Minimally Invasive Treatment of Achalasia and Other Esophageal Dysmotility
Michael S. Nussbaum
Introduction
Most disorders of esophageal motility affect both the esophageal body and the lower esophageal sphincter (LES). The best known and most common of these disorders is achalasia, a primary disorder of the LES with secondary absence of peristalsis in the esophageal body. Achalasia is characterized primarily by dysphagia. Diffuse esophageal spasm and nutcracker esophagus, on the other hand, are primary disorders of esophageal body motility, which are characterized primarily by substernal chest pain and, to a lesser degree, by dysphagia. Hypertensive LES is the least common of the disorders, characterized by symptoms of dysphagia, chest pain, and, at times, associated gastroesophageal reflux disease (GERD). The distinguishing manometric features of hypertensive LES include elevated LES basal pressure, with normal swallow-induced relaxation and normal esophageal body peristalsis.
Achalasia
Anatomy/PhysiologyThe LES is a high-pressure segment separating the gastric cavity from the esophageal lumen. The main function of this sphincter is to prevent the reflux of gastric contents into the esophagus, which has a lower intraluminal pressure than the stomach. The LES must relax with swallowing to allow the passage of ingested material from the esophagus into the stomach. Abnormalities of either one of these functions are major causes of esophageal symptoms. Defects in the antireflux barrier function result in GERD and its complications. Defective relaxation of this sphincter results in dysphagia.
The LES is not a static barrier, but responds to a variety of stimuli with changes in the force of its closure. Multiple factors are responsible for the maintenance of the resting tone of the LES. Neural, humoral, and myogenic factors all contribute to basal sphincter pressure. The specific mechanism responsible for relaxation of LES pressure with swallowing remains to be elucidated. The response appears to be mediated through the vagus nerves. The neurotransmitter for sphincter relaxation is not adrenergic or cholinergic mediated, since adrenergic and cholinergic blockade fails to inhibit relaxation. The general nerve poison tetrodotoxin will abolish neurally mediated responses with little or no effect on smooth muscle. Tetrodotoxin will inhibit vagus-stimulated relaxation of the LES, indicating that this is a neurogenic mechanism. The neurotransmitter responsible for vagus-stimulated LES relaxation by definition is a nonadrenergic, noncholinergic inhibitor. Vasoactive intestinal polypeptide (VIP) is found in rich supply in the nerves in the region of the LES and is the most likely candidate for the specific LES inhibitory stimulus.
Esophageal achalasia is a complex motor abnormality of the esophageal body and LES, characterized by incomplete relaxation of the LES and aperistalsis. The prevalence of achalasia is ∼10 cases per 100,000 population, with an estimated incidence of ∼0.5 cases per 100,000 people per year and, after GERD, is the second most common functional disorder of the esophagus requiring surgery. The etiology is unknown, with data suggesting the possibility of several inciting mechanisms for achalasia, including infection, genetic inheritance, autoimmune disease, and neuronal degeneration as possible causes. Various studies have been performed investigating the possibility of several inciting mechanisms for achalasia. However, the sequence of events leading to this mechanism continues to be poorly understood. Currently, achalasia remains an idiopathic condition that is associated with a patchy inflammatory response consisting of cytotoxic T-lymphocyte, eosinophil, and mast cell infiltration in the esophageal myenteric (Auerbach’s) plexus with myenteric neural fibrosis, loss of ganglion cells, hypertrophy of the two muscle layers, and hypertrophy of nerve fibers. Preganglionic vagal neurons originating in the dorsal motor nucleus innervate two types of postganglionic nerves in the myenteric plexus of the lower esophagus smooth muscles: (1) the excitatory acetylcholine-secreting neurons and (2) the inhibitory VIP- and nitric oxide (NO)-secreting neurons. It is hypothesized that the aperistalsis of achalasia is secondary to interruption of normal vagal cholinergic motor function, whereas the failure of LES relaxation is due to derangement of the vagal inhibitory (VIP and NO) nerves. Multiple histopathologic studies have confirmed the loss of inhibitory neurons in the esophageal myenteric plexus as the pathologic hallmark of achalasia. There is a selective loss of postganglionic inhibitory neurons, which contain both NO and VIP, whereas, there is sparing of the postganglionic