Seminar

Achalasia
Guy E Boeckxstaens, Giovanni Zaninotto, Joel E Richter

Achalasia is a rare motility disorder of the oesophagus characterised by loss of enteric neurons leading to absence of Lancet 2014; 383: 83–93
peristalsis and impaired relaxation of the lower oesophageal sphincter. Although its cause remains largely unknown, Published Online
ganglionitis resulting from an aberrant immune response triggered by a viral infection has been proposed to underlie July 17, 2013
http://dx.doi.org/10.1016/
the loss of oesophageal neurons, particularly in genetically susceptible individuals. The subsequent stasis of ingested
S0140-6736(13)60651-0
food not only leads to symptoms of dysphagia, regurgitation, chest pain, and weight loss, but also results in an
Department of
increased risk of oesophageal carcinoma. At present, pneumatic dilatation and Heller myotomy combined with an Gastroenterology,
anti-reflux procedure are the treatments of choice and have comparable success rates. Per-oral endoscopic myotomy Translational Research Center
has recently been introduced as a new minimally invasive treatment for achalasia, but there have not yet been any for Gastrointestinal Disorders
(TARGID), University Hospital
randomised clinical trials comparing this option with pneumatic dilatation and Heller myotomy.
Leuven, Catholic University of
Leuven, Leuven, Belgium
Introduction whereas it was 10·8 per 100 000 people in a Canadian (Prof G E Boeckxstaens MD);
Achalasia is a motility disorder of the oesophagus that population-based study.14 In both studies, the prevalence Department of Surgical and
Gastroenterological Sciences,
presents with symptoms of dysphagia, regurgitation increased over time whereas the incidence remained
University of Padova, UOC
of undigested food, respiratory symptoms (nocturnal constant, most likely because achalasia is a chronic General Surgery, Sts Giovanni e
cough, recurrent aspiration, and pneumonia), chest pain, disorder with a low disease-related mortality rate. In an Paolo Hospital, Venice, Italy
and weight loss.1,2 Since its first description in 1674 by attempt to identify potential causative or environmental (Prof G Zaninotto MD); and
Division of Digestive Diseases
Sir Thomas Willis,3 spasm or failure to relax the lower factors, Farrukh and colleagues13 studied the epidemiology
and Nutrition, Joy McCann
oesophageal sphincter (LOS) has been identified as the of achalasia in the immigrant south Asian population in Culverhouse Center for
cause of achalasia, resulting in impaired flow of ingested Leicester (UK). Over 20 years, no changes in frequency Esophageal and Swallowing
food into the stomach and subsequent stasis of food and of achalasia were reported, arguing against potential Disorders, University of South
Florida Morsani College of
secretions in the oesophagus. Achalasia results from the environmental factors as triggers of the disease. The Medicine, Tampa, FL, USA
disappearance of the myenteric neurons that coordinate finding that autoimmune diseases such as type 1 dia- (Prof J E Richter MD)
oesophageal peristalsis and LOS relaxation.4 betes mellitus, hypothyroidism, Sjögren’s syndrome, and Correspondence to:
The most common form of achalasia is idiopathic uveitis are more prevalent in patients with achalasia than Prof Guy E Boeckxstaens,
achalasia, which mostly occurs as sporadic cases. in the general population suggests that achalasia might Department of Gastroenterology,
Translational Research Center for
However, a similar clinical presentation can occur in have an autoimmune component.19
Gastrointestinal Disorders
patients with pseudoachalasia (2–4% of patients with (TARGID), University Hospital
suspected achalasia)5 or Chagas disease—diseases Pathophysiology Leuven, Catholic University of
characterised by degeneration of the myenteric plexus Immune-mediated ganglionitis Leuven, Herestraat 49,
3000 Leuven, Belgium
due to neoplastic infiltration6,7 or infection with Oesophageal peristalsis and relaxation of the LOS are guy.boeckxstaens@med.
Trypanosoma cruzi, respectively.8–10 Moreover, sporadic mediated and coordinated by myenteric neurons.4 In kuleuven.be
cases of paraneoplastic pseudoachalasia associated with achalasia, these myenteric neurons are decreased in
anti-Hu antibodies have been reported, especially in number or are absent, resulting in aperistalsis and
patients with small-cell lung cancer.11 Although rare, impaired relaxation of the LOS. Most likely, the myenteric
achalasia can also be part of other complex syndromes neurons disappear because of chronic ganglionitis.
such as Allgrove syndrome (also known as triple A Detailed examination of resection specimens shows
syndrome—ie, alacrima, achalasia, adrenocorticotropic infiltration of cytotoxic lymphocytes expressing activation
hormone deficiency), Down’s syndrome, or familial markers20–22 and evidence of complement activation
visceral neuropathy.12 In this Seminar, we mainly focus within myenteric ganglia.23 In accordance, antibodies
on the present insights and recent developments in the against myenteric neurons have been shown in serum
management of idiopathic achalasia. samples of patients with achalasia,24,25 especially in those

Epidemiology
Idiopathic achalasia is rare, with mean incidences of Search strategy and selection criteria
0·3–1·63 per 100 000 people per year in adults13–16 and We searched PubMed and the Cochrane library with no date limits set for medical subject
0·18 per 100 000 people per year in children younger heading terms “achalasia”, “epidemiology”, “etiology”, “pathophysiology”, “genetics”,
than 16 years.17 In adults, achalasia occurs with equal “diagnosis”, “manometry”, “radiology”, “symptoms”, “endoscopy”, “treatment”,
frequency in men and women14,15 and in white and non- “pharmacological”, “botulinum toxin”, “pneumodilation”, “myotomy”, “POEM”, “end-stage”,
white people,18 but incidence increases with age. In most “dysplasia”, “carcinoma”, and “stem cells”. We did the last search in January, 2013. We
studies, the mean age at diagnosis was over 50 years.13,14,18 reviewed all relevant articles published in English. For treatment strategy, we regarded
Mean incidence in those aged over 80 years is 17 per randomised trials and meta-analyses as the most important study types. Where appropriate,
100 000 people per year (95% CI 2–61).13 Mean prevalence we reviewed relevant abstracts presented at major gastrointestinal meetings.
was 8·7 per 100 000 people in a study from Iceland15

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 Seminar

with HLA DQA1*0103 and DQB1*0603 alleles.26 Because predilection for squamous epithelium, this hypothesis
HLA proteins are crucial for antigen recognition, these would fit with the selective loss of enteric neurons in the
findings suggest the involvement of an aberrant immune oesophagus. However, HSV-1 DNA was as frequently
response to so far unknown antigens. Viruses, such as identified in the oesophagus of control individuals,28
herpes simplex virus 1 (HSV-1), measles, and human suggesting that HSV-1 only triggers persistent immune
papillomavirus have been proposed as potential antigens. activation with subsequent loss of enteric neurons in
HSV-1 DNA has been identified in oesophageal tissue, genetically susceptible individuals (figure 1).29 However,
and evidence suggests that isolated oesophageal T cells other investigators have not found HSV-1 or other viruses
are oligoclonal in nature in achalasia and specifically such as measles or human papillomavirus in oesophageal
proliferate and release cytokines on exposure of HSV-1 resection specimens from patients with achalasia.22,30,31
antigens.27,28 Because HSV-1 is a neurotropic virus with a
Genetics
Candidate gene studies, albeit in a small number of
Initial insult: viral, toxin? Immunogenetics:
HLA DQA1*0103 or patients, have identified an association between achalasia
HLA DQB1*0603 and gene polymorphisms in HLA class II molecules,32–34
vasoactive intestinal peptide receptor 1,35 KIT,36 inter-
Chronic infection Aberrant autoimmune leukin 10 promoter,37 and interleukin 23 receptor.38
response Moreover, familial achalasia has been reported, albeit
rarely, further supporting a role for genetic factors in the
pathogenesis of achalasia.12 An ongoing genome-wide
Cytotoxic T cells
Autoimmune antibodies association study will hopefully yield more clarity
regarding this topic.

