Ineffective esophageal motility: Concepts, future directions, and conclusions from the Stanford 2018 symposium

Abstract

Background:

Ineffective esophageal motility (IEM) is a heterogenous minor motility disorder diagnosed when ≥50% ineffective peristaltic sequences (distal contractile integral <450 mm Hg cm s) coexist with normal lower esophageal sphincter relaxation (integrated relaxation pressure < upper limit of normal) on esophageal high-resolution manometry (HRM). Ineffective esophageal motility is not consistently related to disease states or symptoms and may be seen in asymptomatic healthy individuals.

Purpose:

A 1-day symposium of esophageal experts reviewed existing literature on IEM, and this review represents the conclusions from the symposium. Severe IEM (>70% ineffective sequences) is associated with higher esophageal reflux burden, particularly while supine, but milder variants do not progress over time or consistently impact quality of life. Ineffective esophageal motility can be further characterized using provocative maneuvers during HRM, especially multiple rapid swallows, where augmentation of smooth muscle contraction defines contraction reserve. The presence of contraction reserve may predict better prognosis, lesser reflux burden and confidence in a standard fundoplication for surgical management of reflux. Other provocative maneuvers (solid swallows, standardized test meal, rapid drink challenge) are useful to characterize bolus transit in IEM. No effective pharmacotherapy exists, and current managements target symptoms and concurrent reflux. Novel testing modalities (baseline and mucosal impedance, functional lumen imaging probe) show promise in elucidating pathophysiology and stratifying IEM phenotypes. Specific prokinetic agents targeting esophageal smooth muscle need to be developed for precision management.

1 |. INTRODUCTION

The widespread use of high-resolution manometry (HRM) has led to increasing recognition of esophageal motor dysfunction.¹ Currently designated a minor esophageal motility disorder, ineffective esophageal motility (IEM) is reported in as many as 30% of patients undergoing HRM^2,3 with unclear clinical implications and management. An international group of esophageal motor physiologists, clinicians, endoscopists, and surgeons who are international thought leaders in esophageal physiology and pathophysiology met at Stanford, CA, in July 2018 for a one-day symposium to discuss the pathophysiologic basis and clinical implications of IEM. This review is a synopsis of the content of the symposium, describing the current understanding of IEM and future research goals.

2 |. DEFINITION OF IEM

Esophageal hypomotility is commonly described as a defect in peristaltic amplitude, contraction vigor, and/or peristaltic integrity on manometry, with normal lower esophageal sphincter (LES) relaxation.^2,4 Synchronous conventional manometry and fluoroscopy described 30 mm Hg as the esophageal body threshold amplitude for effective bolus transit,⁵ which corresponds to a distal contractile integral (DCI) of 450 mm Hg cm s on HRM.^2,6 The Chicago Classification 3.0 defines IEM as ≥50% ineffective sequences (DCI < 450 mm Hg cm s), with normal integrated relaxation pressure (IRP) (Figure 1).² This has limitations: Both weak (DCI 100–450 mm Hg cm s) and failed (DCI < 100 mm Hg cm s) sequences are considered ineffective (Table 1), but bolus transit and reflux exposure implications of failed sequences and >70% primary ineffective sequences are more profound.^7,8 As many as 17% of asymptomatic subjects may have IEM detected on routine esophageal manometry.¹⁰ Bolus transit assessment is not part of the clinical IEM diagnosis; the 30 mm Hg threshold pressure only establishes a threshold above which transit is reliably normal rather than the contrary.^5,11,12

FIGURE 1.

High-resolution impedance manometry showing ineffective esophageal motility (IEM) with contraction reserve. There were 60% ineffective swallows with distal contractile integral (DCI) <450 mm Hg cm s, meeting the Chicago Classification 3.0 criteria for IEM (≥50% ineffective swallows). There was a combination of weak (DCI < 450 mm Hg cm s but >100 mm Hg cm s) and failed (DCI < 100 mm Hg cm s) swallows. The violet overlay represents bolus presence on stationary impedance. (A) A weak swallow with DCI 420 mm Hg cm s and incomplete bolus transit on stationary impedance. (B) A failed swallow with no contraction and incomplete bolus transit. (C) Multiple rapid swallows, demonstrating augmentation of smooth muscle contraction following the final swallow of the sequence (contraction reserve), and adequate bolus transit

TABLE 1.

