achalasia a systematic review

7/26/2019 Achalasia a Systematic Review

1/12

Copyright 2015 American Medical Association. All rig hts reserved.

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

Author AudioInterview at

jama.com

JAMAPatientPage page1876

Supplementalcontent at

jama.com

CME Quiz at

jamanetworkcme.com and

CME Questions page1859

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

Review

jama.com (Reprinted) JAMA May 12,2015 Volume 313, Number18 1841


wnloaded From: http://jama.jamanetwork.com/ by a Florida International University Medical Library User on 05/13/2015


2/12


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

Clinical Review& Education Review Achalasia

1 842 JA MA May 12,2015 Volume 313, Number18 (Reprinted) jama.com




3/12


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.

Achalasia Review ClinicalReview & Education





4/12


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 (


5/12


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.






6/12


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-






7/12


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


Absent peristalsis

Increased pan-esophagealpressure


Absent peristalsis

Normal esophageal pressure


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.






8/12


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


9/12


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


10/12


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

[email protected].

REFERENCES

1. Gidda JS,Goyal RK.Regionalgradientof initial

inhibition and refractorinessin esophageal smooth

muscle. Gastroenterology. 1985;89(4):843-851.

2. VanekAW, Diamant NE.Responses of the

humanesophagusto pairedswallows.

Gastroenterology. 1987;92(3):643-650.

3. AskP,TibblingL. Effectof time interval between

swallows on esophageal peristalsis.Am J Physiol.

1980;238(6):G485-G490.

4. LeceaB, Gallego D,FarrR, Clav P. Origin and

modulation of circular smoothmuscle layer

contractions in theporcine esophagus.

Neurogastroenterol Motil. 2012;24(8):779-789.

5. Broad J,Hughes F, Chin-AleongJ, SifrimD,

Sanger GJ.Regionallydependent neuromuscular

functionsof motilinand 5-HT receptors in human

isolated esophageal body and gastric fundus.

Neurogastroenterol Motil. 2014;26(9):1311-1322.

6. MuinuddinA, XueS, Diamant NE.Regional

differencesin the response of feline esophageal

smoothmuscle to stretch and cholinergic

stimulation.Am J Physiol Gastrointest Liver Physiol.

2001;281(6):G1460-G1467.

7. Wrl J,Neuhuber WL. Enteric co-innervation of

motor endplatesin theesophagus: stateof theart

ten years after.Histochem Cell Biol. 2005;123(2):

117-130.

8. Mittal RK, HongSJ, Bhargava V. Longitudinal

muscledysfunction in achalasia esophagus and its

relevance.J Neurogastroenterol Motil. 2013;19(2):

126-136.

9. MittalRK, Ren J,McCallumRW,Shaffer HAJr,

SlussJ. Modulation of feline esophagealcontractions by bolus volumeand outflow

obstruction.Am J Physiol. 1990;258(2,pt 1):G208-

G215.

10. FarrukhA, DeCaestecker J, Mayberry JF.

An epidemiological studyof achalasia amongthe

SouthAsian population of Leicester, 1986-2005.

Dysphagia. 2008;23(2):161-164.

11. Birgisson S,Richter JE.Achalasia in Iceland,

1952-2002: an epidemiologicstudy. DigDisSci.

2007;52(8):1855-1860.

12. Sadowski DC,Ackah F, JiangB, Svenson LW.

Achalasia: incidence,prevalence and survival:

a population-based study. Neurogastroenterol Motil.

2010;22(9):e256-e261.

13. EnestvedtBK, Williams JL, SonnenbergA.

Epidemiology andpracticepatterns of achalasia in a

large multi-centre database.AlimentPharmacol Ther.

2011;33(11):1209-1214.

14. Gennaro N, Portale G, Gallo C, etal. Esophageal

achalasia in the Veneto region: epidemiologyand

treatment:epidemiology and treatmentof

achalasia.J Gastrointest Surg. 2011;15(3):423-428.

15. SonnenbergA. Hospitalization for achalasia in

the United States 1997-2006. DigDisSci. 2009;54

(8):1680-1685.

16. NenshiR, Takata J,StegienkoS, etal. Thecost

of achalasia:quantifyingthe effectof symptomatic

disease on patient costburden, treatmenttime,

and workproductivity.Surg Innov. 2010;17(4):291-

294.

17. JohnstonBT, Colcher A, Li Q,GideonRM,

Castell JA, Castell DO.Repetitive proximalesophagealcontractions: a new manometricfinding

and a possible further link between Parkinsons

disease and achalasia. Dysphagia. 2001;16(3):186-

189.

