and not explained by an obstruction or inflammatory process. Responses to treatment vary based on which achalasia subtype is present.

Clinical Review & Education Review A Systematic Review John E. Pandolfino, MD, MSCI; Andrew J. Gawron, MD, PhD, MS IMPORTANCE significantly affects patients quality of life and can be difficult to diagnose and treat. OBJECTIVE To review the diagnosis and management of achalasia, with a focus on phenotypic classification pertinent to therapeutic outcomes. EVIDENCE REVIEW Literature review and MEDLINE search of articles from January 2004 to February 2015. A total of 93 articles were included in the final literature review addressing facets of achalasia epidemiology, pathophysiology, diagnosis, treatment, and outcomes. Nine randomized controlled trials focusing on endoscopic or surgical therapy for achalasia were included (734 total patients). FINDINGS A diagnosis of achalasia should be considered when patients present with dysphagia, chest pain, and refractory reflux symptoms after an endoscopy does not reveal a mechanical obstruction or an inflammatory cause of esophageal symptoms. Manometry should be performed if achalasia is suspected. Randomized controlled trials support treatments focused on disrupting the lower esophageal sphincter with pneumatic dilation (70%-90% effective) or laparoscopic myotomy (88%-95% effective). Patients with achalasia have a variable prognosis after endoscopic or surgical myotomy based on subtypes, with type II (absent peristalsis with abnormal pan-esophageal high-pressure patterns) having a very favorable outcome (96%) and type I (absent peristalsis without abnormal pressure) having an intermediate prognosis (81%) that is inversely associated with the degree of esophageal dilatation. In contrast, type III (absent peristalsis with distal esophageal spastic contractions) is a spastic variant with less favorable outcomes (66%) after treatment of the lower esophageal sphincter. CONCLUSIONS AND RELEVANCE should be considered when dysphagia is present and not explained by an obstruction or inflammatory process. Responses to treatment vary based on which achalasia subtype is present. JAMA. 2015;313(18):1841-1852. doi:10.1001/jama.2015.2996 Author Audio Interview at jama.com JAMAPatient Page page 1876 Supplemental content at jama.com CME Quiz at jamanetworkcme.com and CME Questions page 1859 Author Affiliations: Division of Gastroenterology and Hepatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois (Pandolfino); Division of Gastroenterology, Hepatology, and Nutrition, University of Utah, Salt Lake City (Gawron). Corresponding Author: John E. Pandolfino, MD, MSCI, Division of Gastroenterology and Hepatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, 676 N St Clair St, Ste 1409, Chicago, IL 60611 (j-pandolfino @northwestern.edu). Section Editor: Mary McGrae McDermott, MD, Senior Editor. 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 reflux disease, malignancy, mechanical obstruction (strictures, rings, or diverticula), and achalasia and other motility disorders. is derived from the Greek khalasis, translated as not loosening or relaxing. A common historical definition of achalasia is the inability of the lower esophageal sphincter to relax in the setting of absent peristalsis. An initial trial of acid suppression (6-8 weeks) is reasonable, but when dysphagia symptoms persist or are dominated by the report of dysphagia, endoscopy should be performed to evaluate for mechanical obstruction or inflammatory processes. When these are not found, achalasia should be considered, especially in the setting of dysphagia primarily to liquids. Liquids can pool and accumulate above a tight, unrelaxing lower esophageal sphincter, whereas they are usually less of an issue in the setting of structural causes of dysphagia. Recent advances in diagnostic testing for achalasia, especially high-resolution esophageal manometry, have provided new insights into the pathogenesis and clinical manifestation of this disorder. The purpose of this review is to highlight the epidemiology, pathogenesis, and clinical approach to patients with achalasia, emphasizing published evidence pertinent to both primary care clinicians and specialist physicians. Evidence Acquisition and Synthesis The literature was reviewed based on an initial broad MEDLINE searchusingtheterms((((esophagealmotility) ORachalasia) ORhigh jama.com (Reprinted) JAMA May 12, 2015 Volume 313, Number 18 1841

Clinical Review & Education Review Figure 1. Anatomy and Innervation of the Esophagus A Anatomy of the esophagus and relationship to adjacent structures C Esophageal wall Cricoid cartilage Upper esophageal sphincter (UES) Esophagus Diaphragm (cut) Striated Transition zone Smooth B Longitudinal (reflected) Myenteric plexus Circular Esophagogastric junction Myenteric plexus ganglion with postganglionic neurons Esophageal plexus Adventitia Muscularis propria Lower esophageal sphincter (LES) Stomach ESOPHAGUS Submucosal plexus Muscularis mucosa Stratified squamous epithelium Submucosa Mucosa Circular Level of section Lumen Longitudinal Crural diaphragm LES Esophagogastric junction LES Crural diaphragm Proximal gastric cardia STOMACH resolution manometry) OR Chicago classification) OR esophageal peristalsis. Articles published from January 2004 to February 2015 in English were included. This search yielded 6194 references, of which 5788 were in English. Case reports (n = 521) and review articles (n = 899) were excluded. Articles were further searched using terms specific for epidemiology, genetics, diagnosis, manometry, surgery, pneumatic dilation, botulinum toxin, and per-oral endoscopic myotomy. Other pertinent articles and guidelines were obtained through citations or were known to the authors. We reviewed titles and abstracts to determine relevance to the article sections and ultimately included 93 articles in the review (n = 4276 excluded). A total of 9 randomized controlled