Clinical features

Achalasia can be diagnosed at any age but most commonly presents in patients between the ages of 25 and 60 years. An increasing incidence with age has been observed with an equal male-to-female gender distribution. It has an estimated prevalence in the United States of 10 cases per 100,000 with an incidence of 0.6 cases per 100,000 per year. Dysphagia to solids and liquids is the most common presenting symptom, experienced by greater than 90% of patients. A small subgroup of patients deny the presence of dysphagia despite having radiographic and manometric features consistent with achalasia. This situation may be due to several factors, including impaired visceral sensation, the absence of primary and secondary peristalsis in response to retained esophageal contents, and the adaptation to chronic esophageal obstruction and dilation. Regurgitation is the second most common symptom, occurring in approximately 60% of patients and usually in the postprandial period. Nocturnal regurgitation of esophageal contents can lead to nighttime cough and aspiration. Difficulty belching is reported in a large proportion of patients, most likely reflecting the inability of the upper and lower esophageal sphincters to relax in response to esophageal and gastric distension, respectively. The absent belch reflex is an important factor responsible for rare cases of upper airway obstruction secondary to a massively dilated esophagus that extrinsically compresses the posterior aspect of the trachea. Weight loss occurs in end-stage disease and usually does not exceed 5 to 10 kg before patients seek medical attention.

Chest pain is reported in 20% to 60% of patients. It is more common in younger patients and often diminishes over the course of the disease. Proposed etiologies include secondary or tertiary esophageal contractions, esophageal distension by retained food, gastroesophageal reflux, neuropathic pain related to the enteric neuropathy, and esophageal irritation by retained food and bacteria. The presence of pain cannot be predicted from radiographic or manometric findings. Improvement in pain does not necessarily accompany improvement in dysphagia after either pneumatic dilation or Heller myotomy. This discrepancy likely reflects the varied mechanisms responsible for chest pain. Pain due to esophageal distension, stasis esophagitis, or secondary peristalsis should improve following reduction of LES pressure, whereas neuropathic pain or pain associated with spastic contractions will persist.

Heartburn is reported in a large number of patients with achalasia, which is surprising given that achalasia is mechanistically the antithesis of gastroesophageal reflux disease. One study reported this symptom in 30% of achalasia patients. Although heartburn disappeared at the onset of dysphagia in one third of the patients, the remaining two thirds reported persistent heartburn at the time of their presentation with achalasia. The etiology of heartburn in patients with impaired LES relaxation may be related to direct irritation of the esophageal lining by retained food, pills, or acidic byproducts of bacterial metabolism of retained food. Poor esophageal clearance of even small amounts of refluxed gastric acid may also be an important factor. Abnormal amounts of acid reflux have been detected in as many as 20% of untreated achalasia patients by 24-hour ambulatory pH monitoring. Gastroesophageal reflux is, of course, a recognized sequela of successful treatment of achalasia.

Diagnosis

Upper endoscopy is often the first diagnostic test in a patient with dysphagia or suspected achalasia ( Fig. 1 ). Findings can include a dilated esophagus with retained food or secretions; however, endoscopy appears normal in as many as 44% of patients with achalasia. Difficulty traversing the esophagogastric junction should raise suspicion for pseudoachalasia due to neoplastic infiltration of the distal esophagus or gastric cardia. A barium esophagram can be highly suggestive of the diagnosis of achalasia, particularly when there is the combination of esophageal dilatation with retained food and barium and a smooth tapered constriction of the gastroesophageal junction. Nevertheless, in the series mentioned previously, the diagnosis of achalasia was suggested in only 64% of barium examinations.

Endoscopic findings in idiopathic achalasia. The esophageal lumen is markedly distended with retained food and saliva. Following evacuation, the underlying esophageal mucosa shows changes of stasis esophagitis that include nodularity and patchy erosions.

Esophageal manometry has the highest sensitivity for the diagnosis of achalasia, with the defining characteristics of aperistalsis of the distal esophageal body and incomplete or absent LES relaxation. Supportive features include a hypertensive LES and low amplitude esophageal body contractions. Because variations of typical manometric findings exist, additional features and methodology have been used to reinforce the diagnosis. An increase in the intraesophageal basal pressure that exceeds the intra-abdominal or intragastric pressure is a significant finding in achalasia, as are “common cavity” phenomena that represent bolus entrapment within the tubular esophagus.

