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Achalasia
A Systematic Review
John E. Pandolfino,MD, MSCI;AndrewJ. Gawron, MD, PhD, MS
The constellation of dysphagia(difficulty swallowing), chest
pain, and reflux symptoms may be caused by a variety of
diseases of the esophagus such as gastroesophageal re-
flux disease, malignancy, mechanical obstruction (strictures, rings,
or diverticula), and achalasia and other motility disorders.Achalasia is derived fromthe Greekkhalasis, translated as not
loosening or relaxing. A common historical definition of achalasia
is theinabilityof thelower esophageal sphincterto relaxin theset-
ting of absent peristalsis. An initial trial of acid suppression (6-8
weeks) is reasonable, but whendysphagia symptomspersistor are
dominated by the report of dysphagia, endoscopy should be per-
formedto evaluate formechanical obstruction or inflammatorypro-
cesses. Whenthese are notfound, achalasia should be considered,
especially in thesettingof dysphagiaprimarily toliquids. Liquidscan
pool and accumulate above a tight, unrelaxing lower esophageal
sphincter, whereas they areusually less ofan issue in thesettingof
structural causes of dysphagia.
Recent advances in diagnostic testing for achalasia, especially
high-resolution esophageal manometry, have provided new in-
sights into the pathogenesis and clinical manifestation of this dis-order. The purpose of this review is to highlight the epidemiology,
pathogenesis,and clinicalapproachto patientswith achalasia, em-
phasizing published evidence pertinent to both primary care clini-
cians and specialist physicians.
Evidence Acquisition and Synthesis
The literature was reviewed based on an initial broad MEDLINE
searchusingtheterms((((esophagealmotility)ORachalasia)ORhigh
IMPORTANCE Achalasiasignificantlyaffects patients quality of life andcan be difficultto
diagnose and treat.
OBJECTIVE To review thediagnosis andmanagementof achalasia, with a focuson phenotypic
classification pertinent to therapeutic outcomes.
EVIDENCE REVIEW Literature reviewand MEDLINE searchof articles from January 2004 to
February 2015. A totalof 93 articles were included in thefinal literature reviewaddressing
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 diagnosisof achalasiashould be considered when patients presentwith
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 achalasiais suspected. Randomized controlled trials support
treatments focused on disruptingthe lower esophageal sphincter with pneumatic dilation
(70%-90%effective) or laparoscopic myotomy (88%-95% effective). Patients with achalasia
have a variableprognosis 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 treatmentof thelower
esophageal sphincter.
CONCLUSIONS AND RELEVANCE Achalasiashould be consideredwhen dysphagiais present
and notexplained by an obstruction or inflammatory process. Responses to treatmentvary
based on which achalasiasubtype is present.
JAMA. 2015;313(18):1841-1852. doi:10.1001/jama.2015.2996
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Author Affiliations: Division of
Gastroenterology and Hepatology,
Feinberg Schoolof Medicine,
Northwestern University, Chicago,
Illinois(Pandolfino); Division of
Gastroenterology,Hepatolog y,and
Nutrition, Universityof Utah,Salt
LakeCity (Gawron).
Corresponding Author: John E.
Pandolfino,MD, MSCI,Division ofGastroenterology and Hepatology,
Departmentof Medicine,Feinberg
Schoolof Medicine,Northwestern
University, 676N StClair St,Ste 1409,
Chicago, IL 60611 (j-pandolfino
@northwestern.edu).
Section Editor: Mary McGrae
McDermott,MD, Senior Editor.
ClinicalReview & Education
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resolution manometry) OR Chicago classification) OR esophageal
peristalsis. Articles published fromJanuary2004 to February2015
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. Articleswere furthersearchedusing termsspecific forepi-
demiology, genetics, diagnosis,manometry,surgery, pneumaticdi-
lation, botulinum toxin, and per-oral endoscopic myotomy. Other
pertinentarticlesand guidelines wereobtainedthroughcitations or
wereknown tothe authors.We reviewed titles andabstracts to de-
termine relevanceto thearticlesections andultimatelyincluded93
articles in thereview (n = 4276 excluded). A totalof 9 randomized
controlled trialswere includedwhen evaluatingendoscopicand sur-
gical treatment modalities (comprising 734 total patients). Details
are shown in theeFigure in theSupplement.
