Clinical Review & Education

Edson Guzman Firmado digitalmente por Edson Guzman

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Fecha: 2015.05.18 20:23:27 -05'00'

Review

Achalasia
A Systematic Review
John E. Pandolfino, MD, MSCI; Andrew J. Gawron, MD, PhD, MS

Author Audio Interview at

IMPORTANCE Achalasia significantly affects patients’ quality of life and can be difficult to jama.com
diagnose and treat. JAMAPatient Page page 1876

Supplemental content at
OBJECTIVE To review the diagnosis and management of achalasia, with a focus on phenotypic
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classification pertinent to therapeutic outcomes.
CME Quiz at
jamanetworkcme.com and
EVIDENCE REVIEW Literature review and MEDLINE search of articles from January 2004 to
CME Questions page 1859
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 Author Affiliations: Division of
have a variable prognosis after endoscopic or surgical myotomy based on subtypes, with type Gastroenterology and Hepatology,
II (absent peristalsis with abnormal pan-esophageal high-pressure patterns) having a very Feinberg School of Medicine,
Northwestern University, Chicago,
favorable outcome (96%) and type I (absent peristalsis without abnormal pressure) having an Illinois (Pandolfino); Division of
intermediate prognosis (81%) that is inversely associated with the degree of esophageal Gastroenterology, Hepatology, and
dilatation. In contrast, type III (absent peristalsis with distal esophageal spastic contractions) Nutrition, University of Utah, Salt
Lake City (Gawron).
is a spastic variant with less favorable outcomes (66%) after treatment of the lower
esophageal sphincter. Corresponding Author: John E.
Pandolfino, MD, MSCI, Division of
Gastroenterology and Hepatology,
CONCLUSIONS AND RELEVANCE Achalasia should be considered when dysphagia is present Department of Medicine, Feinberg
and not explained by an obstruction or inflammatory process. Responses to treatment vary School of Medicine, Northwestern
University, 676 N St Clair St, Ste 1409,
based on which achalasia subtype is present.
Chicago, IL 60611 (j-pandolfino
@northwestern.edu).
JAMA. 2015;313(18):1841-1852. doi:10.1001/jama.2015.2996 Section Editor: Mary McGrae
McDermott, MD, Senior Editor.

T
he constellation of dysphagia (difficulty swallowing), chest sphincter, whereas they are usually less of an issue in the setting of
pain, and reflux symptoms may be caused by a variety of structural causes of dysphagia.
diseases of the esophagus such as gastroesophageal re- Recent advances in diagnostic testing for achalasia, especially
flux disease, malignancy, mechanical obstruction (strictures, rings, high-resolution esophageal manometry, have provided new in-
or diverticula), and achalasia and other motility disorders. sights into the pathogenesis and clinical manifestation of this dis-
Achalasia is derived from the Greek khalasis, translated as “not order. The purpose of this review is to highlight the epidemiology,
loosening or relaxing.” A common historical definition of achalasia pathogenesis, and clinical approach to patients with achalasia, em-
is the inability of the lower esophageal sphincter to relax in the set- phasizing published evidence pertinent to both primary care clini-
ting of absent peristalsis. An initial trial of acid suppression (6-8 cians and specialist physicians.
weeks) is reasonable, but when dysphagia symptoms persist or are
dominated by the report of dysphagia, endoscopy should be per-
formed to evaluate for mechanical obstruction or inflammatory pro-
Evidence Acquisition and Synthesis
cesses. When these are not found, achalasia should be considered,
especially in the setting of dysphagia primarily to liquids. Liquids can The literature was reviewed based on an initial broad MEDLINE
pool and accumulate above a tight, “unrelaxing” lower esophageal 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 C Esophageal wall
Cricoid Myenteric plexus ganglion
Longitudinal
cartilage with postganglionic neurons
muscle (reflected)
Upper Striated
esophageal muscle Myenteric plexus
sphincter
(UES) Transition zone Circular Esophageal plexus
muscle
Adventitia
Esophagus
Smooth
muscle
Diaphragm B Esophagogastric junction Muscularis
(cut) propria