High resolution esophageal manometry (HRM) combined with contour plots topographic analysis is a recent enhancement to conventional manometry that improves the accuracy of esophageal manometry. HRM allows for automated analysis of more detailed quantitative data. An example of the utility of this methodology is the interpretation of impaired LES deglutitive relaxation in the setting of exaggerated respiratory contractions of the crural diaphragm. Intrabolus pressure elevations are more readily apparent and quantified using HRM. A recent retrospective study subclassified 99 achalasia patients into those with classic achalasia with minimal esophageal pressurization, those with achalasia with esophageal compression pan esophageal pressurization in excess of 30 mm Hg, and those with achalasia with spasm. Examples of these three patterns are illustrated in Fig. 2 . Pan esophageal pressurization was a positive predictor of treatment response, whereas esophageal spasm was a negative predictor.

Contour plot topographic analysis of esophageal motility in achalasia. Topographic analysis is a method of axial data interpolation derived from computerized plotting of data from multiple, closely spaced, solid state recording transducers. The interpolated pressure information is plotted as a two-dimensional contour plot in which pressure amplitude is coded by color. ( A ) Plot depicts achalasia with complete esophageal aperistalsis and absent pressure activity within the esophageal body. The LES is hypertensive and demonstrates incomplete deglutitive relaxation. ( B ) Plot illustrates achalasia with pan esophageal pressurization or common cavity phenomena in response to a water swallow. Failed deglutitive relaxation of the LES is evident. An esophagogastric pressure gradient is seen in the esophagus before the swallow. ( C ) Plot depicts achalasia with spastic contractile activity in the distal esophageal body with long duration contractions that exceed 300 mm Hg.

Characteristics of achalasia using multichannel intraluminal impedance have also been described. The main feature identified as characteristic of achalasia was a low baseline impedance thought to be secondary to chronic fluid retention. Although this finding has been confirmed in subsequent studies, the low baseline impedance and air trapping in the proximal esophagus may prevent this modality from being able to accurately assess esophageal emptying. Further investigation is required before multichannel intraluminal impedance is integrated into the routine diagnostic evaluation for achalasia.

Manometric variants of achalasia exist. The best known is vigorous achalasia, defined by the presence of normal to high amplitude esophageal body contractions in the presence of a nonrelaxing LES. The distinction between esophageal pressurization, also referred to as common cavity phenomena, and esophageal spastic contractions may be an important one as suggested in a recent HRM study ( Fig. 2 B, C). In some cases, vigorous achalasia may represent an early stage of achalasia in which myenteric ganglion cells remain intact. Vigorous achalasia is indistinguishable from classic achalasia with respect to the age of onset, gender, and the duration of dysphagia before presentation. Botulinum toxin has been reported to be more effective in patients with vigorous achalasia. Additional manometric variants of achalasia include patients with intact peristalsis through the majority of the esophageal body and others with preservation of either deglutitive or transient LES relaxation. These manometric variants, although appearing to challenge the typical manometric criteria for achalasia, can still be consistent with the diagnosis. Esophageal functional testing with HRM or impedance should improve the recognition of achalasia that presents with atypical manometric features.

Secondary forms of achalasia are important considerations during the diagnostic evaluation ( Box 1 ).

These entities are all less common than the diagnosis of idiopathic achalasia, with the exception of Chagas’ disease in endemic areas of Central and South America. Chagas’ disease is a parasitic infection caused by Trypanosoma cruzi . The esophagus is the most common area of the gastrointestinal tract involved, and the disease manifests as secondary achalasia in 7% to 10% of chronically infected individuals. Chagas’ disease should be a consideration in the evaluation of achalasia patients in the United States given that the gastrointestinal sequela can manifest years or decades following the acute infection and in view of the large number of immigrants from Mexico and South America. The most concerning secondary etiology is cancer, which can present as achalasia through mechanical obstruction of the gastroesophageal junction, infiltration of the submucosa and muscularis of the LES, or paraneoplastic syndrome associated with small cell lung carcinoma with production of type I antineuronal nuclear autoantibodies, also known as anti-Hu antibodies. Progressive symptoms for less than 6 months in patients older than 60 years with associated weight loss and difficult passage of the endoscope across the esophagogastric junction increase the likelihood of a patient having cancer-associated achalasia.

