Achalasia

Clinical Review & Education
Review
Achalasia
A Systematic Review
John E. Pandolfino, MD, MSCI; Andrew J. Gawron, MD, PhD, MS
IMPORTANCE Achalasia significantly affects patients quality of life and can be difficult to
Author Audio Interview at

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diagnose and treat.
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OBJECTIVE To review the diagnosis and management of achalasia, with a focus on phenotypic
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classification pertinent to therapeutic outcomes.

EVIDENCE REVIEW Literature review and MEDLINE search of articles from January 2004 to
February 2015. A total of 93 articles were included in the final literature review addressing
facets of achalasia epidemiology, pathophysiology, diagnosis, treatment, and outcomes. Nine
randomized controlled trials focusing on endoscopic or surgical therapy for achalasia were
included (734 total patients).
FINDINGS A diagnosis of achalasia should be considered when patients present with
dysphagia, chest pain, and refractory reflux symptoms after an endoscopy does not reveal a
mechanical obstruction or an inflammatory cause of esophageal symptoms. Manometry
should be performed if achalasia is suspected. Randomized controlled trials support
treatments focused on disrupting the lower esophageal sphincter with pneumatic dilation
(70%-90% effective) or laparoscopic myotomy (88%-95% effective). Patients with achalasia
have a variable prognosis after endoscopic or surgical myotomy based on subtypes, with type
II (absent peristalsis with abnormal pan-esophageal high-pressure patterns) having a very
favorable outcome (96%) and type I (absent peristalsis without abnormal pressure) having an
intermediate prognosis (81%) that is inversely associated with the degree of esophageal
dilatation. In contrast, type III (absent peristalsis with distal esophageal spastic contractions)
is a spastic variant with less favorable outcomes (66%) after treatment of the lower
esophageal sphincter.
CONCLUSIONS AND RELEVANCE Achalasia should be considered when dysphagia is present
and not explained by an obstruction or inflammatory process. Responses to treatment vary
based on which achalasia subtype is present.
JAMA. 2015;313(18):1841-1852. doi:10.1001/jama.2015.2996
he constellation of dysphagia (difficulty swallowing), chest

pain, and reflux symptoms may be caused by a variety of
diseases of the esophagus such as gastroesophageal reflux disease, malignancy, mechanical obstruction (strictures, rings,
or diverticula), and achalasia and other motility disorders.
Achalasia is derived from the Greek khalasis, translated as not
loosening or relaxing. A common historical definition of achalasia
is the inability of the lower esophageal sphincter to relax in the setting of absent peristalsis. An initial trial of acid suppression (6-8
weeks) is reasonable, but when dysphagia symptoms persist or are
dominated by the report of dysphagia, endoscopy should be performed to evaluate for mechanical obstruction or inflammatory processes. When these are not found, achalasia should be considered,
especially in the setting of dysphagia primarily to liquids. Liquids can
pool and accumulate above a tight, unrelaxing lower esophageal
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Author Affiliations: Division of

Gastroenterology and Hepatology,
Feinberg School of Medicine,
Northwestern University, Chicago,
Illinois (Pandolfino); Division of
Gastroenterology, Hepatology, and
Nutrition, University of Utah, Salt
Lake City (Gawron).
Corresponding Author: John E.
Pandolfino, MD, MSCI, Division of
Gastroenterology and Hepatology,
Department of Medicine, Feinberg
School of Medicine, Northwestern
University, 676 N St Clair St, Ste 1409,
Chicago, IL 60611 (j-pandolfino
@northwestern.edu).
Section Editor: Mary McGrae
McDermott, MD, Senior Editor.
sphincter, whereas they are usually less of an issue in the setting of

structural causes of dysphagia.
Recent advances in diagnostic testing for achalasia, especially
high-resolution esophageal manometry, have provided new insights into the pathogenesis and clinical manifestation of this disorder. The purpose of this review is to highlight the epidemiology,
pathogenesis, and clinical approach to patients with achalasia, emphasizing published evidence pertinent to both primary care clinicians and specialist physicians.
Evidence Acquisition and Synthesis

The literature was reviewed based on an initial broad MEDLINE
search using the terms ((((esophageal motility) OR achalasia) OR high
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Clinical Review & Education Review
Achalasia
Figure 1. Anatomy and Innervation of the Esophagus

A Anatomy of the esophagus
and relationship to adjacent structures
Cricoid
cartilage
Upper
esophageal
sphincter
(UES)
Esophageal wall
Myenteric plexus ganglion
with postganglionic neurons
Longitudinal
muscle (reflected)
Striated
muscle
Myenteric plexus
Circular
muscle
Transition zone
Esophageal plexus
Adventitia
Esophagus
Smooth
muscle
Diaphragm
(cut)
Lower
esophageal
sphincter
(LES)
Muscularis
propria
Esophagogastric junction
Submucosal
plexus
Stomach
ESOPHAGUS
Stratified
squamous
epithelium
Level
of section
Circular
muscle
Submucosa
Muscularis
mucosa
Mucosa
Lumen
Longitudinal
muscle
Crural
diaphragm
Esophagogastric
junction
LES
Crural diaphragm
Proximal gastric cardia
LES
STOMACH
resolution manometry) OR Chicago classification) OR esophageal

peristalsis. Articles published from January 2004 to February 2015
in English were included.
This search yielded 6194 references, of which 5788 were in
English. Case reports (n = 521) and review articles (n = 899) were
excluded. Articles were further searched using terms specific for epidemiology, genetics, diagnosis, manometry, surgery, pneumatic dilation, botulinum toxin, and per-oral endoscopic myotomy. Other
pertinent articles and guidelines were obtained through citations or
were known to the authors. We reviewed titles and abstracts to determine relevance to the article sections and ultimately included 93
articles in the review (n = 4276 excluded). A total of 9 randomized
controlled trials were included when evaluating endoscopic and surgical treatment modalities (comprising 734 total patients). Details
are shown in the eFigure in the Supplement.
Structure and Normal Function of the Esophagus