stimulatory (cholinergic) neurons. This produces a loss of inhibitory input, resulting in a nonrelaxing, hypertensive LES. This is demonstrated by an exaggerated motor response (spasm) to injection of cholinergic agonists, demonstrating a classic supersensitive response of the denervated tissue. Similarly, the LES is also supersensitive to both methacholine and pentagastrin in achalasia. The elevated LES tone may be the consequence of disproportionate loss of inhibitory influence. In addition, nitric oxide synthetase levels in the LES muscle are considerably lower in achalasia compared with normals. Depletion of interstitial cells of Cajal (ICC) networks and potential changes in the electrical activity of smooth muscle cells may also play a crucial role. The reduction in CD117-positive ICC and the associated reduced nitric oxide synthetase release might underlie the profound ICC impairment and could possibly be responsible for the lack of LES relaxation, because of missing inhibitory neurotransmission. It is unclear, however, whether the ICC loss is primarily caused by the accelerated attrition of mature cells or their impaired regeneration. It is further unclear whether the diminished availability of the potent smooth-muscle relaxant, nitric oxide, is a primary or a secondary phenomenon. The aperistalsis of the esophageal body is attributed to the loss of the latency gradient along the esophageal body that permits sequential contractions along the esophageal body, a process also thought to be mediated by NO. While several theories have been proposed based on known pathologic disease processes, contemporary thought has suggested that several biologic processes may lead to a common mechanism of neuron loss, which subsequently manifests as achalasia. As more studies have come out, the complexity of possible pathogenic mechanisms has increased.
While the underlying pathogenesis of achalasia is far from being completely defined or understood, the various clinical
and histopathologic data have led to a working model for the mechanism of the disease. Specifically, it is a neurodegenerative process that involves genetic susceptibility and an immune-mediated mechanism, involving a combination of genetic factors, including genetic characteristics of the immune system, which establish some potential to develop the disease. Among susceptible individuals, this process may be precipitated by exposure to infectious agents that stimulate the immune system and provoke a deleterious immune response on the inhibitory myenteric neurons. Some data suggest that age- and gender-based differences may exist. However, further study is needed into the genetic, immune, and infectious disease components of the process to provide further insight to and understanding of the mechanism of achalasia.
and histopathologic data have led to a working model for the mechanism of the disease. Specifically, it is a neurodegenerative process that involves genetic susceptibility and an immune-mediated mechanism, involving a combination of genetic factors, including genetic characteristics of the immune system, which establish some potential to develop the disease. Among susceptible individuals, this process may be precipitated by exposure to infectious agents that stimulate the immune system and provoke a deleterious immune response on the inhibitory myenteric neurons. Some data suggest that age- and gender-based differences may exist. However, further study is needed into the genetic, immune, and infectious disease components of the process to provide further insight to and understanding of the mechanism of achalasia.
Clinical PresentationWhatever the etiology, esophageal motor disorders such as achalasia lead to a combination of three esophageal symptom complexes. First and foremost is the insidious development of dysphagia caused by failure of propulsive force, obstruction to flow, and incoordination of contraction and relaxation. The diagnosis of achalasia should be suspected in patients complaining of dysphagia for solids and liquids with regurgitation of bland food and saliva. Frequent associated symptoms may include regurgitation, cough, and aspiration. In addition to dysphagia, some individuals with achalasia describe esophageal pain as well as gastroesophageal reflux symptoms. The cause of these symptoms is speculative, but may be due to an inability to adequately clear the refluxed acid. Conversely, these symptoms may also be related to retention of acid beverages, such as carbonated or fruit drinks and, in some cases, the production of lactic acid from retained food in a markedly dilated esophagus. Most achalasia patients have some degree of mild to moderate weight loss of 5 to 20 lb at presentation.
