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Esophageal Motility Disorders
Introduction
Esophageal motility disorders are ubiquitous in gastroenterology practice today, and developments in technology have led to a revolution in both their diagnosis and treatment. This chapter focuses on clinically significant esophageal motility disorders relevant to gastrointestinal endoscopy practice, primarily achalasia, but also on other potentially related disorders, including esophagogastric junction (EGJ) outflow obstruction, distal esophageal spasm, hypercontractile esophagus, and ineffective esophageal motility (IEM). For each disorder, we will review what is known regarding etiology and pathophysiology, followed by an exploration of diagnostic options available (both endoscopic and non-endoscopic) and review therapy. We will examine other potential areas in which endoscopic techniques could be employed in the management of esophageal dysmotility, including deep tissue acquisition and potentially endoscopic implantation applications. Finally, we will speculate as to what the near future may hold in the endoscopic management of these challenging conditions.
Achalasia
Achalasia is characterized by loss of inhibitory neurons in the esophagus, leading to tonic contraction of the lower esophageal sphincter (LES) and altered or absent peristalsis. The term achalasia itself is derived from the Greek words a and Khalasis , meaning “not loosening or relaxing.” The first clinical case was described by Sir Thomas Willis in 1674, where he described successfully treating a patient with associated dysphagia with a sponge-tipped whalebone, which was applied as needed after meals for approximately 15 years. The first pneumatic dilatation was performed in 1898, and the first surgical myotomy was described in 1913 by Ernst Heller. Therapies for achalasia were relatively quiescent thereafter for much of the 20th century; however, the past 25 years have seen significant diagnostic and therapeutic advancements.
Etiology and Pathophysiology
Achalasia is a rare disorder with a traditionally reported incidence of approximately 1 : 100,000. However, two reports from early 2017 suggest a two- to fourfold increase in incidence. In the vast majority of cases, no underlying etiology is found to explain disease onset, and it is labeled as idiopathic. Achalasia can also be labeled as secondary (pseudoachalasia) if there is a defined underlying etiology leading to degeneration of the myenteric plexus due to local invasion by neoplasia or other causes, such as amyloidosis or sarcoidosis. This is relatively rare, however, and believed to account for only 2% to 4% of patients with suspected achalasia. Chagas disease, or infection with Trypanosoma cruzi , is endemic in parts of South America and can also present with an indistinguishable clinical picture (at least from the esophageal standpoint). Other cases of pseudoachalasia may occur, resulting from circulating antibodies in the setting of non-local malignancy (usually small-cell lung cancer). Achalasia can also be seen rarely in certain systemic syndromes, such as Allgrove syndrome (familial adrenal insufficiency with alacrima and achalasia), Down's syndrome, and familial visceral neuropathy. We will focus our discussion primarily on idiopathic achalasia, as this is by far the most commonly encountered in clinical practice.
The pathogenesis of achalasia is still unclear, but it affects the myenteric neurons that mediate and coordinate esophageal peristalsis and relaxation. The pathologic hallmark of achalasia is a functional loss of these neurons resulting in tonic contraction of the LES and discoordinated or absent peristalsis. The trigger for this neuronal degeneration is not entirely clear, but there are data to suggest a potential autoimmune process triggered by infection in the context of genetic susceptibility.
Prior to the 1990s, the leading hypothesis with regard to pathogenesis was the degeneration of the myenteric plexus. In the early 1990s, pathology from patients with early achalasia showed inflammatory infiltration, with subsequent studies showing T-cell predominance (in particular CD8 + ). The question remained, however, as to what prompted this inflammation. An autoimmune hypothesis was suggested, based on evidence of circulating antibodies to myenteric neurons in patients with achalasia, links to specific HLA subtypes in affected patients, and the observation that patients with achalasia were also more likely to have other perceived autoimmune disorders. However, data have not been universally supportive of this theory, as myenteric antibodies have been found to be present equally in patients with achalasia and reflux (arguing that these antibodies are not causative, but simply a marker of esophageal injury). Arguments have also been made in favor of a potential infection. This was supported by early case reports linking achalasia to varicella, measles and polio ; however, subsequent detailed analyses of esophageal tissue for potential viral infection/inclusions have been negative in most affected patients, while HSV-1 has also been found in analysis of control subjects. Interestingly, parrots (and over 50 other tropical birds) suffer from proventricular dilatation disease, which is histopathologically indistinguishable from achalasia, but in contrast to human disease, it occurs in outbreaks. Recently, avian bornavirus was identified as the cause, but it does not have any human equivalent. At present, most authorities subscribe to a combination of the aforementioned theories, that prior viral infection triggers immune-mediated ganglionitis, resulting in loss of myenteric neurons in a genetically-susceptible host.
