- Slowly progressive esophageal dysphagia to both solids and liquids.
- Absence of acid reflux.
- Regurgitation of undigested food without acid or bile; episodes of pneumonia.
- Chest radiograph may show a mediastinal mass with air-fluid levels.
- Barium esophagogram shows a dilated esophagus without peristalsis and a "bird beak" in the distal esophagus.
- Esophageal manometry shows nonperistalsis esophageal contractions and failure of LES relaxation on swallowing.
Achalasia is a disorder of the thoracic esophagus characterized by nonperistaltic esophageal contractions and impaired relaxation of the LES in response to swallowing. It results primarily from degeneration of nitrergic inhibitory neurons in the myenteric plexus. Achalasia is an important but uncommon clinical disorder with an incidence of 1 in 100,000 persons. It most often manifests between the ages of 25 and 50 years but affects patients of all ages and both sexes. Diagnosis is generally established on the basis of radiologic findings and manometric studies, and by ruling out secondary causes such as cancer. Definitive therapy is surgical myotomy, but various medical and endoscopic treatments have been employed for symptomatic relief.
Achalasia is associated with degeneration of postganglionic inhibitory neurons, which release nitric oxide and VIP (Figure 13–7). Postganglionic excitatory neurons may also be affected in advanced disease. Preganglionic vagal fibers and vagal nuclei may also be involved.
Schematic diagram of different parts of a nitrergic neuron that may be affected by various kinds of pathology, resulting in esophageal neuromuscular diseases. NO, nitric oxide.
Most cases in the United States are of no known cause and are classified as idiopathic achalasia. A viral etiology for the inflammation has also been proposed, and elevated antibody titers to measles and varicella zoster have been described in a high proportion of patients with idiopathic achalasia. Autoimmunity has been proposed as contributing to the etiology based on observation of T-lymphocyte infiltration in the myenteric plexus, and there is a higher prevalence of the disorder in patients with certain human leukocyte antigen (HLA) types. Autoantibodies to neurons are also found in many patients with achalasia.
Familial achalasia comprises about 2–5% of all cases and generally involves an autosomal-recessive mode of inheritance, particularly in children younger than 4 years of age. In children, this may be part of the AAA syndrome (achalasia, alacrima, achlorhydria), which may also be associated with adrenocorticotropic hormone insensitivity, microcephaly, and nerve deafness. Additionally, a small percentage of patients have associated neurodegenerative diseases such as Parkinson disease and hereditary cerebellar ataxia.
Secondary achalasia refers to inhibitory neuronal degeneration caused by a known etiologic agent such as Trypanosoma cruzi (the causative organism in Chagas disease) and carcinoma.
Although the cause of primary achalasia is largely unknown, degenerative changes have been noted in the dorsal motor nucleus (Lewy bodies), along with degeneration of vagal fibers and loss of ganglion cells in the esophageal body and LES. In particular, there may be an inflammatory response, predominantly of T-cell lymphocytes. However, these changes are not consistent and may be secondary to an enteric nervous system disease involving loss of nitrergic and VIP-containing neurons (the main relaxatory mediators of the esophageal smooth muscle) and a decrease in the number of interstitial cells of Cajal. Muscular hypertrophy, possibly secondary to the denervation, and variable extent of muscle degeneration has also been described. However, these muscular and neuronal changes cannot be assessed by evaluation of mucosal biopsies obtained during endoscopy. Newer approaches are being assessed for obtaining full-thickness biopsies to facilitate evaluation of neuromuscular pathology.
Fraser H, Neshev E, Storr M, et al. A novel method of full-thickness gastric biopsy via a percutaneous, endoscopically assisted, transenteric approach. Gastrointest Endosc. 2010;71:831–834.
Goyal RK, Chaudhury A. Pathogenesis of achalasia: lessons from mutant mice. Gastroenterology. 2010;139:1086–1090.
Pasricha PJ, Pehlivanov ND, Gomez G, et al. Changes in the gastric enteric nervous system and muscle: a case report on two patients with diabetic gastroparesis. BMC Gastroenterol. 2008;8:21.
