall of the stomach, which was then folded anteriorly and secured to theright edge of the myotomy with another row of sutures. In 1963, a posterior partial fundoplicationadded to the myotomy was devised by Andre’ Toupet.110 These new techniques were able to providerelief of dysphagia whereas limiting gastroesophageal reflux.


At the beginning of the 1990s, minimally invasive techniques were introduced for the surgicaltreatment of foregut diseases. In 1991, the group of Dr. Cuschieri from the University of Dundee,United Kingdom, reported the first laparoscopic cardiomyotomy, stressing the advantage ofdiminished surgical trauma and faster recovery.111 In 1992, Pellegrini and colleagues from theUniversity of California San Francisco described the results of 17 patients who underwent a leftthoracoscopic myotomy with excellent relief of dysphagia. The myotomy extended for 5 mm ontothe gastric wall and no fundoplication was added.112 However, the thoracoscopic approach hadsignificant drawbacks such as the need for a double lumen endotracheal intubation to exclude theleft lung, the need for a chest tube, and the inability to add a fundoplication to prevent reflux. Thesame group compared later the results of 35 patients who had a thoracoscopic myotomy with 133patients who had a laparoscopic myotomy with a Dor fundoplication.113 Although the improvementof dysphagia was excellent with both approaches, the incidence of postoperative reflux decreasedfrom 60% with the thoracoscopic approach to 17% when the operation was performed laparoscopi-cally and a fundoplication was added.113

At the end of the 1990s, the laparoscopic myotomy became the standard of care worldwide andrelegated the thoracoscopic approach to patients with a hostile abdomen and multiple priorabdominal operations.

LHM technique

Step 1—placement of ports. Five 10 mm ports are used for the procedure (Fig 10). The first port isused for the insertion of the scope and it is placed approximately 14 cm below the xiphoid process.The second port is placed in the right midclavicular line at the same level of port 1, and it is used forthe liver retractor. The third port is placed in the left midclavicular line at the same level of the other2 ports. The fourth and fifth ports are placed under the right and left costal margins so that theiraxes and the camera form an angle of about 120°. These ports are used for the insertion of graspers,scissors, and dissecting and suturing instruments.

Step 2—Division of gastrohepatic ligament and identification of right crus of the diaphragm andposterior vagus nerve. The gastrohepatic ligament is divided beginning above the caudate lobe of theliver and continuing proximally until the right crus is identified. The crus is then separated from theesophagus by blunt dissection and the posterior vagus nerve is identified.

Step 3—Division of peritoneum and phrenoesophageal membrane above the esophagus andidentification of the left crus of the diaphragm and anterior vagus nerve. The peritoneum and thephrenoesophageal membrane above the esophagus are divided and the anterior vagus nerve isidentified. The left pillar of the crus is separated from the esophagus. Dissection is limited to theanterior and lateral aspects of the esophagus, and no posterior dissection is needed if a Dorfundoplication is planned.

Step 4—Division of short gastric vessels. The short gastric vessels are taken down all the way to theleft pillar of the crus, starting from a point midway along the greater curvature of the stomach.

Fig. 10. Positions of trocars for laparoscopic Heller myotomy.


Step 5—Esophageal myotomy. The myotomy is performed at the 11 o’clock position, and is startedapproximately 3 cm above the gastroesophageal junction by reaching the proper submucosal plane.The myotomy is then extended proximally for about 6 cm above the esophagogastric junction, anddistally for approximately 2.5 cm onto the gastric wall. Thus, the total length of the myotomy istypically approximately 8.5 cm (Fig 11).

Step 6—Dor fundoplication. The Dor fundoplication (180° anterior) has 2 rows of sutures, 1 leftand 1 right. The left row comprises 3 stitches: the uppermost stitch incorporates the fundus of thestomach, the esophageal wall, and the left pillar of the crus; the other 2 incorporate the stomach andthe esophageal wall (Fig 12). The gastric fundus is then folded over the exposed mucosa. The secondrow of stitches includes 3 stitches between the fundus and the right pillar of the crus, and anadditional stitch between the superior aspect of the fundoplication and the rim of the esophagealhiatus (Fig 12).