18. ZrateN, MearinF, Gil-Vernet JM, Camarasa F,

Malagelada JR. Achalasia and Downs syndrome:

coincidental association or something else?Am J

Gastroenterol. 1999;94(6):1674-1677.

19. Jung KW, YoonIJ, KimH, etal. Genetic

evaluationof ALADIN genein early-onsetachalasia

and alacrima patients. J Neurogastroenterol Motil.

2011;17(2):169-173.

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-

flow obstruction suchas myotomy(laparoscopicor endoscopic)

or pneumatic dilation should be offeredto patients without con-

traindications to surgery.






11/12


20. Stuckey BG,Mastaglia FL,ReedWD, PullanPT.

Glucocorticoidinsufficiency, achalasia, alacrima

withautonomic motorneuropathy.Ann Intern Med.

1987;106(1):61-63.

21. SarathiV, ShahNS. Triple-A syndrome.Adv Exp

MedBiol. 2010;685:1-8.

22. Gordillo-GonzlezG, GuatibonzaYP,Zarante I,

RoaP,Jacome LA,Hani A. Achalasiafamiliar:report

of a familywithan autosomaldominantpatternof

inherence. Dis Esophagus. 2011;24(1):E1-E4.

23. VigoAG, Martnez A, dela ConchaEG, Urcelay

E, Ruiz de Len A. Suggestedassociation of NOS2A

polymorphismin idiopathic achalasia: no evidence

in a large case-control study. Am J Gastroenterol.

2009;104(5):1326-1327.

24. deLen AR, dela Serna JP, Santiago JL, etal.

Association between idiopathic achalasia and IL23R

gene. NeurogastroenterolMotil. 2010;22(7):734-738,

e218.

25. Nuez C, Garca-Gonzlez MA, Santiago JL,

et al. Associationof IL10promoter polymorphisms

with idiopathic achalasia. Hum Immunol. 2011;72

(9):749-752.

26. Goldblum JR,Whyte RI,OrringerMB,

Appelman HD. Achalasia:a morphologic studyof 42

resected specimens.Am J Surg Pathol. 1994;18(4):

327-337.

27. Boeckxstaens GE. Achalasia: virus-induced

euthanasiaof neurons?Am J Gastroenterol. 2008;

103(7):1610-1612.

28. Booy JD, Takata J,TomlinsonG, UrbachDR.

Theprevalenceof autoimmunedisease in patients

withesophagealachalasia. Dis Esophagus. 2012;25

(3):209-213.

29. KraichelyRE, Farrugia G, Pittock SJ, Castell DO,

Lennon VA.Neural autoantibodyprofile of primary

achalasia. Dig Dis Sci. 2010;55(2):307-311.

30. deOliveira RB,RezendeFilhoJ, DantasRO,

Iazigi N.The spectrum of esophageal motor

disorders in Chagas disease.Am J Gastroenterol.

1995;90(7):1119-1124.31. Gockel I, Bohl JRE,EckardtVF,Junginger T.

Reductionof interstitialcellsof Cajal (ICC)

associated withneuronal nitricoxide synthase

(n-NOS) in patients withachalasia.Am J

Gastroenterol. 2008;103(4):856-864.

32. Gockel I, Bohl JRE, DoostkamS, EckardtVF,

Junginger T. Spectrum of histopathologic findings

in patients withachalasia reflects different

etiologies.J Gastroenterol Hepatol. 2006;21(4):

727-733.

33. TsuboiK, Hoshino M, Srinivasan A, etal.

Insights gainedfrom symptom evaluationof

esophageal motility disorders: a review of 4,215

patients. Digestion. 2012;85(3):236-242.

34. SinanH, Tatum RP, SoaresRV,Martin AV,

PellegriniCA, Oelschlager BK. Prevalenceofrespiratory symptoms in patients withachalasia. Dis

Esophagus. 2011;24(4):224-228.

35. NgKY,Li KF, LokKH, et al.Ten-yearreview of

epidemiology, clinical features, and treatment

outcome of achalasia in a regional hospital inHong

Kong. HongKong MedJ. 2010;16(5):362-366.

36. Bhattacharyya N. Theprevalenceof dysphagia

among adultsin theUnitedStates. Otolaryngol

Head Neck Surg. 2014;151(5):765-769.

37. Gupta M,Ghoshal UC,Jindal S,MisraA, Nath A,

Saraswat VA.Respiratorydysfunction is commonin

patients withachalasia and improves after

pneumatic dilation. DigDisSci. 2014;59(4):744-752.