trials were included when evaluating endoscopic and surgical treatment modalities (comprising 734 total patients). Details are shown in the efigure in the Supplement. Structure and Normal Function of the Esophagus The esophagus is an 18- to 26-cm muscular hollow tube that transports food from the oropharynx into the stomach (Figure 1). There are 4 primary layers of esophageal tissue the mucosa, submucosa, muscularis propria, and adventitia. The esophagus originates at the level of the cricoid cartilage and normally terminates below the hiatus in the right crura of the diaphragm. The muscularis propria gradually changes from predominant skeletal in the upper esophagus to predominantly smooth in the distal esophagus, with mixing of types along the length of the esophagus (Figure 1). Both circular and longitudinal layers are present, and within the diaphragmatic hiatus there exists a 2- to 4-cm thickened circular layer, the lower esophageal sphincter. Esophageal innervation consists of both parasympathetic and sympathetic nerves, with peristalsis regulated via the parasympathetic pathway from the vagus nerve and the intrinsic enteric nervous system. Despite the seemingly simple task of food transport, the mechanism and control of esophageal function is complex, largely owing to the neural coordination required with the oropharynx and transition through different anatomical domains with mixed types. Onceafoodorliquidbolusenterstheesophagus, primaryperistalsis strips the food bolus down the length of the esophagus. Peristaltic contraction in the striated esophagus is dependent on central mechanisms that involve sequential activation of excitatory activity of lower motor neurons in the vagal nucleus am- 1842 JAMA May 12, 2015 Volume 313, Number 18 (Reprinted) jama.com

Review Clinical Review & Education Figure 2. Neural Control of Esophageal Motility and Plot From High-Resolution Esophageal Manometry, With Anatomical Correlates A Parasympathetic esophageal innervation B Esophageal pressure topography (EPT) plot from high resolution manometry (normal study) C Anatomical correlation with EPT plot POSTERIOR Dorsal motor nucleus of vagus Rostral Caudal PONS Nucleus ambiguus ANTERIOR Esophagus Color pressure scale, mm Hg 0 30 60 90 120 150 180 UES Cricoid cartilage Vagus nerve Striated Cervical esophagus Transition zone Thoracic esophagus Smooth Striated innervation Parasympathetic efferent Neuromuscular junction Smooth innervation Preganglionic excitatory neuron Preganglionic inhibitory neuron Postganglionic excitatory neuron cell body Postganglionic inhibitory neuron cell body UES LES Diaphragm (cut) Abdominal esophagus LES 0 3 6 9 12 Swallow Time, s Schematic representation of esophageal motor activity during a swallow A, The esophagus is controlled by both centrally mediated and peripheral intrinsic processes that are compartmentalized based on location in the esophagus and type. B, Output from high-resolution manometry, displayed as esophageal pressure topography (Clouse plot), showing esophageal pressures over time after a single swallow. The x-axis indicates time; the y-axis indicates location from the oropharynx to the stomach, as shown in panel C. Pressure is displayed on a color scale instead of the conventional tracings; thus, a seamless dynamic representation of motor activity is displayed that provides anatomical representation of the pressure profile. The striated esophagus can be distinguished from the smooth esophagus, as there is a pressure gap at the transition zone that demarcates the introduction of smooth activity. The sphincters are distinguished by the 2 areas of high pressure between the striated and smooth esophagus. LES indicates lower esophageal sphincter; UES, upper esophageal sphincter. Esophageal pressure topography plot reproduced with permission from the Esophageal Center at Northwestern Medicine. biguus (Figure 2). 1 This promotes peristaltic propagation through a sequenced top-to-bottom excitation mediated by release of acetylcholine at the motor end plates (Figure 2). 1 Primary peristalsis in esophageal smooth is preceded by inhibition, which stops a progressing peristaltic wave when another swallow is initiated. 2,3 This involves patterned activation of preganglionic neurons in the dorsal motor nucleus of the vagus that project onto inhibitory and excitatory neurons in the esophageal myenteric plexus (Figure 2). Under normal circumstances, the inhibitory pathway is activated first to relax the esophagus to promotefillingandtransportthroughtheesophagus. Theinhibitoryneurons activated by the preganglionic neurons from the caudal dorsal motor neuron release nitric oxide to promote deglutitive inhibition. This is followed by sequential activation of excitatory neurons, which releases acetylcholine in response to activation by preganglionic neurons arising from the rostral dorsal motor nucleus. The direction and rate of propagation is modulated by the increasing inhibitory influence in the distal esophagus, called the latency gradient. 2,3 This essentially delays contractions in the distal esophagus and allows propagation to proceed in an aboral direction. Secondary peristalsis related to distention of the esophagus will elicit a local reflex independent of the vagal input from the dorsal jama.com (Reprinted) JAMA May 12, 2015 Volume 313, Number 18 1843