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 are4 primary layers of esophageal tissuethe 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.
Despitethe seeminglysimpletask of foodtransport,the mecha-
nism and control of esophageal function is complex, largely owing
to the neuralcoordination required with the oropharynx and tran-
sition through different anatomical domains with mixed muscle
types.Onceafoodorliquidbolusenterstheesophagus,primaryperi-
stalsisstripsthe foodbolusdown thelengthof theesophagus.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-
Figure 1. Anatomyand Innervationof theEsophagus
Crural
diaphragm
Esophagus
Cricoid
cartilage
LES
Circular
muscle
Circular
muscle
Submucosa
Lumen
Longitudinal
muscle
Longitudinal
muscle (reflected)
STOMACH
ESOPHAGUS
Diaphragm
(cut)
Esophagogastric
junction
LES
Crural diaphragm
Proximal gastric cardia
Mucosa
Muscularis
propria
Adventitia
Esophageal plexus
Myenteric plexus ganglion
with postganglionic neurons
Myenteric plexusStriated
muscle
Transition zone
Smooth
muscle
Upper
esophageal
sphincter(UES)
Lower
esophageal
sphincter
(LES)
Level
of section
Muscularis
mucosa
Stratifiedsquamous
epithelium
Submucosal
plexus
A Anatomy of the esophagus
and relationship to adjacent structures C Esophageal wall
B Esophagogastric junction
Stomach
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biguus(Figure 2).
1
Thispromotes peristaltic propagation throughasequenced top-to-bottom excitation mediated by release of ace-
tylcholine at themotor end plates(Figure 2).1
Primaryperistalsis inesophagealsmoothmuscleis precededby
inhibition, which stops a progressing peristaltic wave when an-
other swallow is initiated.2,3 This involves patterned activation of
preganglionicneurons in thedorsalmotornucleusof thevagusthat
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-
motefillingandtransportthrough theesophagus.The inhibitoryneu-
ronsactivated by thepreganglionicneuronsfrom thecaudal dorsalmotor neuron release nitric oxide to promote deglutitive inhibi-
tion. This is followed by sequential activation of excitatory neu-
rons, which releases acetylcholinein 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.Secondaryperistalsis relatedto distentionof theesophaguswill
elicit a local reflex independent of the vagal input from the dorsal
Figure 2. Neural Control of Esophageal Motility and PlotFrom High-Resolution Esophageal Manometry,With Anatomical Correlates
B Esophageal pressure topography (EPT) plot from high
resolution manometry (normal study)C Anatomical correlation with EPT plotParasympathetic esophageal innervationA
0 30 60 90 120 150 180
Color pressure scale, mm Hg
Striated muscle innervation
Parasympathetic efferent
Neuromuscular junction
Smooth muscle innervation
Preganglionic excitatory neuron
Preganglionic inhibitory neuron
Postganglionic excitatory
neuron cell body
Postganglionic inhibitory
neuron cell body
ANTER I ORPOSTER I OR
PONS
Esophagus
Nucleusambiguus
Vagus nerve
Dorsal motor
nucleus
of vagus
Rostral
Caudal
Cricoid
cartilage
Cervical esophagus
Thoracic esophagus
Abdominal esophagus
Diaphragm (cut)
UES
LES
Schematic representation of esophageal motor activity during a swallow
UES
LES
Time, sSwallow
0 3 126 9
Striated
muscle
Transition
zone
Smooth
muscle
A, Theesophagus is controlled byboth centrallymediatedand peripheral
intrinsic processes thatare compartmentalizedbased on location in the
esophagus and muscletype. B, Output from high-resolution manometry,
displayed as esophagealpressure topography(Clouse plot),showing
esophageal pressures over timeafter a singleswallow. Thex-axis indicates time;
they-axis indicateslocationfrom theoropharynx to thestomach, as shownin
panel C. Pressure is displayedon a color scaleinstead of theconventional
tracings; thus,a seamless dynamic representation of motoractivity is displayed
thatprovides anatomical representation of the pressure profile. Thestriated
muscleesophaguscan be distinguished from the smoothmuscle esophagus,as
there is a pressure gapat thetransitionzonethat demarcates theintroduction
of smoothmuscleactivity. The sphinctersare distinguished bythe 2 areas of
highpressure between thestriated and smoothmuscle esophagus. LES
indicates loweresophageal sphincter;UES, upperesophagealsphincter.