Additional secondary forms of achalasia exist. Esophageal manometry cannot reliably distinguish primary from secondary forms of achalasia. Additional evaluation, such as a CT scan, esophageal biopsy, and endoscopic ultrasonography, may be necessary to confirm the diagnosis. An increasingly recognized etiology is post fundoplication achalasia caused by mechanical obstruction of the gastroesophageal junction by the fundoplication or diaphragmatic crural closure. Similar cases have been described following bariatric surgery using a gastric band device which constricts the proximal stomach a few centimeters below the LES. It is important to distinguish this complication from the inadvertent surgery in a patient with achalasia whose symptoms were mistaken for “refractory gastroesophageal reflux disease.” A preceding history of dysphagia and preoperative manometry can generally differentiate postoperative achalasia from primary achalasia. Eosinophilic esophagitis can produce secondary achalasia that may respond to medical or dietary therapy, thereby obviating the need for invasive therapeutic procedures.

Diagnosis

Upper endoscopy is often the first diagnostic test in a patient with dysphagia or suspected achalasia ( Fig. 1 ). Findings can include a dilated esophagus with retained food or secretions; however, endoscopy appears normal in as many as 44% of patients with achalasia. Difficulty traversing the esophagogastric junction should raise suspicion for pseudoachalasia due to neoplastic infiltration of the distal esophagus or gastric cardia. A barium esophagram can be highly suggestive of the diagnosis of achalasia, particularly when there is the combination of esophageal dilatation with retained food and barium and a smooth tapered constriction of the gastroesophageal junction. Nevertheless, in the series mentioned previously, the diagnosis of achalasia was suggested in only 64% of barium examinations.

Endoscopic findings in idiopathic achalasia. The esophageal lumen is markedly distended with retained food and saliva. Following evacuation, the underlying esophageal mucosa shows changes of stasis esophagitis that include nodularity and patchy erosions.

Esophageal manometry has the highest sensitivity for the diagnosis of achalasia, with the defining characteristics of aperistalsis of the distal esophageal body and incomplete or absent LES relaxation. Supportive features include a hypertensive LES and low amplitude esophageal body contractions. Because variations of typical manometric findings exist, additional features and methodology have been used to reinforce the diagnosis. An increase in the intraesophageal basal pressure that exceeds the intra-abdominal or intragastric pressure is a significant finding in achalasia, as are “common cavity” phenomena that represent bolus entrapment within the tubular esophagus.

High resolution esophageal manometry (HRM) combined with contour plots topographic analysis is a recent enhancement to conventional manometry that improves the accuracy of esophageal manometry. HRM allows for automated analysis of more detailed quantitative data. An example of the utility of this methodology is the interpretation of impaired LES deglutitive relaxation in the setting of exaggerated respiratory contractions of the crural diaphragm. Intrabolus pressure elevations are more readily apparent and quantified using HRM. A recent retrospective study subclassified 99 achalasia patients into those with classic achalasia with minimal esophageal pressurization, those with achalasia with esophageal compression pan esophageal pressurization in excess of 30 mm Hg, and those with achalasia with spasm. Examples of these three patterns are illustrated in Fig. 2 . Pan esophageal pressurization was a positive predictor of treatment response, whereas esophageal spasm was a negative predictor.

Contour plot topographic analysis of esophageal motility in achalasia. Topographic analysis is a method of axial data interpolation derived from computerized plotting of data from multiple, closely spaced, solid state recording transducers. The interpolated pressure information is plotted as a two-dimensional contour plot in which pressure amplitude is coded by color. ( A ) Plot depicts achalasia with complete esophageal aperistalsis and absent pressure activity within the esophageal body. The LES is hypertensive and demonstrates incomplete deglutitive relaxation. ( B ) Plot illustrates achalasia with pan esophageal pressurization or common cavity phenomena in response to a water swallow. Failed deglutitive relaxation of the LES is evident. An esophagogastric pressure gradient is seen in the esophagus before the swallow. ( C ) Plot depicts achalasia with spastic contractile activity in the distal esophageal body with long duration contractions that exceed 300 mm Hg.