DiagnosisMany patients with achalasia are initially misdiagnosed with GERD. Nearly 40% of achalasia patients will complain of some degree of heartburn due to either poor clearance of refluxed acid or from exogenous ingested acid. Upon further questioning, the most common complaint in achalasia is dysphagia of both solids and liquids with regurgitation of saliva and food. Most will have some degree of weight loss, although not usually excessive. About 40% of patients with achalasia will complain of substernal chest pain.
When achalasia is suspected, the best initial screening study is a barium esophagram, which will show some degree of dilation of the esophagus, loss of primary peristalsis, and a smooth tapering of the lower esophagus. An epiphrenic diverticulum may also be present in this setting. Richter has popularized a modification of the barium esophagram known as the “timed barium swallow,” which assesses esophageal emptying of barium in the upright position over 5 minutes. The test can be repeated serially after therapy to evaluate the patient’s response to various treatment modalities. Esophagogastroduodenoscopy should be carried out to rule out pseudoachalasia due to extrinsic compression by a tumor, especially adenocarcinoma of the proximal stomach, at the level of the gastroesophageal (GE) junction. Pseudoachalasia should be suspected in elderly patients, when there is a short duration of symptoms, and in the setting of marked weight loss. Endoscopic ultrasound may be a useful adjunct in such patients where there is a high suspicion for pseudoachalasia.
The gold standard test for confirming the diagnosis of achalasia is esophageal manometry, demonstrating esophageal body aperistalsis and incomplete LES relaxation. There are four classic manometric characteristics, which usually include: hypertensive LES, present in ∼50% of patients; nonrelaxing LES; esophageal aperistalsis; and elevated lower esophageal baseline pressure. A subset of achalasia patients can have simultaneous contraction waves of variable amplitudes, consistent with preserved muscle function; this is termed vigorous achalasia. Esophageal manometry is required to establish the diagnosis of achalasia and must be done in any patient where invasive treatments, such as pneumatic dilation (PD) or surgical myotomy, are planned. Esophageal manometry is typically performed with a water-perfused catheter with five pressure transducers placed 5 cm apart. A typical catheter is 4 to 5-mm in diameter and contains eight channels oriented around the circumference. Water-perfused systems are relatively cheap, require little maintenance, and rarely malfunction. However, they are subject to many limitations and inaccuracies. They are uncomfortable for the patient and can induce uncontrollable swallowing. The studies are time consuming due to the need for evaluating multiple swallows and the use of a pull-through technique to assess the function of the LES. Since the entire esophageal body is usually sampled at only five or fewer points along its length, localized or segmental abnormalities may be missed and the side holes may not be consistently parallel to the bank of pressure transducers, especially in curved locations such as the pharynx or the GE junction. These difficulties are even greater in analysis of the LES because of its short length and its frequent movement with swallowing and respiration. Finally, interpretation of motility tracings is prone to subjectivity and inter-observer variability.
High-resolution manometry (HRM) is faster to perform, more comfortable and acceptable to patients, and appears to provide more accurate and precise evaluation of a wide range of esophageal motility problems. The combination of solid-state miniaturized transducers spaced at very close intervals, coupled with the analytical capacity of modern sophisticated software systems has allowed the evolution of this manometric technology. By greatly increasing the number of sensors and reducing the distance between them, it provides a comprehensive representation of the entire pressure profile along the esophagus. The visual display or topographic contour plot makes interpretation more intuitive. In addition to the advantage of the user-friendly visual representation, the software permits the easy calculation of many new parameters. The baseline may be easily adjusted to either gastric pressure or atmospheric pressure depending on the area of interest. In addition, the closely spaced transducers extending from the pharynx to the stomach and straddling the LES allow for simultaneous recording with fewer artifacts than required with the time-consuming traditional water-perfused manometry with pull-through technique. Once it is located in the stomach, the entire topography of the esophagus and the upper and lower sphincters is identifiable at a glance.