Esophagealpressure topographyplot reproduced withpermissionfrom the
EsophagealCenter at Northwestern Medicine.
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motor nucleus thatcausescontraction above thedistentionand re-
laxation below the distention via the intrinsic inhibitory and excit-
atory myenteric neurons.
Regionaldifferences in thedensity of the inhibitory andexcit-
atory neurons in the enteric nervous system determine the direc-
tionandvigorofthecontraction,andthismaybemodulatedbyvari-
able smooth muscle response to the same quantum of
neurotransmitter.4-6Thepathogenesisof achalasiacan be concep-
tualized as a disruption of the balance between the regional excit-
atoryand inhibitoryresponse elicitedalong theaxial locationof 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 themuscle.The activationoverlapswith thepropagatingcircularmuscle
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, theprogressingperistalticwavesmust advancethe
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 restinglower esophageal sphinctertone is 10 to 30 mm Hg,
which helps preventrefluxof gastriccontentsback into theesopha-
gus. Relaxation of theloweresophagealsphincter to allow empty-
ingof the esophagusis triggered by swallowing or esophageal dis-tention mediated by both peripheral and central mechanisms.
Relaxation of thesphincteris 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 000worldwide.10-13 In Iceland,62 casesof achalasia weredi-
agnosed overthe courseof 51years(overallincidence,0.6/100 000
per year; mean prevalence, 8.7 cases /100 000).11 Gennaro et al14
recentlyreported anincident rate inItalyof 1.59 cases/100 000per
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
(85 years).
15
Althoughthe 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 theAAASgene (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 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 degenerationmay 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-
siteTrypanosoma 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-
Box. SymptomsSuggestiveof AchalasiaThat MayPrompt
Referralfor Esophageal MotilityTestinga
Esophageal Symptoms
Dysphagia (90%of patients)
Heartburn(75% of patients)
Regurgitation or vomiting (45%of patients)
Noncardiacchest pain (20%of patients)
Epigastricpain (15%of patients)
Odynophagia (
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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.
Symptoms and SignsThe most common symptoms of achalasia are listed in theBox3-35
and may prompt referral for a motility evaluation after more com-
mon disorders are ruled out, such as gastroesophageal reflux dis-
ease, mechanical obstruction (stricture, rings), or malignancy. Pro-
gressive 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 approximately4%36 and is
associated witha 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 epi-
gastric pain.33
Respiratory symptoms are also common in patients with acha-
lasia, 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 respiratorysymptoms by an average of 24 months, indicating the progressive
nature of symptoms with lack of treatment.37 It is also importantto
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 symp-
toms. Dysphagiaandregurgitationare commonamongall ages, but
younger patients with achalasia have been found to have a higher
prevalenceof heartburn andchest painthan olderpatients.38Obese
patients (body mass index30) may have more frequent symp-
tomsof choking andvomiting,possiblyrelated toincreased abdomi-
nal pressure.39Chestpainwasmorecommonlyreportedbywomen
than menin a single-centerretrospectivereviewof 213patientswithachalasia.40 However, another group reported similar reports of
chest pain regardless of ageor sex.41
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
Table 1. Differential Diagnosis of Dysphagia Symptoms and Initial Testing
Signs and Symptoms Testing
Esophageal Dysphagia
Structural esophageal disorders
Peptic str ict ure Esophagogastro du ode no scopy,barium esophagram
Esophageal (Schatzki) ring or webs Esophagogastroduodenoscopy,barium esophagram
Eosinophilic esophagitis Esophagogastroduodenoscopy
Malignancy Esophagogastroduodenoscopy,barium esophagram
Radiation- or medication-inducedstrictures
Esophagogastroduodenoscopy,barium esophagram
Foreign body or food impaction Esophagogastroduodenoscopy
Vascular compression Computed tomography, magneticresonance imaging, endoscopicultrasound
Mediastinal mass/externalcompression
Computed tomography, magneticresonance imaging, endoscopicultrasound
Motility esophageal disorders
Achalasia and esophagogastricjunction outflow obstruction
High-resolution manometry,barium esophagram
Absent contracti li ty High-resolution manometry
Distal esophageal spasm High-resolution manometry
Hypercontractile esophagus(jackhammer)
High-resolution manometry
Minor disorders of peristalsis High-resolution manometry