LHM and fundoplication. What type?

It is well-recognized that a fundoplication is needed after a LHM in order to preventpostoperative gastroesophageal reflux.114 The type of fundoplication that should be added, however,remains under discussion. A previous study stated that a Nissen fundoplication (360°) eliminatesreflux without adding dysphagia in the majority of patients.115 However, a more recent randomizedcontrolled trial showed a significant difference in dysphagia rates between LHMwith Dor and Nissenfundoplication (2% vs 15%, respectively), concluding that a Nissen fundoplication should be avoidedbecause of the higher incidence of postoperative dysphagia.116

The choice between a Dor fundoplication (180° anterior) and a Toupet fundoplication (220°-240°posterior) is usually based on surgeon’s preference. The advantages of a Dor fundoplication are thatit does not require posterior dissection (avoiding a possible injury to the posterior vagus nerve), andcovers the exposed esophageal mucosa. The advantages of a Toupet fundoplication are that it keepsthe edges of the myotomy separated, and theoretically may provide better reflux control.

Two RCTs tried to determine which fundoplication was most beneficial for achalasia patients.Rawlings and colleagues117 randomized 60 patients undergoing LHM to either Dor fundoplication (n¼ 36) or Toupet fundoplication (n ¼ 24). No significant difference in control of symptoms was notedbetween the 2 groups during follow-up, and both groups presented similar postoperative refluxprofiles. Kumagai and colleagues118 randomized 42 patients to either a Dor fundoplication (n ¼ 20)or a Toupet fundoplication (n ¼ 22) after LHM. Eckardt scores improved dramatically with bothprocedures, and there was no significant difference concerning objective assessment of gastro-esophageal reflux.

Fig. 11. Esophageal myotomy. GEJ, gastroesophageal junction.

Fig. 12. Dor fundoplication. First row of stitches (A) and second row of stiches (B).


Overall, a partial fundoplication should be favored over a total fundoplication. Both Dor andToupet fundoplications offer similar reflux control.

LHM outcomes

LHM for esophageal achalasia has shown excellent results. Zaninotto and colleagues119 studied407 consecutive patients who underwent LHM and Dor fundoplication during the period 1992-2007,and reported a 90% success rate at a median follow-up of 30 months. Perrone and colleagues120

analyzed a consecutive series of patients who underwent LHM and Toupet fundoplication anddescribed excellent results in 97% of patients at a median follow-up of 26 months. Similarly,Schlottmann and colleagues121 studied a consecutive series of 147 patients who underwent LHMand Dor fundoplication, and at a median follow-up of 22 months, 128 patients (87%) did well andrequired no further treatment. A recent European multicenter randomized trial showed a successrate of 84% after 5 years of LHM.96 Another randomized trial found that at the minimal follow-up of5 years only 8% of the patients after LHM had recurrence of symptoms.98

Regarding the incidence of GERD after LHM, a randomized trial comparing the Dor and theToupet fundoplication after myotomy showed an incidence of pathologic reflux of 32.5%.117 Theseresults, however, should be considered cautiously because only one-half of the patients originallyenrolled in the study underwent postoperative pH monitoring. The European achalasia trial foundabnormal acid exposure after LHM and Dor fundoplication in 33% of the patients, but this studypresents a similar limitation because only one-third of the enrolled patients were evaluated bypostoperative pH monitoring.96 Campos and colleagues69 conducted a meta-analysis showing anincidence of post LHM reflux of 8.8% with a fundoplication and of 31.5% with a myotomy alone.Recently, Salvador and colleagues122 reported that the incidence of reflux by pH monitoring afterLHM and Dor fundoplication among 463 patients was only 8.6%.

