Motor abnormalities of the esophagus that fit the category ‘weak and absent peristalsis’ are probably the least studied manifestations of esophageal dysfunction, likely because of the apparent lack of therapeutic options. It is important to recognize that the manometric diagnosis of esophageal hypomotility does not necessarily imply abnormal esophageal transit or presence of symptoms, including dysphagia.
Background Weak and absent esophageal peristalsis are frequently encountered esophageal motility disorders, which may be associated with dysphagia and which may contribute to gastroesophageal reflux disease. Recently, rapid developments in the diagnostic armamentarium have taken place, in particular, in high-resolution manometry with or without concurrent intraluminal impedance monitoring.
Purpose This article aims to review the current insights in the terminology, pathology, pathophysiology, clinical manifestations, diagnostic work-up,and management of weak and absent peristalsis.
Definitions and Terms
Until 1997, the term ‘nonspecific esophageal motor abnormalities’ was generally used by physiologists to denote any dysmotility pattern that was not achalasia, spasm, nutcracker or LES dysfunction. Then, Leite and coworkers published their finding that ‘ineffective esophageal motility’ (IEM) was the primary finding in patients with nonspecific esophageal motility disorder.1 In 2001, this was incorporated into Spechler and Castell’s2 classification of esophageal motor disorders, based on conventional manometry. In their classification, IEM was defined as distal-esophageal hypocontractility in at least 30% of wet swallows, characterized either as low-amplitude peristaltic waves (<30 mmHg), low-amplitude simultaneous waves (<30 mmHg) or peristaltic waves that are not propagated to the distal-esophagus, or absent peristalsis. The 30-mmHg criterion was derived from the observation that amplitudes <30 mmHg were frequently associated with bolus escape and incomplete bolus clearance.3
High-resolution manometry (HRM), with or without concurrent intraluminal impedance monitoring, allows a more complete definition of peristalsis. In the recently developed Chicago classification, frequent failed peristalsis (>30% of wet swallows) is separated from weak peristalsis (defined as breaks in the 20-mmHg isobaric contour). Weak peristalsis with large defects is judged to be present when breaks >5 cm are present in >20% of swallows (Fig. 1). Weak peristalsis with small defects is present when breaks of 2–5 cm in length are present in >30% of swallows.4 This classification of manometric abnormalities as abnormal is also based on the likelihood that such defects are associated with esophageal dysfunction (i.e. bolus escape); however, the clinical relevance of such observations remains uncertain. Indeed, it is likely that several abnormal swallows in series are required before symptoms are experienced.5
Formally, normal values for esophageal manometry should be population-specific and stratified by age and gender such that, by definition, 5% have hypotensive contractions in every group. This quality of data does not exist. Normal values for conventional manometry are based on observations in 95 healthy subjects with a mean age of 43 years (range 22–79 years),6 whereas the two HRM studies upon which the cutoff values for peristaltic breaks were based included only volunteers under the age of 50.4,7 Data gathered with conventional manometry suggest that the amplitude of esophageal contractions is higher in men than women, rises with increasing age and is higher in Afro-Caribbean than Hispanic and Caucasian populations.6,8 This variation between demographic and racial groups may be due to specific effects of age, gender and race, or common factors such as increased outflow resistance caused by central obesity. What is beyond doubt is that esophageal hypocontractility (weak, absent or failed peristalsis) is the most prevalent finding in clinical series. In our own experience, IEM with or without hypotensive LES was found in 58% of 2610 patients referred for (conventional) manometry. In a series of 350 consecutive patients who underwent manometry for various indications IEM was found in 20.2%.9 IEM was observed in 27–32% of patients presenting with non-obstructive dysphagia without GERD.10,11 Hypocontractility is also the most prevalent esophageal motor disorder in GERD, found in 21–38% of patients in large series, and its presence is associated with the severity of acid exposure and reflux symptoms.12,13 Similarly, in a group of patients with respiratory symptoms associated with reflux, IEM was found in 53% of asthmatics, 41% of chronic coughers and 31% of those with laryngitis.14
Pathogenesis and Pathophysiology
In most cases of weak or absent peristalsis identified in the motility lab the pathogenesis of the motility disorder will remain unclear. Autopsy studies of the pathology underlying this disordered function are lacking.