Ganglionitis or loss
of neurons
Diagnosis
Symptomatology
The most frequently occurring symptoms of achalasia
Achalasia are dysphagia (>90%) for solids and liquids, regurgitation
of undigested food (76–91%), respiratory complications
Figure 1: Present hypothesis proposing virus-induced (nocturnal cough [30%] and aspiration [8%]), chest
autoimmune-mediated ganglionitis in achalasia pain (25–64%), heartburn (18–52%), and weight loss
Insert shows infiltration of myenteric ganglion with T cells. Arrow shows
myenteric nerves and ganglion cells. Reproduced with permission from (35–91%).1,39–41 Heartburn can lead to an erroneous diag-
Goldblum and colleagues.21 nosis of gastro-oesophageal reflux disease, which might
culminate in antireflux surgery. Nocturnal coughing
A B mainly occurs in patients with substantial stasis of large
amounts of food and secretions. Chest pain is pre-
dominantly present in patients with type III disease (see
later)42 and responds less well to treatment than do
dysphagia and regurgitation, which probably explains the
less favourable therapeutic results obtained in patients
with type III disease compared with those with type I
or II disease.40,42 However, symptoms of achalasia are not
specific, which explains the long delay between onset of
symptoms and the final diagnosis (up to 5 years in some
studies).43,44 Although some patients lose a lot of weight
(more than 20 kg),1 achalasia should also be considered
in obese patients.

Radiology and endoscopy

The first diagnostic step is to rule out anatomical lesions,
neoplasia, or pseudoachalasia using endoscopy or
radiology. Pseudoachalasia should particularly be sus-
pected in cases of rapidly progressing dysphagia,
significant weight loss, and old age,6 and should be
excluded by endoscopic ultrasound or CT scan. These
Figure 2: Achalasia findings on radiological examination
investigations will reveal unusual thickening of the
(A) Typical bird-beak appearance in early achalasia. (B) Sigmoid-like appearance of decompensated oesophagus. oesophageal wall, mass lesions, or even an infiltrating
Modified from Moonen and Boeckxstaens47 and Triadafilopoulos and colleagues,48 respectively, with permission. pancreatic carcinoma.7

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Especially in the early stage of achalasia, both endoscopy new parameter to quantify LOS relaxation has been
and radiology are less sensitive than manometry and only introduced: integrated relaxation pressure,55 which calcu-
identify about half (or even less) of patients with early- lates the mean post-swallow LOS pressure of a 4-s period
stage achalasia.41,45,46 In advanced cases, endoscopy might during which the LOS pressure was lowest, skipping
reveal a dilated oesophagus with retained food and periods of crural contractions if necessary. The upper limit
increased resistance at the gastro-oesophageal junction. of normal for the integrated relaxation pressure is
Radiological examination often shows a typical bird-beak 10 mm Hg for type I achalasia, 15 mm Hg for type II
image at the junction (figure 2), with a dilated oesophageal achalasia, and 17 mm Hg for type III achalasia, which
body, sometimes with an air–fluid level and absence of an differentiates best the impaired relaxation in achalasia
intragastric air bubble. In more advanced achalasia, from non-achalasic individuals and from patients with
severe dilatation with stasis of food and a sigmoid-like diffuse oesophageal spasm.56
appearance can occur. Although radiology is not as
sensitive as manometry, this investigation remains Treatment
important to rule out structural abnormalities, estimate Pharmacological compounds
the diameter of the oesophagus, and assess the presence The two most often used pharmacological drugs are
of epiphrenic diverticula.48 To assess emptying of the nitrates and calcium-channel blockers.57–60 Nitrates inhibit
oesophagus, a timed barium swallow can be done, in normal LOS contraction by dephosphorylation of the
which the height of the barium column 5 min after myosin light chain. In a Cochrane review, Wen and
ingestion of diluted barium is a measure of emptying.49,50 colleagues61 identified only two (poorly designed)
randomised studies that assessed the clinical success of
Manometry nitrates in achalasia and concluded that no solid recom-
On conventional manometry, absence of peristalsis, mendations could be given. Nifedipine, in sublingual
sometimes with increased intraoesophageal pressure doses of 10–20 mg 15–60 min before meals, is the most
owing to stasis of food and saliva, and incomplete widely used drug for achalasia. It inhibits LOS muscle
relaxation of the LOS on deglutition (residual pressure contraction by blocking cellular calcium uptake and
>10 mm Hg) are the hallmarks of achalasia.2 Additionally, lowers the LOS resting pressure by 30–60%.57–59 However,
the resting tone of the LOS is often raised. High-resolution a substantial drawback of its use is the occurrence of
manometry (HRM) is increasingly being used to provide side-effects such as hypotension, headache, and dizziness
more detailed information on oesophageal motility.51 By in up to 30% of patients.57–59 Moreover, drug tolerance
means of catheters incorporating 36 or more pressure develops with time.62
sensors spaced only 1 cm apart, HRM allows detailed A more widely used pharmacological treatment is
pressure recording from the pharynx to the stomach and botulinum toxin A, a neurotoxin that blocks the release of
is regarded as the gold standard for diagnosis of achalasia.52 acetylcholine from the nerve terminals. It is directly
The use of HRM has led to the subclassification of injected, at a dose of 80–100 units in four or eight
achalasia into three clinically relevant groups on the basis quadrants, into the LOS through a sclerotherapy needle
of the pattern of contractility in the oesophageal body:53 during upper-gastrointestinal endoscopy.63,64 Botulinum
type I (classical achalasia; no evidence of pressurisation), toxin is a safe and effective treatment with few side-effects.
type II (achalasia with compression or compartmental- More than 80% of cases have a clinical response by
isation in the distal oesophagus >30 mm Hg), and type III 1 month, but response fades rapidly, with less than 60% of
(two or more spastic contractions; figure 3). Additionally, a patients in remission at 1 year.65 Findings from five

Type I Type II Type III

Figure 3: Manometric types of achalasia

Type I is characterised by absence of distal pressurisation to greater than 30 mm Hg. In type II, pressurisation to greater than 30 mm Hg occurs in at least two of
ten test swallows, whereas patients with type III disease have spastic contractions with or without periods of compartmentalised pressurisation. Modified from
Boeckxstaens and Zaninotto,54 with permission.

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randomised trials that compared botulinum toxin with 40 mm balloons, respectively. Over 4–6 years, nearly a
pneumodilatation66–70 and one that compared botulinum third of patients have symptom relapse;39,76,78 however,
toxin with laparoscopic myotomy71 showed initially com- long-term remission can be achieved in nearly all these
parable relief from dysphagia, but a rapid deterioration in patients by repeat dilatation by an on-demand strategy on
patients treated with botulinum toxin after 6–12 months. the basis of symptom recurrence.78 Patients with the best
Hence botulinum toxin, as is the case for nitrates and outcomes after pneumatic dilatation are those older than
calcium-channel blockers, should be used only as an 40 years, women, and those with a type II pattern by
interim option before treatment with more durable HRM.1,42,49,53,76,79 The most cost-effective treatment for
treatments or in high-risk patients. achalasia over a 5–10-year period after the procedure is
pneumatic dilatation.80,81
Pneumatic dilatation Contraindications to pneumatic dilatation are poor
Pneumatic dilatation, which tears the LOS by forceful cardiopulmonary status or other comorbid illnesses that
stretching with air-filled balloons, has become simpli- would prevent surgery should an oesophageal perforation
fied by the microinvasive Rigiflex balloon system occur. Pneumatic dilatation can be done safely after a
(Boston Scientific, Marlborough, MA, USA). These non- failed Heller myotomy, although larger diameter balloons
compliant polyethylene balloons are available in three are often needed.82 Up to 33% of patients have procedure-
diameters (30, 35, and 40 mm), mounted on a flexible related complications after pneumatic dilatation, but most
catheter placed over a guide wire at endoscopy. The are minor including chest pain, aspiration pneumonia,
general technique of pneumatic dilatation is summarised bleeding, transient fever, mucosal tear without perforation,
in the panel and figure 4, although the actual protocol and oesophageal haematoma. Oesophageal perforation is
varies across centres.2 Under fluoroscopic guidance, the the most serious complication, with an overall rate in
balloon is positioned across the LOS and gradually experienced endoscopists of 2·0% (range 0–16%), of
inflated until the waist is flattened. The most popular which 50% needed surgery.83 However, in a recent series
technique is a graded dilation protocol starting with a of 16 transmural perforations, all cases were managed
30 mm balloon.73 Subsequent dilations are spaced over conservatively.84 Small perforations and painful deep tears
2–4-week intervals on the basis of symptom relief can be treated with antibiotics and total parenteral
associated with repeat LOS pressure measurements39,74 or nutrition for days to weeks.84 However, surgical repair by
improvement in oesophageal emptying.75,76 Pneumatic thoracotomy is best for large, symptomatic perforations
dilatation is usually done in an outpatient setting; the with extensive soilage of the mediastinum. Most per-
patient is observed for 2–6 h and can return to normal forations occur during the initial dilatation; difficulty
activities the next day. keeping the balloon in position is a potential risk factor.85
In a review of more than 1100 patients (24 studies) with Although no other predictors for perforation have been
an average follow-up of 37 months,77 Rigiflex pneumatic identified, a European achalasia trial reported more
dilatation resulted in good to excellent symptom relief in perforations, primarily in older patients, when the first
74%, 86%, and 90% of patients treated with 30, 35, and pneumatic dilatation was done with a 35 mm compared
with a 30 mm balloon.79 Complications of severe gastro-
oesophageal reflux disease are rare after pneumatic
Panel: General techniques for pneumatic dilatation with the Rigiflex balloon system2 dilatation, but 15–35% of patients have heartburn, which
• Patients are on a liquid diet for several days and fast for 12 h before endoscopy. Those improves with proton-pump inhibitors.77
with mega-oesophagus might need oesophageal lavage with a large-bore tube.
• The procedure is usually done as outpatient surgery in the morning. Laparoscopic Heller myotomy
• Upper endoscopy with conscious sedation in the left lateral position is done. Surgical myotomy of the muscle layer of the distal
• Savary guide wire is placed in the stomach and a Rigiflex balloon is passed over it. oesophagus and LOS, also known as Heller myotomy,
• The smallest balloon (30 mm) is usually used first. Beginning with a 35 mm balloon is a time-honoured treatment for achalasia. It was first
might be preferred in patients with previous pneumatic dilatation failures, young described in 1913 by the German surgeon, Ernst
patients (<40 years), or after previous Heller myotomy. Heller,86 and has been widely used, with few technical
• Accurate balloon placement is usually done with fluoroscopy (sometimes endoscopy). changes, ever since. The two most important modi-
The key is careful location of the balloon so the waist caused by the non-relaxing lower fications to the original procedure are cutting of the
oesophageal sphincter impinges on the middle portion of the distending balloon. cardia muscle fibres only on the anterior side87 and
• The balloon is gradually distended until the waist is flattened. The pressure needed is addition of a fundoplication to reduce the risk of gastro-
usually 7–15 psi of air, held for 15–60 s. oesophageal reflux (figure 5).90
• The patient is repositioned in the left lateral position to minimise aspiration before the The advent of minimally invasive surgery has pro-
balloon is deflated and removed. foundly changed the approach to Heller myotomy.
• Post-procedure observation is done for 2–6 h to exclude perforation and assess for Pellegrini and colleagues91 initially described a thoraco-
chest pain and fever. Patients with significant pain should be sent for a Gastrografin scopic approach for myotomy in 1992. However, laparo-
swallowing assessment to exclude oesophageal perforation. scopy offers better visualisation of the distal oesophageal
muscle layers and the sling fibres of the gastric fundus,