Clinical Manifestations
The most common symptoms of achalasia are dysphagia and regurgitation. Dysphagia occurs with both solids and liquids, and is seen in over 90% of patients. Of note, a proportion of patients will not have dysphagia in both consistencies, and a distinct minority (< 5%) will not report dysphagia at all. Regurgitation of undigested foods is reported in 59% to 91% of patients and may be the dominant symptom at presentation. Chest pain occurs to a variable degree (17%–64%) and is more pronounced in spastic variants and perhaps in younger patients. Patients may also report heartburn (18%–75%), which, although counterintuitive, is likely related to stasis of ingested contents or intraesophageal reflux. Weight loss and aspiration are more worrisome but fortunately are seen less frequently (10%–30%).
Symptoms associated with achalasia can be non-specific and the diagnosis is often not straightforward. Dysphagia is reported in approximately 4% of American adults on a weekly basis and achalasia has an incidence of approximately 1 : 100,000, so, not surprisingly, the vast majority of patients who present with dysphagia will not have achalasia, nor is it at the top of the differential diagnosis given its relatively rarity. Dysphagia is not seen in all patients with achalasia, and the presence of heartburn and chest pain can often sway presumptive management toward more common entities, such as gastroesophageal acid reflux. Despite the colloquial association of achalasia with weight loss, it is not unusual to see obese patients with achalasia. At tertiary facilities, a small percentage (< 3%) of patients referred for evaluation of refractory reflux will eventually be diagnosed with achalasia. Because of these factors, many series report a relatively long delay (up to 5 years) between symptom onset and establishment of a final diagnosis. With regard to other key demographics, men and women are affected evenly, and there is no reported gender discrepancy. Achalasia has increasing incidence with age, with an estimated incidence of greater than 10 : 100,000 above 80 years of age and less than 1 : 100,000 below 16 years of age; however, it can be reported at any age, and in our practice we have seen patients diagnosed at both younger than 1 year of age and older than 90 years.
Diagnosis
Accurate diagnosis of achalasia depends on recognition of associated symptoms and careful employment of diagnostic modalities to identify the underlying etiology and exclude mimicking conditions. For those patients who present with dysphagia, the key first step is to exclude a mechanical or infiltrative process using endoscopy or barium esophagraphy. Due to improvement in endoscopic technology and the clinical emergence of eosinophilic esophagitis, endoscopy is often the first-line study employed for evaluation of dysphagia in community and academic practices; however, there are no guidelines that specifically recommend endoscopy over a barium esophagraphy in the initial evaluation of dysphagia, and either approach would be reasonable, based on local practice patterns and expertise.
Endoscopy
Patients presenting with dysphagia and suspicion for achalasia should undergo endoscopy for evaluation and exclusion of potential neoplasms masquerading as pseudoachalasia. Esophageal biopsies to exclude eosinophilic esophagitis or other infiltrative disorders should be performed. In many patients with achalasia, especially early cases without significant esophageal dilatation, the endoscopy is unremarkable. Subtle endoscopic findings include frothy secretions in the esophagus and subjective feeling of tightness to the passage of the endoscope at the EGJ. In more advanced cases, esophageal distention, tortuosity, retention of pooled liquid or food, or frank food impaction can be seen; however, these are usually later findings denoting advanced disease. Due to stasis, it is also not unusual to see associated Candidiasis and, in the absence of immunosuppression, this finding on endoscopy should raise warning with regards to potentially significant dysmotility ( Fig. 19.1 ). Endoscopy cannot definitively establish the diagnosis of achalasia and additional evaluation is required.
Radiology
A barium esophagram allows objective assessment of esophageal emptying, diameter, and contour, and can provide information relative to structural abnormalities, including epiphrenic diverticula, that may not be appreciated on endoscopy. In early cases or cases not associated with esophageal dilatation, it is important to recognize that the barium study may be interpreted as normal, and in fact some series report that almost half of early achalasia cases may be missed if relying on barium study alone. However, although not sensitive, esophageal fluoroscopy can be quite specific in advanced cases. Characteristic findings include a dilated esophagus with retained food or an air-fluid level, and narrowing at the EGJ, often referred to as a bird-beak . Other findings seen in advanced cases include a large intragastric air bubble and severe esophageal dilatation with a sigmoid-like appearance ( Fig. 19.2 ). A timed barium esophagram can also be employed, where the patient ingests a fixed amount of barium and then retention is measured at 5 minutes while the patient is upright. This allows objective assessment of functional esophageal emptying and can be followed longitudinally after therapy.
Esophageal fluoroscopy remains an invaluable part of the diagnostic evaluation due to its unique ability to visualize anatomy and diameter. It is our practice to always obtain a barium esophagram before proceeding with more invasive treatment options in a patient with suspected achalasia.
In select cases, one could also consider other imaging modalities, including computed tomography (CT). CT scans in achalasia had characteristic findings highlighted by esophageal dilatation with normal wall thickness; however, patients with suspected achalasia who were found to have secondary achalasia had atypical radiographic manifestations. CT is useful in separating primary and secondary achalasia, with nodular/lobulated or asymmetric distal wall thickening, mediastinal lymphadenopathy, or a soft-tissue mass being supportive of a secondary process. We do not routinely obtain cross-sectional imaging on all patients with achalasia; however, for complicated cases or patients with atypical features there may be a role.