Scleroderma High-resolution manometry
Gastroesophageal reflux disease Esophagogastroduodenoscopy,high-resolution manometry, pHtestinga
Chagas disease Bar ium esophagram, sero lo gy
Oropharyngeal Dysphagia
Structural oropharyngeal disorders
Malignancy Laryngoscopy
Spinal osteophytes Video fluoroscopy, computedtomography
Zenker divert iculum Video fluoroscopy,esophagogastroduodenoscopy
Proximal strictures, rings, or webs Esophagogastroduodenoscopy,barium esophagram
Radiation injury Video fluoroscopy,esophagogastroduodenoscopy
Oropharynx infe ct ion Laryngoscopy
Thyroid enlargement Ultrasound, computed tomography
Neuromuscular (systemic) disorders
Cerebral vascular accident Computed tomography, magneticresonance imaging
Multiple sclerosis
Focused neurologic examination,disease-specific laboratory testing
and imaging
Parkinson disease
Myasthenia gravis
Amyotrophic lateral sclerosis
Muscular dystrophy
Dermatomyositis
Thyroid disorders
a pH testing indicates ambulatory pH and refluxmonitoring.
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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-
fiedbarium cookie swallow study performed by speechpathology(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-
uidfood 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 shouldprompt an evaluation for esophageal dysmotility. Although endos-
copy may suggest achalasia, other testing must be performed to
confirm the diagnosis.
Barium Esophagram
The classic birds-beak appearance of achalasiaon a barium swal-
low study is a well-known image in clinical medicine (Figure 3C).
Otherradiographicfeaturessuggestiveof an esophagealmotility dis-
order include esophageal dilation, contrastfilling 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
accurate44 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
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 relaxationof 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 maybe confused with scleroderma owing to thecomplexities
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-
mentmodalitiesislistedin Table2. Ninerandomized trialshavecom-pared endoscopic and surgical treatments for achalasia (Table 3).
Physiologically, manytreatments are directed at reducing contrac-
tilityin theloweresophagealsphincterto allow foradequateesoph-
ageal emptying. The primary goalof management should be based
on early diagnosis toprevent late complications of thedisease 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, orthostatichypotension, 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
(10-30mg, given 30-45 minutesbefore 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 treatachalasia 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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zyme that degrades cyclic guanosine monophosphate induced by
nitric oxide.Sildenafil is a viable alternativein patientsnot respond-
ing to or proving intolerant of calcium channel blockers or nitrates.
However, minimallong-termtreatmentdata existpertinent to using
5-phosphodiesterase inhibitors to treatachalasia.
Botulinum Toxin
Botulinumtoxin injectioninto themuscle 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
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.
Pneumatic Dilation
A pneumatic dilatoris a noncompliant, cylindrical balloonthatis po-
sitionedfluoroscopicallyacross the loweresophageal sphincterand
inflated with air using a handheld manometer. The reported effi-
cacy of pneumatic dilation in randomized controlled trials ranges
from 62% to90% (Table 3).Patients with a poor resultor rapidre-
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
dilationranges from 0% to16%, a recentsystematicreview onthe
Figure 3. Conceptual Model of Esophageal DiseasePresentationand ProgressionBased on Phenotypes DescribedUsing High-Resolution Manometry
and Barium Esophagrams
10 s 10 s5 s 5 s
B C D
Impaired LES relaxation
Normal or impaired peristalsis
Impaired LES relaxation
Absent peristalsis
Increased pan-esophagealpressure
Impaired LES relaxation
Absent peristalsis
Normal esophageal pressure
Impaired LES relaxation
Absent peristalsis
Distal esophageal spastic
contractions
EGJ outflow obstruction Type II achalasia Type I achalasia Type III achalasiaA
Birds
beak
Smooth muscle innervation
Postganglionic excitatory neuron
Postganglionic inhibitory neuron0 30 60 90 120 150 180
Color pressure scale, mm Hg
Somepatients may present withan esophagogastric junction (EGJ) outflow
obstruction pattern (panel A) inwhichthereis impaired lower esophageal
sphincter (LES)relaxationwith evidence of propagatingcontractions. Thismay
represent the pointwhere theesophagealbody is progressingto aperistalsis
andthereis variable loss of theexcitatory(bluecircles) andinhibitory (red
circles) influence.As preferential loss of theinhibitory neurons continues to
progress, themanometricpattern mayprogressto a type II pattern (panelB)