The esophagus is an 18- to 26-cm muscular hollow tube that
transports food from the oropharynx into the stomach (Figure 1).
There are 4 primary layers of esophageal tissuethe mucosa, sub1842
mucosa, muscularis propria, and adventitia. The esophagus originates at the level of the cricoid cartilage and normally terminates
below the hiatus in the right crura of the diaphragm. The muscularis propria gradually changes from predominant skeletal muscle
in the upper esophagus to predominantly smooth muscle in the
distal esophagus, with mixing of muscle types along the length of
the esophagus (Figure 1). Both circular and longitudinal muscle
layers are present, and within the diaphragmatic hiatus there
exists a 2- to 4-cm thickened circular muscle layer, the lower
esophageal sphincter. Esophageal innervation consists of both
parasympathetic and sympathetic nerves, with peristalsis regulated via the parasympathetic pathway from the vagus nerve and
the intrinsic enteric nervous system.
Despite the seemingly simple task of food transport, the mechanism and control of esophageal function is complex, largely owing
to the neural coordination required with the oropharynx and transition through different anatomical domains with mixed muscle
types. Once a food or liquid bolus enters the esophagus, primary peristalsis strips the food bolus down the length of the esophagus. Peristaltic contraction in the striated muscle esophagus is dependent
on central mechanisms that involve sequential activation of excitatory activity of lower motor neurons in the vagal nucleus am-
JAMA May 12, 2015 Volume 313, Number 18 (Reprinted)
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Achalasia
Review Clinical Review & Education
Figure 3. Conceptual Model of Esophageal Disease Presentation and Progression Based on Phenotypes Described Using High-Resolution Manometry
and Barium Esophagrams
A EGJ outflow obstruction
B Type II achalasia
Impaired LES relaxation

Normal or impaired peristalsis
C Type I achalasia

Absent peristalsis
Increased pan-esophageal
pressure
D Type III achalasia

Absent peristalsis
Normal esophageal pressure

Absent peristalsis
Distal esophageal spastic
contractions
Birds
beak
Smooth muscle innervation

Postganglionic excitatory neuron
Postganglionic inhibitory neuron
10 s
5s
30
5s
Color pressure scale, mm Hg

60
90
120
150
180
10 s
Some patients may present with an esophagogastric junction (EGJ) outflow

obstruction pattern (panel A) in which there is impaired lower esophageal
sphincter (LES) relaxation with evidence of propagating contractions. This may
represent the point where the esophageal body is progressing to aperistalsis
and there is variable loss of the excitatory (blue circles) and inhibitory (red
circles) influence. As preferential loss of the inhibitory neurons continues to
progress, the manometric pattern may progress to a type II pattern (panel B)
associated with impaired LES relaxation and panesophageal pressurization, akin
to a filled water balloon being squeezed.42 Type I achalasia (panel C) is the
classic presentation of achalasia, in which there is complete loss of contractile
activity in the body of the esophagus; this is typically a later phase of disease
progression where there is evidence of moderate to severe esophageal

dilatation. Type III achalasia (panel D) is associated with premature
simultaneous contractions that compartmentalize the bolus before it can empty
the esophagus, as evidenced by the corkscrew appearance on esophagram. This
may represent a distinct entity that does not fall into the typical presentation of
progressive neuron loss seen with the progression of EGJ outlet obstruction to
type II achalasia, to type I achalasia. Corresponding barium esophagrams are
also shown for each subtype. Barium esophagrams and esophageal pressure
topography plots reproduced with permission from the Esophageal Center at
Northwestern Medicine.
zyme that degrades cyclic guanosine monophosphate induced by

nitric oxide. Sildenafil is a viable alternative in patients not responding to or proving intolerant of calcium channel blockers or nitrates.
However, minimal long-term treatment data exist pertinent to using
5-phosphodiesterase inhibitors to treat achalasia.
within 12 months, and repeated treatments have been shown to

make subsequent Heller myotomy more challenging. 68 Thus,
botulinum toxin injection should rarely be used as a first-line
therapy for achalasia and is primarily reserved for patients who
are not candidates for definitive therapy.
Botulinum Toxin
Pneumatic Dilation
Botulinum toxin injection into the muscle of the lower esophageal

sphincter was initially proposed as an achalasia treatment based
on its ability to block acetylcholine release from nerve endings.
Using this technique, Pasricha et al54 reported improved dysphagia in 66% of patients with achalasia for 6 months. No increase in
efficacy has been demonstrated with greater doses.65 The effect
is temporary and is eventually reversed by axonal regeneration;
subsequent clinical series report minimal continued efficacy after
1 year.54,65-67 Most patients relapse and require re-treatment
A pneumatic dilator is a noncompliant, cylindrical balloon that is positioned fluoroscopically across the lower esophageal sphincter and
inflated with air using a handheld manometer. The reported efficacy of pneumatic dilation in randomized controlled trials ranges
from 62% to 90% (Table 3). Patients with a poor result or rapid recurrence of dysphagia are unlikely to respond to additional dilations, but subsequent response to myotomy is not influenced. Although the reported incidence of perforation from pneumatic
dilation ranges from 0% to 16%, a recent systematic review on the
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Achalasia
Box. Symptoms Suggestive of Achalasia That May Prompt

Referral for Esophageal Motility Testinga
Esophageal Symptoms
Dysphagia (90% of patients)

Heartburn (75% of patients)
Regurgitation or vomiting (45% of patients)
Noncardiac chest pain (20% of patients)
Epigastric pain (15% of patients)
Odynophagia (<5% of patients)
Other Associated Signs and Symptoms
Cough or asthma (20%-40% of patients)