The exceptions to this rule are scleroderma and related connective tissue disorders, in which esophageal pathology has been studied extensively. There are three stages in the development of esophageal involvement in scleroderma: neuropathy, myopathy, and fibrosis.15 The neuronal abnormalities in the first stage are thought to be the consequence of arteriolar changes in the vasa nervorum. In the second stage, ischemia leads to focal degeneration and atrophy of the muscle layers. Finally, the muscle tissue is replaced by fibrosis, and collagen is deposited. These changes lead to severely disturbed esophageal motility, in particular in the smooth-muscle segment. In advanced disease manometry shows absent peristalsis, with only simultaneous pressure waves in the mid- and distal-esophageal body, and low LES pressure. This combination of abnormalities leads to increased gastroesophageal reflux and impaired esophageal clearance, in particular during the night. Consequently, esophagitis and its complications (ulcer, stenosis and Barrett’s esophagus) are frequently observed in scleroderma.
Knowledge about the mechanisms underlying esophageal hypomotility associated with GERD is accumulating. In cats with experimentally induced esophagitis, inflammatory mediators, such as interleukin-6 and platelet activating factor, were found to reduce acetylcholine release from excitatory myenteric neurons.16 Similarly, the mucosa of human patients with reflux esophagitis produces significantly greater amounts of cytokines than that of healthy controls.17 However, it is uncertain whether IEM associated with GERD is always the consequence of inflammation. It is also possible that it is a primary motor disorder leading to GERD.18 Whereas, animal studies suggest that acute esophagitis-associated esophageal hypomotility can disappear after healing, studies in humans with chronic erosive GERD have shown that healing of esophagitis, either medically or surgically, is not associated with complete recovery of esophageal dysmotility.19,20
Finally, IEM can also be observed in patients without any evidence of GERD in present or past. The pathogenesis of this idiopathic disorder is almost unknown, although Kim and coworkers21 have provided initial evidence that an imbalance between the excitatory and inhibitory innervation of the esophagus, reflected in the ratio between choline acetyltransferase (ChAT) and nitric oxide synthase (nNOS) expressed in the esophageal muscle wall, may be present in IEM patients.
Esophageal symptoms in impaired esophageal peristalsis include dysphagia, odynophagia, heartburn and regurgitation. However, the correlation between the severity of the manometric findings and the symptoms is extremely poor. Even in patients with complete absence of peristalsis, as is often the case in scleroderma, symptoms may be absent. On the other end of the spectrum, one can find patients who complain of severe dysphagia but who have completely normal esophageal peristalsis, LES function, and bolus transit on barium studies.
Endoscopic examination of the esophagus is not a valuable tool to diagnose esophageal motility; endoscopy should always be carried out to exclude ulceration, stenosis, and neoplastic lesions before the patient is referred for evaluation of esophageal function. The good old barium esophagogram, still is a useful technique in the work-up of patients with a suspected esophageal motility disorder. It will detect obstructive lesions, esophageal dilation, and hiatus hernia at least as well as endoscopy. In addition, and most importantly, the barium esophagogram provides information about esophageal transit. For this purpose, not only barium suspension should be used, but swallowing a solid bolus, such as a marshmallow or a piece of bread, should be part of the examination. Scintigraphy does not provide structural information but is the only technique that quantifies esophageal transit.
Manometry is often considered to be the gold standard, being able to detect subtle impairment of esophageal peristalsis. The most characteristic findings in scleroderma, low-amplitude simultaneous waves, can also be observed in other connective tissue diseases and in diabetes, amyloidosis, myxedema, multiple sclerosis, chronic idiopathic intestinal pseudoobstruction, and in severe end-stage GERD without scleroderma.