38. SchechterRB, LemmeEMO, NovaisP,Biccas B.

Achalasia in theelderly patient: a comparative

study.Arq Gastroenterol. 2011;48(1):19-23.

39. RakitaSS, VilladolidD, KalipersadC, Thometz

D,RosemurgyA. BMI affects presentingsymptoms

of achalasia and outcome after Heller myotomy.

Surg Endosc. 2007;21(2):258-264.

40. Mikaeli J, Farrokhi F,BishehsariF, Mahdavinia

M, MalekzadehR. Gender effect on clinical features

of achalasia:a prospectivestudy. BMC Gastroenterol.

2006;6:12.

41. Wuller C, Bessell JR,Watson DI.Chest pain

beforeand afterlaparoscopiccardiomyotomy for

achalasia.ANZ J Surg. 2011;81(9):590-594.

42. Hong SJ, Bhargava V, JiangY, Denboer D,Mittal

RK.A uniqueesophageal motor pattern that

involves longitudinalmuscles is responsiblefor

emptyingin achalasia esophagus. Gastroenterology.

2010;139(1):102-111.

43. BogteA, BredenoordAJ,Oors J,SiersemaPD,

SmoutAJPM. Reproducibility of esophageal

high-resolution manometry.Neurogastroenterol Motil.

2011;23(7):e271-e276.

44. Fox M, Hebbard G, JaniakP,et al.

High-resolution manometry predicts the success of

oesophagealbolus transport and identifies clinically

important abnormalities not detected by

conventional manometry. Neurogastroenterol Motil.

2004;16(5):533-542.

45. Pandolfino JE,GhoshSK, ZhangQ, JaroszA,

ShahN, Kahrilas PJ. QuantifyingEGJ morphology

and relaxation withhigh-resolutionmanometry:

a studyof 75 asymptomatic volunteers.Am J

Physiol Gastrointest LiverPhysiol. 2006;290(5):

G1033-G1040.

46. PandolfinoJE, GhoshSK, Rice J,Clarke JO,

Kwiatek MA, Kahrilas PJ. Classifying esophageal

motility by pressure topographycharacteristics:

a study of 400patientsand 75 controls.Am J

Gastroenterol. 2008;103(1):27-37.

47. GhoshSK,Pandolfino JE,Zhang Q, JaroszA,

ShahN, Kahrilas PJ. Quantifyingesophageal

peristalsis withhigh-resolutionmanometry: a study

of 75 asymptomatic volunteers.Am J Physiol

Gastrointest Liver Physiol. 2006;290(5):G988-G997.

48. Scherer JR,KwiatekMA, SoperNJ, Pandolfino

JE, Kahrilas PJ. Functionalesophagogastricjunction

obstructionwith intactperistalsis: a heterogeneous

syndrome sometimes akin to achalasia.

J Gastrointest Surg. 2009;13(12):2219-2225.

49. Ghosh SK,Pandolfino JE,RiceJ, ClarkeJO,

Kwiatek M, Kahrilas PJ. Impaired deglutitiveEGJ

relaxation in clinical esophagealmanometry:

a quantitativeanalysisof 400patients and75

controls.Am J Physiol Gastrointest Liver Physiol.

2007;293(4):G878-G885.

50. Kahrilas PJ,Bredenoord AJ, FoxM, etal;

International HighResolutionManometryWorking

Group. TheChicago Classificationof esophageal

motility disorders, v3.0. Neurogastroenterol Motil.

2015;27(2):160-174.

51. Pandolfino JE, Kahrilas PJ; American

Gastroenterological Association.American

Gastroenterological Association medical position

statement:clinicaluse of esophageal manometry.


52. Pandolfino JE, Kwiatek MA, Nealis T, Bulsiewicz

W,PostJ, Kahrilas PJ.Achalasia: a newclinically

relevant classificationby high-resolution

manometry. Gastroenterology. 2008;135(5):1526-

1533.

53. Krishnan K, LinC-Y, Keswani R, PandolfinoJE,

Kahrilas PJ, Komanduri S. Endoscopic ultrasound as

an adjunctiveevaluationin patients with

esophageal motordisorders subtyped by

high-resolution manometry.Neurogastroenterol Motil.2014;26(8):1172-1178.

54. Pasricha PJ,Rai R, RavichWJ, HendrixTR,

KallooAN. Botulinum toxinfor achalasia: long-term

outcome and predictors of response.


55. Boeckxstaens GE, Annese V, des VarannesSB,

et al; European Achalasia Trial Investigators.

Pneumaticdilation versuslaparoscopicHellers

myotomy for idiopathic achalasia. N EnglJ Med.

2011;364(19):1807-1816.