Robotic Heller myotomy

Advantages of robotic-assisted surgery include improved visibility of the operative field with3-dimensional imaging, increased degrees of freedom of surgical movements, and improvedergonomics. A retrospective, study comparing LHM (62 patients) with robotic myotomy (59 patients)found that the incidence of esophageal perforation was higher during a LHM (16% vs 0%), and bothtechniques had similar rates of success.123 Huffmanm and colleagues124 found similar results with8% of operative esophageal perforations during laparoscopic myotomy, which were all repaired


intraoperatively, and no perforations in the robotic group. Similarly, Perry and colleagues125 showedthat robotic myotomy was associated with a decreased mucosal injury rate as compared tolaparoscopic myotomy (0% vs 16%, respectively) with similar long-term success rates with bothtechniques. A multicenter, retrospective analysis of a large administrative database including 2116laparoscopic myotomies and 149 robotic myotomies showed comparable results between bothgroups, but increased costs in the robotic cohort.126

Overall, the robotic myotomy seems to diminish the risk of intraoperative esophageal perforationwhile offering similar postoperative outcomes than LHM. However, costs remain a significant barrierto widespread use of the robotic platform for the treatment of esophageal achalasia.

Surgical treatment end-stage achalasia

The treatment of achalasia patients with a dilated and sigmoid-shape esophagus, so called “end-stage achalasia,” remains controversial (Fig 13). Traditionally, management for the sigmoidesophagus has been esophagectomy. A LHM is challenging in these patients because an extensivedissection in the posterior mediastinum is needed to straighten the esophageal axis. In addition,there is usually significant periesophageal inflammation secondary to prior interventions oresophagitis due to long-standing retention of food.

Interestingly, previous studies have shown good results after a LHM in end-stage achalasiapatients. Mineo and colleagues127 reported their experience in a small cohort of patients and LHMproved to be effective in improving subjective, objective, and quality-of-life outcome measures inpatients with sigmoid esophagus. Similarly, Sweet and colleagues128 showed that the outcome ofLHM was not influenced by the degree of esophageal dilatation. In 12 patients with an esophageal

Fig. 13. End-stage achalasia.


diameter of more than 6 cm and sigmoid-shaped esophagus, excellent or good results wereobtained in 91% of patients, and none required esophagectomy. In line with these findings,Panchanatheeswaran and colleagues129 showed that in 8 patients with sigmoid esophagus, LHMprovided significant improvement of dysphagia, regurgitation, and quality of life. In patients withChagas and a massively dilated esophagus (diameter 410 cm), a LHM can also relieve dysphagia inthe majority of patients.130

On the other hand, some surgeons recommend an esophagectomy as primary treatment for end-stage achalasia patients, on the assumption that a myotomy cannot improve the swallowingstatus.131,132 An esophageal resection, however, is quite complex in these patients as the enlargedesophagus occupies a major part of the posterior mediastinum, and the vessels feeding theesophagus are usually quite enlarged. Devaney and colleagues132 reported their experience in 93patients undergoing esophagectomy for achalasia. The average hospital stay was 12.5 days, andmajor complications included anastomotic leak (10%), recurrent laryngeal nerve injury (5%),bleeding requiring thoracotomy (2%), and chylothorax (2%), whereas 2 patients died (2%). A recentmeta-analysis comprising 1307 patients with 78.7% transthoracic esophagectomies and 21.3%transhiatal esophagectomies for end-stage achalasia, showed an incidence of pneumonia,anastomotic leak, and mortality of 10%, 7%, and 2%, respectively.133

Considering the satisfactory results of a myotomy and the high morbidity associated with anesophagectomy, LHM should be considered as the first-line treatment option in achalasia patientswith sigmoid esophagus. Esophagectomy should be reserved for patients who have failedcardiomyotomy and other interventions.

Fig. 14. Per-oral endoscopic myotomy (POEM). Mucosa incision (A), submucosal tunneling (B), myotomy (C), and closureof the mucosa entry (D). (Color version of the figure available online.)