Clinical Review & Education Review Box. Symptoms Suggestive of That May Prompt Referral for Esophageal Motility Testing a Esophageal Symptoms Dysphagia (90% of patients) Heartburn (75% of patients) Regurgitation or vomiting (45% of patients) Noncardiac chest pain (20% of patients) Epigastric pain (15% of patients) Odynophagia (<5% of patients) Other Associated Signs and Symptoms Cough or asthma (20%-40% of patients) Chronic aspiration (20%-30% of patients) Hoarseness or sore throat (33% of patients) Unintentional weight loss (10% of patients) a Data from Tsuboi et al, 33 Sinan et al, 34 and Ng et al. 35 motor nucleus that causes contraction above the distention and relaxation below the distention via the intrinsic inhibitory and excitatory myenteric neurons. Regional differences in the density of the inhibitory and excitatory neurons in the enteric nervous system determine the direction and vigor of the contraction, and this may be modulated by variable smooth response to the same quantum of neurotransmitter. 4-6 The pathogenesis of achalasia can be conceptualized as a disruption of the balance between the regional excitatory and inhibitory response elicited along the axial location of the esophageal body. 4,7 Although most research on peristalsis has focused on the circular, the longitudinal outer layer plays an important role. Esophageal shortening occurs as a response to longitudinal contraction and is mediated by sequential cholinergic activation of the. The activation overlaps with the propagating circular to provide mechanical advantages to bolus transit and a lack of coordination of these effects, and exaggerated longitudinal contractions may be important in esophageal dysmotility and generation of symptoms. 8,9 Ultimately, the progressing peristaltic waves must advance the food bolus into the stomach across the esophagogastric junction. This junction is a high-pressure zone comprising the lower esophageal sphincter, the crural diaphragm, and proximal gastric cardia. Normal resting lower esophageal sphincter tone is 10 to 30 mm Hg, which helps prevent reflux of gastric contents back into the esophagus. Relaxation of the lower esophageal sphincter to allow emptying of the esophagus is triggered by swallowing or esophageal distention mediated by both peripheral and central mechanisms. Relaxation of the sphincter is related to a number of nonadrenergic noncholinergic neurotransmitters, the most prominent being nitric oxide. Epidemiology and Genetics of has an annual reported incidence of approximately 1/100 000 worldwide. 10-13 In Iceland, 62 cases of achalasia were diagnosed over the course of 51 years (overall incidence, 0.6/100 000 per year; mean prevalence, 8.7 cases /100 000). 11 Gennaro et al 14 recently reported an incident rate in Italy of 1.59 cases/100 000 per year (2001-2005). Due to the chronicity of achalasia, the estimated prevalence of achalasia is approximately 9/100 000 to 10/100 000. 11,12 In the United States, rates of hospitalization for achalasia depend on patient age, ranging from 0.25/100 000 (<18 years) to a high of 37/100 000 (>85 years). 15 Although the incidence is low, the chronicity of achalasia significantly affects patients health-related quality of life, work productivity, and functional status compared with the general US population. 16 Evidence supporting genetic underpinnings for achalasia come from twin and sibling studies and from the association of achalasia with other diseases such as Parkinson disease, Allgrove syndrome, and Down syndrome. 17-19 Familial adrenal insufficiency with alacrima and achalasia (Allgrove syndrome) is a rare genetic syndrome associated with defects in the AAAS gene (chromosome 12q13) and subsequent defective tryptophan aspartic acid repeat protein. 20,21 A few reports have described familial achalasia, most recently in a single family with an autosomal dominant pattern with 6 affected members. 22 Polymorphisms in the nitric oxide synthase gene have been investigated, but polymorphisms were found to be no different between patients with achalasia and controls. 23 Because of a possible autoimmune etiology of achalasia, studies have suggested possible roles of interleukin polymorphisms (IL-23 and IL-10). 24,25 Currently, genetic testing for achalasia has no role in clinical management outside of research endeavors. Pathophysiology is associated with functional loss of myenteric plexus ganglion cells in the distal esophagus and lower esophageal sphincter. 26 The cause for an initial reduction of inhibitory neurons in achalasia is unknown. Initiation of neuronal degeneration may be an autoimmune process triggered by an indolent viral infection (herpes, measles) in conjunction with a genetically susceptible host. 27 Patients with achalasia are more likely to have concomitant autoimmune diseases than the general population 28 and the prevalence of serum neural autoantibodies is higher, 29 lending further credence to an autoimmune etiology. The inflammatory reaction is associated with a T-cell lymphocyte infiltrate that leads to a slow destruction of ganglion cells. The distribution and end result of this plexitis is variable and may be modified by the host response or the etiologic stimulus. can also be one manifestation of the widespread myenteric plexus destruction in Chagas disease, a consequence of infection with the parasite Trypanosoma cruzi. 30 The consequence of the myenteric plexus inflammation is degeneration or dysfunction of inhibitory postganglionic neurons in the distal esophagus, including the lower esophageal sphincter. 31,32 These neurons use nitric oxide and vasoactive intestinal peptide as neurotransmitters, and their dysfunction results in an imbalance between excitatory and inhibitory control of the sphincter and adjacent esophagus. Unopposed cholinergic stimulation can result in impaired relaxation of the lower esophageal sphincter, hypercontractility of the distal esophagus, and rapidly propagated contractions in the distal esophagus. Longitu- 1844 JAMA May 12, 2015 Volume 313, Number 18 (Reprinted) jama.com