The HRM catheter is heavier and more rigid, making it easier to pass into position without endoscopic guidance. This is particularly important in patients with a dilated esophagus or a large hiatal hernia. This new technology has provided the opportunity to develop novel parameters for classifying functional abnormalities, which is particularly important in achalasia. New studies of achalasia using HRM have revealed three distinct subtypes of this condition: (a) classic achalasia with minimal pressurization, (b) achalasia with esophageal compression, and (c) achalasia with spasm. These groups had different responses to medical or surgical therapies, with group 2 having the best response and group 3, the worst. Thus, HRM may offer advantages over conventional methods, including improved
identification of motility disorders, hiatal hernia, outflow obstruction, and ease of interpretation. HRM studies are shorter than those using conventional methods, interpretation is image based, and correlates with objective endoscopic and physiologic findings. The introduction of HRM in the evaluation of motility disorders appears to provide a significant advance in the outpatient evaluation of esophageal function.
identification of motility disorders, hiatal hernia, outflow obstruction, and ease of interpretation. HRM studies are shorter than those using conventional methods, interpretation is image based, and correlates with objective endoscopic and physiologic findings. The introduction of HRM in the evaluation of motility disorders appears to provide a significant advance in the outpatient evaluation of esophageal function.
Treatment/IndicationsIt is important to acknowledge that achalasia is an incurable disease and treatment should be directed toward the relief of symptoms. The goal of any treatment for achalasia is directed toward reducing the pressure gradient across the LES, in order to eliminate the outflow obstruction and to relieve a patient’s symptoms of dysphagia and regurgitation, improve esophageal emptying, and prevent the development of mega esophagus while maintaining a barrier against GERD. Historically, the most popular treatment for achalasia has been by forceful PD. The first case of achalasia was reported over 300 years ago by Thomas Willis and the patient was successfully treated by dilation with a whale bone. Pneumatic dilation has become much easier and more standardized with the development of the Rigiflex® balloon system (Boston Scientific Corp., MA, USA). The success rate of PD is 55% to 70% with a single dilation but can be increased to nearly 90% with multiple dilations. However, the risk of perforation with each dilation is at least 2% and has been reported as high as 16% in some series. Furthermore, when stratified by age, balloon dilation is <50% effective in patients younger than 40 years; male gender; single dilation with a 3.0 cm balloon; posttreatment LES pressure above 10 mm Hg; and poor esophageal emptying. The only absolute contraindication to PD is poor cardiopulmonary status or other comorbid illnesses preventing surgery should an esophageal perforation occur. In the only prospective, randomized trial performed comparing surgery with balloon dilation using an older single balloon system, surgical myotomy outperformed balloon dilation 95% to 65%. Other more recent studies have failed to show a difference in outcome between the two procedures, both for short- and long-term follow-up. In a recent large series of 209 patients with achalasia who were treated with PD between 1992 and 2002, initial dilation and then surgery for short-term failures yielded good long-term results in more than 70% and treatment satisfaction in more than 80% of patients. The postdilation resting LES pressure is a major determinant of long-term success and the postdilation LES pressure can be used as a therapeutic target to determine the number of dilations needed. High long-term success rates can be obtained with repeat dilations for late recurrences and operation for early recurrences. Thus, management with initial dilation followed by a rigorous dilation protocol can provide good or excellent long-term results and high patient satisfaction rates. However, while PD has been found to have a more lasting effect on dysphagia than other nonsurgical treatments, outside of a rigorous dilation protocol, most studies have not demonstrated the long-term outcomes seen after surgical myotomy.
Botulinum toxin (BOTOX) injection is less effective than balloon dilation and requires retreatment to maintain an efficacy rate of 65%. The use of BOTOX injection for early recurrences after initial failed dilations is even less successful. Of greater concern is the fact that BOTOX injection leads to scar formation in the submucosal plane, which results in a more difficult myotomy and higher mucosal perforation rate (up to 30%) during dissection. Thus, BOTOX should be reserved for the treatment of patients who are poor candidates for surgery and balloon dilation (dilated sigmoid esophagus) or as a bridge to surgery. An additional utility for BOTOX is in aiding in the diagnosis of patients who have equivocal findings on initial evaluation. A good response to BOTOX is usually an indication that the patient will have long-term relief following successful dilation or surgical myotomy.
