ClinicalReview&Education Review Achalasia ASystematicRevie · Copyright 2015 American Medical...

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AchalasiaA Systematic ReviewJohn E. Pandolfino, MD, MSCI; Andrew J. Gawron, MD, PhD, MS

T he constellation of dysphagia (difficulty swallowing), chestpain, and reflux symptoms may be caused by a variety ofdiseases 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 from the Greek khalasis, translated as “notloosening or relaxing.” A common historical definition of achalasiais the inability of the lower esophageal sphincter to relax in the set-ting of absent peristalsis. An initial trial of acid suppression (6-8weeks) is reasonable, but when dysphagia symptoms persist or aredominated by the report of dysphagia, endoscopy should be per-formed to evaluate for mechanical obstruction or inflammatory pro-cesses. When these are not found, achalasia should be considered,especially in the setting of dysphagia primarily to liquids. Liquids canpool and accumulate above a tight, “unrelaxing” lower esophageal

sphincter, whereas they are usually less of an issue in the setting ofstructural causes of dysphagia.

Recent advances in diagnostic testing for achalasia, especiallyhigh-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 clinical approach to patients with achalasia, em-phasizing published evidence pertinent to both primary care clini-cians and specialist physicians.

Evidence Acquisition and SynthesisThe literature was reviewed based on an initial broad MEDLINEsearch using the terms ((((esophageal motility) OR achalasia) OR high

IMPORTANCE Achalasia significantly affects patients’ quality of life and can be difficult todiagnose and treat.

OBJECTIVE To review the diagnosis and management of achalasia, with a focus on phenotypicclassification pertinent to therapeutic outcomes.

EVIDENCE REVIEW Literature review and MEDLINE search of articles from January 2004 toFebruary 2015. A total of 93 articles were included in the final literature review addressingfacets of achalasia epidemiology, pathophysiology, diagnosis, treatment, and outcomes. Ninerandomized controlled trials focusing on endoscopic or surgical therapy for achalasia wereincluded (734 total patients).

FINDINGS A diagnosis of achalasia should be considered when patients present withdysphagia, chest pain, and refractory reflux symptoms after an endoscopy does not reveal amechanical obstruction or an inflammatory cause of esophageal symptoms. Manometryshould be performed if achalasia is suspected. Randomized controlled trials supporttreatments focused on disrupting the lower esophageal sphincter with pneumatic dilation(70%-90% effective) or laparoscopic myotomy (88%-95% effective). Patients with achalasiahave a variable prognosis after endoscopic or surgical myotomy based on subtypes, with typeII (absent peristalsis with abnormal pan-esophageal high-pressure patterns) having a veryfavorable outcome (96%) and type I (absent peristalsis without abnormal pressure) having anintermediate prognosis (81%) that is inversely associated with the degree of esophagealdilatation. In contrast, type III (absent peristalsis with distal esophageal spastic contractions)is a spastic variant with less favorable outcomes (66%) after treatment of the loweresophageal sphincter.

CONCLUSIONS AND RELEVANCE Achalasia should be considered when dysphagia is presentand not explained by an obstruction or inflammatory process. Responses to treatment varybased on which achalasia subtype is present.

JAMA. 2015;313(18):1841-1852. doi:10.1001/jama.2015.2996

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Author Affiliations: Division ofGastroenterology and Hepatology,Feinberg School of Medicine,Northwestern University, Chicago,Illinois (Pandolfino); Division ofGastroenterology, Hepatology, andNutrition, University of Utah, SaltLake City (Gawron).

Corresponding Author: John E.Pandolfino, MD, MSCI, Division ofGastroenterology and Hepatology,Department of Medicine, FeinbergSchool of Medicine, NorthwesternUniversity, 676 N St Clair St, Ste 1409,Chicago, IL 60611 ([email protected]).

Section Editor: Mary McGraeMcDermott, MD, Senior Editor.

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resolution manometry) OR Chicago classification) OR esophagealperistalsis. Articles published from January 2004 to February 2015in English were included.

This search yielded 6194 references, of which 5788 were inEnglish. Case reports (n = 521) and review articles (n = 899) wereexcluded. Articles were further searched using terms specific for epi-demiology, genetics, diagnosis, manometry, surgery, pneumatic di-lation, botulinum toxin, and per-oral endoscopic myotomy. Otherpertinent articles and guidelines were obtained through citations orwere known to the authors. We reviewed titles and abstracts to de-termine relevance to the article sections and ultimately included 93articles in the review (n = 4276 excluded). A total of 9 randomizedcontrolled trials were included when evaluating endoscopic and sur-gical treatment modalities (comprising 734 total patients). Detailsare shown in the eFigure in the Supplement.

Structure and Normal Function of the EsophagusThe esophagus is an 18- to 26-cm muscular hollow tube thattransports food from the oropharynx into the stomach (Figure 1).There are 4 primary layers of esophageal tissue—the mucosa, sub-

mucosa, muscularis propria, and adventitia. The esophagus origi-nates at the level of the cricoid cartilage and normally terminatesbelow the hiatus in the right crura of the diaphragm. The muscu-laris propria gradually changes from predominant skeletal musclein the upper esophagus to predominantly smooth muscle in thedistal esophagus, with mixing of muscle types along the length ofthe esophagus (Figure 1). Both circular and longitudinal musclelayers are present, and within the diaphragmatic hiatus thereexists a 2- to 4-cm thickened circular muscle layer, the loweresophageal sphincter. Esophageal innervation consists of bothparasympathetic and sympathetic nerves, with peristalsis regu-lated via the parasympathetic pathway from the vagus nerve andthe intrinsic enteric nervous system.

Despite the seemingly simple task of food transport, the mecha-nism and control of esophageal function is complex, largely owingto the neural coordination required with the oropharynx and tran-sition through different anatomical domains with mixed muscletypes. Once a food or liquid bolus enters the esophagus, primary peri-stalsis strips the food bolus down the length of the esophagus. Peri-staltic contraction in the striated muscle esophagus is dependenton central mechanisms that involve sequential activation of excit-atory activity of lower motor neurons in the vagal nucleus am-

Figure 1. Anatomy and Innervation of the Esophagus

Cruraldiaphragm

Esophagus

Cricoidcartilage

LES

Circularmuscle

Circularmuscle

Submucosa

Lumen

Longitudinalmuscle

Longitudinalmuscle (reflected)

S T O M A C H

E S O P H A G U S

Diaphragm(cut)

Esophagogastricjunction LES Crural diaphragm Proximal gastric cardia

Mucosa

Muscularispropria

Adventitia

Esophageal plexus

Myenteric plexus ganglion with postganglionic neurons

Myenteric plexusStriatedmuscle

Transition zone

Smoothmuscle

Upperesophageal

sphincter(UES)

Loweresophageal

sphincter(LES)

Level of section

Muscularismucosa

Stratifiedsquamousepithelium

Submucosalplexus

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 This promotes peristaltic propagation through asequenced top-to-bottom excitation mediated by release of ace-tylcholine at the motor end plates (Figure 2).1

Primary peristalsis in esophageal smooth muscle is preceded byinhibition, which stops a progressing peristaltic wave when an-other swallow is initiated.2,3 This involves patterned activation ofpreganglionic neurons in the dorsal motor nucleus of the vagus thatproject onto inhibitory and excitatory neurons in the esophagealmyenteric plexus (Figure 2). Under normal circumstances, the in-hibitory pathway is activated first to relax the esophagus to pro-mote filling and transport through the esophagus. The inhibitory neu-

rons activated by the preganglionic neurons from the caudal dorsalmotor neuron release nitric oxide to promote deglutitive inhibi-tion. This is followed by sequential activation of excitatory neu-rons, which releases acetylcholine in response to activation by pre-ganglionic neurons arising from the rostral dorsal motor nucleus.