Submucosal
Lower Stomach plexus Submucosa
esophageal ESOPHAGUS
sphincter Muscularis Mucosa
(LES) mucosa
Stratified
Level squamous
Circular of section Lumen
muscle epithelium

Longitudinal
muscle

Crural Esophagogastric
diaphragm 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 epi-
demiology, genetics, diagnosis, manometry, surgery, pneumatic di-
lation, 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 de-
termine 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 sur-
gical 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 tissue—the mucosa, sub-
mucosa, muscularis propria, and adventitia. The esophagus origi-
nates at the level of the cricoid cartilage and normally terminates
below the hiatus in the right crura of the diaphragm. The muscu-
laris 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 regu-
lated via the parasympathetic pathway from the vagus nerve and
the intrinsic enteric nervous system.
Despite the seemingly simple task of food transport, the mecha-
nism and control of esophageal function is complex, largely owing
to the neural coordination required with the oropharynx and tran-
sition through different anatomical domains with mixed muscle
types. Once a food or liquid bolus enters the esophagus, primary peri-
stalsis strips the food bolus down the length of the esophagus. Peri-
staltic contraction in the striated muscle esophagus is dependent
on central mechanisms that involve sequential activation of excit-
atory activity of lower motor neurons in the vagal nucleus am-

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 Achalasia Review Clinical Review & Education

Figure 2. Neural Control of Esophageal Motility and Plot From High-Resolution Esophageal Manometry, With Anatomical Correlates

A Parasympathetic esophageal innervation B Esophageal pressure topography (EPT) plot from high C Anatomical correlation with EPT plot
resolution manometry (normal study)

POSTERIOR ANTERIOR Color pressure scale, mm Hg

0 30 60 90 120 150 180
Dorsal motor
PONS
nucleus
Esophagus
of vagus Nucleus Cricoid
Rostral ambiguus cartilage
Caudal UES

Striated
muscle Cervical esophagus
Vagus nerve

Transition
zone

Thoracic esophagus

Smooth
muscle

Striated muscle innervation Diaphragm (cut)

Parasympathetic efferent
Neuromuscular junction
Smooth muscle innervation LES Abdominal esophagus
Preganglionic excitatory neuron
Preganglionic inhibitory neuron
Postganglionic excitatory
neuron cell body
Postganglionic inhibitory
neuron cell body UES

LES

0 3 6 9 12
Swallow Time, s
Schematic representation of esophageal motor activity during a swallow

A, The esophagus is controlled by both centrally mediated and peripheral
intrinsic processes that are compartmentalized based on location in the
esophagus and muscle type. B, Output from high-resolution manometry,
displayed as esophageal pressure topography (Clouse plot), showing
esophageal pressures over time after a single swallow. The x-axis indicates time;
the y-axis indicates location from the oropharynx to the stomach, as shown in
panel C. Pressure is displayed on a color scale instead of the conventional
tracings; thus, a seamless dynamic representation of motor activity is displayed
that provides anatomical representation of the pressure profile. The striated
muscle esophagus can be distinguished from the smooth muscle esophagus, as
there is a pressure gap at the transition zone that demarcates the introduction
of smooth muscle activity. The sphincters are distinguished by the 2 areas of
high pressure between the striated and smooth muscle esophagus. LES
indicates lower esophageal sphincter; UES, upper esophageal sphincter.
Esophageal pressure topography plot reproduced with permission from the
Esophageal Center at Northwestern Medicine.

