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From Whalebone to Laparoscope

Anita E. Spiess, MD; Peter J. Kahrilas, MD

JAMA. 1998;280:638-642.

ABSTRACT
Objective.— To review the pathophysiology and management of achalasia.

Data Sources.— Peer-reviewed publications located via MEDLINE using the search term esophageal achalasia (subheadings: complications, drug therapy, epidemiology, etiology, physiopathology, surgery, and therapy) published in English from 1966 to December 1997.

Study Selection.— Of 2632 citations identified, 4.5% were selected for inclusion by authors' blinded review of the abstracts. New developments in the understanding of achalasia or reports of therapeutic efficacy in either controlled trials or uncontrolled consecutive series involving 10 patients or more observed for a year or longer were reviewed in detail.

Data Extraction.— All 6 controlled therapeutic trials were included, and therapeutic efficacy in uncontrolled series was assessed by the authors extracting the patients with a good-to-excellent response from each study and calculating a pooled estimate of response rate with individual studies weighted proportionally to sample size.

Data Synthesis.— Achalasia results from irreversible destruction of esophageal myenteric plexus neurons causing aperistalsis and failed lower sphincter relaxation. The only therapies that adequately compensate for this dysfunction for a sustained time are pneumatic dilation and Heller myotomy. The single controlled trial comparing these treatments found surgery superior to dilation (95% vs 51% nearly complete symptom resolution, P<.01). In uncontrolled trials pneumatic dilation (weighted mean [SD]) is 72% (26%) effective vs 84% (20%) for Heller myotomy. The limitation of dilation is a 3% risk of perforation; thoracotomy morbidity has been the major limitation of myotomy. Surgical morbidity has been sharply reduced by laparoscopic techniques.

Conclusions.— Both pneumatic dilation and surgical myotomy are effective therapies for achalasia; laparoscopic Heller myotomy is emerging as the optimal surgical therapy.

INTRODUCTION

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ACHALASIA was first recognized more than 300 years ago. The disorder was initially labeled cardiospasm, recognizing it as a functional obstruction of the esophagus at the cardiac sphincter. The first reported treatment was to pass through the esophagus a piece of carved whalebone with a sponge affixed to the distal end.¹ In 1937, Lendrum proposed our current concept of the disease as a syndrome caused by incomplete relaxation of the lower esophageal sphincter (LES) and renamed the disease achalasia ("failure to relax").² This review summarizes the current knowledge of the pathophysiology and management of achalasia. The primary data source was a MEDLINE search of peer-reviewed articles, using the search term esophageal achalasia (subheadings: complications, drug therapy, epidemiology, etiology, physiopathology, surgery, and therapy), that were published in English from 1966 to December 1997. Reports of advances in the understanding of achalasia or of therapeutic efficacy in consecutive series of patients were reviewed in detail.

Achalasia is rare, with an estimated annual incidence of 1 per 100000 persons.^3-5 The physiologic alterations in achalasia (impaired LES relaxation with swallowing and aperistalsis in the smooth muscle esophagus) result from damaged innervation. Neuroanatomic data suggest the esophageal myenteric plexus as the primary neurologic target. Several reports,^6-8 including a recent study of 42 resected achalasic esophagi,⁹ reveal fewer ganglion cells and ganglion cells surrounded by mononuclear inflammatory cells in the smooth muscle. The ultimate cause of ganglion cell degeneration in achalasia is unknown but there is an association with the class II HLA antigen DQw1,¹⁰ and it has been hypothesized to be related to herpes zoster¹¹ or measles virus infections.¹² Support for an autoimmune pathogenesis comes from the description of antimyenteric neuron antibodies in a subset of achalasia patients.¹³

Physiologic studies also demonstrate myenteric plexus dysfunction in achalasia. Excitatory (cholinergic) and/or inhibitory ganglionic neurons (nitric oxide ± vasoactive intestinal polypeptide)¹⁴ are potentially affected. Physiologic and pharmacological evidence suggests partial preservation of the postganglionic cholinergic pathway in most cases.¹⁵ On the other hand, it is clear that the inhibitory ganglionic neurons must necessarily be impaired as an early manifestation of achalasia.^{14, 16} These inhibitory neurons mediate LES relaxation and the proximal to distal sequencing of esophageal peristalsis¹⁷; their absence offers a unifying hypothesis for the key physiologic abnormalities of achalasia: impaired LES relaxation and aperistalsis.