The direction and rate of propagation is modulated by the in-creasing inhibitory influence in the distal esophagus, called the la-tency gradient.2,3 This essentially delays contractions in the distalesophagus and allows propagation to proceed in an aboral direc-tion. Secondary peristalsis related to distention of the esophagus willelicit a local reflex independent of the vagal input from the dorsal

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

B Esophageal pressure topography (EPT) plot from highresolution 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 innervationParasympathetic efferentNeuromuscular junction

Smooth muscle innervationPreganglionic excitatory neuronPreganglionic inhibitory neuron Postganglionic excitatory neuron cell bodyPostganglionic inhibitory neuron cell body

A N T E R I O RP O S T E R I O R

P O N S

EsophagusNucleus ambiguus

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

Striatedmuscle

Transitionzone

Smooth muscle

A, The esophagus is controlled by both centrally mediated and peripheralintrinsic processes that are compartmentalized based on location in theesophagus and muscle type. B, Output from high-resolution manometry,displayed as esophageal pressure topography (Clouse plot), showingesophageal pressures over time after a single swallow. The x-axis indicates time;the y-axis indicates location from the oropharynx to the stomach, as shown inpanel C. Pressure is displayed on a color scale instead of the conventionaltracings; thus, a seamless dynamic representation of motor activity is displayed

that provides anatomical representation of the pressure profile. The striatedmuscle esophagus can be distinguished from the smooth muscle esophagus, asthere is a pressure gap at the transition zone that demarcates the introductionof smooth muscle activity. The sphincters are distinguished by the 2 areas ofhigh pressure between the striated and smooth muscle esophagus. LESindicates lower esophageal sphincter; UES, upper esophageal sphincter.Esophageal pressure topography plot reproduced with permission from theEsophageal Center at Northwestern Medicine.

Achalasia Review Clinical Review & Education





motor nucleus that causes contraction above the distention and re-laxation below the distention via the intrinsic inhibitory and excit-atory myenteric neurons.

Regional differences in the density of the inhibitory and excit-atory neurons in the enteric nervous system determine the direc-tion and vigor of the contraction, and this may be modulated by vari-able smooth muscle response to the same quantum ofneurotransmitter.4-6 The pathogenesis of achalasia can be concep-tualized as a disruption of the balance between the regional excit-atory and inhibitory response elicited along the axial location of theesophageal 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 activation overlaps with the propagating circular muscleto 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 generationof symptoms.8,9

Ultimately, the progressing peristaltic waves must advance thefood bolus into the stomach across the esophagogastric junction.This junction is a high-pressure zone comprising the lower esoph-ageal sphincter, the crural diaphragm, and proximal gastric cardia.Normal resting lower esophageal sphincter tone is 10 to 30 mm Hg,which helps prevent reflux of gastric contents back into the esopha-gus. Relaxation of the lower esophageal sphincter to allow empty-ing of the esophagus is triggered by swallowing or esophageal dis-tention mediated by both peripheral and central mechanisms.Relaxation of the sphincter is related to a number of nonadrenergicnoncholinergic neurotransmitters, the most prominent being ni-tric oxide.

Epidemiology and Genetics of AchalasiaAchalasia has an annual reported incidence of approximately1/100 000 worldwide.10-13 In Iceland, 62 cases of achalasia were di-

agnosed over the course of 51 years (overall incidence, 0.6/100 000per year; mean prevalence, 8.7 cases /100 000).11 Gennaro et al14

recently reported an incident rate in Italy of 1.59 cases/100 000 peryear (2001-2005). Due to the chronicity of achalasia, the esti-mated prevalence of achalasia is approximately 9/100 000 to10/100 000.11,12 In the United States, rates of hospitalization forachalasia depend on patient age, ranging from 0.25/100 000(<18 years) to a high of 37/100 000 (>85 years).15 Although the in-cidence is low, the chronicity of achalasia significantly affects pa-tients’ health-related quality of life, work productivity, and func-tional status compared with the general US population.16

Evidence supporting genetic underpinnings for achalasia comefrom twin and sibling studies and from the association of achalasiawith 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 syndromeassociated with defects in the AAAS gene (chromosome 12q13) andsubsequent defective tryptophan–aspartic acid repeat protein.20,21

A few reports have described familial achalasia, most recently in asingle family with an autosomal dominant pattern with 6 affectedmembers.22 Polymorphisms in the nitric oxide synthase gene havebeen investigated, but polymorphisms were found to be no differ-ent between patients with achalasia and controls.23 Because of apossible autoimmune etiology of achalasia, studies have suggestedpossible 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.

PathophysiologyAchalasia is associated with functional loss of myenteric plexusganglion cells in the distal esophagus and lower esophagealsphincter.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 viralinfection (herpes, measles) in conjunction with a genetically sus-ceptible host.27 Patients with achalasia are more likely to haveconcomitant 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 infiltratethat leads to a slow destruction of ganglion cells. The distributionand end result of this plexitis is variable and may be modified bythe host response or the etiologic stimulus. Achalasia can also beone manifestation of the widespread myenteric plexus destruc-tion in Chagas disease, a consequence of infection with the para-site Trypanosoma cruzi.30

The consequence of the myenteric plexus inflammation isdegeneration or dysfunction of inhibitory postganglionic neuronsin the distal esophagus, including the lower esophagealsphincter.31,32 These neurons use nitric oxide and vasoactiveintestinal peptide as neurotransmitters, and their dysfunctionresults in an imbalance between excitatory and inhibitory controlof the sphincter and adjacent esophagus. Unopposed cholinergicstimulation can result in impaired relaxation of the lower esopha-geal sphincter, hypercontractility of the distal esophagus, andrapidly propagated contractions in the distal esophagus. Longitu-

Box. Symptoms Suggestive of Achalasia That May PromptReferral for Esophageal Motility Testinga

Esophageal SymptomsDysphagia (90% of patients)

Heartburn (75% of patients)

Regurgitation or vomiting (45% of patients)

Noncardiac chest pain (20% of patients)

Epigastric pain (15% of patients)

Odynophagia (<5% of patients)

Other Associated Signs and SymptomsCough or asthma (20%-40% of patients)

Chronic aspiration (20%-30% of patients)

Hoarseness or sore throat (33% of patients)

Unintentional weight loss (10% of patients)

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






dinal muscle contractions and esophageal shortening can persistin achalasia. There is variable expression of these abnormalitiesamong individuals, and only impaired deglutitive relaxation of thelower esophageal sphincter is universally required as a definingfeature of achalasia.