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resulting in a shorter operation time and better results.

In a recent review, Campos and colleagues92 showed that
symptomatic improvement was significantly better with
laparoscopic (n=3086 patients) than with thoracoscopic
(n=211 patients) Heller myotomy (89·3% vs 77·6%, odds
ratio 1·9, 95% CI 1·1–3·7; p=0·048) and reduced the
incidence of postoperative gastro-oesophageal reflux Pneumatic
dilator
(14·9% vs 28·3%, odds ratio 2·8, 95% CI 1·1–7·2;
p=0·03). Because the antireflux barrier function of the Restored
LOS is lost after myotomy, the need to add an antireflux Oesophageal flow complete
dilatation Stomach
procedure (fundoplication) to Heller myotomy has been Balloon
LOS
debated for many years. Findings from the meta-analysis completely inflated
Balloon inserted and
by Campos and colleagues92 showed similar therapeutic Guide wire
inflated, expanding LOS
success but a significant reduction of gastro-oesophageal
reflux symptoms when a fundoplication was added to Figure 4: Pneumatic dilatation with the Rigiflex system
Heller myotomy (31·5% vs 8·8%; p=0·001). Similar Schematic representation of the pneumodilatation procedure. The deflated balloon is inserted over a guide wire,
results were reported in a randomised controlled trial.93 after which the slightly inflated balloon is positioned at the oesophagogastric junction with the indentation still
visible. Finally, the balloon is fully inflated and the indentation disappears. After removal of the balloon, the LOS is
In view of the absence of peristalsis in achalasia, the distended, allowing adequate passage. LOS=lower oesophageal splinter. Reproduced from Johns Hopkins
type of fundoplication applied might have a major effect Medicine, Gastroenterology and Hepatology.72 Illustration Copyright ©1998–2003 by The Johns Hopkins Health
on outcome. Postoperative dysphagia is higher after System Corporation; used with permission www.hopkins-gi.org. Illustration created by Mike Linkinhoker.
Nissen fundoplication than after partial anterior fun-
doplication (15·0% vs 2·8% p=0·001).93,94 Findings from
a recent multicentre trial suggest that both anterior
(Dor) and posterior (Toupet) partial fundoplication
provide comparable control of reflux after laparoscopic
Heller myotomy.95
Laparoscopic Heller myotomy combined with partial
fundoplication is a safe operation with a reported
mortality of 0·1% (three deaths in 3086 patients).92 The
most common complication of laparoscopic Heller
myotomy is perforation of the oesophageal or gastric
mucosa during the myotomy, which is usually recognised
during the procedure and repaired immediately without
any consequences. The overall complication rate of
laparoscopic Heller myotomy is 6·3% (range 0–35%),
but clinical consequences are reported in only 0·7%
(range 0–3%) of cases.96–105 The table summarises the
outcome data of studies with 100 patients or more.96–105 In
a systematic review, the mean success rate was 89%
(range 76–100%) at a median follow-up of 35 months
(range 8–38).92 However, success rates decrease
(depending on the definition used) to 65–85% at 5 years’ Figure 5: Schematic representation of laparoscopic Heller myotomy with Dor fundoplication (left) and
per-oral endoscopic myotomy (right)
follow-up, probably because of disease progression.102,106,107 Left panels show the dissection of the muscle layer (top) and the creation of the Dor fundoplication (bottom). The
Positive prognostic factors after laparoscopic Heller right panel shows the endoscope positioned in the tunnel created between the muscle layer and mucosa, allowing
myotomy are young age (<40 years), a LOS resting pressure endoscopic myotomy of the circular muscle layer. Reproduced from Zaninotto and Costantini88 and Inoue and
greater than 30 mm Hg, and a straight oesophagus (ie, colleagues,89 respectively, with permission.
with no tortuosities at its distal end, as in sigmoid
oesophagus).99,101 As for pneumodilatation, the manometric dilatation.108 The effect of past endoscopic treatment on the
pattern at diagnosis also affects clinical success rates after outcome of laparoscopic Heller myotomy is controversial:
Heller myotomy—ie, patients with achalasia type II have findings from some studies102–104 suggested that multiple
the best outcome.108 Although no difference in outcome endoscopic treatments could hamper the results of sur-
between Heller myotomy and pneumodilatation has been gery, whereas Portale and colleagues109 reported that only
noted for patients with type I and II achalasia, patients patients previously treated with both botulinum toxin
with type III disease seem to respond better to Heller injection and pneumodilation had a less favourable out-
myotomy than to pneumodilatation,42 probably because come than did those who had not had such procedures
myotomy entails a more extensive and more proximal previously. However, to what extent these patients are less
disruption of the oesophageal muscle than does responsive to any treatment remains unclear.

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myotomy (hazard ratio 2·37; 95% CI 1·86–3·02). This