CLINICAL MANIFESTATIONS AND COMPLICATIONS

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The consequences of achalasia can be subtle early in its course, becoming more obvious with progression. The dilated esophagus with retained food and an air fluid level visible on a chest x-ray film is a late finding. Prior to the esophageal dilatation, the main symptoms are dysphagia and chest pain. In fact, the diagnosis is often delayed by the reported symptoms of chest pain and heartburn, leading the clinician to suspect reflux disease. The etiology of these symptoms is unclear, and antireflux therapy provides no relief. Experimental data show that, despite up to 47% of patients reporting the symptom of "heartburn," little reflux can be verified by pH monitoring.^18-19 Furthermore, esophageal pH monitoring is deceptive in achalasia because fermentation of food retained in the esophagus produces lactic acid, which can lead to an abnormal result.²⁰

Achalasia is best detected by functional studies, either fluoroscopy during a barium swallow or esophageal manometry. The radiographic features are aperistalsis, esophageal dilatation, and minimal LES opening with a bird-beak appearance; defining manometric features are aperistalsis and incomplete LES relaxation. Patients with spasmodic esophageal contractions define the variant known as vigorous achalasia and tend not to have esophageal dilatation, making them difficult to diagnose radiographically.^21-22 Because manometry can detect the functional abnormalities of achalasia with or without esophageal dilatation, it is the most sensitive diagnostic method.²³ However, both Chagas disease and pseudoachalasia can duplicate the manometric findings of achalasia. Chagas disease, caused by a parasite (Trypanosoma cruzi) and endemic in South America, tends to have multiorgan involvement and can be detected by a serum antibody.²⁴ Tumor-related pseudoachalasia (carcinoma of the gastric cardia in >50% of cases) accounts for up to 5% of cases and can completely mimic the clinical and manometric presentation of achalasia.²⁵ Malignant tumors produce an achalasia syndrome by infiltrating the gastroesophageal junction and creating a relative obstruction with secondary esophageal dilatation. It is this potential pitfall that mandates endoscopy as part of the diagnostic evaluation. Furthermore, the anatomic findings with pseudoachalasia can be subtle; if clinical suspicion is high, computerized tomography and endoscopic ultrasound should be considered.

Dysphagia for both solids and liquids is a major symptom of achalasia.²⁶ The pattern of dysphagia, especially in individuals with a dilated esophagus, is unique. They often augment food passage by drinking a lot while eating or applying maneuvers such as straightening the back, raising their arms over their heads, standing, or jumping. Long-term esophageal food retention leads to progressive esophageal dilatation, in which setting regurgitation, especially nocturnal regurgitation, becomes a prominent symptom. Pulmonary complications can result from regurgitation and chronic aspiration. Theoretically, early therapy should minimize these problems by its demonstrated ability to halt and even reverse the progression of esophageal dilatation.²⁷ Thus, therapeutic efficacy in achalasia should be assessed not only by symptom relief but also by improvement in esophageal emptying.

Another potential complication of achalasia is the development of esophageal carcinoma, first recognized by Fagge in 1872.²⁸ Estimates of the relative risk of developing squamous cell carcinoma with achalasia range from 0- to 33-fold.^29-33 The only population-based study found a 16-fold risk among 1062 achalasia patients with 9864 patient-years of follow-up.³⁴ Therapy does not eliminate the cancer risk, evident by reported cases occurring years after either medical or surgical therapy.^{27, 35} However, despite the 16-fold relative risk, the absolute risk of cancer remains slight, and an estimated 681 annual surveillance endoscopies would detect only 1 incident cancer among achalasia patients; surveillance is not advocated by national gastroenterology societies.