Symptoms and SignsThe most common symptoms of achalasia are listed in the Box3-35

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 hallmarksymptom associated with a diagnosis of achalasia. The prevalenceof weekly dysphagia among US adults is approximately 4%36 and isassociated with a broad differential diagnosis and workup (Table 1).Esophageal motility testing should only be done after a structuralor mechanical obstruction has been ruled out and oropharyngealcauses are not apparent. In a single-center review of all patientswith manometry over a period of 24 years (1984-2008), Tsuboi etal33 found that patients with achalasia most commonly presentedwith dysphagia and heartburn. Other common symptoms includedchest 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 decreasedclearance of food and liquid from the esophagus, predisposingpatients to aspiration. Sinan et al34 found that of 110 patients withachalasia, 40% reported at least 1 respiratory symptom daily.Another study of 38 patients with achalasia found that 71% hadsore throat, hoarseness, or postnasal drip and 61% had cough.37 Inaddition, 17 patients (45%) had abnormal spirometry findings and12 had abnormal imaging findings such as septal thickening andnecrotizing pneumonia.37 The dysphagia preceded respiratorysymptoms by an average of 24 months, indicating the progressivenature of symptoms with lack of treatment.37 It is also important toconsider a diagnosis of connective tissue disease (eg, scleroderma)in patients with chronic respiratory issues and abnormalities ofesophageal motility.

Demographic and clinical factors may affect clinical symp-toms. Dysphagia and regurgitation are common among all ages, butyounger patients with achalasia have been found to have a higherprevalence of heartburn and chest pain than older patients.38 Obesepatients (body mass index �30) may have more frequent symp-toms of choking and vomiting, possibly related to increased abdomi-nal pressure.39 Chest pain was more commonly reported by womenthan men in a single-center retrospective review of 213 patients withachalasia.40 However, another group reported similar reports ofchest pain regardless of age or sex.41

DiagnosisDiagnosis of achalasia requires recognition of symptoms andappropriate use and interpretation of diagnostic testing (Table 1).Diagnoses can be difficult to make, and many patients havesymptoms 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 patientsprimarily 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 stricture Esophagogastroduodenoscopy,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 contractility 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 Barium esophagram, serology

Oropharyngeal Dysphagia

Structural oropharyngeal disorders

Malignancy Laryngoscopy

Spinal osteophytes Video fluoroscopy, computedtomography

Zenker diverticulum Video fluoroscopy,esophagogastroduodenoscopy

Proximal strictures, rings, or webs Esophagogastroduodenoscopy,barium esophagram

Radiation injury Video fluoroscopy,esophagogastroduodenoscopy

Oropharynx infection Laryngoscopy

Thyroid enlargement Ultrasound, computed tomography

Neuromuscular (systemic) disorders

Cerebral vascular accident Computed tomography, magneticresonance imaging

Multiple sclerosis

Focused neurologic examination,disease-specific laboratory testingand imaging

Parkinson disease

Myasthenia gravis

Amyotrophic lateral sclerosis

Muscular dystrophy

Dermatomyositis

Thyroid disorders

a pH testing indicates ambulatory pH and reflux monitoring.






of swallowing by watching the patient drink water can be helpfulin distinguishing between oropharyngeal dysphagia and esopha-geal dysphagia. Patients with oropharyngeal dysphagia will typi-cally struggle to move the bolus into the esophagus duringwater swallows and will often have coughing and immediateregurgitation. Primary oropharyngeal symptoms should firstprompt an evaluation for oropharyngeal etiologies, with a modi-fied barium cookie swallow study performed by speech pathology(Table 1).

Patients with intact oropharyngeal swallowing and dysphagiashould be evaluated for esophageal causes, and the differentialshould focus on distinguishing between a structural mechanicalobstruction and a motility disorder (Table 1). Mechanical obstruc-tion should be ruled out first, via either upper gastrointestinal tractendoscopy or radiologic imaging, prior to evaluation for abnormalmotility. Patients with a previous fundoplication or bariatric proce-dure (lap-band, gastric bypass) may also present with signs andsymptoms that mimic achalasia, and it is extremely difficult tomake the diagnosis of achalasia in the context of these operations.In these cases, it is important to look for mechanical causes ofobstruction, such as anastomotic stricture, tight lap-band, and anobstructed fundoplication.

EsophagogastroduodenoscopyEsophagogastroduodenoscopy with mucosal biopsy should be per-formed in most patients presenting with solid food dysphagia, liq-uid food dysphagia, or both. This is done to rule out erosive gastro-esophageal reflux disease, eosinophilic esophagitis, structurallesions (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 andfluid pooling in the esophagus, and resistance to intubation of thegastroesophageal junction. Patients with achalasia may alsodevelop candidiasis attributable to esophageal stasis, and evidenceof 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 toconfirm the diagnosis.

Barium EsophagramThe classic “bird’s-beak” appearance of achalasia on a barium swal-low study is a well-known image in clinical medicine (Figure 3C).Other radiographic features suggestive of an esophageal motility dis-order include esophageal dilation, contrast filling the esophagus, a“corkscrew appearance,” and aperistalsis.

Esophageal ManometryEsophageal manometry to assess esophageal pressures and con-tractions along the length of a flexible catheter has become thestandard for diagnosing and classifying achalasia. Major techno-logical advances have occurred during the last decade, whereinconventional water-perfused or strain gauge systems with a linetracing output have been replaced by more reproducible43 andaccurate44 high-resolution manometry systems that presentpressure data in the context of esophageal pressure topographyplots (Figure 2 and Figure 3). These methods were originallydeveloped by Clouse and led to an improved understanding ofperistaltic contractile activity. Seminal work that characterized

high-resolution manometry metrics using Clouse plots in bothasymptomatic and symptomatic individuals45-49 eventually led tothe creation of a new classification scheme for motility disorders,called the Chicago Classification (Figure 4).50

One important advantage of esophageal pressure topographyhas been the ability to further refine conventional diagnoses, suchas achalasia, into clinically relevant phenotypes. The diagnosis ofachalasia is classically made by demonstrating impaired relaxationof the lower esophageal sphincter and absent peristalsis in theabsence of esophageal obstruction near the lower esophagealsphincter attributable to a stricture, tumor, vascular structure,implanted device, or infiltrating process.51 Three distinct subtypesof achalasia (types I, II, and III) are defined with high-resolutionmanometry that have both prognostic and potential therapeuticimplications (Figure 3).52 If criteria for achalasia subtypes are notmet, a validated hierarchical analysis is used to determine ifpatients have nonachalasia motor disorders, as shown inFigure 4.50 However, a possible diagnosis of achalasia should beconsidered 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 toconsider achalasia in patients with absent contractility, as thesecases may be confused with scleroderma owing to the complexitiesof measuring relaxation of the lower esophageal sphincter. Equivo-cal cases may require further workup with endoscopic ultrasoundin the case of EGJ outflow obstruction to rule out a subtleobstruction53 and a barium esophagram in the case of absent con-tractility to document bolus retention, which would favor a diagno-sis of achalasia.

TreatmentThere are no curative therapies for achalasia; a summary of treat-ment modalities is listed in Table 2. Nine randomized trials have com-pared endoscopic and surgical treatments for achalasia (Table 3).Physiologically, many treatments are directed at reducing contrac-tility in the lower esophageal sphincter to allow for adequate esoph-ageal emptying. The primary goal of management should be basedon early diagnosis to prevent late complications of the disease andpreserve remaining esophageal structure and function.