Per-Oral endoscopic myotomy

In 2010, Haruhiro Inoue from the Showa University Northern Yokohama Hospital, Japanpublished the results of a new endoscopic technique called per-oral endoscopic myotomy (POEM) in17 patients with esophageal achalasia.134 POEM significantly improved the Eckardt score in everypatient (frommean 10-1.3), and reduced the resting LES pressure (from a mean of 52.4-19.9 mm Hg),without serious complications related to the procedure. This report represented a milestone in thehistory of the treatment of achalasia. Following Inoue’s study, POEM was introduced in thetreatment algorithm of achalasia across the world, and soon many gastroenterologists and surgeonsstarted considering POEM as the primary treatment for achalasia.

POEM technique

POEM is performed with the patient under general anesthesia, in supine position. The procedureincludes 4 major steps (Fig 14).

Step 1—Submucosal injection and mucosal incision. The site for the mucosotomy is selected bycorrelating high-resolution manometry parameters and the upper border of the endoscopicallyvisualized forceful esophageal contraction (usually 10-12 cm above the gastroesophageal junction).After injection of methylene blue into the submucosal layer, a 1.5-2 cm longitudinal mucosotomy isperformed. The mucosotomy can be performed on either the anterior wall (1 o’clock position) or theposterior wall of the esophagus (5 o’clock position).

Step 2—Submucosal tunneling. The endoscope with a distal cap is advanced into the submucosa,and a submucosal tunnel is then created using spray coagulation and intermittent saline-methyleneblue injection. The tunnel is extended past the esophagogastric junction for 2-3 cm onto thestomach.

Step 3—Myotomy. A proximal to distal myotomy starting 2 cm distal to the mucosa entry isperformed, with care to preserve the longitudinal muscle layers of the esophagus. The myotomyshould extend at least 2 cm onto the stomach. Smooth endoscope passage through the esophagogastricjunction, retroflexed evaluation of the valve, and a blanched gastric mucosa (distal dissection) indicatean adequate myotomy.

Step 4—Closure of the mucosal entry. The mucosal entry is closed using endoscopic clips or endoscopicsuturing.

POEM outcomes

In 2012, Swanstrom and colleagues135 reported the outcome of POEM in 18 patients withesophageal achalasia, and at a mean follow-up of 11.4 months dysphagia was relieved in all patients.The same group compared 2 years later the results of LHM (n ¼ 64) and POEM (n ¼ 37), and at amean follow-up of 6 months both groups had sustained similar improvements in their Eckardtscores (1.7 vs 1.2, P ¼ 0.1).136 Interestingly, postmyotomy resting pressures were higher for POEMthan for LHM (16 vs 7.1 mm Hg, P ¼ 0.006). Von Renteln and colleagues137 conducted a prospective,international, multicenter study involving 70 patients who underwent POEM in 5 centers in Europeand North America, showing improvement at 12 months in 82.4% of patients. In 2016, Familiari andcolleagues138 reported the results of POEM in 94 patients, and at a mean follow-up of 11 months,clinical success was achieved in 94.5% of patients. The same year, Werner and colleagues139 analyzeda cohort of 80 patients who underwent POEMwith a mean follow-up of 29 months and their successrate was 77.5%. In this study, 1 patient developed a peptic stricture and 2 patients develop de novoBarrett’s esophagus. A recent meta-analysis including 36 studies with 2373 patients reported thatclinical success (Eckardt score ≤ 3) was achieved in 98% of the patients after POEM.140

Postprocedure GERD after POEM is a concern because this procedure ablates the LES withoutadding any type of antireflux mechanism. Considering that reflux can be silent in many patients withachalasia after treatment, it is unfortunate that only a few studies have evaluated the incidence ofreflux after POEM by pH monitoring. Sharata and colleagues141 studied with pH monitoring 68


patients after a mean follow-up of 20 months, and found an incidence of reflux of 38.2%. Worrell andcolleagues142 found that 70% of the patients studied with pH monitoring 12 months after POEM hadpathologic reflux. In a recent multicenter case-control study analyzing 282 patients, the pH studyperformed at a median follow-up of 12 months showed a DeMeester score ≥ 14.72 in 57.8% of thepatients.143