Review Clinical Review & Education dinal 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 Signs The most common symptoms of achalasia are listed in the Box 3-35 and may prompt referral for a motility evaluation after more common disorders are ruled out, such as gastroesophageal reflux disease, mechanical obstruction (stricture, rings), or malignancy. Progressive dysphagia to both solids and liquids is the hallmark symptom associated with a diagnosis of achalasia. The prevalence of weekly dysphagia among US adults is approximately 4% 36 and is associated with a broad differential diagnosis and workup (Table 1). Esophageal motility testing should only be done after a structural or mechanical obstruction has been ruled out and oropharyngeal causes are not apparent. In a single-center review of all patients with manometry over a period of 24 years (1984-2008), Tsuboi et al 33 found that patients with achalasia most commonly presented with dysphagia and heartburn. Other common symptoms included chest pain, regurgitation, cough or asthma, odynophagia, and epigastric pain. 33 Respiratory symptoms are also common in patients with achalasia, because primary motor abnormalities result in decreased clearance of food and liquid from the esophagus, predisposing patients to aspiration. Sinan et al 34 found that of 110 patients with achalasia, 40% reported at least 1 respiratory symptom daily. Another study of 38 patients with achalasia found that 71% had sore throat, hoarseness, or postnasal drip and 61% had cough. 37 In addition, 17 patients (45%) had abnormal spirometry findings and 12 had abnormal imaging findings such as septal thickening and necrotizing pneumonia. 37 The dysphagia preceded respiratory symptoms by an average of 24 months, indicating the progressive nature of symptoms with lack of treatment. 37 It is also important to consider a diagnosis of connective tissue disease (eg, scleroderma) in patients with chronic respiratory issues and abnormalities of esophageal motility. Demographic and clinical factors may affect clinical symptoms. Dysphagia and regurgitation are common among all ages, but younger patients with achalasia have been found to have a higher prevalence of heartburn and chest pain than older patients. 38 Obese patients (body mass index 30) may have more frequent symptoms of choking and vomiting, possibly related to increased abdominal pressure. 39 Chest pain was more commonly reported by women than men in a single-center retrospective review of 213 patients with achalasia. 40 However, another group reported similar reports of chest pain regardless of age or sex. 41 Table 1. Differential Diagnosis of Dysphagia Symptoms and Initial Testing Signs and Symptoms Esophageal Dysphagia Structural esophageal disorders Peptic stricture Esophageal (Schatzki) ring or webs Eosinophilic esophagitis Malignancy Radiation- or medication-induced strictures Foreign body or food impaction Vascular compression Mediastinal mass/external compression Motility esophageal disorders and esophagogastric junction outflow obstruction Absent contractility Distal esophageal spasm Hypercontractile esophagus (jackhammer) Minor disorders of peristalsis Scleroderma Gastroesophageal reflux disease Chagas disease Oropharyngeal Dysphagia Structural oropharyngeal disorders Malignancy Spinal osteophytes Zenker diverticulum Proximal strictures, rings, or webs Radiation injury Oropharynx infection Thyroid enlargement Neuromuscular (systemic) disorders Cerebral vascular accident Multiple sclerosis Parkinson disease Myasthenia gravis Amyotrophic lateral sclerosis Muscular dystrophy Dermatomyositis Thyroid disorders Testing Esophagogastroduodenoscopy, barium esophagram Esophagogastroduodenoscopy, barium esophagram Esophagogastroduodenoscopy Esophagogastroduodenoscopy, barium esophagram Esophagogastroduodenoscopy, barium esophagram Esophagogastroduodenoscopy Computed tomography, magnetic resonance imaging, endoscopic ultrasound Computed tomography, magnetic resonance imaging, endoscopic ultrasound High-resolution manometry, barium esophagram High-resolution manometry High-resolution manometry High-resolution manometry High-resolution manometry High-resolution manometry Esophagogastroduodenoscopy, high-resolution manometry, ph testing a Barium esophagram, serology Laryngoscopy Video fluoroscopy, computed tomography Video fluoroscopy, esophagogastroduodenoscopy Esophagogastroduodenoscopy, barium esophagram Video fluoroscopy, esophagogastroduodenoscopy Laryngoscopy Ultrasound, computed tomography Computed tomography, magnetic resonance imaging Focused neurologic examination, disease-specific laboratory testing and imaging a ph testing indicates ambulatory ph and reflux monitoring. Diagnosis Diagnosis of achalasia requires recognition of symptoms and appropriate use and interpretation of diagnostic testing (Table 1). Diagnoses can be difficult to make, and many patients have symptoms for many years prior to correct diagnosis and treatment. This is most common when patients present with symptoms that mimic gastroesophageal reflux disease, such as heartburn, chest pain, and regurgitation. In contrast, when patients primarily present with dysphagia, a careful history and evaluation jama.com (Reprinted) JAMA May 12, 2015 Volume 313, Number 18 1845

Clinical Review & Education Review of swallowing by watching the patient drink water can be helpful in distinguishing between oropharyngeal dysphagia and esophageal dysphagia. Patients with oropharyngeal dysphagia will typically struggle to move the bolus into the esophagus during water swallows and will often have coughing and immediate regurgitation. Primary oropharyngeal symptoms should first prompt an evaluation for oropharyngeal etiologies, with a modified barium cookie swallow study performed by speech pathology (Table 1). Patients with intact oropharyngeal swallowing and dysphagia should be evaluated for esophageal causes, and the differential should focus on distinguishing between a structural mechanical obstruction and a motility disorder (Table 1). Mechanical obstruction should be ruled out first, via either upper gastrointestinal tract endoscopy or radiologic imaging, prior to evaluation for abnormal motility. Patients with a previous fundoplication or bariatric procedure (lap-band, gastric bypass) may also present with signs and symptoms that mimic achalasia, and it is extremely difficult to make the diagnosis of achalasia in the context of these