Characteristics of achalasia using multichannel intraluminal impedance have also been described. The main feature identified as characteristic of achalasia was a low baseline impedance thought to be secondary to chronic fluid retention. Although this finding has been confirmed in subsequent studies, the low baseline impedance and air trapping in the proximal esophagus may prevent this modality from being able to accurately assess esophageal emptying. Further investigation is required before multichannel intraluminal impedance is integrated into the routine diagnostic evaluation for achalasia.

Manometric variants of achalasia exist. The best known is vigorous achalasia, defined by the presence of normal to high amplitude esophageal body contractions in the presence of a nonrelaxing LES. The distinction between esophageal pressurization, also referred to as common cavity phenomena, and esophageal spastic contractions may be an important one as suggested in a recent HRM study ( Fig. 2 B, C). In some cases, vigorous achalasia may represent an early stage of achalasia in which myenteric ganglion cells remain intact. Vigorous achalasia is indistinguishable from classic achalasia with respect to the age of onset, gender, and the duration of dysphagia before presentation. Botulinum toxin has been reported to be more effective in patients with vigorous achalasia. Additional manometric variants of achalasia include patients with intact peristalsis through the majority of the esophageal body and others with preservation of either deglutitive or transient LES relaxation. These manometric variants, although appearing to challenge the typical manometric criteria for achalasia, can still be consistent with the diagnosis. Esophageal functional testing with HRM or impedance should improve the recognition of achalasia that presents with atypical manometric features.

Secondary forms of achalasia are important considerations during the diagnostic evaluation ( Box 1 ).

These entities are all less common than the diagnosis of idiopathic achalasia, with the exception of Chagas’ disease in endemic areas of Central and South America. Chagas’ disease is a parasitic infection caused by Trypanosoma cruzi . The esophagus is the most common area of the gastrointestinal tract involved, and the disease manifests as secondary achalasia in 7% to 10% of chronically infected individuals. Chagas’ disease should be a consideration in the evaluation of achalasia patients in the United States given that the gastrointestinal sequela can manifest years or decades following the acute infection and in view of the large number of immigrants from Mexico and South America. The most concerning secondary etiology is cancer, which can present as achalasia through mechanical obstruction of the gastroesophageal junction, infiltration of the submucosa and muscularis of the LES, or paraneoplastic syndrome associated with small cell lung carcinoma with production of type I antineuronal nuclear autoantibodies, also known as anti-Hu antibodies. Progressive symptoms for less than 6 months in patients older than 60 years with associated weight loss and difficult passage of the endoscope across the esophagogastric junction increase the likelihood of a patient having cancer-associated achalasia.

Additional secondary forms of achalasia exist. Esophageal manometry cannot reliably distinguish primary from secondary forms of achalasia. Additional evaluation, such as a CT scan, esophageal biopsy, and endoscopic ultrasonography, may be necessary to confirm the diagnosis. An increasingly recognized etiology is post fundoplication achalasia caused by mechanical obstruction of the gastroesophageal junction by the fundoplication or diaphragmatic crural closure. Similar cases have been described following bariatric surgery using a gastric band device which constricts the proximal stomach a few centimeters below the LES. It is important to distinguish this complication from the inadvertent surgery in a patient with achalasia whose symptoms were mistaken for “refractory gastroesophageal reflux disease.” A preceding history of dysphagia and preoperative manometry can generally differentiate postoperative achalasia from primary achalasia. Eosinophilic esophagitis can produce secondary achalasia that may respond to medical or dietary therapy, thereby obviating the need for invasive therapeutic procedures.

Pathophysiology

In addition to pathologic demonstration of the diminution of neurons within the myenteric plexus in achalasia ( Fig. 3 ), physiologic studies have shown an imbalance between excitatory and inhibitory elements of the enteric nervous system. Intact cholinergic, excitatory neural function was demonstrated in a controlled study of achalasia patients by administering cholinergic and anticholinergic agents. This paradigm provides the rationale for the use of botulinum toxin, a potent anticholinergic agent. Many studies have also confirmed the finding of abnormal or absent inhibitory myenteric innervation. These data support the concept that the loss of inhibitory neurons is the primary insult responsible for the failed LES relaxation and loss of deglutitive inhibition that characterizes achalasia.

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