Chronic aspiration (20%-30% of patients)
Hoarseness or sore throat (33% of patients)
Unintentional weight loss (10% of patients)
a
Data from Tsuboi et al,33 Sinan et al,34 and Ng et al.35
motor nucleus that causes contraction above the distention and relaxation below the distention via the intrinsic inhibitory and excitatory myenteric neurons.
Regional differences in the density of the inhibitory and excitatory neurons in the enteric nervous system determine the direction and vigor of the contraction, and this may be modulated by variable smooth muscle response to the same quantum of
neurotransmitter.4-6 The pathogenesis of achalasia can be conceptualized as a disruption of the balance between the regional excitatory and inhibitory response elicited along the axial location of the
esophageal body.4,7
Although most research on peristalsis has focused on the circular muscle, the longitudinal outer layer plays an important role.
Esophageal shortening occurs as a response to longitudinal contraction and is mediated by sequential cholinergic activation of the
muscle. The activation overlaps with the propagating circular muscle
to provide mechanical advantages to bolus transit and a lack of coordination of these effects, and exaggerated longitudinal contractions may be important in esophageal dysmotility and generation
of symptoms.8,9
Ultimately, the progressing peristaltic waves must advance the
food bolus into the stomach across the esophagogastric junction.
This junction is a high-pressure zone comprising the lower esophageal sphincter, the crural diaphragm, and proximal gastric cardia.
Normal resting lower esophageal sphincter tone is 10 to 30 mm Hg,
which helps prevent reflux of gastric contents back into the esophagus. Relaxation of the lower esophageal sphincter to allow emptying of the esophagus is triggered by swallowing or esophageal distention mediated by both peripheral and central mechanisms.
Relaxation of the sphincter is related to a number of nonadrenergic
noncholinergic neurotransmitters, the most prominent being nitric oxide.
Epidemiology and Genetics of Achalasia

Achalasia has an annual reported incidence of approximately
1/100 000 worldwide.10-13 In Iceland, 62 cases of achalasia were di1844
agnosed over the course of 51 years (overall incidence, 0.6/100 000

per year; mean prevalence, 8.7 cases /100 000).11 Gennaro et al14
recently reported an incident rate in Italy of 1.59 cases/100 000 per
year (2001-2005). Due to the chronicity of achalasia, the estimated prevalence of achalasia is approximately 9/100 000 to
10/100 000.11,12 In the United States, rates of hospitalization for
achalasia depend on patient age, ranging from 0.25/100 000
(<18 years) to a high of 37/100 000 (>85 years).15 Although the incidence is low, the chronicity of achalasia significantly affects patients health-related quality of life, work productivity, and functional status compared with the general US population.16
Evidence supporting genetic underpinnings for achalasia come
from twin and sibling studies and from the association of achalasia
with other diseases such as Parkinson disease, Allgrove syndrome,
and Down syndrome.17-19 Familial adrenal insufficiency with alacrima and achalasia (Allgrove syndrome) is a rare genetic syndrome
associated with defects in the AAAS gene (chromosome 12q13) and
subsequent defective tryptophanaspartic acid repeat protein.20,21
A few reports have described familial achalasia, most recently in a
single family with an autosomal dominant pattern with 6 affected
members.22 Polymorphisms in the nitric oxide synthase gene have
been investigated, but polymorphisms were found to be no different between patients with achalasia and controls.23 Because of a
possible autoimmune etiology of achalasia, studies have suggested
possible roles of interleukin polymorphisms (IL-23 and IL-10).24,25
Currently, genetic testing for achalasia has no role in clinical management outside of research endeavors.
Pathophysiology
Achalasia is associated with functional loss of myenteric plexus
ganglion cells in the distal esophagus and lower esophageal
sphincter.26 The cause for an initial reduction of inhibitory neurons in achalasia is unknown. Initiation of neuronal degeneration
may be an autoimmune process triggered by an indolent viral
infection (herpes, measles) in conjunction with a genetically susceptible host.27 Patients with achalasia are more likely to have
concomitant autoimmune diseases than the general population28
and the prevalence of serum neural autoantibodies is higher,29
lending further credence to an autoimmune etiology. The inflammatory reaction is associated with a T-cell lymphocyte infiltrate
that leads to a slow destruction of ganglion cells. The distribution
and end result of this plexitis is variable and may be modified by
the host response or the etiologic stimulus. Achalasia can also be
one manifestation of the widespread myenteric plexus destruction in Chagas disease, a consequence of infection with the parasite Trypanosoma cruzi.30
The consequence of the myenteric plexus inflammation is
degeneration or dysfunction of inhibitory postganglionic neurons
in the distal esophagus, including the lower esophageal
sphincter. 31,32 These neurons use nitric oxide and vasoactive
intestinal peptide as neurotransmitters, and their dysfunction
results in an imbalance between excitatory and inhibitory control
of the sphincter and adjacent esophagus. Unopposed cholinergic
stimulation can result in impaired relaxation of the lower esophageal sphincter, hypercontractility of the distal esophagus, and
rapidly propagated contractions in the distal esophagus. Longitu-
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Achalasia
dinal muscle contractions and esophageal shortening can persist

in achalasia. There is variable expression of these abnormalities
among individuals, and only impaired deglutitive relaxation of the
lower esophageal sphincter is universally required as a defining
feature of achalasia.
Table 1. Differential Diagnosis of Dysphagia Symptoms and Initial Testing

Signs and Symptoms
Testing
Esophageal Dysphagia
Structural esophageal disorders
Symptoms and Signs