Whether conventional or high-resolution manometry is used, care must be taken to avoid circumstances that can lead to a spurious diagnosis of IEM. Examples of these are the use of drugs that inhibit esophageal contractions (anticholinergic agents and calcium channel blockers), failure to have an appropriate time interval between swallows, and inclusion of dry swallows. Additionally, depending on the examination position, the appropriate normal values must be applied because contractile vigor decreases on moving from the supine to the upright position.22
The combination of esophageal manometry and intraluminal impedance measurement allows assessment of the functional impact of ineffective esophageal contractions. In a study of 350 patients, it was found that one-third of patients with a manometric diagnosis of IEM had ‘effective’ transit for both liquid and viscous swallows.9 Similar findings were reported by others, suggesting that the definition of weak peristalsis should include functional correlates.4,23 High-resolution manometry, ideally combined with fluoroscopy or impedance, clarifies the relationship between dysmotility and bolus retention.4,24–26 The introduction of solid swallows or a test meal to manometric studies may further increase sensitivity to dysfunction associated with symptoms in ‘functional’ dysphagia25,26 and mucosal disease in GERD.27
Specific treatment is clearly desirable for patients with evidence of symptoms related to hypotensive dysmotility or reflux; however, the options are limited because there is no pharmacologic intervention that reliably restores smooth-muscle contractility and esophageal function. Thus, dietary and lifestyle advice together with effective control of acid reflux, if present, are the mainstays of clinical management.
Dietary and lifestyle management
A ‘common sense’ approach can reduce the risk of symptomatic bolus retention. Patients should favor liquid and semi-solid nutrition over solids, consume meals in the upright position, chew well and take plenty of fluids as these measures all promote esophageal clearance.28 Indeed, it appears that the ‘pharyngeal pump’ together with gravity and hydrostatic forces can move not only liquids but also most solid food through the esophagus without the need for active esophageal contraction.28,29 Many experts also recommend liberal use of carbonated beverages, because this may prevent as well as resolve bolus retention.30,31
Treatment of gastroesophageal reflux disease associated with hypotensive dysmotility
Patients with hypotensive motility with weak lower esophageal sphincter function often experience severe symptoms and complications of GERD because poor clearance leads to prolonged acid exposure, particularly at night.15 These problems are marked in patients with systemic sclerosis in whom the combination of poor motility and poor salivation impacts on both volume and chemical (i.e. acid) clearance.32 Dietary and lifestyle measures may be helpful, although these are rarely sufficient in severe GERD. A systematic review identified several such interventions that reduce esophageal acid exposure,33 some of which may be of particular benefit in patients with hypotensive dysmotility. These included (i) weight loss, (ii) keeping the upper body in an elevated position after a meal, (iii) lying down in the right lateral position, (iv) not smoking, (v) not consuming alcohol, (vi) reduction of meal size, and (vii) reduction in calorie load. Reduction in fat intake may be of additional value as this has high caloric density and also appears to sensitize the esophagus to acid reflux events.34 In addition, chewing gum for half an hour after meals may be helpful,35 as this stimulates salivation and swallowing, improving both volume and chemical clearance.
High-dose acid suppression taken twice a day is often required to suppress gastric acid, heal esophagitis and provide effective symptom relief in patients with severe hypotensive disease.36 Some patients benefit also from alginate preparations taken after the meal that suppress both acid and non-acid reflux events by forming a viscous layer over the gastric contents.37 The addition of ranitidine to suppress basal, nocturnal acid secretion appears to be helpful in individual patients but was not effective in a randomized controlled trial in 14 patients with systemic sclerosis.38
Procholinergic agents Medications that increase the concentration of acetylcholine in the synaptic cleft or directly stimulate muscarinic receptors promote smooth-muscle contractility. Bethanechol, a direct-acting muscarinic receptor agonist, has been shown in healthy volunteers and patients with hypotensive esophageal dysmotility to increase peristaltic amplitude in the distal-esophagus.39 Using combined multichannel intraluminal impedance- manometry in seven patients with severe IEM, Agrawal and coworkers39 demonstrated that a single oral dose of 50 mg bethanechol increased both contractile pressure and bolus clearance. Similar effects on contractile pressure were reported by Blonski and coworkers40 for a range of oral procholinergic agents, including bethanechol (25 mg), pyridostygmine (60 mg), and buspirone (20 mg), with pyridostigmine also promoting bolus transport. No trials demonstrating clinical efficacy have been published. Nevertheless, some experts report benefit of these medications in individual patients, although side-effects such as excessive salivation and diarrhea may limit use.