MANAGEMENT

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No therapy for achalasia reverses the underlying neuropathology or associated impaired LES relaxation and aperistalsis. Instead, the target of treatment is to reduce the LES pressure. Gravity then facilitates esophageal emptying, reducing the symptoms associated with esophageal retention and, hopefully, preventing complications. However, there are no data on the prevention of complications, and therapeutic efficacy can only be assessed by symptomatic or functional improvement. An analysis of pneumatic dilation found that a postdilation LES pressure greater than 10 mm Hg was the best predictor of prolonged remission, while patients with values greater than 20 mm Hg had little benefit.³⁶ Direct assessments of esophageal emptying can be performed with either fluoroscopy or scintigraphy. Radionuclide studies quantifying the esophageal retention of swallowed technetium-labeled sulfur colloid are described but rarely used. Alternatively, the height of the barium column within the esophagus 5 minutes after swallowing directly measures esophageal emptying. Although a column of less than 1 cm was initially described as indicative of inadequate emptying,³⁷ a subsequent evaluation could not correlate this measure and symptom improvement.³⁸ Evaluating symptom improvement is equally difficult. Although a descriptive symptom classification system has been proposed,³⁹ most series simply report "excellent" or "good" results and emphasize relief of dysphagia. The meaning of such descriptions varies with the initial symptom severity, making comparisons difficult.

Therapeutic Modalities

Proposed treatments include drugs, mechanical dilation, or surgery. Many drugs reduce LES pressure. Although anticholinergics, amyl nitrite, sublingual nitroglycerin, theophylline, and ₂ agonists have been tried,^40-41 the largest reported experience has been with isosorbide dinitrate or nifedipine, administered orally or sublingually prior to eating. Isosorbide dinitrate, 5 to 10 mg sublingual, reduces the resting LES pressure by 66% for 90 minutes.⁴² Calcium channel blockers (diltiazem hydrochloride, nifedipine, verapamil) reduce the LES pressure by 30% to 40% for more than 1 hour.^43-44 Another recently proposed achalasia treatment is intrasphincteric injection of botulinum toxin, which inhibits acetylcholine release from nerve endings,⁴⁵ reducing the LES pressure by 60% in pigs and 33% in people.^46-47 The site of action may be ganglionic or postganglionic. Its effect is eventually reversed by sprouting terminal axons that form new synapses.⁴⁸

Forceful dilation of the LES is accomplished with a balloon dilator, designed to distend the LES to a diameter of 3 to 4 cm and reduce LES pressure by partially disrupting the sphincteric muscle.^49-50 In instances of an unsatisfactory result, pneumatic dilation can be repeated once or twice. The major complication of pneumatic dilation is esophageal perforation. If perforation is suspected because of postprocedural pain or subcutaneous emphysema a Gastrografin followed by barium swallow should be obtained.^51-52 Any substantial perforation requires surgical repair. Patients with perforations that are promptly recognized and treated surgically within 6 to 8 hours have outcomes comparable to patients undergoing elective thoracotomy and Heller myotomy.⁵³

The surgical objective in the treatment of achalasia is to disrupt the LES enough to eliminate dysphagia without causing excessive reflux. Heller first described the technique in 1913, proposing anterior and posterior gastroesophageal junction incisions after accessing the area by thoracotomy.⁵⁴ Subsequent modifications include eliminating the posterior myotomy, shortening the anterior myotomy, and accessing the area by laparotomy, thoracoscopy, or laparoscopy. Debate persists regarding the necessity and type of accompanying antireflux procedure. The current trend is to use a laparoscopic approach, which requires division of the phrenoesophageal ligament and partial mobilization of the esophagus.⁵⁵ With this approach, at least a partial anterior fundoplication (Dohr procedure) is requisite.