The most common symptoms of achalasia are listed in the Box3-35
and may prompt referral for a motility evaluation after more common disorders are ruled out, such as gastroesophageal reflux disease, mechanical obstruction (stricture, rings), or malignancy. Progressive dysphagia to both solids and liquids is the hallmark
symptom associated with a diagnosis of achalasia. The prevalence
of weekly dysphagia among US adults is approximately 4%36 and is
associated with a broad differential diagnosis and workup (Table 1).
Esophageal motility testing should only be done after a structural
or mechanical obstruction has been ruled out and oropharyngeal
causes are not apparent. In a single-center review of all patients
with manometry over a period of 24 years (1984-2008), Tsuboi et
al33 found that patients with achalasia most commonly presented
with dysphagia and heartburn. Other common symptoms included
chest pain, regurgitation, cough or asthma, odynophagia, and epigastric pain.33
Respiratory symptoms are also common in patients with achalasia, because primary motor abnormalities result in decreased
clearance of food and liquid from the esophagus, predisposing
patients to aspiration. Sinan et al34 found that of 110 patients with
achalasia, 40% reported at least 1 respiratory symptom daily.
Another study of 38 patients with achalasia found that 71% had
sore throat, hoarseness, or postnasal drip and 61% had cough.37 In
addition, 17 patients (45%) had abnormal spirometry findings and
12 had abnormal imaging findings such as septal thickening and
necrotizing pneumonia.37 The dysphagia preceded respiratory
symptoms by an average of 24 months, indicating the progressive
nature of symptoms with lack of treatment.37 It is also important to
consider a diagnosis of connective tissue disease (eg, scleroderma)
in patients with chronic respiratory issues and abnormalities of
esophageal motility.
Demographic and clinical factors may affect clinical symptoms. Dysphagia and regurgitation are common among all ages, but
younger patients with achalasia have been found to have a higher
prevalence of heartburn and chest pain than older patients.38 Obese
patients (body mass index 30) may have more frequent symptoms of choking and vomiting, possibly related to increased abdominal pressure.39 Chest pain was more commonly reported by women
than men in a single-center retrospective review of 213 patients with
achalasia.40 However, another group reported similar reports of
chest pain regardless of age or sex.41
Peptic stricture
Esophagogastroduodenoscopy,
barium esophagram
Esophageal (Schatzki) ring or webs
barium esophagram
Eosinophilic esophagitis
Esophagogastroduodenoscopy
Malignancy
barium esophagram
Radiation- or medication-induced
strictures
barium esophagram
Foreign body or food impaction
Vascular compression
Computed tomography, magnetic

resonance imaging, endoscopic
ultrasound
Mediastinal mass/external
compression

resonance imaging, endoscopic
ultrasound
Motility esophageal disorders

Achalasia and esophagogastric
junction outflow obstruction
High-resolution manometry,
barium esophagram
Absent contractility
High-resolution manometry
Distal esophageal spasm
Hypercontractile esophagus
(jackhammer)
Minor disorders of peristalsis
Scleroderma
Gastroesophageal reflux disease
high-resolution manometry, pH
testinga
Chagas disease
Barium esophagram, serology
Oropharyngeal Dysphagia
Structural oropharyngeal disorders
Malignancy
Laryngoscopy
Spinal osteophytes
Video fluoroscopy, computed

tomography
Zenker diverticulum
Video fluoroscopy,
esophagogastroduodenoscopy
Proximal strictures, rings, or webs
barium esophagram
Radiation injury
Video fluoroscopy,
esophagogastroduodenoscopy
Oropharynx infection
Laryngoscopy
Thyroid enlargement
Ultrasound, computed tomography
Neuromuscular (systemic) disorders

Cerebral vascular accident

resonance imaging
Multiple sclerosis
Parkinson disease
Myasthenia gravis
Amyotrophic lateral sclerosis
Muscular dystrophy
Focused neurologic examination,

disease-specific laboratory testing
and imaging
Dermatomyositis
Thyroid disorders
a
pH testing indicates ambulatory pH and reflux monitoring.
Diagnosis
Diagnosis of achalasia requires recognition of symptoms and
appropriate use and interpretation of diagnostic testing (Table 1).
Diagnoses can be difficult to make, and many patients have
symptoms for many years prior to correct diagnosis and treat-
ment. This is most common when patients present with symptoms that mimic gastroesophageal reflux disease, such as heartburn, chest pain, and regurgitation. In contrast, when patients
primarily present with dysphagia, a careful history and evaluation
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Achalasia
of swallowing by watching the patient drink water can be helpful

in distinguishing between oropharyngeal dysphagia and esophageal dysphagia. Patients with oropharyngeal dysphagia will typically struggle to move the bolus into the esophagus during
water swallows and will often have coughing and immediate
regurgitation. Primary oropharyngeal symptoms should first
prompt an evaluation for oropharyngeal etiologies, with a modified barium cookie swallow study performed by speech pathology
(Table 1).
Patients with intact oropharyngeal swallowing and dysphagia
should be evaluated for esophageal causes, and the differential
should focus on distinguishing between a structural mechanical
obstruction and a motility disorder (Table 1). Mechanical obstruction should be ruled out first, via either upper gastrointestinal tract
endoscopy or radiologic imaging, prior to evaluation for abnormal
motility. Patients with a previous fundoplication or bariatric procedure (lap-band, gastric bypass) may also present with signs and
symptoms that mimic achalasia, and it is extremely difficult to
make the diagnosis of achalasia in the context of these operations.
In these cases, it is important to look for mechanical causes of
obstruction, such as anastomotic stricture, tight lap-band, and an
obstructed fundoplication.
Esophagogastroduodenoscopy with mucosal biopsy should be performed in most patients presenting with solid food dysphagia, liquid food dysphagia, or both. This is done to rule out erosive gastroesophageal reflux disease, eosinophilic esophagitis, structural
lesions (strictures, webs, or rings), and esophageal cancer or pseudoachalasia. Endoscopic features of an esophageal motility disorder include a dilated or tortuous esophagus, food impactions and
fluid pooling in the esophagus, and resistance to intubation of the
gastroesophageal junction. Patients with achalasia may also
develop candidiasis attributable to esophageal stasis, and evidence
of candidiasis in the context of intact immune function should
prompt an evaluation for esophageal dysmotility. Although endoscopy may suggest achalasia, other testing must be performed to
confirm the diagnosis.
Barium Esophagram
The classic birds-beak appearance of achalasia on a barium swallow study is a well-known image in clinical medicine (Figure 3C).
Other radiographic features suggestive of an esophageal motility disorder include esophageal dilation, contrast filling the esophagus, a
corkscrew appearance, and aperistalsis.
Esophageal Manometry
Esophageal manometry to assess esophageal pressures and contractions along the length of a flexible catheter has become the
standard for diagnosing and classifying achalasia. Major technological advances have occurred during the last decade, wherein
conventional water-perfused or strain gauge systems with a line
tracing output have been replaced by more reproducible43 and
accurate 44 high-resolution manometry systems that present
pressure data in the context of esophageal pressure topography
plots (Figure 2 and Figure 3). These methods were originally
developed by Clouse and led to an improved understanding of
peristaltic contractile activity. Seminal work that characterized
1846
high-resolution manometry metrics using Clouse plots in both