Dopamine antagonists Domperidone is a D2 receptor antagonist that promotes gastrointestinal motility by antagonizing the inhibitory effects of dopamine on postsynaptic cholinergic neurons in the myenteric plexus.41 Metoclopramide augments this peripheral effect with procholinergic properties and also has central anti-emetic actions at the chemoreceptor trigger zone.42 These medications increase LES pressure, accelerate gastric emptying and improve symptoms in patients with GERD and also diabetic gastroparesis.43,44 Effects on esophageal peristalsis and clearance are less well established. No effect of 20 mg domperidone on esophageal emptying was found on scintigraphy in 12 patients with diabetic autonomic neuropathy and esophageal dysfunction.45 In contrast, a significant improvement in clearance was reported after administration of 10 mg intravenous metoclopramide in 14 patients with systemic sclerosis.46
Motilin agonists Erythromycin and other macrolide antibiotics have pronounced prokinetic side-effects that are utilized by physicians treating patients with severe gastrointestinal dysmotility such as gastroparesis and pseudo-obstruction.47 This effect is mediated by motilin receptors that play a key role in the initiation of phase III migrating motor complex (MMC), inter-digestive ‘housekeeping’ contractions that sweep the stomach, and bowel clear of undigested material and bacterial overgrowth.47 Chrysos and coworkers48 showed that intravenous erythromycin (200 mg i.v. bolus) increased contractile vigor and LES pressure in 15 GERD patients, and in a 2-week clinical study Chang and coworkers49 reported that erythromycin (250 mg tid) significantly shortened esophageal and gastric transit and improved glycemic control in diabetic patients. Although these findings are impressive, the clinical use of erythromycin is limited by tachyphylaxis and side-effects including dyspepsia and diarrhea. New motilin agonists that may be better tolerated are in development. However, one recent example, ABT-229, had no effect on LES function, esophageal motility ,and reflux, in GERD patients.50
Serotonin agonists Cisapride and mosapride are prokinetic agents with mixed 5-HT4 agonist/5-HT3 antagonist action. Tegaserod, prucalopride, and other selective 5HT4 agonists have similar actions.42 Serotonin is released from enterochromaffin cells on mechanical stimulation and 5-HT4 receptors facilitate acetylcholine release in the myenteric plexus that triggers peristaltic contraction and clearance.51 Thus, in contrast to muscarinic antagonists and motilin agonists, 5-HT4 agonists promote normal gastrointestinal transit rather than inducing powerful but unphysiological contractions. These agents have prokinetic effects throughout the gastrointestinal tract and proven clinical efficacy in various conditions characterized by slow-transit, including GERD, diabetic gastroparesis and constipation.52 Studies have demonstrated that cisapride and mosapride increase LES pressure, promote esophageal clearance, and reduce acid exposure in health and GERD patients.53,54 However, the mechanism of this action was not evident on conventional motility studies.53–55 Soon after the introduction of high-resolution manometry with esophageal pressure topography Staiano and Clouse56 observed that cisapride enhanced contraction in the proximal smooth-muscle segment of the esophageal body. The functional significance of this effect was confirmed by combined HRM-videofluoroscopy that showed tegaserod improved co-ordination between contractile segments, leading to more effective solid-bolus transport (Fig. 2).57 Cisapride and tegaserod have been withdrawn due to rare, but occasionally life-threatening, side-effects; however, new 5-HT4 agonists are in the pipeline or are in the market approved for other indications.52 Clinical trials in GERD are in progress and, hopefully, studies in symptomatic, hypotensive esophageal motility will follow.
In patients with severe GERD, impaired peristalsis, impaired esophageal clearance, and dysphagia are common. The dysphagia can be not only due to the hypotensive dysmotility3, but also to mechanical outflow obstruction at the esophagogastric junction in the presence of hiatus hernia.58 In some cases anti-reflux surgery may not only improve reflux symptoms but also reduce dysphagia.20,59,60 This may be due to improvement of esophageal motility and visceral hypersensitivity with normalization of acid exposure or due to reduction of the hiatus hernia. However, the literature on the effect of fundoplication on esophageal motility and the relationship between preoperative motility and outcome of surgery should be interpreted with caution. Flaws in the design of these studies and manometric techniques employed should be taken into account. Some of these studies concluded that hypotensive dysmotility is not a contra-indication to surgical management of GERD, many experts in the field hold the opinion that fundoplication should not be carried out in patients with severe IEM.
AS and MF performed the literature search underlying this article, analyzed the data and wrote the article.
Conflict of Interests
The authors heave no competing interests.