Number of patients Follow-up (months) Patients in remission (%)
risk difference occurred only when repeat pneumatic
Oelschlager et al (2003)96 110 46 100 (91%) dilatation was recorded as an adverse event.
Perrone et al (2004)97 100 26 92 (92%) In 2011, a prospective randomised comparative study
Rossetti et al (2005)98 195 83 179 (92%) was published that compared pneumatic dilatation and
Torquati et al (2006)99 200 43 170 (85%) laparoscopic myotomy undertaken by physicians highly
Schuchert et al (2008)100 194 32 180 (93%) skilled in both procedures.79 In the European Achalasia
Zaninotto et al (2008)101 400 30 348 (87%) Trial,79 patients from five countries were randomly assigned
Snyder et al (2009)102 134 22 115 (86%) to Rigiflex dilatation (n=94; 30 and 35 mm with up to three
Finley et al (2010)103 261 36 181 (69%) repeat dilations allowed) or laparoscopic myotomy with
Rosemurgy et al (2010)104 505 31 404 (80%) Dor fundoplication (n=106). Both treatments had com-
Carter et al (2011)105 165 62 125 (76%) parable success in relieving symptoms at 2 years: 86% for
Total 2264 42* 84% dilatation and 90% for myotomy. Barium emptying and
LOS pressure were both improved to similar extents in
*Mean.
both groups. However, the follow-up was short (at least
Table: Remission of symptoms after laparoscopic myotomy in series of 100 or more patients 2 years) and retreatment was allowed. Pre-existing daily
chest pain, oesophageal width less than 4 cm before
treatment, and post-treatment poor oesophageal emptying
Recurrence of dysphagia most often develops within with barium column greater than 10 cm were identified as
12–18 months after surgery.100,110 Incomplete myotomy, predictors of treatment failure. Although not a predictor of
especially on the gastric side (where the myotomy is clinical success for either treatment, patients younger than
more difficult), late scarring of the myotomy, and an 40 years more often needed repeat pneumatic dilatations
excessively tight anti-reflux wrap are possible causes of than did those older than 40 years.
treatment failure.110 As mentioned earlier, chest pain is
more difficult to treat than the other symptoms and Per-oral endoscopic myotomy
patients should be informed about this issue.40 Recurrent Per-oral endoscopic myotomy (POEM) is a recently
symptoms after Heller myotomy can be safely treated developed endoscopic technique for treatment of
with pneumodilatation or, if such conservative treatment achalasia.89 In brief, the endoscopist creates a submucosal
fails, by repeat laparoscopic Heller myotomy.110 tunnel to reach the LOS and to dissect the circular muscle
fibres over a 7 cm oesophageal and 2 cm gastric length
Pneumatic dilatation versus laparoscopic Heller myotomy (figure 5). Inoue and colleagues89 reported a success rate
Until recently, addressing the question of whether to of 100% and a significant reduction in LOS pressure
undertake pneumatic dilatation or laparoscopic Heller in 17 patients. Subsequent studies of 11–18 patients
myotomy was difficult because large prospective, confirmed the high success rate (89–100%), even after
randomised comparative studies were not available. In a several previous pneumatic dilatations.112–116 However,
review of case series from 1989 to 2006, Campos and physiological data are limited and follow-up was short
colleagues92 reported an overall 68% improvement rate in (mean 6 months). Moreover, especially because no
1065 patients undergoing pneumatic dilatation with antireflux procedure is included in this technique, the
Rigiflex balloons whereas laparoscopic myotomy had an risk of gastro-oesophageal reflux is substantial (up to
89% improvement rate in 3086 patients. In a study from 46% in one study113) and might represent an important
the Cleveland Clinic (Cleveland, OH, USA),76 106 patients drawback. Longer follow-up is needed and randomised
were treated with pneumatic dilatation and 73 patients studies to compare POEM with pneumatic dilatation or
underwent laparoscopic myotomy. Success, defined as laparoscopic Heller myotomy should be done before
dysphagia or regurgitation fewer than three times per accepting POEM as new treatment option for achalasia.
week or freedom from alternative treatments, was similar
between groups: 96% for dilatation versus 98% for Oesophagectomy for end-stage achalasia
surgery at 6 months, decreasing to 44% versus 57% at Despite the efficacy of pneumodilatation and laparo-
6 years. A large retrospective longitudinal study from scopic Heller myotomy, 2–5% of patients will develop
Ontario, Canada,111 provides the best estimate of long- end-stage disease,117 defined as a massive dilatation of
term outcomes with the procedures in typical practice the oesophagus with retention of food, unresponsive
settings. From 1991 to 2002, 1461 adults were treated for reflux disease, or the presence of preneoplastic lesions.48
achalasia; 81% had pneumatic dilatation and 19% had In these cases, oesophageal resection might be
surgical myotomy as their first procedure. The cumula- necessary to improve the patient’s quality of life and
tive risk of any subsequent treatment (dilatation, avoid the risk of invasive carcinoma. The risk of
myotomy, or oesophagectomy) after 1, 5, and 10 years was needing oesophagectomy is higher if the oesophagus is
36·8%, 56·2%, and 63·5% after initial pneumatic already markedly dilated at the first intervention than if
dilatation versus 16·4%, 30·3%, and 37·5% after initial it is mildly dilated (<4 cm).118

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The ideal reconstruction method after oesophagectomy patients or those with severe comorbid illnesses because it
has not yet been established. Gastric interposition has is safe, improves symptoms, and might need retreatment
the advantage of needing only one anastomosis, but no more than yearly. However, pneumatic dilatation is a
gastro-oesophageal reflux can cause severe damage if reasonable alternative in high-risk patients if done in
the anastomosis is intrathoracic. If a total oesopha- high-volume (ie, experienced) centres with surgical
gectomy is done and the anastomosis is in the neck, the expertise, should the rare perforation occur. The role of
critical vascular supply to the gastric tube can be POEM as a substitute for myotomy will be defined in time
compromised, resulting in anastomotic leakage and once there has been longer term follow-up of symptoms
stricture.48 Alternatively, a long colonic interposition can and physiological studies.
be constructed, but anastomotic failure or stricture due
to ischaemia might occur. Short-segment colon inter- Long-term management
position with an intrathoracic anastomosis might be a To screen or not to screen for dysplasia?
valid option in such patients.48 In a recent review that As a result of functional obstruction, large amounts of
included 295 patients,119 an optimum outcome (defined food and saliva can be retained within the oesophagus,
as unrestricted or regular diet) was present in 65–100% especially if treatment is suboptimal. Increased bacterial
of patients at a medium follow-up of 44 months growth and chemical irritation from the continuous
(range 25–72), irrespective of the technique used. decomposition of food and saliva can induce chronic
hyperplastic oesophagitis, dysplasia, and eventually
Risk factors and therapeutic guidelines malignant transformation of oesophageal epithelial cells.122
Standardisation of balloon systems and development of The risk of oesophageal carcinoma varies substantially,
laparoscopic myotomy and, most recently, HRM has ranging from ten to 50 times in patients with achalasia
helped better define the types of patient who will respond compared with the general population.43,123–129 In a large
well to pneumatic dilatation versus laparoscopic long-term prospective trial, a hazard ratio of 28 was
myotomy. These predictors are age, sex, and manometric reported for development of oesophageal squamous-cell
type by HRM. The favourable effects of older age carcinoma in patients with achalasia compared with
(>40 years) on the success of pneumatic dilatation are the matched control individuals.129
most reproducible, from as far back as 1971.1,74,76,79 Findings Because one of the main symptoms of oesophageal
from several studies suggest that young men respond carcinoma, dysphagia, is frequently attributed to exacer-
less well than do women to pneumatic dilatation.76,120 For bation or recurrence of achalasia, diagnosis of oesophageal
example, in a study at the Cleveland Clinic (106 patients, carcinoma is often delayed, explaining the poor prognosis
51 women),76 men up to age 50 years had poor outcomes in achalasia.130 This situation raises the question of whether
after a 30 mm Rigiflex pneumatic dilatation. However, an endoscopic surveillance programme should be initiated
young women (<35 years) also did not respond well, for early detection of cancer. However, so far no consensus
whereas most women aged 35 years or older had
sustained relief over at least 5 years after a pneumatic
dilatation. Although not well studied, this finding is Low surgical risk High surgical risk
probably a result of stronger LOS tone in young patients,
Age <40 years Age >40 years
especially men.121 Pandolfino and colleagues53 reported
that HRM patterns in achalasia predicted treatment Manometric Refer to oesophageal centre of
type III disease excellence
success, especially after pneumatic dilatation. Success
rates were significantly higher for type II achalasia Laparoscopic Failure Graded pneumatic
myotomy dilatation
(96%) than for type I (56%) and type III (29%) achalasia.
These findings were supported by the prospective Success Graded pneumatic Failure Botulinum toxin
Failure dilatation
European Achalasia Trial, which reporting that type III
disease might be best treated by laparoscopic myotomy.42 Repeat as needed Success Failure
Identification of predictors of success can guide our
recommendation for treatment of achalasia (figure 6).2 Repeat as needed Calcium-channel
Refer to oesophageal centre of
Healthy patients with achalasia should be given the option blocker or nitrates
excellence
of graded pneumatic dilatation or myotomy. Myotomy will
be the more effective treatment in adolescents and
younger adults, especially men and possibly patients with
Pneumatic Oesophagectomy
type III achalasia. Myotomy is also the treatment of choice dilatation
in uncooperative patients and those in whom pseudo-
achalasia cannot be excluded. Women and patients older Repeat myotomy
than 40–50 years can expect good outcomes with either
pneumatic dilatation or myotomy. Botulinum toxin Figure 6: Proposed therapeutic algorithm for achalasia
injection should be the first-line treatment for elderly Modified from Richter and Boeckxstaens.2