operations. In these cases, it is important to look for mechanical causes of obstruction, such as anastomotic stricture, tight lap-band, and an obstructed fundoplication. Esophagogastroduodenoscopy Esophagogastroduodenoscopy with mucosal biopsy should be performed in most patients presenting with solid food dysphagia, liquid food dysphagia, or both. This is done to rule out erosive gastroesophageal reflux disease, eosinophilic esophagitis, structural lesions (strictures, webs, or rings), and esophageal cancer or pseudoachalasia. Endoscopic features of an esophageal motility disorder include a dilated or tortuous esophagus, food impactions and fluid pooling in the esophagus, and resistance to intubation of the gastroesophageal junction. Patients with achalasia may also develop candidiasis attributable to esophageal stasis, and evidence of candidiasis in the context of intact immune function should prompt an evaluation for esophageal dysmotility. Although endoscopy may suggest achalasia, other testing must be performed to confirm the diagnosis. Barium Esophagram The classic bird s-beak appearance of achalasia on a barium swallow study is a well-known image in clinical medicine (Figure 3C). Other radiographic features suggestive of an esophageal motility disorder include esophageal dilation, contrast filling the esophagus, a corkscrew appearance, and aperistalsis. Esophageal Manometry Esophageal manometry to assess esophageal pressures and contractions along the length of a flexible catheter has become the standard for diagnosing and classifying achalasia. Major technological advances have occurred during the last decade, wherein conventional water-perfused or strain gauge systems with a line tracing output have been replaced by more reproducible 43 and accurate 44 high-resolution manometry systems that present pressure data in the context of esophageal pressure topography plots (Figure 2 and Figure 3). These methods were originally developed by Clouse and led to an improved understanding of peristaltic contractile activity. Seminal work that characterized high-resolution manometry metrics using Clouse plots in both asymptomatic and symptomatic individuals 45-49 eventually led to the creation of a new classification scheme for motility disorders, called the Chicago Classification (Figure 4). 50 One important advantage of esophageal pressure topography has been the ability to further refine conventional diagnoses, such as achalasia, into clinically relevant phenotypes. The diagnosis of achalasia is classically made by demonstrating impaired relaxation of the lower esophageal sphincter and absent peristalsis in the absence of esophageal obstruction near the lower esophageal sphincter attributable to a stricture, tumor, vascular structure, implanted device, or infiltrating process. 51 Three distinct subtypes of achalasia (types I, II, and III) are defined with high-resolution manometry that have both prognostic and potential therapeutic implications (Figure 3). 52 If criteria for achalasia subtypes are not met, a validated hierarchical analysis is used to determine if patients have nonachalasia motor disorders, as shown in Figure 4. 50 However, a possible diagnosis of achalasia should be considered when patients present with an esophagogastric junction outflow obstruction, because this may represent an incomplete or early form of the disease. Similarly, it is also important to consider achalasia in patients with absent contractility, as these cases may be confused with scleroderma owing to the complexities of measuring relaxation of the lower esophageal sphincter. Equivocal cases may require further workup with endoscopic ultrasound in the case of EGJ outflow obstruction to rule out a subtle obstruction 53 and a barium esophagram in the case of absent contractility to document bolus retention, which would favor a diagnosis of achalasia. Treatment There are no curative therapies for achalasia; a summary of treatment modalities is listed in Table 2. Nine randomized trials have compared endoscopic and surgical treatments for achalasia (Table 3). Physiologically, many treatments are directed at reducing contractility in the lower esophageal sphincter to allow for adequate esophageal emptying. The primary goal of management should be based on early diagnosis to prevent late complications of the disease and preserve remaining esophageal structure and function. Medical Treatment Oral calcium channel blockers or nitrates cause a prompt reduction in lower esophageal sphincter pressure of up to 47% to 64%, with mild benefit for dysphagia. 63 These medications can have limiting adverse effects (headache, orthostatic hypotension, or edema) and do not halt disease progression. Consequently, they are poor longterm treatment options and should be reserved for patients who are poor candidates for surgical or endoscopic therapy. Nifedipine (10-30 mg, given 30-45 minutes before meals) or isorbide dinitrate (5-10 mg, given 15 minutes before meals) may be useful as shortacting temporizing treatments. Absorption and effect of oral medications can be unpredictable in achalasia. 5 -Phosphodiesterase inhibitors, such as sildenafil, have also been used (off-label) to treat achalasia and spastic disorders of the esophagus. 64 Sildenafil lowers esophagogastric junction pressure and attenuates distal esophageal contractions by blocking the en- 1846 JAMA May 12, 2015 Volume 313, Number 18 (Reprinted) jama.com

