Pseudo or secondary achalasia
What is pseudoachalasia, what are its causes?
P.J. Kahrilas (Chicago)
Achalasia was first recognized more than 300 years ago. The disorder was initially labeled cardiospasm reflecting the observation that it was caused by a functional rather than an anatomic obstruction of the esophagus at the cardiac sphincter, with no obstructing lesions evident in autopsy specimens. Apparently, even at that point in time it was recognized that this was the main element in the differential diagnosis. In 1937, Lendrum proposed that the functional esophageal obstruction resulted from incomplete relaxation of the lower esophageal sphincter (LES) and renamed the disease achalasia ("failure to relax") . Although achalasia is almost universally idiopathic in etiology in North America, the disease can be closely mimicked by the esophageal involvement in Chagas' disease caused by infection with the parasite Trypanosoma cruzi which is endemic in areas of South America. A key distinction between idiopathic achalasia and that resultant from the late stages of Chagas' disease is that there whereas there is selective involvement of the esophagus with idiopathic achalasia, Chagas disease afflicts other organs as well resulting in cardiomyopathy, megaureter, megaduodenum, or megacolon .
Achalasia is characterized by:
- failure of the LES to relax completely with swallowing,
- aperistalsis in the smooth muscle esophagus.
The associated finding of an elevated LES pressure is found in about 60% of cases. If there are nonperistaltic, spasm-like contractions in the esophageal body, the disease is referred to as vigorous achalasia. Achalasia is thought to result from post-ganglionic denervation of the smooth muscle esophagus either as a result of parasitic infestation as in Chagas' disease or, more commonly, as an idiopathic entity. A recent morphologic study of 42 esophagi resected from patients with advanced achalasia revealed diminished myenteric ganglion cells and inflammation within the myenteric plexus in all cases . It is unclear whether the disease selectively affects excitatory or inhibitory neurons but functionally, it is clear that the inhibitory neurons are necessarily impaired as an early manifestation of the disease. Previously referred to as nonadrenergic, noncholinergic neurons, it is increasingly evident that the neurons responsible for deglutitive inhibition (including sphincter relaxation) utilize nitric oxide as a neurotransmitter . In support of this conclusion, patients with achalasia have been shown to lack nitric oxide synthase in the gastroesophageal junction  and animal models of achalasia have been established using nitric oxide inhibitors .
The diagnosis of achalasia is made by barium swallow X-ray or esophageal manometry. The characteristic X-ray is of a dilated intrathoracic esophagus with an air-fluid level. The LES tapers to a point giving the distal esophagus a beak-like appearance. The beak does not open with swallowing but will open following the inhalation of amyl nitrite (a smooth muscle relaxant) . It is important to recognize that neither the radiographic nor the manometric features of achalasia are specific for idiopathic achalasia or achalasia associated with Chagas' disease. Distal esophageal obstruction by tumor, stricture, or surgical manipulation will result in the same functional characteristics, e.g. narrowing of the distal esophagus with aperistalsis and dilation proximal to the narrowing. This clinical scenario has been labeled secondary achalasia or pseudoachalasia. Of the two possible names, pseudoachalasia seems more accurate because, as detailed below, the resultant situation mimics achalasia somewhat imperfectly rather than representing achalasia from another cause.
Ogilvie first reported that neoplastic involvement of the distal esophagus could result in a clinical picture that closely mimics idiopathic achalasia . Following Ogilvie's observation, Park  in 1952 and Asherson  in 1953 reported on patients with apparent "cardiospasm" in whom gastric cancer was subsequently diagnosed at surgery. Since then, numerous case reports have established pseudoachalasia as a distinct pathophysiologic entity. Patients with pseudoachalasia generally complain of progressive dysphagia, chest pain, regurgitation, and weight loss. Radiographically, the esophagus is commonly dilated and aperistaltic with a smooth tapering at its distal end. Esophageal manometry shows evidence of aperistalsis, hypertensive LES pressure, and incomplete LES relaxation with deglutition. In many instances, patients with pseudoachalasia have an initial diagnosis of achalasia thereby creating the potential for ill-advised dilations. The most common causative lesion of pseudoachalasia is adenocarcinoma originating in the gastric fundus. In addition, metastases from neoplasms originating in the prostate, liver, pancreas, and lung as well as lymphoma have all been reported to cause what has been variably termed secondary achalasia or pseudoachalasia [10-12].