Medical TreatmentOral calcium channel blockers or nitrates cause a prompt reductionin lower esophageal sphincter pressure of up to 47% to 64%, withmild benefit for dysphagia.63 These medications can have limitingadverse effects (headache, orthostatic hypotension, or edema) anddo not halt disease progression. Consequently, they are poor long-term treatment options and should be reserved for patients whoare poor candidates for surgical or endoscopic therapy. Nifedipine(10-30 mg, given 30-45 minutes before meals) or isorbide dinitrate(5-10 mg, given 15 minutes before meals) may be useful as short-acting temporizing treatments. Absorption and effect of oral medi-cations can be unpredictable in achalasia.

5′-Phosphodiesterase inhibitors, such as sildenafil, have alsobeen used (off-label) to treat achalasia and spastic disorders of theesophagus.64 Sildenafil lowers esophagogastric junction pressureand attenuates distal esophageal contractions by blocking the en-






zyme that degrades cyclic guanosine monophosphate induced bynitric oxide. Sildenafil is a viable alternative in patients not respond-ing to or proving intolerant of calcium channel blockers or nitrates.However, minimal long-term treatment data exist pertinent to using5′-phosphodiesterase inhibitors to treat achalasia.

Botulinum ToxinBotulinum toxin injection into the muscle of the lower esophagealsphincter was initially proposed as an achalasia treatment basedon 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 inefficacy has been demonstrated with greater doses.65 The effectis temporary and is eventually reversed by axonal regeneration;subsequent clinical series report minimal continued efficacy after1 year.54,65-67 Most patients relapse and require re-treatment

within 12 months, and repeated treatments have been shown tomake subsequent Heller myotomy more challenging.68 Thus,botulinum toxin injection should rarely be used as a first-linetherapy for achalasia and is primarily reserved for patients whoare not candidates for definitive therapy.

Pneumatic DilationA pneumatic dilator is a noncompliant, cylindrical balloon that is po-sitioned fluoroscopically across the lower esophageal sphincter andinflated with air using a handheld manometer. The reported effi-cacy of pneumatic dilation in randomized controlled trials rangesfrom 62% to 90% (Table 3). Patients with a poor result or rapid re-currence of dysphagia are unlikely to respond to additional dila-tions, but subsequent response to myotomy is not influenced. Al-though the reported incidence of perforation from pneumaticdilation ranges from 0% to 16%, a recent systematic review on the

Figure 3. Conceptual Model of Esophageal Disease Presentation and Progression Based on Phenotypes Described Using High-Resolution Manometryand Barium Esophagrams

10 s 10 s5 s 5 s

B C D

Impaired LES relaxation

Normal or impaired peristalsis


Absent peristalsis

Increased pan-esophageal pressure


Absent peristalsis

Normal esophageal pressure


Absent peristalsis

Distal esophageal spastic contractions

EGJ outflow obstruction Type II achalasia Type I achalasia Type III achalasiaA

Bird’s beak

Smooth muscle innervationPostganglionic excitatory neuronPostganglionic inhibitory neuron

0 30 60 90 120 150 180

Color pressure scale, mm Hg

Some patients may present with an esophagogastric junction (EGJ) outflowobstruction pattern (panel A) in which there is impaired lower esophagealsphincter (LES) relaxation with evidence of propagating contractions. This mayrepresent the point where the esophageal body is progressing to aperistalsisand there is variable loss of the excitatory (blue circles) and inhibitory (redcircles) influence. As preferential loss of the inhibitory neurons continues toprogress, the manometric pattern may progress to a type II pattern (panel B)associated with impaired LES relaxation and panesophageal pressurization, akinto a filled water balloon being squeezed.42 Type I achalasia (panel C) is theclassic presentation of achalasia, in which there is complete loss of contractileactivity in the body of the esophagus; this is typically a later phase of disease

progression where there is evidence of moderate to severe esophagealdilatation. Type III achalasia (panel D) is associated with prematuresimultaneous contractions that compartmentalize the bolus before it can emptythe esophagus, as evidenced by the corkscrew appearance on esophagram. Thismay represent a distinct entity that does not fall into the typical presentation ofprogressive neuron loss seen with the progression of EGJ outlet obstruction totype II achalasia, to type I achalasia. Corresponding barium esophagrams arealso shown for each subtype. Barium esophagrams and esophageal pressuretopography plots reproduced with permission from the Esophageal Center atNorthwestern Medicine.






topic concluded that using modern technique the risk was less than1%, comparable to the risk of unrecognized perforation during Hellermyotomy.69 Pneumatic dilation should be performed by experi-enced physicians, and surgical backup is required.

Studies using pneumatic dilation as the initial treatment ofachalasia have reported excellent long-term symptom control. Athird of patients will relapse in 4 to 6 years and may requirerepeat dilation. Response to therapy may be related to preproce-dural clinical parameters, such as age (favorable if >45 years), sex(more favorable among females than males),70 esophageal diam-eter (inversely related to response), and achalasia subtype (type IIbetter than I and III).52,71 Although surgical myotomy has a greaterresponse rate than a single pneumatic dilation, it appears that aseries of dilations is a reasonable alternative to surgery. A recentrandomized 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 appearto improve outcomes.62

MyotomyHeller myotomy, which divides the circular muscle fibers of thelower esophageal sphincter, is the standard surgical approach forachalasia. Laparoscopy is the preferred surgical approach becauseof its lower morbidity and comparable long-term outcome com-pared with that achieved with thoracotomy.72 LaparoscopicHeller myotomy is superior to a single pneumatic dilation in termsof efficacy and durability, with reported efficacy rates in the 88%to 95% range.55,56,60,61 However, the superiority of surgicalmyotomy over pneumatic dilation is less evident when comparedwith a graded approach to pneumatic dilation using repeat dila-tions as mandated by the clinical response.55,72 An antirefluxrepair has been shown to significantly decrease gastroesophagealreflux disease,57 and this can range from an anterior 180° fundo-plasty (Dor) to a 270° partial fundoplication (Toupet).59 There isgeneral agreement that a full 360° Nissen fundoplication is con-traindicated, as 1 randomized trial showed that 15% of patientshad recurrent dysphagia.58

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

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 function a

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 from Kahrilas et al.50 Classification algorithm based on results ofhigh-resolution manometry with ten 5-mL water swallows. Note that achalasiashould be considered in patients presenting with esophagogastric junctionoutflow obstruction and absent contractility. Failed peristalsis denotes swallowswith a distal contractile integral (DCI) less than 100 mm Hg·sec·cm (the DCIquantifies the distal contractile pressure exceeding 20 mm Hg from thetransition zone to the proximal aspect of the lower esophageal sphincter [LES][amplitude × time × length in units of mm Hg·sec·cm]).Panesophagealpressurization denotes uniform pressurization greater than 30 mm Hgextending from the upper esophageal sphincter to the esophagogastricjunction. Contractile vigor denotes the strength of distal contraction as defined

by the DCI. Ineffective esophageal motility (IEM) is diagnosed when a patientexhibits greater than 50% ineffective swallows (ineffective swallows are eitherfailed [DCI <100 mm Hg·sec·cm] or weak [DCI <450 mm Hg·sec·cm]).Fragmented swallow denotes a swallow with DCI greater than or equal to450 mm Hg·sec·cm and and a greater than 5-cm break in the pressure domain,corresponding to an intact esophageal contraction, required to push aswallowed bolus forward.a Rapid contraction and hypertensive peristalsis are not considered distinct

clinical pathological entities in Chicago Classification version 3.0.