Review Clinical Review & Education Figure 3. Conceptual Model of Esophageal Disease Presentation and Progression Based on Phenotypes Described Using High-Resolution Manometry and Barium Esophagrams A EGJ outflow obstruction B Type II achalasia C Type I achalasia D Type III achalasia Impaired LES relaxation Normal or impaired peristalsis Impaired LES relaxation Absent peristalsis Increased pan-esophageal pressure Impaired LES relaxation Absent peristalsis Normal esophageal pressure Impaired LES relaxation Absent peristalsis Distal esophageal spastic contractions Bird s beak Smooth innervation Postganglionic excitatory neuron Postganglionic inhibitory neuron Color pressure scale, mm Hg 0 30 60 90 120 150 180 10 s 5 s 5 s 10 s Some patients may present with an esophagogastric junction (EGJ) outflow obstruction pattern (panel A) in which there is impaired lower esophageal sphincter (LES) relaxation with evidence of propagating contractions. This may represent the point where the esophageal body is progressing to aperistalsis and there is variable loss of the excitatory (blue circles) and inhibitory (red circles) influence. As preferential loss of the inhibitory neurons continues to progress, the manometric pattern may progress to a type II pattern (panel B) associated with impaired LES relaxation and panesophageal pressurization, akin to a filled water balloon being squeezed. 42 Type I achalasia (panel C) is the classic presentation of achalasia, in which there is complete loss of contractile activity in the body of the esophagus; this is typically a later phase of disease progression where there is evidence of moderate to severe esophageal dilatation. Type III achalasia (panel D) is associated with premature simultaneous contractions that compartmentalize the bolus before it can empty the esophagus, as evidenced by the corkscrew appearance on esophagram. This may represent a distinct entity that does not fall into the typical presentation of progressive neuron loss seen with the progression of EGJ outlet obstruction to type II achalasia, to type I achalasia. Corresponding barium esophagrams are also shown for each subtype. Barium esophagrams and esophageal pressure topography plots reproduced with permission from the Esophageal Center at Northwestern Medicine. zyme that degrades cyclic guanosine monophosphate induced by nitric oxide. Sildenafil is a viable alternative in patients not responding to or proving intolerant of calcium channel blockers or nitrates. However, minimal long-term treatment data exist pertinent to using 5 -phosphodiesterase inhibitors to treat achalasia. Botulinum Toxin Botulinum toxin injection into the 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 al 54 reported improved dysphagia in 66% of patients with achalasia for 6 months. No increase in efficacy has been demonstrated with greater doses. 65 The effect is temporary and is eventually reversed by axonal regeneration; subsequent clinical series report minimal continued efficacy after 1 year. 54,65-67 Most patients relapse and require re-treatment 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 dilator is a noncompliant, cylindrical balloon that is positioned fluoroscopically across the lower esophageal sphincter and inflated with air using a handheld manometer. The reported efficacy of pneumatic dilation in randomized controlled trials ranges from 62% to 90% (Table 3). Patients with a poor result or rapid recurrence of dysphagia are unlikely to respond to additional dilations, but subsequent response to myotomy is not influenced. Although the reported incidence of perforation from pneumatic dilation ranges from 0% to 16%, a recent systematic review on the jama.com (Reprinted) JAMA May 12, 2015 Volume 313, Number 18 1847

Clinical Review & Education Review Figure 4. Chicago Classification Version 3.0 for Esophageal Motility Disorders, Including LES relaxation upper limit of normal AND 100% failed peristalsis or spasm No Yes Type I: 100% failed peristalsis Type II: 100% failed peristalsis with panesophageal pressurization Type III: 20% premature contractions Disorders of esophagogastric junction outflow obstruction LES relaxation upper limit of normal AND sufficient evidence of peristalsis such that criteria for type I-III achalasia are not met Yes Esophagogastric junction outflow obstruction Incompletely expressed achalasia Mechanical obstruction No LES relaxation is normal AND premature contractions or hypercontractile vigor No Yes Distal esophageal spasm (DES) 20% premature contractions Must consider type III achalasia Jackhammer esophagus 20% of swallows with contractile vigor Major disorders of peristalsis (entities not seen in normal controls) LES relaxation is normal AND 100% failed peristalsis Yes Absent contractility Should consider achalasia in cases of borderline LES relaxation No LES relaxation is normal AND 50% of swallows are ineffective based on contractile vigor measurements No Yes Ineffective esophageal motility (IEM) 50% ineffective swallows Fragmented peristalsis 50% fragmented swallows and not meeting criteria for IEM Minor disorders of peristalsis (impaired bolus clearance) LES relaxation is normal AND >50% of swallows are effective without criteria for spasm or jackhammer esophagus Yes Normal esophageal motor function a Modified from Kahrilas et al. 50 Classification algorithm based on results of high-resolution manometry with ten 5-mL water swallows. Note that achalasia should be considered in patients presenting with esophagogastric junction outflow obstruction and absent contractility. Failed peristalsis denotes swallows with a distal contractile integral (DCI) less than 100 mm Hg sec cm (the DCI quantifies the distal contractile pressure exceeding 20 mm Hg from the transition zone to the proximal aspect of the lower esophageal sphincter [LES] [amplitude time length in units of mm Hg sec cm]).panesophageal pressurization denotes uniform pressurization greater than 30 mm Hg extending from the upper esophageal sphincter to the esophagogastric junction. Contractile vigor denotes the strength of distal contraction as defined by the DCI. Ineffective esophageal motility (IEM) is diagnosed when a patient exhibits greater than 50% ineffective swallows (ineffective swallows are either failed [DCI <100 mm Hg sec cm] or weak [DCI <450 mm Hg sec cm]). Fragmented swallow denotes a swallow with DCI greater than or equal to 450 mm Hg sec cm and and a greater than 5-cm break in the pressure domain, corresponding to an intact esophageal contraction, required to push a swallowed bolus forward. a Rapid contraction and hypertensive peristalsis are not considered distinct clinical pathological entities in Chicago Classification version 3.0. topic concluded that using modern technique the risk was less than 1%, comparable to the risk of unrecognized perforation during Heller myotomy. 