associated withimpaired LES relaxationand panesophageal pressurization, akin
to a filledwaterballoon beingsqueezed.42 TypeI achalasia(panel C) is the
classicpresentation of achalasia,in which there is completeloss of contractile
activity in thebodyof theesophagus;thisis typicallya later phaseof disease
progression wherethere is evidence of moderate to severe esophageal
dilatation. Type III achalasia (panel D) is associatedwith premature
simultaneouscontractions thatcompartmentalizethe bolusbefore it can empty
the esophagus,as evidenced by the corkscrew appearanceon esophagram.This
mayrepresent a distinct entitythatdoes notfallinto thetypicalpresentationof
progressive neuronloss seen with theprogressionof EGJ outletobstructionto
type IIachalasia, to type I achalasia.Corresponding bariumesophagramsare
also shownfor eachsubtype.Barium esophagramsand esophageal pressure
topographyplots reproduced withpermissionfrom theEsophagealCenter at
Northwestern Medicine.
Achalasia Review ClinicalReview & Education
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topic concludedthatusing modern techniquethe riskwas lessthan
1%, comparableto therisk of unrecognizedperforation duringHeller
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), andachalasia subtype (type II
better than I andIII).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 f ibers 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
Figure 4. Chicago ClassificationVersion 3.0for Esophageal MotilityDisorders, IncludingAchalasia
LES relaxation upper limit of normal AND100% failed peristalsis or spasm
AchalasiaType I: 100% failed peristalsisType II: 100% failed peristalsis withpanesophageal pressurizationType III: 20% premature contractions
LES relaxation is normal AND prematurecontractions or hypercontractile vigor
Distal esophageal spasm (DES) 20% premature contractions Must consider type III achalasia
Jackhammer esophagus 20% of swallows with contractile vigor
LES relaxation is normal AND 100%failed peristalsis
Absent contractility Should consider achalasia in cases ofborderline LES relaxation
LES relaxation upper limit of normal ANDsufficient evidence of peristalsis such thatcriteria for type I-III achalasia are not met
Esophagogastric junction outflow obstruction Incompletely expressed achalasia Mechanical obstruction
Disorders of esophagogastric junctionoutflow obstruction
Major disorders of peristalsis(entities not seen in normal controls)
LES relaxation is normal AND >50% ofswallows are effective without criteriafor spasm or jackhammer esophagus
Normal esophageal motor functiona
Ineffective esophageal motility (IEM) 50% ineffective swallows
Fragmented peristalsis 50% fragmented swallows and notmeeting criteria for IEM
Minor disorders of peristalsis(impaired bolus clearance)
LES relaxation is normal AND 50%of swallows are ineffective based oncontractile vigor measurements
No
No
No
No
No
Yes
Yes
Yes
Yes
Yes
Yes
Modified fromKahrilaset al.50 Classificationalgorithm basedon resultsof
high-resolution manometry withten 5-mLwater swallows. Notethat achalasia
shouldbe consideredin patients presentingwith esophagogastric junction
outflowobstruction and absent contractility.Failed peristalsis denotes swallows
with a distalcontractileintegral(DCI)less than 100mm Hgseccm(theDCI
quantifiesthedistalcontractilepressureexceeding 20mm Hgfrom the
transition zone to theproximal aspectof thelower esophageal sphincter[LES]
[amplitude time length in unitsof mm Hgseccm]).Panesophageal
pressurizationdenotesuniform pressurizationgreaterthan 30 mm Hg
extendingfrom the upperesophagealsphincterto theesophagogastric
junction. Contractile vigor denotes the strength of distal contraction as defined
bythe DCI. Ineffectiveesophageal motility (IEM)is diagnosedwhena patient
exhibits greater than50% ineffectiveswallows(ineffective swallows are either
failed[DCI
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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 endo-
scope, 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 esopha-gus and 2 cm distal to the squamocolumnar junction onto the
gastric cardia. Initial success rates of the POEM procedure in pro-
spective 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 symp-
toms and postmyotomy integrated relaxation pressures were not
different between patients undergoing laparoscopic Heller my-
otomy or POEM.78 Preliminary results comparing more than 30
POEM cases with laparoscopic Heller myotomy suggest compa-
rable perioperative outcomes.79 A recent retrospective multi-
center study reported a greater than 90% response rate in pa-
tientswithtypeIIIachalasia,perhapsduetolongermyotomylength
with the endoscopicapproach.80 Therehave been no randomized
trials comparingPOEM to laparoscopic myotomy or pneumatic di-
lation,and itsrelativeefficacyin termsof long-termdysphagia con-
trol, progression of esophageal dilatation, and postprocedure re-
flux remains to be established.