Dysphagia is the most common presenting symptom of achalasia and is present in nearly all patients. Dysphagia to both liquids and solids is characteristic of this disease; however, symptoms may initially involve primarily solids, followed by liquids. Dysphagia is mainly localized to the lower chest, although it may be localized to the neck. Generally, it is worsened by emotional stress or hurried eating. Patients often complain of taking longer to eat a meal or of drinking a large amount of liquid to clear the food from the esophagus. They may even describe having to stand up, perform the Valsalva maneuver, or arch their backs to help clear food from the esophagus.
The second most frequent presenting symptom is regurgitation of food, which is generally undigested, nonbilious, and nonacidic. Patients may wake in the middle of the night as a result of coughing or choking after regurgitation, the content of which is often described as white and foamy, arising from an inability to clear saliva from the esophagus. Chest pain and heartburn occur in approximately 40% of patients and can be misdiagnosed as GERD. However, the heartburn is generally not postprandial or responsive to antacids.
Mild weight loss is noted in approximately 85% of patients and may even mimic cancer when profound. However, the interval from the presenting symptom to the point at which the patient seeks medical attention is quite variable, sometimes extending beyond a decade.
Some patients with idiopathic achalasia have increased antineuronal antibodies, including anti–Hu-1 antineuronal antibodies. Enzyme-linked immunosorbent assay (ELISA) tests, agglutination tests, and confirmatory assays, including immunofluorescence, immunoblot, Western blot, and radioimmunoprecipitation tests, may aid in identifying T cruzi in patients with achalasia caused by Chagas disease.
Barium esophagogram, the preferred initial method of evaluation in patients with dysphagia, may reveal characteristically smooth, symmetric narrowing or "bird-beaking" of the distal esophagus, and often a dilated esophagus with no peristaltic activity and poor esophageal emptying. In severe achalasia, chest radiographs may reveal a dilated esophagus containing food, possibly air-fluid level within the esophagus in the upright position, absence of gastric air bubble, and sometimes a tubular mediastinal mass beside the aorta. Administration of a smooth muscle relaxant such as sublingual nitroglycerin or inhaled amyl nitrate may cause relaxation of the LES and distinguish achalasia from pseudoachalasia arising from mechanical causes. Severe cases may reveal a markedly dilated and tortuous esophagus, called a sigmoid esophagus (see Figure 13–4).
Esophagogastroduodenoscopy is not sensitive in the diagnosis of esophageal motility disorders. However, it is very useful in excluding mechanical disorders, particularly those that may be the cause of the motility disorder (eg, infiltration by gastroesophageal junction cancer, causing secondary achalasia).
The diagnosis is confirmed by esophageal manometry, which typically reveals complete absence of peristalsis, incomplete LES relaxation (<50% of baseline pressure), and often but not necessarily increased lower esophageal basal tone (>30 mm Hg). Weak contractions may be noted in the esophageal body, which are simultaneous or appear simultaneous but identical if the esophageal body becomes a single lumen (common cavity effect) (see Figure 13–5). Esophageal pressures may also exceed gastric pressures when the esophagus is filled with food or fluid.
The differential diagnosis of achalasia begins with the broad differential diagnosis of dysphagia and exclusion of mechanical causes of dysphagia. Strictures, benign neoplasms, vascular rings, webs, foreign bodies, and severe esophagitis (peptic, infectious, chemical, drug induced) are among the frequently encountered entities.
Achalasia must be distinguished from other motility disorders such as diffuse esophageal spasm and scleroderma that has been complicated by a peptic stricture. The next step is to determine whether it is due to an identifiable cause. These cases, termed secondary achalasia, may be due to infection with T cruzi (Chagas disease) or neural degeneration as a paraneoplastic syndrome associated with many malignancies. Gastroesophageal junction carcinoma may produce myenteric plexus degeneration by local tumor invasion, resulting in achalasia. The term pseudoachalasia is used when there is no functional cause of achalasia but the gastroesophageal junction is narrowed due to outside compression or fibrosis and the esophageal body is dilated due to obstruction. Patients with secondary achalasia due to tumor at the gastroesophageal junction present with more recent and progressive onset of dysphagia or with progressive weight loss. Careful retroflexed inspection of the cardia and gastroesophageal junction by upper endoscopy is necessary.