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 Seminar

on this topic has been reached for several reasons.131 First, More recently, these investigators used the new Endoflip
the death rate from oesophageal cancer diagnosed during system (MMS, Enschede, Netherlands), which measures
a surveillance programme is not different from that of the the distensibility of the oesophagogastric junction with
normal population.129 Second, endoscopic surveillance is a balloon catheter passed across the LOS, to measure
difficult in patients with achalasia because the whole the cross-sectional area of the sphincter using
segment is at risk, the mucosa is often covered with food impedance planimetry.137,138 In patients with achalasia,
debris and has a cobblestone appearance, and random oesophagogastric junction distensibility was associated
biopsies might not be representative. Third, the cost- with oesophageal emptying by barium and a low total
effectiveness of a surveillance programme is dubious symptom score and was significantly increased with
because the incidence of cancer is low. However, screening treatment. Patients with normal oesophagogastric
programmes undertaken so far used standard white light junction distensibility (>2·9 mm²/mm Hg) usually had
endoscopy.43,123–129 With the introduction of high-resolution complete upright oesophageal emptying by 5 min,
endoscopy and chromoendoscopy with Lugol’s staining, whereas those with persistent impaired distensibility
the sensitivity to detect premalignant lesions has signifi- had a mean barium column height of 5–8 cm at 5 min.137
cantly improved.132 In a recent study, Lugol’s staining On the basis of these data, we believe that all patients,
detected more dysplastic lesions than did white light irrespective of treatment or symptoms, need physiological
endoscopy in patients with longstanding achalasia.133 These follow-up of their achalasia. Assessment of symptoms and
lesions were detected in patients diagnosed with achalasia an upright time barium oesophagram done 1–3 months
for more than 20 years. Hence, a possible screening after treatment seems a practical approach. Those with
strategy could be to start an endoscopic surveillance symptom relief and good oesophageal emptying will do
programme 10 years after initial treatment using Lugol’s well long term and should be followed up on a regular
staining,133 particularly in high-risk patients (ie, men);128,134 basis (ie, every 2–3 years). Those with persistent
however, more studies are needed. An additional (but symptoms, poor oesophageal emptying, or both warrant
costly) strategy might be to use biomarkers such as p53, further treatment or close follow-up at 1 year.
which precede the appearance of oesophageal carcinoma
in patients with achalasia by several years.135 Future treatment
Present approaches used to treat achalasia destroy the
How to predict need for retreatment LOS rather than try to correct the underlying abnor-
Nearly 90% of patients with achalasia can return to near mality and to restore function. Assuming that the
normal swallowing and good quality of life with present disappearance of myenteric neurons results from an
treatments.136 However, few are cured with one treatment, immune-mediated process, one could theoretically
many relapse over time, and intermittent top-up pro- consider immune modulatory drugs. However, at the
cedures might be needed. How can we predict which time of diagnosis the number of neurons has already
patients will need re-treatment? Physiological studies are decreased to a critical level, questioning whether
the best predictors of long-term success of treatment. arresting the inflammatory process will restore function.
Eckardt and colleagues74 reported that all patients with a However, a recent case report of a patient with achalasia
post-procedure LOS pressure less than 10 mm Hg were and eosinophilic oesophagitis showed improved
in remission after 2 years, 71% were in remission for oesophageal motility and disappearance of dysphagia
pressures between 10 and 20 mm Hg, and 23% for after treatment with 50 mg prednisolone.139
pressures over 20 mm Hg. More recently, Hulselmans An alternative possible treatment option is trans-
and colleagues39 noted that 66% of patients with post- plantation of neural stem cells. Recent advances in
procedure LOS pressure less than 15 mm Hg were in stem-cell research will hopefully shift treatment
symptomatic remission after 6 years. towards functional recovery.140 In particular, the
The timed barium oesophagram assesses upright discovery that neural stem cells (or so-called neuro-
oesophageal emptying over 5 min, is readily available, is spheres) can be isolated and cultured from mucosal
non-invasive,50 and is a better predictor of success than biopsies141 will undoubtedly provide new options for
is LOS pressure if there is good oesophageal emptying treatment of aganglionic gastrointestinal diseases,
even if LOS pressure was below 10 mm Hg.75 Vaezi and including achalasia. Metzger and colleagues141 generated
colleagues49 reported that patients with complete neurosphere-like bodies from mucosal biopsies capable
symptom relief associated with marked improvement in of proliferating and generating multiple neuronal
oesophageal emptying were more likely to do well at subtypes. On transplantation, neurosphere-like bodies
3 years than those with symptom relief but poor colonised cultured aganglionic human hindgut to
oesophageal emptying (82% vs 10%, respectively). This generate ganglia-like structures and enteric neurons
finding was confirmed in the prospective European and glia. Comparable findings were reported by another
Achalasia Trial79 and was shown in a subsequent analysis group;142,143 however, after transplantation in vivo into
to be more predictive of success than post-treatment the mouse pylorus, the grafted neurosphere-like bodies
LOS pressure, with a sensitivity of 88% versus 20%.75 failed to adopt a neuronal phenotype.142 More research