biguus (Figure 2).1 This promotes peristaltic propagation through a
sequenced top-to-bottom excitation mediated by release of ace-
tylcholine at the motor end plates (Figure 2).1
Primary peristalsis in esophageal smooth muscle is preceded by
inhibition, which stops a progressing peristaltic wave when an-
other swallow is initiated.2,3 This involves patterned activation of
preganglionic neurons in the dorsal motor nucleus of the vagus that
project onto inhibitory and excitatory neurons in the esophageal
myenteric plexus (Figure 2). Under normal circumstances, the in-
hibitory pathway is activated first to relax the esophagus to pro-
mote filling and transport through the esophagus. The inhibitory neu-
rons activated by the preganglionic neurons from the caudal dorsal
motor neuron release nitric oxide to promote deglutitive inhibi-
tion. This is followed by sequential activation of excitatory neu-
rons, which releases acetylcholine in response to activation by pre-
ganglionic neurons arising from the rostral dorsal motor nucleus.
The direction and rate of propagation is modulated by the in-
creasing inhibitory influence in the distal esophagus, called the la-
tency gradient.2,3 This essentially delays contractions in the distal
esophagus and allows propagation to proceed in an aboral direc-
tion. Secondary peristalsis related to distention of the esophagus will
elicit a local reflex independent of the vagal input from the dorsal

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 Clinical Review & Education Review
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 re-
laxation below the distention via the intrinsic inhibitory and excit-
atory myenteric neurons.
Regional differences in the density of the inhibitory and excit-
atory neurons in the enteric nervous system determine the direc-
tion and vigor of the contraction, and this may be modulated by vari-
able smooth muscle response to the same quantum of
neurotransmitter.4-6 The pathogenesis of achalasia can be concep-
tualized as a disruption of the balance between the regional excit-
atory and inhibitory response elicited along the axial location of the
esophageal body.4,7
Although most research on peristalsis has focused on the cir-
cular muscle, the longitudinal outer layer plays an important role.
Esophageal shortening occurs as a response to longitudinal con-
traction 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 co-
ordination of these effects, and exaggerated longitudinal contrac-
tions 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 esoph-
ageal 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 esopha-
gus. Relaxation of the lower esophageal sphincter to allow empty-
ing of the esophagus is triggered by swallowing or esophageal dis-
tention mediated by both peripheral and central mechanisms.
Relaxation of the sphincter is related to a number of nonadrenergic
noncholinergic neurotransmitters, the most prominent being ni-
tric 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 di-
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Achalasia
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 esti-
mated 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 in-
cidence is low, the chronicity of achalasia significantly affects pa-
tients’ health-related quality of life, work productivity, and func-
tional 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 alac-
rima and achalasia (Allgrove syndrome) is a rare genetic syndrome
associated with defects in the AAAS gene (chromosome 12q13) and
subsequent defective tryptophan–aspartic 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 differ-
ent 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 man-
agement 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 neu-
rons 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 sus-
ceptible 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 inflam-
matory 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 destruc-
tion in Chagas disease, a consequence of infection with the para-
site 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 esopha-
geal sphincter, hypercontractility of the distal esophagus, and
rapidly propagated contractions in the distal esophagus. Longitu-
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 Achalasia Review Clinical Review & Education

dinal muscle contractions and esophageal shortening can persist

Table 1. Differential Diagnosis of Dysphagia Symptoms and Initial Testing
in achalasia. There is variable expression of these abnormalities
among individuals, and only impaired deglutitive relaxation of the Signs and Symptoms Testing

lower esophageal sphincter is universally required as a defining Esophageal Dysphagia