69 Pneumatic dilation should be performed by experienced physicians, and surgical backup is required. Studies using pneumatic dilation as the initial treatment of achalasia have reported excellent long-term symptom control. A third of patients will relapse in 4 to 6 years and may require repeat dilation. Response to therapy may be related to preprocedural clinical parameters, such as age (favorable if >45 years), sex (more favorable among females than males), 70 esophageal diameter (inversely related to response), and achalasia subtype (type II better than I and III). 52,71 Although surgical myotomy has a greater response rate than a single pneumatic dilation, it appears that a series of dilations is a reasonable alternative to surgery. A recent randomized trial compared this type of graded strategy with surgical myotomy and found it to be noninferior in efficacy (Table 3). 55 Addition of botulinum toxin injection does not appear to improve outcomes. 62 Myotomy Heller myotomy, which divides the circular fibers of the lower esophageal sphincter, is the standard surgical approach for achalasia. Laparoscopy is the preferred surgical approach because of its lower morbidity and comparable long-term outcome compared with that achieved with thoracotomy. 72 Laparoscopic Heller myotomy is superior to a single pneumatic dilation in terms of efficacy and durability, with reported efficacy rates in the 88% to 95% range. 55,56,60,61 However, the superiority of surgical myotomy over pneumatic dilation is less evident when compared with a graded approach to pneumatic dilation using repeat dilations as mandated by the clinical response. 55,72 An antireflux repair has been shown to significantly decrease gastroesophageal reflux disease, 57 and this can range from an anterior 180 fundoplasty (Dor) to a 270 partial fundoplication (Toupet). 59 There is general agreement that a full 360 Nissen fundoplication is contraindicated, as 1 randomized trial showed that 15% of patients had recurrent dysphagia. 58 1848 JAMA May 12, 2015 Volume 313, Number 18 (Reprinted) jama.com

Review Clinical Review & Education Per-Oral Endoscopic Myotomy Per-oral endoscopic myotomy (POEM) is the newest treatment for achalasia. 73,74 The procedure requires making a small mucosal incision in the mid-esophagus and creating a submucosal tunnel all the way to the gastric cardia using a forward-viewing endoscope, transparent distal cap, and submucosal dissection knife. Selective myotomy of the circular is accomplished with electrocautery for a minimum length of 6 cm up the esophagus and 2 cm distal to the squamocolumnar junction onto the gastric cardia. Initial success rates of the POEM procedure in prospective cohorts of patients with achalasia have been greater than 90%, comparable with those of laparoscopic Heller myotomy. 75-77 A recent prospective, single-center study found that symptoms and postmyotomy integrated relaxation pressures were not different between patients undergoing laparoscopic Heller myotomy or POEM. 78 Preliminary results comparing more than 30 POEM cases with laparoscopic Heller myotomy suggest comparable perioperative outcomes. 79 A recent retrospective multicenter study reported a greater than 90% response rate in patients with type III achalasia, perhaps due to longer myotomy length with the endoscopic approach. 80 There have been no randomized trials comparing POEM to laparoscopic myotomy or pneumatic dilation, and its relative efficacy in terms of long-term dysphagia control, progression of esophageal dilatation, and postprocedure reflux remains to be established. Table 2. Summary of Current Treatments for Treatment Durability Procedural Issues Medical therapy a On demand/ None not durable Botulinum toxin injection 6-12 mo 54 Performed in endoscopy laboratory Moderate sedation or monitored anesthesia care Procedure time <30 min 60 min observation Pneumatic dilation 2-5y 55,56 Performed in endoscopy laboratory with fluoroscopy Moderate sedation or monitored anesthesia care Procedure time, 30 min 4-6 h observation Surgical myotomy 5-10 y 56 Operating room General anesthesia Procedure time, 90 min Hospital stay, 1-2 d Per-oral endoscopic myotomy Unknown Operating room or endoscopy laboratory General anesthesia Procedure time, 90 min Requires overnight stay a Oral calcium channel blockers, nifedipine, isosorbide dinitrate, or sildenafil. Table 3. Randomized Clinical Trials Evaluating Treatment Modalities for (2004-2015) Source Inclusion Criteria Sample Size, No. Comparison Outcomes Richards et al, 57 2004 Rebecchi et al, 58 2008 Rawlings et al, 59 2012 Kostic et al, 60 2007 Novais et al, 61 2010 Boeckxstaens et al, 55 2011 Persson et al, 56 2015 Mikaeli et al, 40 2006 Bakhshipour et al, 62 2009 Patient s diagnosis of untreated achalasia Patients with achalasia, including previous treatment with botulinum toxin and pneumatic dilation Patients with achalasia (untreated or previously treated with botulinum toxin or pneumatic dilation) Patients with newly diagnosed untreated achalasia Patients with newly diagnosed achalasia Patients with newly diagnosed achalasia Patients with newly diagnosed achalasia Patients with newly diagnosed achalasia Patients with achalasia with failed 30- and 35-mm pneumatic dilation or botulinum toxin 43 LHM vs LHM with Dor fundoplication 144 (138 for long-term analysis) LHM with Dor fundoplication vs LHM with total fundoplication 60 LHM with Dor fundoplication vs LHM with Toupet fundoplication 51 Pneumatic dilation vs LHM with Toupet fundoplication No significant difference in postoperative LES pressure