Controlled Trials

Only 1 controlled trial has compared the 2 most effective therapies of achalasia. That prospective, randomized trial compared pneumatic dilation (39 patients) to Heller myotomy via thoracotomy (42 patients), reporting 95% nearly complete symptom resolution in the surgical group compared with 51% in the dilation group (P<.01) after 5 years (range, 24-156 months).²⁷ Included among the treatment failures in the dilation group are 2 patients (5.4%) who sustained perforations and 4 (10.8%) who subsequently had a good result with a second dilation. Although that report was criticized for the method of pneumatic dilation,⁵⁶ it remains the best source of comparative data. The only other controlled trials have compared pharmacological therapies either to each other or to pneumatic dilation. A controlled trial comparing botulinum toxin to pneumatic dilation found a sustained symptomatic response in 32% of botulinum toxin patients compared with 70% of the pneumatic dilation group at 12 months (P<.01).⁵⁷ A trial comparing pneumatic dilatation with nifedipine found a significant decrease in LES pressure and significant symptomatic improvement in both groups after 21 months.⁵⁸ In a placebo-controlled trial of 29 patients, nifedipine was significantly better than placebo, yielding good to excellent symptomatic response in 70% of achalasia patients after 6 to 18 months.⁵⁹ However, subsequent placebo-controlled, crossover trials have found only minimal clinical improvement with nifedipine.^60-61 In a prospective controlled trial of botulinum toxin vs placebo (saline injection), botulinum toxin provided significantly better symptomatic, manometric, and radiographic response, but 7 of the 8 patients relapsed after a mean period of 7 months.⁶²

Uncontrolled Trials

Table 1 summarizes medical and surgical treatment data of achalasia.^{27, 37, 55, 57, 62-108} Data in Table 1 are uncontrolled, as the few controlled trials are summarized above. All data included were consecutive series, although some were collected prospectively and others by retrospective review. These were combined in Table 1 because the results were identical. Since there was no uniformity in assessment of efficacy among trials, the proportion of patients with a good-to-excellent response were extracted from each study, regardless of criteria. The response indicated for each therapy is a pooled estimate of response rate over multiple studies with each study weighted proportionally to its sample size. Only studies including more than 10 patients and with a follow-up of at least 1 year were tabulated; since no such reports exist using smooth muscle relaxants or a thoracoscopic Heller myotomy, these treatments are not included. In calculating the response rate of each study, we extracted the number of individuals with a good-to-excellent response that was sustained until the end of the observation period without any further therapy. Thus, if a patient required a second dilation or a second injection or if a laparoscopic operation was converted to an open procedure, these were considered failures of the initial treatment. Also in Table 1 are similar calculations on the efficacy of retreatment. In the case of botulinum toxin and pneumatic dilation, the retreatment data pertain to individuals who either experienced a relapse after an initially successful therapy or had a second try after inadequate benefit from an initial treatment. Evident in Table 1, the 2 efficacious therapies are pneumatic dilation and Heller myotomy. Only 1 of 31 patients in a prospective trial of botulinum toxin had a response sustained for more than 2 years.⁶³

View this table: [in this window] [in a new window] Pooled Estimate of Response Rate of Achalasia Treatments Across Referenced Studies*

The choice between using dilation or myotomy as the primary therapy for achalasia requires consideration of not only efficacy but also morbidity. Pneumatic dilation, an outpatient procedure, has less morbidity than any surgical approach with the caveat that the incidence of esophageal perforation is 3%. Even though these patients do well, if the perforation is recognized and operated on promptly,⁵³ the perforation is invariably into the mediastinum, and there is no minimally invasive surgical option once that has occurred. With respect to Heller myotomy, although clearly efficacious, the greatest proportion of these cases were accomplished by thoracotomy, which has considerable morbidity. More than any other factor, it is the morbidity of thoracotomy that has led most patients to pneumatic dilation as the initial intervention. However, laparoscopic techniques have now been introduced with similar efficacy and substantially reduced morbidity. One recent series of 24 achalasia patients treated either thoracoscopically or laparoscopically had benefit similar to those of open procedures with a median hospitalization of only 3 days.¹⁰⁹ This is compared to laparotomy and thoracotomy, which have an average hospitalization of 7 to 10 days, followed by prolonged morbidity.^{91, 98}