feature of achalasia. Structural esophageal disorders

Peptic stricture Esophagogastroduodenoscopy,
barium esophagram
Esophageal (Schatzki) ring or webs Esophagogastroduodenoscopy,
barium esophagram
Symptoms and Signs Eosinophilic esophagitis Esophagogastroduodenoscopy
The most common symptoms of achalasia are listed in the Box3-35 Malignancy Esophagogastroduodenoscopy,
barium esophagram
and may prompt referral for a motility evaluation after more com-
Radiation- or medication-induced Esophagogastroduodenoscopy,
mon disorders are ruled out, such as gastroesophageal reflux dis- strictures barium esophagram
ease, mechanical obstruction (stricture, rings), or malignancy. Pro- Foreign body or food impaction Esophagogastroduodenoscopy
gressive dysphagia to both solids and liquids is the hallmark Vascular compression Computed tomography, magnetic
symptom associated with a diagnosis of achalasia. The prevalence resonance imaging, endoscopic
ultrasound
of weekly dysphagia among US adults is approximately 4%36 and is
Mediastinal mass/external Computed tomography, magnetic
associated with a broad differential diagnosis and workup (Table 1). compression resonance imaging, endoscopic
Esophageal motility testing should only be done after a structural ultrasound

or mechanical obstruction has been ruled out and oropharyngeal Motility esophageal disorders

causes are not apparent. In a single-center review of all patients Achalasia and esophagogastric High-resolution manometry,
junction outflow obstruction barium esophagram
with manometry over a period of 24 years (1984-2008), Tsuboi et Absent contractility High-resolution manometry
al33 found that patients with achalasia most commonly presented
Distal esophageal spasm High-resolution manometry
with dysphagia and heartburn. Other common symptoms included
Hypercontractile esophagus High-resolution manometry
chest pain, regurgitation, cough or asthma, odynophagia, and epi- (jackhammer)
gastric pain.33 Minor disorders of peristalsis High-resolution manometry
Respiratory symptoms are also common in patients with acha- Scleroderma High-resolution manometry
lasia, because primary motor abnormalities result in decreased Gastroesophageal reflux disease Esophagogastroduodenoscopy,
clearance of food and liquid from the esophagus, predisposing high-resolution manometry, pH
testinga
patients to aspiration. Sinan et al34 found that of 110 patients with Chagas disease Barium esophagram, serology
achalasia, 40% reported at least 1 respiratory symptom daily.
Oropharyngeal Dysphagia
Another study of 38 patients with achalasia found that 71% had
Structural oropharyngeal disorders
sore throat, hoarseness, or postnasal drip and 61% had cough.37 In
Malignancy Laryngoscopy
addition, 17 patients (45%) had abnormal spirometry findings and
Spinal osteophytes Video fluoroscopy, computed
12 had abnormal imaging findings such as septal thickening and tomography
necrotizing pneumonia.37 The dysphagia preceded respiratory Zenker diverticulum Video fluoroscopy,
symptoms by an average of 24 months, indicating the progressive esophagogastroduodenoscopy
Proximal strictures, rings, or webs Esophagogastroduodenoscopy,
nature of symptoms with lack of treatment.37 It is also important to barium esophagram
consider a diagnosis of connective tissue disease (eg, scleroderma) Radiation injury Video fluoroscopy,
in patients with chronic respiratory issues and abnormalities of esophagogastroduodenoscopy
esophageal motility. Oropharynx infection Laryngoscopy
Demographic and clinical factors may affect clinical symp- Thyroid enlargement Ultrasound, computed tomography
toms. Dysphagia and regurgitation are common among all ages, but Neuromuscular (systemic) disorders
younger patients with achalasia have been found to have a higher Cerebral vascular accident Computed tomography, magnetic
resonance imaging
prevalence of heartburn and chest pain than older patients.38 Obese
Multiple sclerosis
patients (body mass index ⱖ30) may have more frequent symp-
Parkinson disease
toms of choking and vomiting, possibly related to increased abdomi-
Myasthenia gravis
nal pressure.39 Chest pain was more commonly reported by women Focused neurologic examination,
than men in a single-center retrospective review of 213 patients with Amyotrophic lateral sclerosis disease-specific laboratory testing
and imaging
achalasia.40 However, another group reported similar reports of Muscular dystrophy

chest pain regardless of age or sex.41 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 symp-
toms that mimic gastroesophageal reflux disease, such as heart-
burn, chest pain, and regurgitation. In contrast, when patients
primarily present with dysphagia, a careful history and evaluation