asymptomatic and symptomatic individuals45-49 eventually led to
the creation of a new classification scheme for motility disorders,
called the Chicago Classification (Figure 4).50
One important advantage of esophageal pressure topography
has been the ability to further refine conventional diagnoses, such
as achalasia, into clinically relevant phenotypes. The diagnosis of
achalasia is classically made by demonstrating impaired relaxation
of the lower esophageal sphincter and absent peristalsis in the
absence of esophageal obstruction near the lower esophageal
sphincter attributable to a stricture, tumor, vascular structure,
implanted device, or infiltrating process.51 Three distinct subtypes
of achalasia (types I, II, and III) are defined with high-resolution
manometry that have both prognostic and potential therapeutic
implications (Figure 3).52 If criteria for achalasia subtypes are not
met, a validated hierarchical analysis is used to determine if
patients have nonachalasia motor disorders, as shown in
Figure 4.50 However, a possible diagnosis of achalasia should be
considered when patients present with an esophagogastric junction outflow obstruction, because this may represent an incomplete or early form of the disease. Similarly, it is also important to
consider achalasia in patients with absent contractility, as these
cases may be confused with scleroderma owing to the complexities
of measuring relaxation of the lower esophageal sphincter. Equivocal cases may require further workup with endoscopic ultrasound
in the case of EGJ outflow obstruction to rule out a subtle
obstruction53 and a barium esophagram in the case of absent contractility to document bolus retention, which would favor a diagnosis of achalasia.
Treatment
There are no curative therapies for achalasia; a summary of treatment modalities is listed in Table 2. Nine randomized trials have compared endoscopic and surgical treatments for achalasia (Table 3).
Physiologically, many treatments are directed at reducing contractility in the lower esophageal sphincter to allow for adequate esophageal emptying. The primary goal of management should be based
on early diagnosis to prevent late complications of the disease and
preserve remaining esophageal structure and function.
Medical Treatment
Oral calcium channel blockers or nitrates cause a prompt reduction
in lower esophageal sphincter pressure of up to 47% to 64%, with
mild benefit for dysphagia.63 These medications can have limiting
adverse effects (headache, orthostatic hypotension, or edema) and
do not halt disease progression. Consequently, they are poor longterm treatment options and should be reserved for patients who
are poor candidates for surgical or endoscopic therapy. Nifedipine
(10-30 mg, given 30-45 minutes before meals) or isorbide dinitrate
(5-10 mg, given 15 minutes before meals) may be useful as shortacting temporizing treatments. Absorption and effect of oral medications can be unpredictable in achalasia.
5-Phosphodiesterase inhibitors, such as sildenafil, have also
been used (off-label) to treat achalasia and spastic disorders of the
esophagus.64 Sildenafil lowers esophagogastric junction pressure
and attenuates distal esophageal contractions by blocking the en-
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Achalasia
Figure 3. Conceptual Model of Esophageal Disease Presentation and Progression Based on Phenotypes Described Using High-Resolution Manometry
and Barium Esophagrams
A EGJ outflow obstruction
B Type II achalasia

Normal or impaired peristalsis
C Type I achalasia

Absent peristalsis
Increased pan-esophageal
pressure
D Type III achalasia

Absent peristalsis
Normal esophageal pressure

Absent peristalsis
Distal esophageal spastic
contractions
Birds
beak
Smooth muscle innervation

Postganglionic excitatory neuron
Postganglionic inhibitory neuron
10 s
5s
30
5s
Color pressure scale, mm Hg

60
90
120
150
180
10 s
Some patients may present with an esophagogastric junction (EGJ) outflow

obstruction pattern (panel A) in which there is impaired lower esophageal
sphincter (LES) relaxation with evidence of propagating contractions. This may
represent the point where the esophageal body is progressing to aperistalsis
and there is variable loss of the excitatory (blue circles) and inhibitory (red
circles) influence. As preferential loss of the inhibitory neurons continues to
progress, the manometric pattern may progress to a type II pattern (panel B)
associated with impaired LES relaxation and panesophageal pressurization, akin
to a filled water balloon being squeezed.42 Type I achalasia (panel C) is the
classic presentation of achalasia, in which there is complete loss of contractile
activity in the body of the esophagus; this is typically a later phase of disease
progression where there is evidence of moderate to severe esophageal