or postoperative dysphagia Pathologic GERD: 48% for LHM vs 9% for LHM + fundoplication Incidence of GERD after 60-mo follow-up: 2.8% for Dor vs 0% for total (P = NS) Recurrence of dysphagia: 2.8% for Dor vs 15% for total (P <.001) Reflux symptoms: no difference Positive 24-h ph testing: no difference Improvement in dysphagia: no difference Cumulative number of treatment failures at 12 mo: 6 treatment failures in pneumatic dilation group vs 1 treatment failure in LHM group (P =.04) 94 Pneumatic dilation vs LHM Clinical response at 3 mo: 73.1% for pneumatic dilation vs 88.3% for LHM (P =.08) Manometric response at 3 mo: no difference between groups Incidence of GERD (24-h ph measurement): 31% for pneumatic dilation vs 5% for LHM (P =.0001) 201 (LHM = 106, pneumatic dilation = 95) 53 (LHM = 25, pneumatic dilation = 28) Pneumatic dilation vs LHM with Dor fundoplication Pneumatic dilation vs LHM with posterior fundoplication 54 Botulinum toxin 1 mo before pneumatic dilation vs pneumatic dilation alone 34 Pneumatic dilation vs pneumatic dilation + botulinum toxin injection Abbreviations: GERD, gastroesophageal reflux disease; LES, lower espophageal sphincter; LHM, laparoscopic Heller myotomy. Decrease in Eckardt score of 3 at 12 mo and 24 mo: (1) 90% for 12-mo pneumatic dilation vs 93% for LHM (P =.46) and (2) 86% for 24-mo pneumatic dilation vs 90% for LHM (P =.46) LES pressure, esophageal emptying, quality of life, complications: (1) no difference in LES pressure, quality of life, or esophageal emptying and (2) 4% perforation rate with pneumatic dilation and 12% mucosal tear rate with LHM Treatment failure: (1) 4% for LHM vs 32% for pneumatic dilation at 3 y and (2) 8% for LHM vs 36% for pneumatic dilation at 5 y Cumulative 1-y remission rate: 77% for botulinum toxin + pneumatic dilation vs 62% for pneumatic dilation alone (P =.10) Symptoms at 1, 6, and 12 mo: no significant difference in symptom scores at all time intervals jama.com (Reprinted) JAMA May 12, 2015 Volume 313, Number 18 1849

Clinical Review & Education Review Prognosis and Follow-up Multiple publications now support the prognostic value of achalasia subtypes: (1) patients with type II achalasia have the best prognosisfromtreatmentinvolvingmyotomyorpneumaticdilation(96% success rate) 81 ; (2) the treatment response of patients with type I islessrobust,at81% 81 (andisreducedfurtherasthedegreeofesophageal dilatation increases); and (3) patients with type III have a worse prognosis (66%), 81 likely because the associated spasm is less likely to respond to therapies directed at the lower esophageal sphincter. 52,71,82-84 The optimal approach in providing follow-up for patients with achalasia is focused on periodic evaluation of symptom relief, nutrition status, and esophageal emptying by timed barium esophagram. 85 Posttreatmentmanometrycanalsobeusedinfollowup, depending on patient tolerance for the procedure and availability. 85 Esophageal contractile activity may return after treatment. In 1 retrospective study, 4 of 7 patients with type I achalasia (57%), 6 of 17 with type II achalasia (35%), and 1 of 5 with type III achalasia (20%) had return of weak esophageal contractile activity after myotomy. 86 Although decisions to intervene are never based solely on barium esophagram or manometry alone, they do identify patients who should be followed up closely to prevent progression. Although the risk of squamous carcinoma is higher in patients with achalasia than in the general population, there are no data to support routine endoscopic surveillance, and this is left to the judgment of the physician. 87,88 Treatment Failures treatment is not curative, and up to 20% of patients have symptoms that may require additional treatments within 5 years. 89-92 Up to 6% to 20% of treated patients may have progressive dilation to megaesophagus or end-stage disease. 93 Management of the care of these patients is difficult, and options include botulinum toxin injection, repeat pneumatic dilation, or repeat myotomy. Esophagectomy is ultimately reserved as a final option in patients with severe esophageal dilatation and symptoms not responding to dilation and myotomy. Clinical Bottom Line is the most well-defined esophageal motility disorder. Presenting symptoms and esophageal contractile patterns may be inconsistent, resulting in delayed or missed diagnosis. Primary liquid dysphagia is a classic symptom suggestive of achalasia. Different achalasia phenotypes have differential responses to treatment. Definitive treatment to alleviate esophagogastric junction outflow obstruction such as myotomy (laparoscopic or endoscopic) or pneumatic dilation should be offered to patients without contraindications to surgery. ARTICLE INFORMATION Author Contributions: Drs Pandolfino and Gawron had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Pandolfino, Gawron. Drafting of the manuscript: Pandolfino, Gawron. Critical revision of the manuscript for important intellectual content: Pandolfino, Gawron. Study supervision: Pandolfino. Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Pandolfino reported receiving consulting and speaking fees from Given Imaging/Covidien and Sandhill Scientific. Dr Gawron reported no disclosures. Submissions: We encourage authors to submit papers for consideration as a Review. Please contact Mary McGrae McDermott, MD, at mdm608@northwestern.edu. REFERENCES 1. Gidda JS, Goyal RK. Regional gradient of initial inhibition and refractoriness in esophageal smooth. Gastroenterology. 1985;89(4):843-851. 2. Vanek AW, Diamant NE. Responses of the human esophagus to paired swallows. Gastroenterology. 1987;92(3):643-650. 3. Ask P, Tibbling L. Effect of time interval between swallows on esophageal peristalsis. Am J Physiol. 1980;238(6):G485-G490. 4. Lecea B, Gallego D, Farré R, Clavé P. Origin and modulation of circular smooth 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. 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