Per-Oral Endoscopic MyotomyPer-oral endoscopic myotomy (POEM) is the newest treatmentfor achalasia.73,74 The procedure requires making a small mucosalincision in the mid-esophagus and creating a submucosal tunnelall the way to the gastric cardia using a forward-viewing endo-scope, transparent distal cap, and submucosal dissectionknife. Selective myotomy of the circular muscle is accomplishedwith electrocautery for a minimum length of 6 cm up the esopha-gus and 2 cm distal to the squamocolumnar junction onto thegastric cardia. Initial success rates of the POEM procedure in pro-spective cohorts of patients with achalasia have been greaterthan 90%, comparable with those of laparoscopic Hellermyotomy.75-77

A recent prospective, single-center study found that symp-toms and postmyotomy integrated relaxation pressures were notdifferent between patients undergoing laparoscopic Heller my-otomy or POEM.78 Preliminary results comparing more than 30POEM 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-tients with type III achalasia, perhaps due to longer myotomy lengthwith the endoscopic approach.80 There have been no randomizedtrials comparing POEM to laparoscopic myotomy or pneumatic di-

lation, and its relative efficacy in terms of long-term dysphagia con-trol, progression of esophageal dilatation, and postprocedure re-flux remains to be established.

Table 2. Summary of Current Treatments for 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 <30 min60 min observation

Pneumatic dilation 2-5y55,56 Performed in endoscopy laboratorywith fluoroscopyModerate sedation or monitoredanesthesia careProcedure time, 30 min4-6 h observation

Surgical myotomy 5-10 y56 Operating roomGeneral anesthesiaProcedure time, 90 minHospital stay, 1-2 d

Per-oralendoscopicmyotomy

Unknown Operating room or endoscopy laboratoryGeneral anesthesiaProcedure time, 90 minRequires overnight stay

a Oral calcium channel blockers, nifedipine, isosorbide dinitrate, or sildenafil.

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

Source Inclusion Criteria Sample Size, No. Comparison Outcomes

Richards et al,57

2004Patient’s diagnosis of untreatedachalasia

43 LHM vs LHM with Dorfundoplication

No significant difference in postoperative LESpressure or postoperative dysphagiaPathologic GERD: 48% for LHM vs 9% forLHM + fundoplication

Rebecchi et al,58

2008Patients with achalasia,including previous treatmentwith botulinum toxin andpneumatic dilation

144 (138 forlong-term analysis)

LHM with Dor fundoplicationvs LHM with totalfundoplication

Incidence of GERD after 60-mo follow-up: 2.8% forDor vs 0% for total (P = NS)Recurrence of dysphagia: 2.8% for Dor vs 15% fortotal (P < .001)

Rawlings et al,59

2012Patients with achalasia(untreated or previously treatedwith botulinum toxin orpneumatic dilation)

60 LHM with Dor fundoplicationvs LHM with Toupetfundoplication

Reflux symptoms: no differencePositive 24-h pH testing: no differenceImprovement in dysphagia: no difference

Kostic et al,60 2007 Patients with newly diagnoseduntreated achalasia

51 Pneumatic dilation vs LHMwith Toupet fundoplication

Cumulative number of treatment failures at 12 mo:6 treatment failures in pneumatic dilation group vs1 treatment failure in LHM group (P = .04)

Novais et al,61

2010Patients with newly diagnosedachalasia

94 Pneumatic dilation vs LHM Clinical response at 3 mo: 73.1% for pneumaticdilation vs 88.3% for LHM (P = .08)Manometric response at 3 mo: no difference betweengroupsIncidence of GERD (24-h pH measurement): 31% forpneumatic dilation vs 5% for LHM (P = .0001)

Boeckxstaenset al,55 2011

Patients with newly diagnosedachalasia

201 (LHM = 106,pneumaticdilation = 95)

Pneumatic dilation vs LHMwith Dor fundoplication

Decrease in Eckardt score of ≤3 at 12 mo and 24 mo:(1) 90% for 12-mo pneumatic dilation vs 93% forLHM (P = .46) and (2) 86% for 24-mo pneumaticdilation vs 90% for LHM (P = .46)LES pressure, esophageal emptying, quality of life,complications: (1) no difference in LES pressure,quality of life, or esophageal emptying and (2) 4%perforation rate with pneumatic dilation and 12%mucosal tear rate with LHM

Persson et al,56


53 (LHM = 25,pneumaticdilation = 28)

Pneumatic dilation vs LHMwith posterior fundoplication

Treatment failure: (1) 4% for LHM vs 32% forpneumatic dilation at 3 y and (2) 8% for LHM vs36% for pneumatic dilation at 5 y

Mikaeli et al,40


54 Botulinum toxin 1 mo beforepneumatic dilation vspneumatic dilation alone

Cumulative 1-y remission rate: 77% for botulinumtoxin + pneumatic dilation vs 62% for pneumaticdilation alone (P = .10)

Bakhshipouret al,62 2009

Patients with achalasia withfailed 30- and 35-mmpneumatic dilation orbotulinum toxin

34 Pneumatic dilation vspneumatic dilation +botulinum toxin injection

Symptoms at 1, 6, and 12 mo: no significantdifference in symptom scores at all time intervals

Abbreviations: GERD, gastroesophageal reflux disease; LES, lower espophageal sphincter; LHM, laparoscopic Heller myotomy.






Prognosis and Follow-up

Multiple publications now support the prognostic value of achala-sia subtypes: (1) patients with type II achalasia have the best prog-nosis from treatment involving myotomy or pneumatic dilation (96%success rate)81; (2) the treatment response of patients with type Iis less robust, at 81%81 (and is reduced further as the degree of esoph-ageal dilatation increases); and (3) patients with type III have a worseprognosis (66%),81 likely because the associated spasm is less likelyto respond to therapies directed at the lower esophagealsphincter.52,71,82-84

The optimal approach in providing follow-up for patients withachalasia is focused on periodic evaluation of symptom relief, nu-trition status, and esophageal emptying by timed bariumesophagram.85 Posttreatment manometry can also be used in follow-up, depending on patient tolerance for the procedure andavailability.85 Esophageal contractile activity may return after treat-ment. In 1 retrospective study, 4 of 7 patients with type I achalasia(57%), 6 of 17 with type II achalasia (35%), and 1 of 5 with type IIIachalasia (20%) had return of weak esophageal contractile activityafter myotomy.86 Although decisions to intervene are never basedsolely on barium esophagram or manometry alone, they do iden-tify patients who should be followed up closely to prevent progres-sion. Although the risk of squamous carcinoma is higher in patientswith achalasia than in the general population, there are no data tosupport routine endoscopic surveillance, and this is left to the judg-ment of the physician.87,88

Treatment Failures

Achalasia treatment is not curative, and up to 20% of patients havesymptoms that may require additional treatments within 5years.89-92 Up to 6% to 20% of treated patients may have progres-sive dilation to megaesophagus or end-stage disease.93 Manage-ment of the care of these patients is difficult, and options includebotulinum toxin injection, repeat pneumatic dilation, or repeat my-otomy. Esophagectomy is ultimately reserved as a final option in pa-tients with severe esophageal dilatation and symptoms not respond-ing to dilation and myotomy.