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is needed to optimise the technique of stem-cell 23 Storch WB, Eckardt VF, Junginger T. Complement components and
transplantation before achalasia can really be cured, but terminal complement complex in oesophageal smooth muscle of
patients with achalasia. Cell Mol Biol (Noisy-le-grand) 2002; 48: 247–52.
there is definitely light at the end of the tunnel. 24 Storch WB, Eckardt VF, Wienbeck M, et al. Autoantibodies to
Contributors Auerbach’s plexus in achalasia. Cell Mol Biol (Noisy-le-grand) 1995;
GEB designed the outline of the manuscript. All authors did the 41: 1033–38.
literature search, data analysis, provided figures or tables, wrote part of 25 Moses PL, Ellis LM, Anees MR, et al. Antineuronal antibodies in
the manuscript, and revised and approved the final manuscript. idiopathic achalasia and gastro-oesophageal reflux disease. Gut
2003; 52: 629–36.
Conflicts of interest 26 Ruiz-de-Leon A, Mendoza J, Sevilla-Mantilla C, et al. Myenteric
We declare that we have no conflicts of interest. antiplexus antibodies and class II HLA in achalasia. Dig Dis Sci
2002; 47: 15–19.
References
1 Vantrappen G, Hellemans J, Deloof W, et al. Treatment of achalasia 27 Castagliuolo I, Brun P, Costantini M, et al. Esophageal achalasia: is
with pneumatic dilatations. Gut 1971; 12: 268–75. the herpes simplex virus really innocent? J Gastrointest Surg 2004;
8: 24–30.
2 Richter JE, Boeckxstaens GE. Management of achalasia: surgery or
pneumatic dilation. Gut 2011; 60: 869–76. 28 Facco M, Brun P, Baesso I, et al. T cells in the myenteric plexus of
achalasia patients show a skewed TCR repertoire and react to HSV-1
3 Willis T. Pharmaceutice Rationalis Sive Diatribe de
antigens. Am J Gastroenterol 2008; 103: 1598–609.
Medicamentorum Operationibus in Human Corpore. London,
England: Hagae Comitis, 1674. 29 Boeckxstaens GE. Achalasia: virus-induced euthanasia of neurons?
Am J Gastroenterol 2008; 103: 1610–12.
4 Boeckxstaens GE. The lower oesophageal sphincter.
Neurogastroenterol Motil 2005; 17 (suppl 1): 13–21. 30 Birgisson S, Galinski MS, Goldblum JR, et al. Achalasia is not
associated with measles or known herpes and human papilloma
5 Kahrilas PJ, Kishk SM, Helm JF, Dodds WJ, Harig JM, Hogan WJ.
viruses. Dig Dis Sci 1997; 42: 300–06.
Comparison of pseudoachalasia and achalasia. Am J Med 1987;
82: 439–46. 31 Niwamoto H, Okamoto E, Fujimoto J, et al. Are human herpes
viruses or measles virus associated with esophageal achalasia?
6 Tracey JP, Traube M. Difficulties in the diagnosis of
Dig Dis Sci 1995; 40: 859–64.
pseudoachalasia. Am J Gastroenterol 1994; 89: 2014–18.
32 De la Concha EG, Fernandez-Arquero M, Mendoza JL, et al.
7 de Borst JM, Wagtmans MJ, Fockens P, et al. Pseudoachalasia
Contribution of HLA class II genes to susceptibility in achalasia.
caused by pancreatic carcinoma. Eur J Gastroenterol Hepatol 2003;
Tissue Antigens 1998; 52: 381–84.
15: 825–28.
33 Verne GN, Hahn AB, Pineau BC, et al. Association of HLA-DR
8 Herbella FA, Aquino JL, Stefani-Nakano S, et al. Treatment of
and -DQ alleles with idiopathic achalasia. Gastroenterology 1999;
achalasia: lessons learned with Chagas’ disease. Dis Esophagus 2008;
117: 26–31.
21: 461–67.
34 de la Concha EG, Fernandez-Arquero M, Conejero L, et al. Presence
9 Pinazo MJ, Canas E, Elizalde JI, et al. Diagnosis, management and
of a protective allele for achalasia on the central region of the major
treatment of chronic Chagas’ gastrointestinal disease in areas where
histocompatibility complex. Tissue Antigens 2000; 56: 149–53.
Trypanosoma cruzi infection is not endemic. Gastroenterol Hepatol
2010; 33: 191–200. 35 Paladini F, Cocco E, Cascino I, et al. Age-dependent association of
idiopathic achalasia with vasoactive intestinal peptide receptor 1
10 Meneghelli UG, Peria FM, Darezzo FM, et al. Clinical, radiographic,
gene. Neurogastroenterol Motil 2009; 21: 597–602.
and manometric evolution of esophageal involvement by Chagas’
disease. Dysphagia 2005; 20: 40–45. 36 Alahdab YO, Eren F, Giral A, et al. Preliminary evidence of an
association between the functional c-kit rs6554199 polymorphism
11 Hejazi RA, Zhang D, McCallum RW. Gastroparesis, pseudoachalasia
and achalasia in a Turkish population. Neurogastroenterol Motil 2012;
and impaired intestinal motility as paraneoplastic manifestations of
24: 27–30.
small cell lung cancer. Am J Med Sci 2009; 338: 69–71.
37 Nunez C, Garcia-Gonzalez MA, Santiago JL, et al. Association of
12 Gockel HR, Schumacher J, Gockel I, et al. Achalasia: will genetic
IL10 promoter polymorphisms with idiopathic achalasia.
studies provide insights? Hum Genet 2010; 128: 353–64.
Hum Immunol 2011; 72: 749–52.
13 Farrukh A, DeCaestecker J, Mayberry JF. An epidemiological study
38 de Leon AR, de la Serna JP, Santiago JL, et al. Association between
of achalasia among the south Asian population of Leicester,
idiopathic achalasia and IL23R gene. Neurogastroenterol Motil 2010;
1986–2005. Dysphagia 2008; 23: 161–64.
22: 734–38, e218.
14 Sadowski DC, Ackah F, Jiang B, et al. Achalasia: incidence,
39 Hulselmans M, Vanuytsel T, Degreef T, et al. Long-term outcome of
prevalence and survival. A population-based study.
pneumatic dilation in the treatment of achalasia.
Neurogastroenterol Motil 2010; 22: e256–61.
Clin Gastroenterol Hepatol 2010; 8: 30–35.
15 Birgisson S, Richter JE. Achalasia in Iceland, 1952–2002:
40 Eckardt VF, Stauf B, Bernhard G. Chest pain in achalasia: patient
an epidemiologic study. Dig Dis Sci 2007; 52: 1855–60.
characteristics and clinical course. Gastroenterology 1999; 116: 1300–04.
16 Gennaro N, Portale G, Gallo C, et al. Esophageal achalasia in the
41 Fisichella PM, Raz D, Palazzo F, et al. Clinical, radiological, and
Veneto region: epidemiology and treatment. Epidemiology and
manometric profile in 145 patients with untreated achalasia.
treatment of achalasia. J Gastrointest Surg 2011; 15: 423–28.
World J Surg 2008; 32: 1974–79.
17 Marlais M, Fishman JR, Fell JM, et al. UK incidence of achalasia:
42 Rohof WO, Salvador R, Annese V, et al. Outcomes of treatment for
an 11-year national epidemiological study. Arch Dis Child 2011;
achalasia depend on manometric subtype. Gastroenterology 2013;
96: 192–94.
144: 718–25.
18 Enestvedt BK, Williams JL, Sonnenberg A. Epidemiology and
43 Eckardt VF. Clinical presentations and complications of achalasia.
practice patterns of achalasia in a large multi-centre database.
Gastrointest Endosc Clin N Am 2001; 11: 281–92, vi.
Aliment Pharmacol Ther 2011; 33: 1209–14.
44 Eckardt VF, Kohne U, Junginger T, et al. Risk factors for diagnostic
19 Booy JD, Takata J, Tomlinson G, et al. The prevalence of
delay in achalasia. Dig Dis Sci 1997; 42: 580–85.
autoimmune disease in patients with esophageal achalasia.
Dis Esophagus 2012; 25: 209–13. 45 El-Takli I, O’Brien P, Paterson WG. Clinical diagnosis of achalasia:
how reliable is the barium x-ray? Can J Gastroenterol 2006;
20 Clark SB, Rice TW, Tubbs RR, et al. The nature of the myenteric
20: 335–37.
infiltrate in achalasia: an immunohistochemical analysis.
Am J Surg Pathol 2000; 24: 1153–58. 46 Howard PJ, Maher L, Pryde A, et al. Five year prospective study of
the incidence, clinical features, and diagnosis of achalasia in
21 Goldblum JR, Rice TW, Richter JE. Histopathologic features in
Edinburgh. Gut 1992; 33: 1011–15.
esophagomyotomy specimens from patients with achalasia.
Gastroenterology 1996; 111: 648–54. 47 Moonen AJ, Boeckxstaens GE. Management of achalasia.
Gastroenterol Clin N Am 2013; 42: 45–55.
22 Villanacci V, Annese V, Cuttitta A, et al. An immunohistochemical
study of the myenteric plexus in idiopathic achalasia. 48 Triadafilopoulos G, Boeckxstaens GE, Gullo R, et al. The Kagoshima
J Clin Gastroenterol 2010; 44: 407–10. consensus on esophageal achalasia. Dis Esophagus 2012; 25: 337–48.