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 Clinical Review & Education Review
of swallowing by watching the patient drink water can be helpful
in distinguishing between oropharyngeal dysphagia and esopha-
geal dysphagia. Patients with oropharyngeal dysphagia will typi-
cally 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 modi-
fied 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 obstruc-
tion 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 proce-
dure (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
Esophagogastroduodenoscopy with mucosal biopsy should be per-
formed in most patients presenting with solid food dysphagia, liq-
uid food dysphagia, or both. This is done to rule out erosive gastro-
esophageal reflux disease, eosinophilic esophagitis, structural
lesions (strictures, webs, or rings), and esophageal cancer or “pseu-
doachalasia.” Endoscopic features of an esophageal motility disor-
der 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 endos-
copy may suggest achalasia, other testing must be performed to
confirm the diagnosis.
Barium Esophagram
The classic “bird’s-beak” appearance of achalasia on a barium swal-
low study is a well-known image in clinical medicine (Figure 3C).
Other radiographic features suggestive of an esophageal motility dis-
order include esophageal dilation, contrast filling the esophagus, a
“corkscrew appearance,” and aperistalsis.
Esophageal Manometry
Esophageal manometry to assess esophageal pressures and con-
tractions along the length of a flexible catheter has become the
standard for diagnosing and classifying achalasia. Major techno-
logical 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
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Achalasia
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 junc-
tion outflow obstruction, because this may represent an incom-
plete 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. Equivo-
cal 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 con-
tractility to document bolus retention, which would favor a diagno-
sis of achalasia.
Treatment
There are no curative therapies for achalasia; a summary of treat-
ment modalities is listed in Table 2. Nine randomized trials have com-
pared endoscopic and surgical treatments for achalasia (Table 3).
Physiologically, many treatments are directed at reducing contrac-
tility in the lower esophageal sphincter to allow for adequate esoph-
ageal 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 long-
term 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 short-
acting temporizing treatments. Absorption and effect of oral medi-
cations 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 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 Impaired LES relaxation
Normal or impaired peristalsis Absent peristalsis
Increased pan-esophageal
pressure
C Type I achalasia
Impaired LES relaxation
Absent peristalsis
Normal esophageal pressure
D Type III achalasia
Impaired LES relaxation
Absent peristalsis
Distal esophageal spastic
contractions

Bird’s
beak

Smooth muscle innervation Color pressure scale, mm Hg

Postganglionic excitatory neuron
0 30 60 90 120 150 180
Postganglionic inhibitory neuron

10 s 5s 5s 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 respond-
ing 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 dyspha-
gia 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 po-
sitioned fluoroscopically across the lower esophageal sphincter and
inflated with air using a handheld manometer. The reported effi-
cacy of pneumatic dilation in randomized controlled trials ranges
from 62% to 90% (Table 3). Patients with a poor result or rapid re-
currence of dysphagia are unlikely to respond to additional dila-
tions, but subsequent response to myotomy is not influenced. Al-
though the reported incidence of perforation from pneumatic
dilation ranges from 0% to 16%, a recent systematic review on the

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 Clinical Review & Education Review Achalasia

Figure 4. Chicago Classification Version 3.0 for Esophageal Motility Disorders, Including Achalasia

LES relaxation ≥upper limit of normal AND Yes Achalasia

100% failed peristalsis or spasm Type I: 100% failed peristalsis
Type II: 100% failed peristalsis with
panesophageal pressurization
No Type III: ≥20% premature contractions
Disorders of esophagogastric junction
outflow obstruction

LES relaxation ≥upper limit of normal AND Yes Esophagogastric junction outflow obstruction
sufficient evidence of peristalsis such that • Incompletely expressed achalasia
criteria for type I-III achalasia are not met • Mechanical obstruction

No

LES relaxation is normal AND premature
contractions or hypercontractile vigor
No
Yes Distal esophageal spasm (DES)
• ≥20% premature contractions
• Must consider type III achalasia
Jackhammer esophagus
• ≥20% of swallows with contractile vigor
Major disorders of peristalsis
(entities not seen in normal controls)