ARTICLE INFORMATION

Author Contributions: Drs Pandolfino and Gawronhad full access to all of the data in the study andtake responsibility for the integrity of the data andthe accuracy of the data analysis.Study concept and design: Pandolfino, Gawron.Drafting of the manuscript: Pandolfino, Gawron.Critical revision of the manuscript for importantintellectual content: Pandolfino, Gawron.Study supervision: Pandolfino.

Conflict of Interest Disclosures: The authors havecompleted and submitted the ICMJE Form forDisclosure of Potential Conflicts of Interest. DrPandolfino reported receiving consulting andspeaking fees from Given Imaging/Covidien andSandhill Scientific. Dr Gawron reported nodisclosures.

Submissions: We encourage authors to submitpapers for consideration as a Review. Pleasecontact Mary McGrae McDermott, MD, [email protected].

REFERENCES

1. Gidda JS, Goyal RK. Regional gradient of initialinhibition and refractoriness in esophageal smoothmuscle. Gastroenterology. 1985;89(4):843-851.

2. Vanek AW, Diamant NE. Responses of thehuman esophagus to paired swallows.Gastroenterology. 1987;92(3):643-650.

3. Ask P, Tibbling L. Effect of time interval betweenswallows on esophageal peristalsis. Am J Physiol.1980;238(6):G485-G490.

4. Lecea B, Gallego D, Farré R, Clavé P. Origin andmodulation of circular smooth muscle layer

contractions in the porcine esophagus.Neurogastroenterol Motil. 2012;24(8):779-789.

5. Broad J, Hughes F, Chin-Aleong J, Sifrim D,Sanger GJ. Regionally dependent neuromuscularfunctions of motilin and 5-HT4 receptors in humanisolated esophageal body and gastric fundus.Neurogastroenterol Motil. 2014;26(9):1311-1322.

6. Muinuddin A, Xue S, Diamant NE. Regionaldifferences in the response of feline esophagealsmooth muscle to stretch and cholinergicstimulation. Am J Physiol Gastrointest Liver Physiol.2001;281(6):G1460-G1467.

7. Wörl J, Neuhuber WL. Enteric co-innervation ofmotor endplates in the esophagus: state of the artten years after. Histochem Cell Biol. 2005;123(2):117-130.

8. Mittal RK, Hong SJ, Bhargava V. Longitudinalmuscle dysfunction in achalasia esophagus and itsrelevance. J Neurogastroenterol Motil. 2013;19(2):126-136.

9. Mittal RK, Ren J, McCallum RW, Shaffer HA Jr,Sluss J. Modulation of feline esophagealcontractions by bolus volume and outflowobstruction. Am J Physiol. 1990;258(2, pt 1):G208-G215.

10. Farrukh A, DeCaestecker J, Mayberry JF.An epidemiological study of achalasia among theSouth Asian population of Leicester, 1986-2005.Dysphagia. 2008;23(2):161-164.

11. Birgisson S, Richter JE. Achalasia in Iceland,1952-2002: an epidemiologic study. Dig Dis Sci.2007;52(8):1855-1860.

12. Sadowski DC, Ackah F, Jiang B, Svenson LW.Achalasia: incidence, prevalence and survival:a population-based study. Neurogastroenterol Motil.2010;22(9):e256-e261.

13. Enestvedt BK, Williams JL, Sonnenberg A.Epidemiology and practice patterns of achalasia in alarge multi-centre database. Aliment Pharmacol Ther.2011;33(11):1209-1214.

14. Gennaro N, Portale G, Gallo C, et al. Esophagealachalasia in the Veneto region: epidemiology andtreatment: epidemiology and treatment ofachalasia. J Gastrointest Surg. 2011;15(3):423-428.

15. Sonnenberg A. Hospitalization for achalasia inthe United States 1997-2006. Dig Dis Sci. 2009;54(8):1680-1685.

16. Nenshi R, Takata J, Stegienko S, et al. The costof achalasia: quantifying the effect of symptomaticdisease on patient cost burden, treatment time,and work productivity. Surg Innov. 2010;17(4):291-294.

17. Johnston BT, Colcher A, Li Q, Gideon RM,Castell JA, Castell DO. Repetitive proximalesophageal contractions: a new manometric findingand a possible further link between Parkinson’sdisease and achalasia. Dysphagia. 2001;16(3):186-189.

18. Zárate N, Mearin F, Gil-Vernet JM, Camarasa F,Malagelada JR. Achalasia and Down’s syndrome:coincidental association or something else? Am JGastroenterol. 1999;94(6):1674-1677.

19. Jung KW, Yoon IJ, Kim H, et al. Geneticevaluation of ALADIN gene in early-onset achalasiaand alacrima patients. J Neurogastroenterol Motil.2011;17(2):169-173.

Clinical Bottom Line

• Achalasia is the most well-defined esophageal motilitydisorder.

• Presenting symptoms and esophageal contractile patternsmay be inconsistent, resulting in delayed or missed diagnosis.Primary liquid dysphagia is a classic symptom suggestive ofachalasia.

• Different achalasia phenotypes have differential responsesto treatment.

• Definitive treatment to alleviate esophagogastric junction out-flow obstruction such as myotomy (laparoscopic or endoscopic)or pneumatic dilation should be offered to patients without con-traindications to surgery.






20. Stuckey BG, Mastaglia FL, Reed WD, Pullan PT.Glucocorticoid insufficiency, achalasia, alacrimawith autonomic motor neuropathy. Ann Intern Med.1987;106(1):61-63.

21. Sarathi V, Shah NS. Triple-A syndrome. Adv ExpMed Biol. 2010;685:1-8.

22. Gordillo-González G, Guatibonza YP, Zarante I,Roa P, Jacome LA, Hani A. Achalasia familiar: reportof a family with an autosomal dominant pattern ofinherence. Dis Esophagus. 2011;24(1):E1-E4.

23. Vigo AG, Martínez A, de la Concha EG, UrcelayE, Ruiz de León A. Suggested association of NOS2Apolymorphism in idiopathic achalasia: no evidencein a large case-control study. Am J Gastroenterol.2009;104(5):1326-1327.

24. de León AR, de la Serna JP, Santiago JL, et al.Association between idiopathic achalasia and IL23Rgene. Neurogastroenterol Motil. 2010;22(7):734-738,e218.

25. Nuñez C, García-González MA, Santiago JL,et al. Association of IL10 promoter polymorphismswith idiopathic achalasia. Hum Immunol. 2011;72(9):749-752.

26. Goldblum JR, Whyte RI, Orringer MB,Appelman HD. Achalasia: a morphologic study of 42resected specimens. Am J Surg Pathol. 1994;18(4):327-337.

27. Boeckxstaens GE. Achalasia: virus-inducedeuthanasia of neurons? Am J Gastroenterol. 2008;103(7):1610-1612.

28. Booy JD, Takata J, Tomlinson G, Urbach DR.The prevalence of autoimmune disease in patientswith esophageal achalasia. Dis Esophagus. 2012;25(3):209-213.

29. Kraichely RE, Farrugia G, Pittock SJ, Castell DO,Lennon VA. Neural autoantibody profile of primaryachalasia. Dig Dis Sci. 2010;55(2):307-311.

30. de Oliveira RB, Rezende Filho J, Dantas RO,Iazigi N. The spectrum of esophageal motordisorders in Chagas’ disease. Am J Gastroenterol.1995;90(7):1119-1124.