Esophageal pseudoachalasia is a rare entity. Although the true incidence of pseudoachalasia is not established, we approximated its prevalence in a referral practice by reviewing all cases of achalasia during a 14-year period . Overall, pseudoachalasia accounted for six of 167, or 4% of patients with esophageal manometric findings suggestive of idiopathic achalasia. However, the age distributions of patients with achalasia and pseudoachalasia are different. Whereas patients with achalasia have a nearly uniform age distribution between 10 and 70 years when initially seen, the youngest reported case of pseudoachalasia occurred in a 32 year old and the frequency of occurrence increased with increasing age. Thus, the possibility of pseudoachalasia is remote in persons less than 32 years old, and the peak incidence occurs in the seventh and eighth decades of life. From our experience, pseudoachalasia accounted for about 6% of persons over 40 years of age, and 9% of persons over 60 years of age who presented with manometric findings of achalasia. Clinical features suggestive of pseudoachalasia are a duration of symptoms of less than one year and substantial weight loss. All of our patients had symptoms for less than 10 months and all but one lost 20 pounds more. These clinical features in a middle-age or elderly patient are suspicious for pseudoachalasia, but they are not specific as shown by Sandler  and in our series. Nevertheless, only 5% of our patients with idiopathic achalasia presented with symptoms for less than 12 months and weight loss in excess of 20 pounds.
Conventional esophageal manometry is of negligible value in discriminating pseudoachalasia from achalasia. This is true regardless of the sophistication of the manometric instrumentation, such as a low-compliance infusion system or a Dent sleeve device for recording lower esophageal sphincter relaxation . Additionally, pharmacologic challenge with methacholine or cholecystokinin octapeptide had no discriminatory value. Pharmacologic provocation with amyl nitrite is potentially more useful in making this discrimination but inadequate data exist to state this with certainty.
Radiographic examination is crucial in discerning pseudoachalasia from achalasia. A thorough double contrast barium swallow usually shows morphologic abnormalities suggestive or diagnostic of malignancy in patients with pseudoachalasia. Amyl nitrite inhalation is a useful adjunct to the radiographic examination in that it discriminates the cardiospasm of achalasia, which is relaxed by amyl nitrite, from fixed malignant strictures, which are unaffected . When performing this test, the examiner must verify, by detecting an increase in pulse rate, that the patient has received an adequate dose of amyl nitrite.
Personal experience and review of the literature suggests that flexible endoscopy with biopsy is diagnostic in at least two thirds of patients with pseudoachalasia . The yield of endoscopy is further enhanced if the endoscopist recognizes the importance of the feel of traversing the LES in the idiopathic achalasia patient. In idiopathic achalasia, the endoscope should pop through with only gentle pressure required. If the endoscopist encounters more than the slightest resistance of passage of the endoscope across the gastroesophageal junction, a diagnosis of pseudoachalasia should be considered. If suspicion persists following endoscopy and biopsy of the cardia, computerized tomography, magnetic resonance imaging, or endoscopic ultrasound should be considered for further evaluation depending upon the special circumstances.
The type of neoplasm causing pseudoachalasia varies, but the most common tumor is adenocarcinoma of the gastric fundus, accounting for about 70% of all cases . The resultant malignant stricture forms a stenotic segment in the region of the LES, although its proximal margin may be slightly above or below the proximal margin of the LES. Pathologic examination reveals a circumferential or nearly circumferential tumor mass involving the cardia. A less common pattern of involvement occurs when the tumor mimics achalasia by submucosal infiltration with impairment of postganglionic LES innervation. This circumstance occurred in only one of our six cases reported in the Milwaukee series and in about a third of the cases reported by others . With either pattern of neoplastic involvement, there is dilation of the esophageal body accompanied by loss of peristalsis in the thoracic esophagus. When the obstructing lesion is removed and the esophagus is allowed to regain normal tone, peristalsis returns in about three fourths of patients that have been tested.
Because pneumatic dilation is often the initial therapy for idiopathic achalasia, the clinician must discriminate pseudoachalasia from achalasia prior to therapy. Pneumatic dilation of a malignant stricture will be ineffective, potentially dangerous, and delay appropriate therapy. Fortunately, despite similarities in the patients' histories and manometric findings, pseudoachalasia usually mimics primary idiopathic achalasia imperfectly. Endoscopic examination and biopsy with particular attention to mucosal irregularity, compliance of the gastroesophageal junction, the gastric cardia, and the gastric fundus are of cardinal importance and generally yield the correct diagnosis. Similarly, a carefully performed barium study with amyl nitrite inhalation is useful in distinguishing pseudoachalasia from achalasia.
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