Laparoscopic myotomy vs POEM

Data comparing LHM with POEM are very limited, and to date there have been no RCTscomparing these treatment modalities. Schlottmann and colleagues144 conducted a systematicreview and meta-analysis which comprised 53 studies reporting data on LHM (5834 patients), and21 studies examining POEM (1958 patients). At 24 months, improvement in dysphagia for LHM andPOEM was 90.0% and 92.7%, respectively (P ¼ 0.01). Patients undergoing POEM were more likely todevelop GERD symptoms (OR ¼ 1.69), GERD evidenced by erosive esophagitis (OR ¼ 9.31), and GERDevidenced by pH monitoring (OR ¼ 4.30).

In patients with type III achalasia (“spastic achalasia”), POEM seems to achieve better outcomes.Kumbhari and colleagues46 reported that in patients with type III achalasia the success rate was80.8% after LHM and 98.0% after POEM (P ¼ 0.01). Khashab and colleagues47 reported a 96.3%successful clinical rate after POEM in 54 patients with type III achalasia refractory to medicaltherapy. Recently, Zhang and colleagues145 studied 32 consecutive patients with type III achalasiatreated with POEM, and at a median follow-up of 27 months treatment success was achieved in90.6% of the patients. The outcomes of LHM and POEM for improvement of dysphagia andpostprocedural GERD by pH monitoring are summarized in Table 4.

Overall, laparoscopic myotomy and POEM seem to achieve comparable symptomatic improve-ment rates. However, patients undergoing POEM have a high risk of postprocedural GERD. Inpatients with type III achalasia, POEM should be considered the primary therapy.

Treatment algorithm for achalasia

Medical therapy or endoscopic Botox injection should be considered in patients with advancedage or significant comorbidities who are not candidates for LHM or POEM. Patients who are deemedgood surgical candidates should undergo LHM (types I and II) or POEM (type III). Patients who have

Table 4Outcomes of laparoscopic Heller myotomy (LHM) and per-oral endoscopic myotomy (POEM)

Study Technique Year N Follow-up(mo)

Improvementdysphagia (%)

Reflux pHmonitoring (%)

Rossetti and colleagues146 LHM 2005 195 83.2 179/195 (91.8) 0/15 (0)Katada and colleagues147 LHM 2006 30 51 24/30 (80) 3/25 (12)Zaninotto and colleagues119 LHM 2008 407 30 368/407 (90.4) 17/260 (6.5)Rebecchi and colleagues116 LHM 2008 138 125 126/138 (91.3) 2/138 (1.4)Sasaki and colleagues148 LHM 2010 35 94 33/35 (94.3) 0/35 (0)Parise and colleagues149 LHM 2011 137 65 130/137 (94.8) 2/15 (13.3)Di Martino and colleagues150 LHM 2011 56 24 52/56 (92.9) 4/56 (7.1)Cuttitta and colleagues151 LHM 2011 49 75 46/49 (93.9) 2/49 (4.1)Rosati and colleagues152 LHM 2013 173 50 172/173 (99.4) 8/47 (17)Salvador and colleagues122 LHM 2016 806 49 712/801 (88.9) 40/463 (8.6)Sharata and colleagues141 POEM 2015 75 20.1 46/47 (97.9) 26/68 (38.2)Schneider and colleagues153 POEM 2016 25 9 23/25 (91) 4/8 (50)Worrell and colleagues142 POEM 2016 35 12 10/11 (90.9) 7/10 (70)Hungness and colleagues154 POEM 2016 112 28 103/112 (92) 10/22 (45.4)Familiari and colleagues138 POEM 2016 100 11 87/92 (94.5) 39/73 (53.4)

Fig. 15. Treatment algorithm for esophageal achalasia (POEM, per-oral endoscopic myotomy).


failed initial treatment should be referred for PD. If symptoms persist, it is reasonable to considerPOEM for those who underwent LHM initially and LHM for those who underwent POEM at first.155-158

Esophagectomy should be reserved for patients who have failed all of these previous interventions(Fig 15).

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