56. Persson J,JohnssonE, KosticS, Lundell L,

SmedhU. Treatment of achalasia with laparoscopic

myotomy or pneumatic dilatation: long-termresults

of a prospective, randomizedstudy. WorldJ Surg.

2015;39(3):713-720.

57. RichardsWO, Torquati A, Holzman MD, et al.Hellermyotomyversus Hellermyotomywith Dor

fundoplication for achalasia: a prospective

randomizeddouble-blind clinical trial.Ann Surg.

2004;240(3):405-412.

58. RebecchiF,GiacconeC, Farinella E, Campaci R,

MorinoM. Randomizedcontrolledtrial of

laparoscopic Heller myotomy plus Dor

fundoplication versusNissen fundoplication for

achalasia: long-termresults.Ann Surg. 2008;248

(6):1023-1030.

59. Rawlings A, Soper NJ, Oelschlager B, etal.

LaparoscopicDor versusToupetfundoplication

followingHellermyotomyfor achalasia:resultsof a

multicenter,pr ospective, randomized-controlled

trial.Surg Endosc. 2012;26(1):18-26.

60. Kostic S,JohnssonE, KjellinA, etal. Healtheconomic evaluationof therapeutic strategiesin

patients withidiopathicachalasia:results of a

randomizedtrial comparing pneumatic dilatation

withlaparoscopiccardiomyotomy.Surg Endosc.

2007;21(7):1184-1189.

61. NovaisPA, LemmeEMO. 24-hpH monitoring

patterns and clinical response afterachalasia

treatment withpneumaticdilation or laparoscopic

Heller myotomy. Aliment Pharmacol Ther. 2010;

32(10):1257-1265.

62. Bakhshipour A, Rabbani R, Shirani S,Soleimani

HA, Mikaeli J.Comparison of pneumatic dilation

withpneumaticdilation plus botulinum toxinfor

treatment of achalasia.Acta Med Iran. 2010;48(2):

107-110.

63. Gelfond M, Rozen P, GilatT. Isosorbide dinitrateand nifedipinetreatmentof achalasia: a clinical,

manometric and radionuclideevaluation.


64. Bortolotti M, Mari C, Lopilato C,Porrazzo G,

Miglioli M.Effectsof sildenafilon esophageal

motility of patients withidiopathicachalasia.


65. AnneseV, Bassotti G,CocciaG, et al;GISMAD

Achalasia StudyGroup. A multicentrerandomised

studyof intrasphinctericbotulinumtoxin in






12/12

C i ht 2015 A i M di l A i ti All i ht d

patients withoesophageal achalasia. Gut. 2000;46

(5):597-600.

66. Vaezi MF, Richter JE,Wilcox CM,et al.

Botulinum toxinversus pneumatic dilatation in the

treatment of achalasia: a randomised trial. Gut.

1999;44(2):231-239.

67. ZaninottoG, AnneseV,Costantini M,et al.

Randomized controlled trialof botulinum toxin

versuslaparoscopicheller myotomy for esophageal

achalasia.Ann Surg. 2004;239(3):364-370.

68. SmithCD, StivalA, HowellDL, SwaffordV.

Endoscopic therapy for achalasia beforeHeller

myotomy results in worseoutcomes thanHeller

myotomy alone.Ann Surg. 2006;243(5):579-584.

69. LynchKL, PandolfinoJE, HowdenCW,Kahrilas

PJ. Majorcomplications of pneumatic dilation and

Heller myotomy for achalasia: single-center

experienceand systematic reviewof theliterature.

Am J Gastroenterol. 2012;107(12):1817-1825.

70. FarhoomandK, Connor JT, Richter JE, Achkar

E, VaeziMF.Predictors of outcome of pneumatic

dilation in achalasia. ClinGastroenterol Hepatol.

2004;2(5):389-394.

71. PratapN, ReddyDN. Canachalasia subtypingby

high-resolution manometry predict thetherapeutic

outcome of pneumaticballoon dilatation? authors

reply.J Neurogastroenterol Motil. 2011;17(2):205.

72. Campos GM,Vittinghoff E, Rabl C, etal.

Endoscopic and surgical treatments for achalasia:

a systematicreview and meta-analysis.Ann Surg.

2009;249(1):45-57.

73. Pasricha PJ,Hawari R, Ahmed I, etal.

Submucosal endoscopic esophagealmyotomy:

a novel experimental approach forthe treatmentof

achalasia. Endoscopy. 2007;39(9):761-764.

74. InoueH, MinamiH, KobayashiY,et al.Peroral

endoscopic myotomy (POEM) for esophageal

achalasia. Endoscopy. 2010;42(4):265-271.