Pharmacologic treatment of achalasia with either oral nitrates or calcium channel blockers attempt to recreate a balance between the stimulatory and inhibitory influences by inhibiting intramural neurons, and thus decreasing the resting and residual pressure of the LES. The success of such treatment is sporadic at best, is unreliable, and is not recommended for long-term management.
Esophagocardiomyotomy was introduced by Ernest Heller in 1914, and remains the most effective long-term treatment for achalasia. When properly performed, a Heller myotomy can be expected to result in permanent relief of dysphagia in 85% to 100% of patients. The operation, as described by Heller, was performed through the abdomen and has remained a popular approach in much of Europe and South America. In 1958, Ellis et al. described the transthoracic approach, which remained the most common approach for performing this procedure in North America, until recently. Despite excellent results with operation and an esophageal perforation incidence of <1%, most patients (75%) opted for balloon dilation as primary therapy because of the significant morbidity associated with a thoracotomy or laparotomy. With advances in videoscopic technology in the early 1990s, this operation was readily transitioned to a minimally invasive approach. By reducing the pain, the incision size, and the postoperative disability, the surgical therapy has become more attractive to patients.
Initially, minimally invasive videoscopic esophagomyotomy was performed with a thoracoscope. Although effective, the thoracoscopic approach is associated with several difficulties. First, the perpendicular approach to the esophagus is less favorable for attaining and maintaining the submucosal plane than is the horizontal approach afforded by laparoscopic access. It is difficult to judge the appropriate distal end of the myotomy, allowing complete division of the LES without inducing postoperative reflux. Outcomes of thoracoscopic myotomy, as measured by both dysphagia relief and development of postoperative reflux, have been shown to be inferior to the laparoscopic approach in numerous studies. Finally, postoperative pain and length of hospital stay are generally greater following the thoracoscopic approach as compared to the laparoscopic. Today, esophageal myotomy is performed almost invariably through a laparoscopic approach.
Following the rapid acceptance of laparoscopic antireflux procedures, the laparoscopic Heller myotomy (LHM) became a natural extension of this experience and has proven to be more effective than the thoracoscopic procedure with less overall morbidity. The procedure is simpler to learn and to perform, and it allows routine hemifundoplication to prevent postoperative reflux. In selected patients such as a hostile, multiply operated abdomen, following a failed abdominal myotomy, or in diffuse esophageal dysmotility, the thoracic approach may still be preferred. LHM is associated with an 80% long-term success rate. Successful LHM may be predicted by high lower esophageal sphincter pressure (LESP), no prior therapy, short symptom duration, or absence of sigmoidal esophagus.
Failure of esophagocardiomyotomy to relieve the dysphagia may be attributable to either incompletely relieving the obstructive achalasia or an obstructing antireflux mechanism distal to the aperistaltic esophagus. In an evaluation of the effect of preoperative PD or BOTOX injection on outcomes after LHM for achalasia in 134 patients, multiple endoscopic treatments were associated with poorer outcomes and these authors suggest that dilation or BOTOX should be limited to achalasia patients, who fail surgical therapy.
Recent data show that both the proximal and distal extent of the myotomy are important. It has been recently recognized that an epiphrenic diverticulum may develop, which is believed to be caused by absence of coverage by the fundoplication over the proximal extent of the myotomy. This increased recognition of the potential for diverticulum formation has led many to limit the proximal extent of the myotomy to that which can be covered by an anterior fundoplication. It has long been the belief that overzealous extension of the myotomy onto the stomach, in an attempt to avoid incomplete myotomy, is associated with a high incidence of reflux and associated esophagitis. However, recent studies have demonstrated that relief of dysphagia is improved with lengthening of the distal extent of myotomy from 2 to 3 cm onto the cardia of the stomach with disruption of the gastric sling fibers, further decreasing LES pressure. Since an effective myotomy should lower esophageal outflow resistance and improve esophageal emptying, it also increases the propensity for development of GE reflux. There is often a poor correlation between symptoms of reflux and pathologic reflux as demonstrated by pH study. The importance of the addition of a fundoplication to the myotomy has, until recently, been debated.
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