Table 2. Summary of Current Treatmentsfor Achalasia
Treatment Durability Procedural Issues
Medical therapya On demand/not durable
None
Botulinum toxininjection
6-12 mo54 Performed in endoscopy laboratoryModerate sedation or monitoredanesthesia careProcedure time
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Prognosis and Follow-up
Multiple publications now support the prognostic value of achala-
siasubtypes: (1)patientswith type II achalasiahave thebest prog-
nosis fromtreatment involvingmyotomyorpneumaticdilation (96%
success rate)81; (2) the treatment response of patients with type I
islessrobust,at81%
81
(and isreducedfurtheras thedegreeof esoph-agealdilatation increases);and(3) patientswithtype IIIhavea worse
prognosis(66%),81 likelybecausetheassociatedspasmislesslikely
to respond to therapies directed at the lower esophageal
sphincter.52,71,82-84
The optimal approach in providingfollow-up for patients with
achalasia is focused on periodic evaluation of symptom relief, nu-
trition status, and esophageal emptying by timed barium
esophagram.85Posttreatmentmanometrycanalsobe usedin follow-
up, depending on patient tolerance for the procedure and
availability.85Esophagealcontractile activitymay return aftertreat-
ment. In 1 retrospectivestudy, 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 returnof weakesophageal contractile activity
after myotomy.86Although decisionsto intervene are never based
solely on barium esophagram or manometry alone, they do iden-
tifypatientswho should be followedup closely to prevent progres-
sion. Althoughthe riskof squamouscarcinoma is higher in patients
with achalasia than in the general population, there are no data to
support routineendoscopic surveillance,and thisis leftto thejudg-
ment of thephysician.87,88
Treatment Failures
Achalasia treatmentis notcurative, andup to 20%of patientshave
symptoms that may require additional treatments within 5
years.89-92Upto6%to20%oftreatedpatientsmayhaveprogres-
sive dilation to megaesophagus or end-stage disease.93 Manage-
ment of the care of these patients is difficult, and options includebotulinumtoxininjection, repeat pneumaticdilation, or repeatmy-
otomy. Esophagectomyis ultimatelyreservedas a final optionin pa-
tients withsevere esophagealdilatationand symptomsnot respond-
ing to dilation and myotomy.
ARTICLE INFORMATION
Author Contributions: Drs Pandolfino and Gawron
had fullaccessto all ofthedatain the studyand
take responsibility forthe integrityof thedataand
theaccuracyof thedataanalysis.
Study concept and design: Pandolfino, Gawron.
Drafting of the manuscript: Pandolfino, Gawron.
Critical revision of the manuscriptfor important
intellectual content: Pandolfino, Gawron.
Study supervision: Pandolfino.
Conflict of Interest Disclosures: Theauthors have
completedand submittedtheICMJEForm for
Disclosure of PotentialConflicts of Interest.Dr
Pandolfino reported receiving consultingand
speaking feesfrom GivenImaging/Covidienand
Sandhill Scientific.Dr Gawronreportedno
disclosures.
Submissions: Weencourageauthors to submit
papersfor consideration as a Review.Please
contact Mary McGraeMcDermott, MD,at
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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. Differentachalasiaphenotypes havedifferentialresponses
to treatment.
Definitivetreatment to alleviate esophagogastric junction out-
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or pneumatic dilation should be offeredto patients without con-
traindications to surgery.
Clinical Review& Education Review Achalasia
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