Manometry
Esophageal manometry is considered the gold standard for the diagnosis of achalasia and has the highest sensitivity for detection of early disease. The past decade has seen the emergence of high-resolution esophageal manometry (HRM) with esophageal pressure topography, which is now the standard of care in most institutions. The concept of HRM stems from Clouse (1998) at Washington University, who speculated that, by increasing the number of monitoring channels and decreasing the distance between those channels, diagnostic yield would be enhanced. Pinnacle work in HRM was performed by investigators in Europe and at Northwestern University in the early 2000s, and their combined work eventually led to the Chicago Classification for Esophageal Motility Disorders, widely considered the core reference for esophageal manometry interpretation today and currently on its third rendition ( Table 19.1 ).
TABLE 19.1
The Chicago Classification for Esophageal Motility Disorders
Adapted from Kahrilas PJ, Bredenoord AJ, Fox M, et al: The Chicago Classification of esophageal motility disorders, v3.0. Neurogastroenterol Motil 27(2):160–174, 2015.
| Diagnosis | HRM Chicago Classification (v.3) Criteria |
|---|---|
| Disorders of Outflow Obstruction | |
| Achalasia | |
| Type I | Elevated median IRP with 100% failed peristalsis |
| Type II | Elevated median IRP with 100% failed peristalsis and intermittent pan-esophageal pressurization (≥ 20% swallows) |
| Type III | Elevated median IRP, premature (spastic) contractions (≥ 20% swallows), no normal peristalsis |
| EGJ outflow obstruction | Elevated median IRP with preserved peristalsis (not meeting criteria for achalasia) |
| Major motility disorders | Never encountered in healthy subjects |
| Absent contractility | Normal median IRP with 100% failed peristalsis |
| Distal esophageal spasm | Normal median IRP; premature (spastic) contractions (≥ 20% swallows) |
| Hypercontractile esophagus (jackhammer esophagus) | Hypercontractile esophagus with DCI > 8000 mm Hg/s per cm (≥ 20% swallows) |
| Minor motility disorders | Seen in some healthy asymptomatic controls and of uncertain clinical significance |
| Ineffective esophageal motility | Intermittent weak or failed contractions (≥ 50% swallows) with periodic normal peristalsis (DCI: > 450 mm Hg/s per cm) |
| Fragmented peristalsis | ≥ 50% fragmented contractions with normal DCI (> 450 mm Hg/s per cm) |
| Normal | Not meeting any of the previous criteria |
DCI, Distal contractile integral; EGJ, esophagogastric junction; HRM, high-resolution esophageal manometry; IRP, integrative relaxation pressure.
When interpreting HRM using the Chicago Classification, the diagnosis of achalasia relies on the identification of impaired LES relaxation (as defined by an elevated integrative relaxation pressure [IRP]) in tandem with identification of absent or aberrant peristalsis. One of the key advantages to HRM has been the ability to recognize clinically meaningful achalasia subtypes that predict clinical course and response to therapy. In 2008, Pandolfino and colleagues at Northwestern University described three distinct manometric achalasia subtypes (types I, II, and III) ( Fig. 19.3 ). In all three, there was abnormal relaxation of the LES/EGJ, defined by an elevated IRP. In type I achalasia, the esophageal body displayed absent peristalsis. In type II, the esophageal body displayed simultaneous, pan-esophageal pressurization with wet swallows. In type III, the esophageal body displayed (for at least some swallows) disorganized contractility akin to spasm. These investigators showed that outcomes to therapeutic intervention varied depending on manometric subtype and, specifically, that patients with a type II pattern (characterized by pan-esophageal pressurization) had excellent outcomes to therapy, whereas patients with a type I pattern required more definitive sphincter disruption and patients with a type III pattern did not respond as well to intervention aimed solely at the LES. This work has now been replicated by others, confirming robust therapeutic response for those with type II achalasia.
The sensitivity of manometry is, however, imperfect, and there are cases that fall outside conventional diagnostic paradigms. The Chicago Classification relies on the IRP as a marker of deglutitive EGJ relaxation; however, there are some patients with achalasia who may have true sphincteric dysfunction with a technically normal IRP. In cases where the manometry is not classic but clinical suspicion for achalasia is high, other complementary tests (such as barium or the Functional Lumen Imaging Probe [FLIP; Crospon, Galway, Ireland]) will need to be employed. Likewise, there are patients who have manometric impairment of deglutitive relaxation but preservation of peristalsis. These patients are currently defined by the Chicago Classification as having EGJ outflow obstruction, a diagnosis of uncertain clinical significance, that in fact could be an achalasia variant or achalasia in transition. Although HRM is considered the most sensitive test for recognition of early achalasia, it is not perfect and there will be some patients (albeit rarely) who clinically have achalasia but may not meet current manometric definitions.
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