LES relaxation is normal AND 100% Yes Absent contractility

failed peristalsis • Should consider achalasia in cases of
borderline LES relaxation

No

LES relaxation is normal AND ≥50%
of swallows are ineffective based on
contractile vigor measurements
No
Yes Ineffective esophageal motility (IEM)
• ≥50% ineffective swallows
Minor disorders of peristalsis
Fragmented peristalsis
(impaired bolus clearance)
• ≥50% fragmented swallows and not
meeting criteria for IEM

LES relaxation is normal AND >50% of Yes

swallows are effective without criteria Normal esophageal motor function a
for spasm or jackhammer esophagus

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 Hg·sec·cm (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 Hg·sec·cm]).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
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 Hg·sec·cm] or weak [DCI <450 mm Hg·sec·cm]).
Fragmented swallow denotes a swallow with DCI greater than or equal to
450 mm Hg·sec·cm 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.

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 experi-
enced 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 preproce-
dural clinical parameters, such as age (favorable if >45 years), sex
(more favorable among females than males),70 esophageal diam-
eter (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 sur-
gical myotomy and found it to be noninferior in efficacy
(Table 3).55 Addition of botulinum toxin injection does not appear
to improve outcomes.62
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 com-
pared 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 dila-
tions 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° fundo-
plasty (Dor) to a 270° partial fundoplication (Toupet).59 There is
general agreement that a full 360° Nissen fundoplication is con-
traindicated, as 1 randomized trial showed that 15% of patients
had recurrent dysphagia.58

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 Achalasia Review Clinical Review & Education

Per-Oral Endoscopic Myotomy lation, and its relative efficacy in terms of long-term dysphagia con-
Per-oral endoscopic myotomy (POEM) is the newest treatment trol, progression of esophageal dilatation, and postprocedure re-
for achalasia.73,74 The procedure requires making a small mucosal flux remains to be established.
incision in the mid-esophagus and creating a submucosal tunnel
all the way to the gastric cardia using a forward-viewing endo- Table 2. Summary of Current Treatments for Achalasia
scope, transparent distal cap, and submucosal dissection Treatment Durability Procedural Issues
knife. Selective myotomy of the circular muscle is accomplished Medical therapya On demand/ None
with electrocautery for a minimum length of 6 cm up the esopha- not durable
Botulinum toxin 6-12 mo54 Performed in endoscopy laboratory
gus and 2 cm distal to the squamocolumnar junction onto the injection Moderate sedation or monitored
gastric cardia. Initial success rates of the POEM procedure in pro- anesthesia care
Procedure time <30 min
spective cohorts of patients with achalasia have been greater 60 min observation
than 90%, comparable with those of laparoscopic Heller Pneumatic dilation 2-5y55,56 Performed in endoscopy laboratory
myotomy.75-77 with fluoroscopy
Moderate sedation or monitored
A recent prospective, single-center study found that symp- anesthesia care
toms and postmyotomy integrated relaxation pressures were not Procedure time, 30 min
4-6 h observation
different between patients undergoing laparoscopic Heller my-
Surgical myotomy 5-10 y56 Operating room
otomy or POEM.78 Preliminary results comparing more than 30 General anesthesia
POEM cases with laparoscopic Heller myotomy suggest compa- Procedure time, 90 min
Hospital stay, 1-2 d
rable perioperative outcomes.79 A recent retrospective multi- Per-oral Unknown Operating room or endoscopy laboratory
center study reported a greater than 90% response rate in pa- endoscopic General anesthesia
myotomy Procedure time, 90 min
tients with type III achalasia, perhaps due to longer myotomy length Requires overnight stay
with the endoscopic approach.80 There have been no randomized a
Oral calcium channel blockers, nifedipine, isosorbide dinitrate, or sildenafil.
trials comparing POEM to laparoscopic myotomy or pneumatic di-