75. InoueH, Kudo S-E. Per-oralendoscopic

myotomy (POEM)for 43 consecutivecasesof

esophagealachalasia [in Japanese]. NihonRinsho.

2010;68(9):1749-1752.

76. SwanstrmLL, RiederE, DunstCM. A stepwise

approach and earlyclinical experience in peroral

endoscopicmyotomy for thetreatmentof achalasia

and esophageal motility disorders. J Am Coll Surg.

2011;213(6):751-756.

77. von Renteln D,InoueH, MinamiH, etal. Peroral

endoscopicmyotomy for thetreatmentof

achalasia: a prospectivesingle center study.Am JGastroenterol. 2012;107(3):411-417.

78. Bhayani NH, KurianAA, DunstCM, Sharata AM,

RiederE, Swanstrom LL.A comparative studyon

comprehensive, objective outcomes of

laparoscopicHeller myotomy withper-oral

endoscopic myotomy (POEM)for achalasia.Ann Surg.

2014;259(6):1098-1103.

79. Hungness ES,Teitelbaum EN,Santos BF, etal.

Comparison of perioperative outcomes between

peroral esophageal myotomy (POEM) and

laparoscopicHeller myotomy.J Gastrointest Surg.

2013;17(2):228-235.

80. KhashabMA, Messallam AA,Onimaru M,et al.

International multicenterexperience withperoral

endoscopicmyotomy for thetreatmentof spastic

esophagealdisorders refractory to medical therapy.Gastrointest Endosc. 2015;3:1-8.

81. Rohof WO, Salvador R, AnneseV,et al.

Outcomes of treatmentfor achalasia depend on

manometric subtype. Gastroenterology. 2013;144

(4):718-725.

82. RomanS, ZerbibF, Queneherv L, Clermidy H,

VarannesSB, MionF. TheChicago classificationfor

achalasia in a French multicentriccohort. DigLiverDis.

2012;44(12):976-980.

83. Salvador R, Costantini M, ZaninottoG, etal.

Thepreoperative manometricpattern predicts the

outcome of surgical treatment for esophageal

achalasia.J GastrointestSurg. 2010;14(11):1635-1645.

84. MinM, PengLH, YangYS, etal. Characteristics

of achalasia subtypes in untreatedChinese

patients: a high-resolution manometry study.J Dig

Dis. 2012;13(10):504-509.

85. VaeziMF,Pandolfino JE,VelaMF.ACG clinical

guideline:diagnosis and management of achalasia.

Am J Gastroenterol. 2013;108(8):1238-1249.

86. RomanS, Kahrilas PJ,Mion F, etal. Partial

recovery of peristalsis aftermyotomy for achalasia:

moretherule than theexception.JAMA Surg. 2013;

148(2):157-164.

87. LeeuwenburghI, Scholten P, AlderliestenJ,

et al. Long-termesophageal cancer risk in patients

with primary achalasia: a prospective study.Am J

Gastroenterol. 2010;105(10):2144-2149.

88. Ravi K, Geno DM,KatzkaDA. Esophageal

cancer screening in achalasia: is therea consensus?

[published online March 6, 2014]. Dis Esophagus.

doi:10.1111/dote.12196.

89. Zaninotto G,Costantini M,RizzettoC, et al.

Four hundred laparoscopicmyotomiesfor

esophageal achalasia:a singlecentre experience.

Ann Surg. 2008;248(6):986-993.

90. Bonatti H, HinderRA, Klocker J,et al.

Long-termresults of laparoscopicHeller myotomy

withpartial fundoplication for the treatmentof

achalasia.Am J Surg. 2005;190(6):874-878.

91. ZaninottoG, Portale G, Costantini M,et al.

Long-termresults (6-10 years) of laparoscopic

fundoplication.J Gastrointest Surg. 2007;11(9):1138-

1145.

92. Costantini M,Zaninotto G,Guirroli E, etal.

ThelaparoscopicHeller-Dor operation remains an

effective treatmentfor esophagealachalasia at a

minimum 6-year follow-up.Surg Endosc. 2005;19

(3):345-351.

93. Eckardt VF, Hoischen T, Bernhard G.Life

expectancy, complications, and causesof deathin

patients withachalasia:results of a 33-year

follow-up investigation. EurJ Gastroenterol Hepatol.

2008;20(10):956-960.


1852 JAMA May 12,2015 Volume 313, Number18 (Reprinted) jama.com

C i ht 2015 A i M di l A i ti All i ht d

achalasia a systematic review

Documents