www.thelancet.com Vol 383 January 4, 2014 91

 Seminar

49 Vaezi MF, Baker ME, Achkar E, et al. Timed barium oesophagram: 72 Johns Hopkins Medicine, Gastroenterology and Hepatology.
better predictor of long term success after pneumatic dilation in Swallowing disorders: therapy. http://www.hopkins-gi.org/GDL_
achalasia than symptom assessment. Gut 2002; 50: 765–70. Disease.aspx?GDL_Cat_ID=AF793A59-B736-42CB-9E1F-
50 de Oliveira JM, Birgisson S, Doinoff C, et al. Timed barium E79D2B9FC358&GDL_Disease_ID=0E11DE8C-7FB7-47AE-BC76-
swallow: a simple technique for evaluating esophageal emptying in 766AC830F7BA (accessed April 30, 2013).
patients with achalasia. AJR Am J Roentgenol 1997; 169: 473–79. 73 Kadakia SC, Wong RK. Graded pneumatic dilation using Rigiflex
51 Bredenoord AJ, Fox M, Kahrilas PJ, et al. Chicago classification achalasia dilators in patients with primary esophageal achalasia.
criteria of esophageal motility disorders defined in high resolution Am J Gastroenterol 1993; 88: 34–38.
esophageal pressure topography. Neurogastroenterol Motil 2012; 74 Eckardt VF, Aignherr C, Bernhard G. Predictors of outcome in
24 (suppl 1): 57–65. patients with achalasia treated by pneumatic dilation.
52 Kahrilas PJ. Esophageal motor disorders in terms of high-resolution Gastroenterology 1992; 103: 1732–38.
esophageal pressure topography: what has changed? 75 Rohof WO, Lei A, Boeckxstaens GE. Esophageal stasis on a timed
Am J Gastroenterol 2010; 105: 981–87. barium esophagogram predicts recurrent symptoms in patients
53 Pandolfino JE, Kwiatek MA, Nealis T, et al. Achalasia: a new with long-standing achalasia. Am J Gastroenterol 2013; 108: 49–55.
clinically relevant classification by high-resolution manometry. 76 Vela MF, Richter JE, Khandwala F, et al. The long-term efficacy of
Gastroenterology 2008; 135: 1526–33. pneumatic dilatation and Heller myotomy for the treatment of
54 Boeckxstaens G, Zaninotto G. Achalasia and esophago-gastric achalasia. Clin Gastroenterol Hepatol 2006; 4: 580–87.
junction outflow obstruction: focus on the subtypes. 77 Richter JE. Update on the management of achalasia: balloons,
Neurogastroenterol Motil 2012; 24 (suppl 1): 27–31. surgery and drugs. Expert Rev Gastroenterol Hepatol 2008; 2: 435–45.
55 Ghosh SK, Pandolfino JE, Rice J, et al. Impaired deglutitive EGJ 78 Zerbib F, Thetiot V, Richy F, et al. Repeated pneumatic dilations as
relaxation in clinical esophageal manometry: a quantitative analysis long-term maintenance therapy for esophageal achalasia.
of 400 patients and 75 controls. Am J Physiol Gastrointest Liver Physiol Am J Gastroenterol 2006; 101: 692–97.
2007; 293: G878–85. 79 Boeckxstaens GE, Annese V, des Varannes SB, et al. Pneumatic
56 Lin Z, Kahrilas PJ, Roman S, et al. Refining the criterion for an dilation versus laparoscopic Heller’s myotomy for idiopathic
abnormal integrated relaxation pressure in esophageal pressure achalasia. N Engl J Med 2011; 364: 1807–16.
topography based on the pattern of esophageal contractility using a 80 O’Connor JB, Singer ME, Imperiale TF, et al. The cost-effectiveness
classification and regression tree model. Neurogastroenterol Motil of treatment strategies for achalasia. Dig Dis Sci 2002; 47: 1516–25.
2012; 24: e356–63. 81 Karanicolas PJ, Smith SE, Inculet RI, et al. The cost of laparoscopic
57 Gelfond M, Rozen P, Gilat T. Isosorbide dinitrate and nifedipine myotomy versus pneumatic dilatation for esophageal achalasia.
treatment of achalasia: a clinical, manometric and radionuclide Surg Endosc 2007; 21: 1198–206.
evaluation. Gastroenterology 1982; 83: 963–69. 82 Guardino JM, Vela MF, Connor JT, et al. Pneumatic dilation for the
58 Bortolotti M, Labo G. Clinical and manometric effects of nifedipine in treatment of achalasia in untreated patients and patients with failed
patients with esophageal achalasia. Gastroenterology 1981; 80: 39–44. Heller myotomy. J Clin Gastroenterol 2004; 38: 855–60.
59 Traube M, Dubovik S, Lange RC, et al. The role of nifedipine 83 Katzka DA, Castell DO. Review article: an analysis of the efficacy,
therapy in achalasia: results of a randomized, double-blind, perforation rates and methods used in pneumatic dilation for
placebo-controlled study. Am J Gastroenterol 1989; 84: 1259–62. achalasia. Aliment Pharmacol Ther 2011; 34: 832–39.
60 Triadafilopoulos G, Aaronson M, Sackel S, et al. Medical treatment 84 Vanuytsel T, Lerut T, Coosemans W, et al. Conservative management
of esophageal achalasia. Double-blind crossover study with oral of esophageal perforations during pneumatic dilation for idiopathic
nifedipine, verapamil, and placebo. Dig Dis Sci 1991; 36: 260–67. esophageal achalasia. Clin Gastroenterol Hepatol 2012; 10: 142–49.
61 Wen ZH, Gardener E, Wang YP. Nitrates for achalasia. 85 Metman EH, Lagasse JP, d’Alteroche L, et al. Risk factors for
Cochrane Database Syst Rev 2004; 1: CD002299. immediate complications after progressive pneumatic dilation for
62 Richter JE. Achalasia—an update. J Neurogastroenterol Motil 2010; achalasia. Am J Gastroenterol 1999; 94: 1179–85.
16: 232–42. 86 Heller E. Extramukose kardioplastik beim chronischen kardiospasm
63 Pasricha PJ, Ravich WJ, Hendrix TR, et al. Intrasphincteric mit dilatation des oesophagus. Mitt Greenzgeb Med Chir 1913;
botulinum toxin for the treatment of achalasia. N Engl J Med 1995; 27: 141–48.
332: 774–78. 87 Zaaijer JH. Cardiospasm in the aged. Ann Surg 1923; 77: 615–17.
64 Annese V, Bassotti G, Coccia G, et al. A multicentre randomised 88 Zaninotto G, Costantini M. Laparoscopic esophageal myotomy:
study of intrasphincteric botulinum toxin in patients with techniques and results. In: Yeo CJ, ed. Shackelfords surgery of the
oesophageal achalasia. GISMAD Achalasia Study Group. Gut 2000; alimentary tract. Philadelphia: Elsevier-Saunders, 2013: 354–61.
46: 597–600. 89 Inoue H, Minami H, Kobayashi Y, et al. Peroral endoscopic myotomy
65 Leyden JE, Moss AC, MacMathuna P. Endoscopic pneumatic (POEM) for esophageal achalasia. Endoscopy 2010; 42: 265–71.
dilation versus botulinum toxin injection in the management of 90 Dor J, Humbert P, Paoli JM, et al. Treatment of reflux by the so-called
primary achalasia. Cochrane Database Syst Rev 2006; 4: CD005046. modified Heller-Nissen technic. Presse Med 1967; 75: 2563–65.
66 Muehldorfer SM, Schneider TH, Hochberger J, et al. Esophageal 91 Pellegrini C, Wetter LA, Patti M, et al. Thoracoscopic
achalasia: intrasphincteric injection of botulinum toxin A versus esophagomyotomy. Initial experience with a new approach for
balloon dilation. Endoscopy 1999; 31: 517–21. the treatment of achalasia. Ann Surg 1992; 216: 291–96;
67 Vaezi MF, Richter JE, Wilcox CM, et al. Botulinum toxin versus discussion 296–99.
pneumatic dilatation in the treatment of achalasia: a randomised 92 Campos GM, Vittinghoff E, Rabl C, et al. Endoscopic and surgical
trial. Gut 1999; 44: 231–39. treatments for achalasia: a systematic review and meta-analysis.
68 Ghoshal UC, Chaudhuri S, Pal BB, et al. Randomized controlled Ann Surg 2009; 249: 45–57.
trial of intrasphincteric botulinum toxin A injection versus balloon 93 Richards WO, Torquati A, Holzman MD, et al. Heller myotomy
dilatation in treatment of achalasia cardia. Dis Esophagus 2001; versus Heller myotomy with Dor fundoplication for achalasia:
14: 227–31. a prospective randomized double-blind clinical trial. Ann Surg 2004;
69 Mikaeli J, Fazel A, Montazeri G, et al. Randomized controlled trial 240: 405–12; discussion 12–15.
comparing botulinum toxin injection to pneumatic dilatation for 94 Rebecchi F, Giaccone C, Farinella E, et al. Randomized controlled
the treatment of achalasia. Aliment Pharmacol Ther 2001; trial of laparoscopic Heller myotomy plus Dor fundoplication
15: 1389–96. versus Nissen fundoplication for achalasia: long-term results.
70 Zhu Q, Liu J, Yang C. Clinical study on combined therapy of Ann Surg 2008; 248: 1023–30.
botulinum toxin injection and small balloon dilation in patients 95 Rawlings A, Soper NJ, Oelschlager B, et al. Laparoscopic Dor versus
with esophageal achalasia. Dig Surg 2009; 26: 493–98. Toupet fundoplication following Heller myotomy for achalasia:
71 Zaninotto G, Annese V, Costantini M, et al. Randomized controlled results of a multicenter, prospective, randomized-controlled trial.
trial of botulinum toxin versus laparoscopic heller myotomy for Surg Endosc 2012; 26: 18–26.
esophageal achalasia. Ann Surg 2004; 239: 364–70.