31. Gockel I, Bohl JRE, Eckardt VF, Junginger T.Reduction of interstitial cells of Cajal (ICC)associated with neuronal nitric oxide synthase(n-NOS) in patients with achalasia. Am JGastroenterol. 2008;103(4):856-864.

32. Gockel I, Bohl JRE, Doostkam S, Eckardt VF,Junginger T. Spectrum of histopathologic findingsin patients with achalasia reflects differentetiologies. J Gastroenterol Hepatol. 2006;21(4):727-733.

33. Tsuboi K, Hoshino M, Srinivasan A, et al.Insights gained from symptom evaluation ofesophageal motility disorders: a review of 4,215patients. Digestion. 2012;85(3):236-242.

34. Sinan H, Tatum RP, Soares RV, Martin AV,Pellegrini CA, Oelschlager BK. Prevalence ofrespiratory symptoms in patients with achalasia. DisEsophagus. 2011;24(4):224-228.

35. Ng KY, Li KF, Lok KH, et al. Ten-year review ofepidemiology, clinical features, and treatmentoutcome of achalasia in a regional hospital in HongKong. Hong Kong Med J. 2010;16(5):362-366.

36. Bhattacharyya N. The prevalence of dysphagiaamong adults in the United States. OtolaryngolHead Neck Surg. 2014;151(5):765-769.

37. Gupta M, Ghoshal UC, Jindal S, Misra A, Nath A,Saraswat VA. Respiratory dysfunction is common in

patients with achalasia and improves afterpneumatic dilation. Dig Dis Sci. 2014;59(4):744-752.

38. Schechter RB, Lemme EMO, Novais P, Biccas B.Achalasia in the elderly patient: a comparativestudy. Arq Gastroenterol. 2011;48(1):19-23.

39. Rakita SS, Villadolid D, Kalipersad C, ThometzD, Rosemurgy A. BMI affects presenting symptomsof achalasia and outcome after Heller myotomy.Surg Endosc. 2007;21(2):258-264.

40. Mikaeli J, Farrokhi F, Bishehsari F, MahdaviniaM, Malekzadeh R. Gender effect on clinical featuresof achalasia: a prospective study. BMC Gastroenterol.2006;6:12.

41. Wuller C, Bessell JR, Watson DI. Chest painbefore and after laparoscopic cardiomyotomy forachalasia. ANZ J Surg. 2011;81(9):590-594.

42. Hong SJ, Bhargava V, Jiang Y, Denboer D, MittalRK. A unique esophageal motor pattern thatinvolves longitudinal muscles is responsible foremptying in achalasia esophagus. Gastroenterology.2010;139(1):102-111.

43. Bogte A, Bredenoord AJ, Oors J, Siersema PD,Smout AJPM. Reproducibility of esophagealhigh-resolution manometry. Neurogastroenterol Motil.2011;23(7):e271-e276.

44. Fox M, Hebbard G, Janiak P, et al.High-resolution manometry predicts the success ofoesophageal bolus transport and identifies clinicallyimportant abnormalities not detected byconventional manometry. Neurogastroenterol Motil.2004;16(5):533-542.

45. Pandolfino JE, Ghosh SK, Zhang Q, Jarosz A,Shah N, Kahrilas PJ. Quantifying EGJ morphologyand relaxation with high-resolution manometry:a study of 75 asymptomatic volunteers. Am JPhysiol Gastrointest Liver Physiol. 2006;290(5):G1033-G1040.

46. Pandolfino JE, Ghosh SK, Rice J, Clarke JO,Kwiatek MA, Kahrilas PJ. Classifying esophagealmotility by pressure topography characteristics:a study of 400 patients and 75 controls. Am JGastroenterol. 2008;103(1):27-37.

47. Ghosh SK, Pandolfino JE, Zhang Q, Jarosz A,Shah N, Kahrilas PJ. Quantifying esophagealperistalsis with high-resolution manometry: a studyof 75 asymptomatic volunteers. Am J PhysiolGastrointest Liver Physiol. 2006;290(5):G988-G997.

48. Scherer JR, Kwiatek MA, Soper NJ, PandolfinoJE, Kahrilas PJ. Functional esophagogastric junctionobstruction with intact peristalsis: a heterogeneoussyndrome sometimes akin to achalasia.J Gastrointest Surg. 2009;13(12):2219-2225.

49. Ghosh SK, Pandolfino JE, Rice J, Clarke JO,Kwiatek M, Kahrilas PJ. Impaired deglutitive EGJrelaxation in clinical esophageal manometry:a quantitative analysis of 400 patients and 75controls. Am J Physiol Gastrointest Liver Physiol.2007;293(4):G878-G885.

50. Kahrilas PJ, Bredenoord AJ, Fox M, et al;International High Resolution Manometry WorkingGroup. The Chicago Classification of esophagealmotility disorders, v3.0. Neurogastroenterol Motil.2015;27(2):160-174.

51. Pandolfino JE, Kahrilas PJ; AmericanGastroenterological Association. AmericanGastroenterological Association medical positionstatement: clinical use of esophageal manometry.Gastroenterology. 2005;128(1):207-208.

52. Pandolfino JE, Kwiatek MA, Nealis T, BulsiewiczW, Post J, Kahrilas PJ. Achalasia: a new clinicallyrelevant classification by high-resolutionmanometry. Gastroenterology. 2008;135(5):1526-1533.

53. Krishnan K, Lin C-Y, Keswani R, Pandolfino JE,Kahrilas PJ, Komanduri S. Endoscopic ultrasound asan adjunctive evaluation in patients withesophageal motor disorders subtyped byhigh-resolution manometry. Neurogastroenterol Motil.2014;26(8):1172-1178.

54. Pasricha PJ, Rai R, Ravich WJ, Hendrix TR,Kalloo AN. Botulinum toxin for achalasia: long-termoutcome and predictors of response.Gastroenterology. 1996;110(5):1410-1415.

55. Boeckxstaens GE, Annese V, des Varannes SB,et al; European Achalasia Trial Investigators.Pneumatic dilation versus laparoscopic Heller’smyotomy for idiopathic achalasia. N Engl J Med.2011;364(19):1807-1816.

56. Persson J, Johnsson E, Kostic S, Lundell L,Smedh U. Treatment of achalasia with laparoscopicmyotomy or pneumatic dilatation: long-term resultsof a prospective, randomized study. World J Surg.2015;39(3):713-720.

57. Richards WO, Torquati A, Holzman MD, et al.Heller myotomy versus Heller myotomy with Dorfundoplication for achalasia: a prospectiverandomized double-blind clinical trial. Ann Surg.2004;240(3):405-412.

58. Rebecchi F, Giaccone C, Farinella E, Campaci R,Morino M. Randomized controlled trial oflaparoscopic Heller myotomy plus Dorfundoplication versus Nissen fundoplication forachalasia: long-term results. Ann Surg. 2008;248(6):1023-1030.

59. Rawlings A, Soper NJ, Oelschlager B, et al.Laparoscopic Dor versus Toupet fundoplicationfollowing Heller myotomy for achalasia: results of amulticenter, prospective, randomized-controlledtrial. Surg Endosc. 2012;26(1):18-26.

60. Kostic S, Johnsson E, Kjellin A, et al. Healtheconomic evaluation of therapeutic strategies inpatients with idiopathic achalasia: results of arandomized trial comparing pneumatic dilatationwith laparoscopic cardiomyotomy. Surg Endosc.2007;21(7):1184-1189.