dilatation. Type III achalasia (panel D) is associated with premature
simultaneous contractions that compartmentalize the bolus before it can empty
the esophagus, as evidenced by the corkscrew appearance on esophagram. This
may represent a distinct entity that does not fall into the typical presentation of
progressive neuron loss seen with the progression of EGJ outlet obstruction to
type II achalasia, to type I achalasia. Corresponding barium esophagrams are
also shown for each subtype. Barium esophagrams and esophageal pressure
topography plots reproduced with permission from the Esophageal Center at
Northwestern Medicine.
zyme that degrades cyclic guanosine monophosphate induced by

nitric oxide. Sildenafil is a viable alternative in patients not responding to or proving intolerant of calcium channel blockers or nitrates.
However, minimal long-term treatment data exist pertinent to using
5-phosphodiesterase inhibitors to treat achalasia.
within 12 months, and repeated treatments have been shown to

make subsequent Heller myotomy more challenging. 68 Thus,
botulinum toxin injection should rarely be used as a first-line
therapy for achalasia and is primarily reserved for patients who
are not candidates for definitive therapy.
Botulinum Toxin
Pneumatic Dilation
Botulinum toxin injection into the muscle of the lower esophageal

sphincter was initially proposed as an achalasia treatment based
on its ability to block acetylcholine release from nerve endings.
Using this technique, Pasricha et al54 reported improved dysphagia in 66% of patients with achalasia for 6 months. No increase in
efficacy has been demonstrated with greater doses.65 The effect
is temporary and is eventually reversed by axonal regeneration;
subsequent clinical series report minimal continued efficacy after
1 year.54,65-67 Most patients relapse and require re-treatment
A pneumatic dilator is a noncompliant, cylindrical balloon that is positioned fluoroscopically across the lower esophageal sphincter and
inflated with air using a handheld manometer. The reported efficacy of pneumatic dilation in randomized controlled trials ranges
from 62% to 90% (Table 3). Patients with a poor result or rapid recurrence of dysphagia are unlikely to respond to additional dilations, but subsequent response to myotomy is not influenced. Although the reported incidence of perforation from pneumatic
dilation ranges from 0% to 16%, a recent systematic review on the
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1847
Achalasia
Figure 4. Chicago Classification Version 3.0 for Esophageal Motility Disorders, Including Achalasia
LES relaxation upper limit of normal AND
100% failed peristalsis or spasm
Yes
No
Achalasia
Type I: 100% failed peristalsis
Type II: 100% failed peristalsis with
panesophageal pressurization
Type III: 20% premature contractions
Disorders of esophagogastric junction
outflow obstruction
LES relaxation upper limit of normal AND

sufficient evidence of peristalsis such that
criteria for type I-III achalasia are not met
Yes
Esophagogastric junction outflow obstruction

Incompletely expressed achalasia
Mechanical obstruction
Yes
Distal esophageal spasm (DES)

20% premature contractions
Must consider type III achalasia
Jackhammer esophagus
20% of swallows with contractile vigor
No
LES relaxation is normal AND premature
contractions or hypercontractile vigor
No
Major disorders of peristalsis

(entities not seen in normal controls)
LES relaxation is normal AND 100%

failed peristalsis
Yes
Absent contractility
Should consider achalasia in cases of
borderline LES relaxation
Yes
Ineffective esophageal motility (IEM)

50% ineffective swallows
Fragmented peristalsis
50% fragmented swallows and not
meeting criteria for IEM
No
LES relaxation is normal AND 50%

of swallows are ineffective based on
contractile vigor measurements
Minor disorders of peristalsis

(impaired bolus clearance)
No
LES relaxation is normal AND >50% of
swallows are effective without criteria
for spasm or jackhammer esophagus
Yes
Modified from Kahrilas et al.50 Classification algorithm based on results of

high-resolution manometry with ten 5-mL water swallows. Note that achalasia
should be considered in patients presenting with esophagogastric junction
outflow obstruction and absent contractility. Failed peristalsis denotes swallows
with a distal contractile integral (DCI) less than 100 mm Hgseccm (the DCI
quantifies the distal contractile pressure exceeding 20 mm Hg from the
transition zone to the proximal aspect of the lower esophageal sphincter [LES]
[amplitude time length in units of mm Hgseccm]).Panesophageal
pressurization denotes uniform pressurization greater than 30 mm Hg
extending from the upper esophageal sphincter to the esophagogastric
junction. Contractile vigor denotes the strength of distal contraction as defined
topic concluded that using modern technique the risk was less than
1%, comparable to the risk of unrecognized perforation during Heller
myotomy.69 Pneumatic dilation should be performed by experienced physicians, and surgical backup is required.
Studies using pneumatic dilation as the initial treatment of
achalasia have reported excellent long-term symptom control. A
third of patients will relapse in 4 to 6 years and may require
repeat dilation. Response to therapy may be related to preprocedural clinical parameters, such as age (favorable if >45 years), sex
(more favorable among females than males),70 esophageal diameter (inversely related to response), and achalasia subtype (type II
better than I and III).52,71 Although surgical myotomy has a greater
response rate than a single pneumatic dilation, it appears that a
series of dilations is a reasonable alternative to surgery. A recent
randomized trial compared this type of graded strategy with surgical myotomy and found it to be noninferior in efficacy
(Table 3).55 Addition of botulinum toxin injection does not appear
to improve outcomes.62
1848
Normal esophageal motor function a
by the DCI. Ineffective esophageal motility (IEM) is diagnosed when a patient

exhibits greater than 50% ineffective swallows (ineffective swallows are either
failed [DCI <100 mm Hgseccm] or weak [DCI <450 mm Hgseccm]).
Fragmented swallow denotes a swallow with DCI greater than or equal to
450 mm Hgseccm and and a greater than 5-cm break in the pressure domain,
corresponding to an intact esophageal contraction, required to push a
swallowed bolus forward.
a
Rapid contraction and hypertensive peristalsis are not considered distinct