92 www.thelancet.com Vol 383 January 4, 2014

 Seminar

96 Oelschlager BK, Chang L, Pellegrini CA. Improved outcome after 120 Ghoshal UC, Kumar S, Saraswat VA, et al. Long-term follow-up after
extended gastric myotomy for achalasia. Arch Surg 2003; pneumatic dilation for achalasia cardia: factors associated with
138: 490–95; discussion 495–97. treatment failure and recurrence. Am J Gastroenterol 2004;
97 Perrone JM, Frisella MM, Desai KM, et al. Results of laparoscopic 99: 2304–10.
Heller-Toupet operation for achalasia. Surg Endosc 2004; 121 Ghoshal UC, Rangan M. A review of factors predicting outcome of
18: 1565–71. pneumatic dilation in patients with achalasia cardia.
98 Rossetti G, Brusciano L, Amato G, et al. A total fundoplication is J Neurogastroenterol Motil 2011; 17: 9–13.
not an obstacle to esophageal emptying after Heller myotomy for 122 Chino O, Kijima H, Shimada H, et al. Clinicopathological studies of
achalasia: results of a long-term follow up. Ann Surg 2005; esophageal carcinoma in achalasia: analyses of carcinogenesis
241: 614–21. using histological and immunohistochemical procedures.
99 Torquati A, Richards WO, Holzman MD, et al. Laparoscopic Anticancer Res 2000; 20: 3717–22.
myotomy for achalasia: predictors of successful outcome after 123 Just-Viera JO, Haight C. Achalasia and carcinoma of the esophagus.
200 cases. Ann Surg 2006; 243: 587–91; discussion 91–93. Surg Gynecol Obstet 1969; 128: 1081–95.
100 Schuchert MJ, Luketich JD, Landreneau RJ, et al. Minimally-invasive 124 Meijssen MA, Tilanus HW, van Blankenstein M, et al. Achalasia
esophagomyotomy in 200 consecutive patients: factors influencing complicated by oesophageal squamous cell carcinoma: a prospective
postoperative outcomes. Ann Thorac Surg 2008; 85: 1729–34. study in 195 patients. Gut 1992; 33: 155–58.
101 Zaninotto G, Costantini M, Rizzetto C, et al. Four hundred 125 Streitz JM Jr, Ellis FH Jr, Gibb SP, et al. Achalasia and squamous
laparoscopic myotomies for esophageal achalasia: a single centre cell carcinoma of the esophagus: analysis of 241 patients.
experience. Ann Surg 2008; 248: 986–93. Ann Thorac Surg 1995; 59: 1604–09.
102 Snyder CW, Burton RC, Brown LE, et al. Multiple preoperative 126 Wychulis AR, Woolam GL, Andersen HA, et al. Achalasia and
endoscopic interventions are associated with worse outcomes after carcinoma of the esophagus. JAMA 1971; 215: 1638–41.
laparoscopic Heller myotomy for achalasia. J Gastrointest Surg 2009; 127 Dunaway PM, Wong RK. Risk and surveillance intervals for
13: 2095–103. squamous cell carcinoma in achalasia. Gastrointest Endosc Clin N Am
103 Finley CJ, Kondra J, Clifton J, et al. Factors associated with 2001; 11: 425–34, ix.
postoperative symptoms after laparoscopic Heller myotomy. 128 Zaninotto G, Rizzetto C, Zambon P, et al. Long-term outcome and
Ann Thorac Surg 2010; 89: 392–96. risk of oesophageal cancer after surgery for achalasia. Br J Surg
104 Rosemurgy AS, Morton CA, Rosas M, et al. A single institution’s 2008; 95: 1488–94.
experience with more than 500 laparoscopic Heller myotomies for 129 Leeuwenburgh I, Scholten P, Alderliesten J, et al. Long-term
achalasia. J Am Coll Surg 2010; 210: 637–45, 645–47. esophageal cancer risk in patients with primary achalasia:
105 Carter JT, Nguyen D, Roll GR, et al. Predictors of long-term a prospective study. Am J Gastroenterol 2010; 105: 2144–49.
outcome after laparoscopic esophagomyotomy and Dor 130 Lehman MB, Clark SB, Ormsby AH, et al. Squamous mucosal
fundoplication for achalasia. Arch Surg 2011; 146: 1024–28. alterations in esophagectomy specimens from patients with
106 Costantini M, Zaninotto G, Guirroli E, et al. The laparoscopic Heller- end-stage achalasia. Am J Surg Pathol 2001; 25: 1413–18.
Dor operation remains an effective treatment for esophageal achalasia 131 Hirota WK, Zuckerman MJ, Adler DG, et al. ASGE guideline: the
at a minimum 6-year follow-up. Surg Endosc 2005; 19: 345–51. role of endoscopy in the surveillance of premalignant conditions of
107 Chen Z, Bessell JR, Chew A, et al. Laparoscopic cardiomyotomy for the upper GI tract. Gastrointest Endosc 2006; 63: 570–80.
achalasia: clinical outcomes beyond 5 years. J Gastrointest Surg 2010; 132 Boller D, Spieler P, Schoenegg R, et al. Lugol chromoendoscopy
14: 594–600. combined with brush cytology in patients at risk for esophageal
108 Salvador R, Costantini M, Zaninotto G, et al. The preoperative squamous cell carcinoma. Surg Endosc 2009; 23: 2748–54.
manometric pattern predicts the outcome of surgical treatment for 133 Rohof WO, Bergman J, Bartelsman JF, et al. Screening for dysplasia
esophageal achalasia. J Gastrointest Surg 2010; 14: 1635–45. in idiopathic achalasia using Lugol staining. Gastroenterology 2011;
109 Portale G, Costantini M, Rizzetto C, et al. Long-term outcome of 140: S227.
laparoscopic Heller-Dor surgery for esophageal achalasia: possible 134 Zendehdel K, Nyren O, Edberg A, et al. Risk of esophageal
detrimental role of previous endoscopic treatment. adenocarcinoma in achalasia patients, a retrospective cohort study
J Gastrointest Surg 2005; 9: 1332–39. in Sweden. Am J Gastroenterol 2011; 106: 57–61.
110 Zaninotto G, Costantini M, Portale G, et al. Etiology, diagnosis, and 135 Leeuwenburgh I, Gerrits MM, Capello A, et al. Expression of p53
treatment of failures after laparoscopic Heller myotomy for as predictor for the development of esophageal cancer in achalasia
achalasia. Ann Surg 2002; 235: 186–92. patients. Dis Esophagus 2010; 23: 506–11.
111 Lopushinsky SR, Urbach DR. Pneumatic dilatation and surgical 136 Vela MF, Richter JE, Wachsberger D, et al. Complexities of
myotomy for achalasia. JAMA 2006; 296: 2227–33. managing achalasia at a tertiary referral center: use of pneumatic
112 von Renteln D, Inoue H, Minami H, et al. Peroral endoscopic dilatation, Heller myotomy, and botulinum toxin injection.
myotomy for the treatment of achalasia: a prospective single center Am J Gastroenterol 2004; 99: 1029–36.
study. Am J Gastroenterol 2012; 107: 411–17. 137 Rohof WO, Hirsch DP, Kessing BF, et al. Efficacy of treatment for
113 Swanstrom LL, Kurian A, Dunst CM, et al. Long-term outcomes of patients with achalasia depends on the distensibility of the
an endoscopic myotomy for achalasia: the POEM procedure. esophagogastric junction. Gastroenterology 2012; 143: 328–35.
Ann Surg 2012; 256: 659–67. 138 Kwiatek MA, Pandolfino JE, Hirano I, et al. Esophagogastric junction
114 Costamagna G, Marchese M, Familiari P, et al. Peroral endoscopic distensibility assessed with an endoscopic functional luminal
myotomy (POEM) for oesophageal achalasia: preliminary results in imaging probe (EndoFLIP). Gastrointest Endosc 2010; 72: 272–78.
humans. Dig Liver Dis 2012; 44: 827–32. 139 Savarino E, Gemignani L, Zentilin P, et al. Achalasia with dense
115 Chiu PW, Wu JC, Teoh AY, et al. Peroral endoscopic myotomy for eosinophilic infiltrate responds to steroid therapy.
treatment of achalasia: from bench to bedside (with video). Clin Gastroenterol Hepatol 2011; 9: 1104–06.
Gastrointest Endosc 2013; 77: 29–38. 140 Shaker A, Rubin DC. Stem cells: one step closer to gut repair.
116 Hungness ES, Teitelbaum EN, Santos BF, et al. Comparison of Nature 2012; 485: 181–82.
perioperative outcomes between peroral esophageal myotomy 141 Metzger M, Caldwell C, Barlow AJ, et al. Enteric nervous system
(POEM) and laparoscopic Heller myotomy. J Gastrointest Surg 2013; stem cells derived from human gut mucosa for the treatment of
17: 228–35. aganglionic gut disorders. Gastroenterology 2009; 136: 2214–25.
117 Duranceau A, Liberman M, Martin J, et al. End-stage achalasia. 142 Sasselli V, Micci MA, Kahrig KM, et al. Evaluation of ES-derived
Dis Esophagus 2012; 25: 319–30. neural progenitors as a potential source for cell replacement
118 Eldaif SM, Mutrie CJ, Rutledge WC, et al. The risk of esophageal therapy in the gut. BMC Gastroenterol 2012; 12: 81.
resection after esophagomyotomy for achalasia. Ann Thorac Surg 143 Kulkarni S, Zou B, Hanson J, et al. Gut-derived factors promote
2009; 87: 1558–62; discussion 62–63. neurogenesis of CNS-neural stem cells and nudge their
119 Molena D, Yang SC. Surgical management of end-stage achalasia. differentiation to an enteric-like neuronal phenotype.
Semin Thorac Cardiovasc Surg 2012; 24: 19–26. Am J Physiol Gastrointest Liver Physiol 2011; 301: G644–55.

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