61. Novais PA, Lemme EMO. 24-h pH monitoringpatterns and clinical response after achalasiatreatment with pneumatic dilation or laparoscopicHeller myotomy. Aliment Pharmacol Ther. 2010;32(10):1257-1265.

62. Bakhshipour A, Rabbani R, Shirani S, SoleimaniHA, Mikaeli J. Comparison of pneumatic dilationwith pneumatic dilation plus botulinum toxin fortreatment of achalasia. Acta Med Iran. 2010;48(2):107-110.

63. Gelfond M, Rozen P, Gilat T. Isosorbide dinitrateand nifedipine treatment of achalasia: a clinical,manometric and radionuclide evaluation.Gastroenterology. 1982;83(5):963-969.

64. Bortolotti M, Mari C, Lopilato C, Porrazzo G,Miglioli M. Effects of sildenafil on esophagealmotility of patients with idiopathic achalasia.Gastroenterology. 2000;118(2):253-257.

65. Annese V, Bassotti G, Coccia G, et al; GISMADAchalasia Study Group. A multicentre randomisedstudy of intrasphincteric botulinum toxin in






patients with oesophageal achalasia. Gut. 2000;46(5):597-600.

66. Vaezi MF, Richter JE, Wilcox CM, et al.Botulinum toxin versus pneumatic dilatation in thetreatment of achalasia: a randomised trial. Gut.1999;44(2):231-239.

67. Zaninotto G, Annese V, Costantini M, et al.Randomized controlled trial of botulinum toxinversus laparoscopic heller myotomy for esophagealachalasia. Ann Surg. 2004;239(3):364-370.

68. Smith CD, Stival A, Howell DL, Swafford V.Endoscopic therapy for achalasia before Hellermyotomy results in worse outcomes than Hellermyotomy alone. Ann Surg. 2006;243(5):579-584.

69. Lynch KL, Pandolfino JE, Howden CW, KahrilasPJ. Major complications of pneumatic dilation andHeller myotomy for achalasia: single-centerexperience and systematic review of the literature.Am J Gastroenterol. 2012;107(12):1817-1825.

70. Farhoomand K, Connor JT, Richter JE, AchkarE, Vaezi MF. Predictors of outcome of pneumaticdilation in achalasia. Clin Gastroenterol Hepatol.2004;2(5):389-394.

71. Pratap N, Reddy DN. Can achalasia subtyping byhigh-resolution manometry predict the therapeuticoutcome of pneumatic balloon dilatation? author’sreply. J Neurogastroenterol Motil. 2011;17(2):205.

72. Campos GM, Vittinghoff E, Rabl C, et al.Endoscopic and surgical treatments for achalasia:a systematic review and meta-analysis. Ann Surg.2009;249(1):45-57.

73. Pasricha PJ, Hawari R, Ahmed I, et al.Submucosal endoscopic esophageal myotomy:a novel experimental approach for the treatment ofachalasia. Endoscopy. 2007;39(9):761-764.

74. Inoue H, Minami H, Kobayashi Y, et al. Peroralendoscopic myotomy (POEM) for esophagealachalasia. Endoscopy. 2010;42(4):265-271.

75. Inoue H, Kudo S-E. Per-oral endoscopicmyotomy (POEM) for 43 consecutive cases of

esophageal achalasia [in Japanese]. Nihon Rinsho.2010;68(9):1749-1752.

76. Swanström LL, Rieder E, Dunst CM. A stepwiseapproach and early clinical experience in peroralendoscopic myotomy for the treatment of achalasiaand esophageal motility disorders. J Am Coll Surg.2011;213(6):751-756.

77. von Renteln D, Inoue H, Minami H, et al. Peroralendoscopic myotomy for the treatment ofachalasia: a prospective single center study. Am JGastroenterol. 2012;107(3):411-417.

78. Bhayani NH, Kurian AA, Dunst CM, Sharata AM,Rieder E, Swanstrom LL. A comparative study oncomprehensive, objective outcomes oflaparoscopic Heller myotomy with per-oralendoscopic myotomy (POEM) for achalasia. Ann Surg.2014;259(6):1098-1103.

79. Hungness ES, Teitelbaum EN, Santos BF, et al.Comparison of perioperative outcomes betweenperoral esophageal myotomy (POEM) andlaparoscopic Heller myotomy. J Gastrointest Surg.2013;17(2):228-235.

80. Khashab MA, Messallam AA, Onimaru M, et al.International multicenter experience with peroralendoscopic myotomy for the treatment of spasticesophageal disorders refractory to medical therapy.Gastrointest Endosc. 2015;3:1-8.

81. Rohof WO, Salvador R, Annese V, et al.Outcomes of treatment for achalasia depend onmanometric subtype. Gastroenterology. 2013;144(4):718-725.

82. Roman S, Zerbib F, Quenehervé L, Clermidy H,Varannes SB, Mion F. The Chicago classification forachalasia in a French multicentric cohort. Dig Liver Dis.2012;44(12):976-980.

83. Salvador R, Costantini M, Zaninotto G, et al.The preoperative manometric pattern predicts theoutcome of surgical treatment for esophagealachalasia. J Gastrointest Surg. 2010;14(11):1635-1645.

84. Min M, Peng LH, Yang YS, et al. Characteristicsof achalasia subtypes in untreated Chinese

patients: a high-resolution manometry study. J DigDis. 2012;13(10):504-509.

85. Vaezi MF, Pandolfino JE, Vela MF. ACG clinicalguideline: diagnosis and management of achalasia.Am J Gastroenterol. 2013;108(8):1238-1249.

86. Roman S, Kahrilas PJ, Mion F, et al. Partialrecovery of peristalsis after myotomy for achalasia:more the rule than the exception. JAMA Surg. 2013;148(2):157-164.

87. Leeuwenburgh I, Scholten P, Alderliesten J,et al. Long-term esophageal cancer risk in patientswith primary achalasia: a prospective study. Am JGastroenterol. 2010;105(10):2144-2149.

88. Ravi K, Geno DM, Katzka DA. Esophagealcancer screening in achalasia: is there a consensus?[published online March 6, 2014]. Dis Esophagus.doi:10.1111/dote.12196.

89. Zaninotto G, Costantini M, Rizzetto C, et al.Four hundred laparoscopic myotomies foresophageal achalasia: a single centre experience.Ann Surg. 2008;248(6):986-993.

90. Bonatti H, Hinder RA, Klocker J, et al.Long-term results of laparoscopic Heller myotomywith partial fundoplication for the treatment ofachalasia. Am J Surg. 2005;190(6):874-878.

91. Zaninotto G, Portale G, Costantini M, et al.Long-term results (6-10 years) of laparoscopicfundoplication. J Gastrointest Surg. 2007;11(9):1138-1145.

92. Costantini M, Zaninotto G, Guirroli E, et al.The laparoscopic Heller-Dor operation remains aneffective treatment for esophageal achalasia at aminimum 6-year follow-up. Surg Endosc. 2005;19(3):345-351.

93. Eckardt VF, Hoischen T, Bernhard G. Lifeexpectancy, complications, and causes of death inpatients with achalasia: results of a 33-yearfollow-up investigation. Eur J Gastroenterol Hepatol.2008;20(10):956-960.





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