Table 3. Randomized Clinical Trials Evaluating Treatment Modalities for Achalasia (2004-2015)

Source Inclusion Criteria Sample Size, No. Comparison Outcomes

Richards et al,57 Patient’s diagnosis of untreated
2004 achalasia
Rebecchi et al,58 Patients with achalasia,
2008 including previous treatment
with botulinum toxin and
pneumatic dilation
Rawlings et al,59 Patients with achalasia
2012 (untreated or previously treated
with botulinum toxin or
pneumatic dilation)
Kostic et al,60 2007 Patients with newly diagnosed
untreated achalasia
Novais et al,61 Patients with newly diagnosed
2010 achalasia
Boeckxstaens Patients with newly diagnosed
et al,55 2011 achalasia
Persson et al,56 Patients with newly diagnosed
2015 achalasia
Mikaeli et al,40 Patients with newly diagnosed
2006 achalasia
Bakhshipour Patients with achalasia with
et al,62 2009 failed 30- and 35-mm
pneumatic dilation or
botulinum toxin
43 LHM vs LHM with Dor
fundoplication
144 (138 for LHM with Dor fundoplication
long-term analysis) vs LHM with total
fundoplication
60 LHM with Dor fundoplication
vs LHM with Toupet
fundoplication
51 Pneumatic dilation vs LHM
with Toupet fundoplication
94 Pneumatic dilation vs LHM
201 (LHM = 106, Pneumatic dilation vs LHM
pneumatic with Dor fundoplication
dilation = 95)
53 (LHM = 25, Pneumatic dilation vs LHM
pneumatic with posterior fundoplication
dilation = 28)
54 Botulinum toxin 1 mo before
pneumatic dilation vs
pneumatic dilation alone
34 Pneumatic dilation vs
pneumatic dilation +
botulinum toxin injection
No significant difference in postoperative LES
pressure or postoperative dysphagia
Pathologic GERD: 48% for LHM vs 9% for
LHM + 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)
Reflux symptoms: no difference
Positive 24-h pH testing: no difference
Improvement in dysphagia: no difference
Cumulative number of treatment failures at 12 mo:
6 treatment failures in pneumatic dilation group vs
1 treatment failure in LHM group (P = .04)
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)
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
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
Cumulative 1-y remission rate: 77% for botulinum
toxin + pneumatic dilation vs 62% for pneumatic
dilation alone (P = .10)
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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 Clinical Review & Education Review Achalasia

Prognosis and Follow-up Treatment Failures

Multiple publications now support the prognostic value of achala-
sia subtypes: (1) patients with type II achalasia have the best prog-
nosis 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 esoph-
ageal 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, nu-
trition status, and esophageal emptying by timed barium
esophagram.85 Posttreatment manometry can also be used in follow-
up, depending on patient tolerance for the procedure and
availability.85 Esophageal contractile activity may return after treat-
ment. 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 iden-
tify patients who should be followed up closely to prevent progres-
sion. 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 judg-
ment 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 progres-
sive dilation to megaesophagus or end-stage disease.93 Manage-
ment of the care of these patients is difficult, and options include
botulinum toxin injection, repeat pneumatic dilation, or repeat my-
otomy. Esophagectomy is ultimately reserved as a final option in pa-
tients with severe esophageal dilatation and symptoms not respond-
ing to dilation and myotomy.
Clinical Bottom Line
• Achalasia is the most well-defined esophageal motility
disorder.
• Presenting symptoms and esophageal contractile patterns
may be inconsistent, resulting in delayed or missed diagnosis.
Primary liquid dysphagia is a classic symptom suggestive of
achalasia.
• Different achalasia phenotypes have differential responses
to treatment.
• Definitive treatment to alleviate esophagogastric junction out-
flow obstruction such as myotomy (laparoscopic or endoscopic)
or pneumatic dilation should be offered to patients without con-
traindications to surgery.

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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