clinical pathological entities in Chicago Classification version 3.0.
Myotomy
Heller myotomy, which divides the circular muscle fibers of the
lower esophageal sphincter, is the standard surgical approach for
achalasia. Laparoscopy is the preferred surgical approach because
of its lower morbidity and comparable long-term outcome compared with that achieved with thoracotomy. 72 Laparoscopic
Heller myotomy is superior to a single pneumatic dilation in terms
of efficacy and durability, with reported efficacy rates in the 88%
to 95% range. 55,56,60,61 However, the superiority of surgical
myotomy over pneumatic dilation is less evident when compared
with a graded approach to pneumatic dilation using repeat dilations as mandated by the clinical response.55,72 An antireflux
repair has been shown to significantly decrease gastroesophageal
reflux disease,57 and this can range from an anterior 180 fundoplasty (Dor) to a 270 partial fundoplication (Toupet).59 There is
general agreement that a full 360 Nissen fundoplication is contraindicated, as 1 randomized trial showed that 15% of patients
had recurrent dysphagia.58
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Achalasia
Per-Oral Endoscopic Myotomy

Per-oral endoscopic myotomy (POEM) is the newest treatment
for achalasia.73,74 The procedure requires making a small mucosal
incision in the mid-esophagus and creating a submucosal tunnel
all the way to the gastric cardia using a forward-viewing endoscope, transparent distal cap, and submucosal dissection
knife. Selective myotomy of the circular muscle is accomplished
with electrocautery for a minimum length of 6 cm up the esophagus and 2 cm distal to the squamocolumnar junction onto the
gastric cardia. Initial success rates of the POEM procedure in prospective cohorts of patients with achalasia have been greater
than 90%, comparable with those of laparoscopic Heller
myotomy.75-77
A recent prospective, single-center study found that symptoms and postmyotomy integrated relaxation pressures were not
different between patients undergoing laparoscopic Heller myotomy or POEM.78 Preliminary results comparing more than 30
POEM cases with laparoscopic Heller myotomy suggest comparable perioperative outcomes.79 A recent retrospective multicenter study reported a greater than 90% response rate in patients with type III achalasia, perhaps due to longer myotomy length
with the endoscopic approach.80 There have been no randomized
trials comparing POEM to laparoscopic myotomy or pneumatic di-
lation, and its relative efficacy in terms of long-term dysphagia control, progression of esophageal dilatation, and postprocedure reflux remains to be established.
Table 2. Summary of Current Treatments for Achalasia
Treatment
Durability
Procedural Issues
Medical therapya
On demand/
not durable
None
Botulinum toxin
injection
6-12 mo54
Performed in endoscopy laboratory

Moderate sedation or monitored
anesthesia care
Procedure time <30 min
60 min observation
2-5y55,56
Performed in endoscopy laboratory

with fluoroscopy
Moderate sedation or monitored
anesthesia care
Procedure time, 30 min
4-6 h observation
Pneumatic dilation
y56
Surgical myotomy
5-10
Per-oral
endoscopic
myotomy
Unknown
Operating room
General anesthesia
Hospital stay, 1-2 d
Operating room or endoscopy laboratory
General anesthesia
Requires overnight stay
Oral calcium channel blockers, nifedipine, isosorbide dinitrate, or sildenafil.
Table 3. Randomized Clinical Trials Evaluating Treatment Modalities for Achalasia (2004-2015)
Source
Inclusion Criteria
Sample Size, No.
Comparison
Outcomes
Richards et al,57
2004
Patients diagnosis of untreated

achalasia
43
LHM vs LHM with Dor

fundoplication
No significant difference in postoperative LES

pressure or postoperative dysphagia
Pathologic GERD: 48% for LHM vs 9% for
LHM + fundoplication
Rebecchi et al,58
2008
Patients with achalasia,

including previous treatment
with botulinum toxin and
pneumatic dilation
144 (138 for

long-term analysis)
LHM with Dor fundoplication

vs LHM with total
fundoplication
Incidence of GERD after 60-mo follow-up: 2.8% for

Dor vs 0% for total (P = NS)
Recurrence of dysphagia: 2.8% for Dor vs 15% for
total (P < .001)
Rawlings et al,59
2012
60
Patients with achalasia
(untreated or previously treated
with botulinum toxin or
pneumatic dilation)
LHM with Dor fundoplication

vs LHM with Toupet
fundoplication
Reflux symptoms: no difference

Positive 24-h pH testing: no difference
Improvement in dysphagia: no difference
Kostic et al,60 2007 Patients with newly diagnosed

untreated achalasia
51
Pneumatic dilation vs LHM

with Toupet fundoplication
Cumulative number of treatment failures at 12 mo:

6 treatment failures in pneumatic dilation group vs
1 treatment failure in LHM group (P = .04)
Novais et al,61
2010
Patients with newly diagnosed

achalasia
94
Clinical response at 3 mo: 73.1% for pneumatic

dilation vs 88.3% for LHM (P = .08)
Manometric response at 3 mo: no difference between
groups
Incidence of GERD (24-h pH measurement): 31% for
pneumatic dilation vs 5% for LHM (P = .0001)
Boeckxstaens
et al,55 2011

achalasia
201 (LHM = 106,

pneumatic
dilation = 95)

with Dor fundoplication
Decrease in Eckardt score of 3 at 12 mo and 24 mo:

(1) 90% for 12-mo pneumatic dilation vs 93% for
LHM (P = .46) and (2) 86% for 24-mo pneumatic
dilation vs 90% for LHM (P = .46)
LES pressure, esophageal emptying, quality of life,
complications: (1) no difference in LES pressure,
quality of life, or esophageal emptying and (2) 4%
perforation rate with pneumatic dilation and 12%
mucosal tear rate with LHM
Persson et al,56
2015

achalasia
53 (LHM = 25,
pneumatic
dilation = 28)

with posterior fundoplication
Treatment failure: (1) 4% for LHM vs 32% for

pneumatic dilation at 3 y and (2) 8% for LHM vs
36% for pneumatic dilation at 5 y
Mikaeli et al,40
2006

achalasia
54
Botulinum toxin 1 mo before

pneumatic dilation vs
pneumatic dilation alone
Cumulative 1-y remission rate: 77% for botulinum

toxin + pneumatic dilation vs 62% for pneumatic
dilation alone (P = .10)
Bakhshipour
et al,62 2009
Patients with achalasia with

failed 30- and 35-mm
pneumatic dilation or
botulinum toxin
34
Pneumatic dilation vs
pneumatic dilation +
botulinum toxin injection
Symptoms at 1, 6, and 12 mo: no significant

difference in symptom scores at all time intervals
Abbreviations: GERD, gastroesophageal reflux disease; LES, lower espophageal sphincter; LHM, laparoscopic Heller myotomy.
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1849
Achalasia
Prognosis and Follow-up
Treatment Failures
Multiple publications now support the prognostic value of achalasia subtypes: (1) patients with type II achalasia have the best prognosis from treatment involving myotomy or pneumatic dilation (96%
success rate)81; (2) the treatment response of patients with type I
is less robust, at 81%81 (and is reduced further as the degree of esophageal dilatation increases); and (3) patients with type III have a worse
prognosis (66%),81 likely because the associated spasm is less likely
to respond to therapies directed at the lower esophageal
sphincter.52,71,82-84
The optimal approach in providing follow-up for patients with
achalasia is focused on periodic evaluation of symptom relief, nutrition status, and esophageal emptying by timed barium
esophagram.85 Posttreatment manometry can also be used in followup, depending on patient tolerance for the procedure and
availability.85 Esophageal contractile activity may return after treatment. In 1 retrospective study, 4 of 7 patients with type I achalasia
(57%), 6 of 17 with type II achalasia (35%), and 1 of 5 with type III
achalasia (20%) had return of weak esophageal contractile activity
after myotomy.86 Although decisions to intervene are never based
solely on barium esophagram or manometry alone, they do identify patients who should be followed up closely to prevent progression. Although the risk of squamous carcinoma is higher in patients
with achalasia than in the general population, there are no data to
support routine endoscopic surveillance, and this is left to the judgment of the physician.87,88
Achalasia treatment is not curative, and up to 20% of patients have

symptoms that may require additional treatments within 5
years.89-92 Up to 6% to 20% of treated patients may have progressive dilation to megaesophagus or end-stage disease.93 Management of the care of these patients is difficult, and options include
botulinum toxin injection, repeat pneumatic dilation, or repeat myotomy. Esophagectomy is ultimately reserved as a final option in patients with severe esophageal dilatation and symptoms not responding to dilation and myotomy.
ARTICLE INFORMATION
Author Contributions: Drs Pandolfino and Gawron
had full access to all of the data in the study and
take responsibility for the integrity of the data and
the accuracy of the data analysis.
Study concept and design: Pandolfino, Gawron.
Drafting of the manuscript: Pandolfino, Gawron.
Critical revision of the manuscript for important
intellectual content: Pandolfino, Gawron.
Study supervision: Pandolfino.
Conflict of Interest Disclosures: The authors have
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest. Dr
Pandolfino reported receiving consulting and
speaking fees from Given Imaging/Covidien and
Sandhill Scientific. Dr Gawron reported no
disclosures.
Submissions: We encourage authors to submit
papers for consideration as a Review. Please
contact Mary McGrae McDermott, MD, at
mdm608@northwestern.edu.
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Clinical Review & Education

Author Audio Interview at

diagnose and treat.

JAMAPatient Page page 1876

classification pertinent to therapeutic outcomes.

he constellation of dysphagia (difficulty swallowing), chest

Author Affiliations: Division of

sphincter, whereas they are usually less of an issue in the setting of

Evidence Acquisition and Synthesis

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Clinical Review & Education Review

Figure 1. Anatomy and Innervation of the Esophagus

and relationship to adjacent structures

resolution manometry) OR Chicago classification) OR esophageal

Structure and Normal Function of the Esophagus

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Review Clinical Review & Education

Impaired LES relaxation

Impaired LES relaxation

D Type III achalasia

Impaired LES relaxation

Impaired LES relaxation

Smooth muscle innervation

Color pressure scale, mm Hg

Some patients may present with an esophagogastric junction (EGJ) outflow

progression where there is evidence of moderate to severe esophageal

zyme that degrades cyclic guanosine monophosphate induced by

within 12 months, and repeated treatments have been shown to

Botulinum toxin injection into the muscle of the lower esophageal

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Clinical Review & Education Review

Box. Symptoms Suggestive of Achalasia That May Prompt

Dysphagia (90% of patients)

Cough or asthma (20%-40% of patients)

Data from Tsuboi et al,33 Sinan et al,34 and Ng et al.35

Epidemiology and Genetics of Achalasia

agnosed over the course of 51 years (overall incidence, 0.6/100 000

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Review Clinical Review & Education

dinal muscle contractions and esophageal shortening can persist

Table 1. Differential Diagnosis of Dysphagia Symptoms and Initial Testing

Symptoms and Signs

Esophageal (Schatzki) ring or webs

Foreign body or food impaction

Computed tomography, magnetic

Computed tomography, magnetic

Motility esophageal disorders

Distal esophageal spasm

Minor disorders of peristalsis

Gastroesophageal reflux disease

Barium esophagram, serology

Video fluoroscopy, computed

Proximal strictures, rings, or webs

Ultrasound, computed tomography

Neuromuscular (systemic) disorders