Although more effective in terms of relieving dysphagia, myotomy also makes reflux more likely, leading some surgeons to perform an antireflux procedure concurrently with the myotomy; others reserve this for patients with an associated hiatal hernia.¹¹⁰ Illustrative of reflux complications is a surgical series in which recurrent dysphagia due to insufficient myotomy or periesophageal scarring occurred in 9% of patients 3 to 30 months postoperatively, while complications due to reflux ranging from esophagitis to Barrett metaplasia occurred in 17% of patients 21 to 23 months postoperatively.⁹⁴ There are also reports of adenocarcinoma developing as a late complication of postmyotomy reflux.^111-113 However, just as surgical techniques have evolved, so has the medical therapy of reflux esophagitis, and these reflux complications would be unlikely if individuals were treated with proton pump inhibitors.

In extremely advanced or refractory cases of achalasia, esophageal resection with gastric pull-up or interposition of a segment of transverse colon may be the only surgical option.^{91, 114-118} Patients with daily dysphagia and a tortuous esophagus with poor emptying, despite multiple previous procedures, are likely candidates.¹¹⁷ This technique is rarely if ever used as a primary intervention and, fortunately, is necessary in less than 1% of the achalasia population.

COMMENT

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Achalasia is a rare disease consequent from esophageal myenteric neuron destruction. In the short term, this defect results in esophageal retention with dysphagia, regurgitation, and chest pain, symptoms that often provoke the misdiagnosis of reflux disease. In the long term, untreated achalasia can lead to profound dysphagia, weight loss, and chronic aspiration. Despite the minimal controlled treatment data in the literature, treatment is desirable because there is no spontaneous recovery from achalasia, and treatment that compensates for the impaired esophageal emptying is the only potential way of preventing long-term complications. Proposed treatments of achalasia can be grouped as pharmacological, dilation, or surgical with efficacy assessed in terms of symptomatic improvement, functional improvement, or both. The above considerations suggest that both sustained symptom relief and functional improvement are desirable objectives. This requirement, in essence, relegates pharmacological therapy to the role of a temporizing measure. The most intriguing data pertain to the use of botulinum toxin injection. However, the limitations of botulinum toxin injection are the following: (1) it has no proven effect in improving esophageal emptying, (2) its effect lasts for only about a year, (3) the consequences of repeated injections are unknown, and (4) it is relatively expensive.¹¹⁹ It would appear, therefore, that this therapeutic option should be reserved for elderly or frail individuals who are poor risks for more definitive treatments.

Definitive treatments of achalasia with the potential of satisfying long-term treatment objectives are dilation or surgical myotomy. Pneumatic dilation, a descendant of the sponge affixed to whalebone technique, results in a good response in the majority of patients, with approximately 20% of patients requiring additional dilations and 3% incurring esophageal perforation. Heller myotomy, though of more predictable efficacy than pneumatic dilation, has historically been a second-line therapy because of the morbidity associated with thoracotomy. Furthermore, even in the event of perforation from a pneumatic dilation, a successful myotomy could still be achieved by thoracotomy. However, with the recent introduction of laparoscopic myotomy, this hierarchical approach to therapy may change. Rapidly accumulating data on this new technique suggest equal efficacy of the laparoscopic procedure when compared to the open approach, but with sharply reduced morbidity. However, because laparoscopic myotomy cannot be done in the setting of esophageal perforation during pneumatic dilation, this option may be lost if not selected as the initial intervention. Given these considerations, it may be time to evolve from the whalebone to the laparoscope.

AUTHOR INFORMATION

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Corresponding author: Peter J. Kahrilas, MD, Division of Gastroenterology & Hepatology, Department of Medicine, Northwestern University Medical School, Passavant Pavilion, Suite 746, 303 E Superior St, Chicago, IL 60611-3053 (e-mail: p-kahrilas{at}nwu.edu).

This study was supported by grant RO1 DC00646 from the Public Health Service, Bethesda, Md.

From the Department of Medicine, Division of Gastroenterology & Hepatology, Northwestern University Medical School, Chicago, Ill.

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