Current options for treatment of achalasia are directed at removing the functional obstruction caused by the nonrelaxing LES. However, these therapeutic modalities do not restore peristalsis. Treatment includes pharmacologic therapy, pneumatic dilation of the LES, surgical myotomy, and botulinum toxin injection therapy.
Sublingual nitroglycerin, calcium channel blockers, phosphodiesterase inhibitors, and anticholinergics are used to relieve the symptoms in the subset of patients who have mild symptoms without esophageal dilation, or are unable to undergo dilations or surgery.
The disruption of muscle requires far larger diameters compared with disruption of mucosal lesions such as strictures. A 3-cm diameter balloon is used initially. Based on patient's response, successive dilations of up to 4 cm can be applied. At each session, a balloon is placed under fluoroscopic guidance to stretch the area of the gastroesophageal junction. In less than 4% of dilations, perforations occur that may require surgical repair. In experienced hands, the efficacy of pneumatic dilation and laparoscopic surgery are nearly equal, and dilation appears to be the more cost-effective initial approach.
A modified Heller cardiomyotomy of the LES and cardia results in good to excellent symptomatic relief in over 85% of patients. GERD is expected to ensue in up to 20% of patients. Myotomy can also be performed using a laparoscopic approach; this is less invasive, reduces postoperative complications, and allows a shorter hospital stay. The success of surgery does not appear to be compromised by prior botulinum or pneumatic dilation treatments.
Botulinum Toxin Injection
Botulinum toxin A is injected directly into the LES using an endoscope. Approximately 20–25 units of the toxin are used per injection into four quadrants in the LES. This results in reduction of lower esophageal pressures in 85% of patients. However, approximately 50% of patients relapse with symptoms over the next 6–9 months. Approximately 25% have a sustained response lasting more than 1 year. Approximately 75% of initial responders who relapse have improvement with repeat injection therapy. Because of the lower efficacy and sustained response compared with surgical myotomy, this method is often reserved for elderly patients or those with multiple medical problems.
Untreated, achalasia can lead to severe weight loss mimicking cancer, and respiratory complications such as stridor. Patients may develop distal esophageal diverticulum and bezoars. After surgery, patients may develop GERD, strictures, and Barrett esophagus.
- Nonperistaltic simultaneous contractions of the esophagus.
- Dysphagia to solids and liquids and chest pain are common presenting symptoms.
- Some patients may progress to achalasia.
The reported incidence of diffuse esophageal spasm depends on the diagnostic criteria used. When large amplitude of contractions is considered in the diagnosis, only 3–5% of patients undergoing manometry for suspected esophageal motility disorders fit the diagnostic criteria. Diffuse esophageal spasm is a disorder of the thoracic esophagus resulting from impairment of inhibitory innervation. It involves the esophagus but spares the LES, leading to nonperistaltic contractions but normal LES relaxation, as evidenced on manometry. The amplitude of the contractions may be normal, increased, or decreased. Acid suppression and other medical and endoscopic treatments may alleviate symptoms. A subset of patients may progress to achalasia.
Nonperistaltic contractions are due to loss of deglutitive inhibition associated with impaired inhibitory nerve function in the esophageal body. The amplitude of contractions involves many components, including the rebound contraction, which is dependent on the inhibitory nerves, cholinergic excitatory nerves, and myogenic factors. Loss of inhibitory nerves alone would be expected to reduce the force of contraction, whereas compensatory cholinergic and myogenic factors may lead to increased force of contraction. However, little is known about the pathology of diffuse esophageal spasm. There appears to be patchy neural degeneration localized to nerve processes rather than degeneration of nerve cell bodies, as evidenced in achalasia. Hypertrophy of the muscularis propria and associated development of distal esophageal diverticula also occur.
Chest pain, dysphagia, and regurgitation are the main presenting symptoms. Chest pain may be particularly prominent in patients with high-amplitude and protracted contractions and can occur at rest, with swallowing, or with emotional stress. The pain is generally retrosternal but can radiate to the back, sides of the chest, arms, or the jaw. Pain can last from seconds to several minutes and can mimic that of cardiac angina. Dysphagia for solids and liquids can be present. Regurgitation of food that fails to move into the stomach may occur.
Findings on barium swallow may be normal or show nonpropagated contractions (called tertiary contractions), particularly below the aortic arch, with the appearance of curling or multiple ripples in the wall, sacculations, and pseudodiverticula, leading to the appearance of a "corkscrew" esophagus in severe cases.
The diagnosis is generally made by esophageal manometry, which reveals more than 20% of wet swallows as simultaneous contractions. However, because the disorder is episodic, manometric findings can be entirely normal at the time of study. Simultaneous contractions must be distinguished from identical contraction patterns suggestive of a common cavity effect from functional or mechanical obstruction in the esophagus during the study. Moreover, occasional nonperistaltic contractions can occur normally. The amplitude of the nonperistaltic contractions can be increased, normal, or even decreased, and sometimes the contractions are multipeaked. However, LES relaxation is normal, and normally conducted peristaltic contraction must be evidenced in at least one swallow.
Methods to provoke esophageal spasm, including cold swallows and edrophonium, can induce chest pain but may not necessarily correlate with motility changes. Thus, provocation tests have limited utility.
Diffuse esophageal spasm must be distinguished from other causes of chest pain, especially cardiac ischemia. Esophageal motility disorders are an uncommon cause of noncardiac chest pain, which is more commonly caused by reflux esophagitis or visceral hypersensitivity.
The mainstay of therapy is reassurance, control of esophageal acidification by proton pump inhibitors or histamine receptor antagonists, and use of smooth muscle relaxants such as nitrates and calcium channel blockers. There are no controlled studies to substantiate any particular treatment modality, although smooth muscle relaxants or anticholinergic agents used for achalasia may be helpful for improving symptoms. Some studies suggest that low-dose tricyclic antidepressant therapy may be a better option for treating chest pain. Empiric bougienage has been advocated, but studies comparing large- versus small-caliber bougies showed no differences in response rate, suggestive of a placebo effect. Similarly, there have been no controlled studies to validate the use of botulinum toxin either into the LES or at intervals along the esophageal body. Long esophageal myotomy is rarely used to treat intractable dysphagia and chest pain, particularly when associated with pulsion diverticula.
Patients may have intermittent dysphagia and chest pain for many years without progression. A small subset of these patients (~5%) develops vigorous or classic achalasia, which should be suspected if patients develop regurgitation with worsening dysphagia.
Inappropriate Transient Lower Esophageal Sphincter Relaxation (TLESR)
Transient LES relaxation normally occurs on swallowing, belching, or vomiting reflexes. When it occurs in the absence of such activities, it has been called inappropriate transient LES relaxation or simply transient LES relaxation (TLESR). TLESR is a vagovagal inhibitory reflex that is mediated via the nitrergic inhibitory nerves to the LES. The frequency of TLESR is increased by gastric distention. Increased frequency of TLESR has been shown to be an important cause of GERD. Diagnosis of TLESR can only be made by long-term manometric recordings, which are employed mainly in research but not in common clinical practice.
Basal LES pressure is dependent on the myogenic tone of the sphincter muscle, and superimposed, counterbalancing influence of inhibitory and excitatory nerves. The force of peristaltic contraction is dependent on the contractile ability of the smooth muscle and influence of the excitatory as well as the inhibitory nerves. The inhibitory nerves are responsible not only for inhibition but also for the rebound contraction that follows the inhibition. Therefore, loss of rebound contraction can only occur if the preceding deglutitive inhibition is also lost. Disorders of TLESR that involve normal deglutitive inhibition and peristaltic sequence can be classified into hypotensive and hypertensive esophageal motility disorders and are described in the following sections.