High-Resolution Manometry Characteristics in the Evaluation of Ineffective Esophageal Motility

	HRM characteristic	Comments
Single swallows (SS)2
Effective	DCI > 450 mm Hg cm s	IRP < upper limit of normal
Ineffective	DCI < 450 mm Hg cm s
Weak	DCI 100–450 mm Hg cm s
Failed	DCI < 100 mm Hg cm s
Fragmented	DCI > 450 mm Hg cm s, ≥5 cm break
Provocative tests
Multiple rapid swallows (MRS)43	Augmentation of DCI compared to single liquid swallows	MRS DCI:SS DCI > 1 indicates contraction reserve
Rapid drink challenge50	Esophageal pressurization	Pressure gradient across EGJ > 4 mm Hg indicates EGJ obstruction
Solid swallows56	Augmentation of DCI compared to liquid swallows	Augmentation is higher in supine compared to upright position
Standardized test meal57	Augmentation of DCI compared to liquid swallows	Dysphagia symptoms and obstructive patterns indicate esophageal body and EGJ obstruction
Diagnosis2
IEM	≥50% ineffective swallows	IRP < upper limit of normal
Fragmented peristalsis	≥50% fragmented swallows
Absent contractility	100% failed swallows
Proposed IEM criteria
Severe IEM	>70% ineffective swallows	IRP < upper limit of normal

DCI, distal contractile integral; HRM, high-resolution manometry; IEM, ineffective esophageal motility; IRP, integrated relaxation pressure (upper limit of normal varies with HRM manufacturer).

3 |. PATHOPHYSIOLOGIC CONCEPTS

Bolus propagation through the esophagus depends on a layered muscle structure with differential viscoelastic properties, muscle-generated forces, and esophagogastric junction (EGJ) resistance. Initial stretching of the esophageal muscle prior to contraction (preload, related to filling and accommodation), resistance against which the esophagus contracts (afterload, reduced during LES relaxation), and intrinsic esophageal muscle contraction vigor (esophageal contractility) are factors that influence esophageal bolus transit. A change in preload and inotropy (from physiologic maneuvers or pharmacologic agents) influences contraction vigor (Laplace’s law). Increased EGJ resistance to flow (afterload) and decreased contractility, for example, would result in impaired esophageal emptying and esophageal bolus retention, especially when increasing bolus volume (preload) does not augment contractility.

3.1 |. Primary peristalsis

Esophageal peristalsis in both the proximal striated muscle esophagus and distal smooth muscle esophagus is dependent on brainstem nuclei. Striated muscle is innervated directly by excitatory vagal efferents from the nucleus ambiguus.¹³ In contrast, preganglionic neurons in the dorsal motor nucleus of the vagus project to myenteric ganglia in the esophagus, from which motor neurons innervate smooth muscle. In addition, stretch-activated relaxation and contraction are mediated through mechanosensitive neurons located in the myenteric plexus.¹⁴ Circular muscle contraction, esophageal shortening (from longitudinal muscle contraction), and esophageal muscle tone participate in normal esophageal peristalsis under cholinergic and nitrergic neural control.^15,16

A balance between intrinsic cholinergic or non-adrenergic, non cholinergic excitatory input, inhibitory nitrergic, and postinhibition rebound excitatory output to the musculature determines contraction vigor, influenced by bolus information transmitted via vagal afferents to the solitary nucleus. Modulating central inputs through intense central stimulation (eg, with transcranial direct current)¹⁷ and peripheral stimulation (eg, with capsaicin)¹⁸ can augment esophageal contraction amplitudes. Proximity of afferent receptors to the esophageal luminal surface can impact sensory perception, and consequently, vigor of peristalsis.¹⁹ Esophageal peristalsis can also occur without central control; interstitial cells of Cajal form sensory units of vagal afferents that provide pacemaker activity to generate peristalsis. Inhibitory motor neurons are mechanosensitive, and electrical impulses can also be transmitted from muscle cell to muscle cell.²⁰ Thus, low-amplitude contraction, observed as IEM, can be influenced by a multitude of central and peripheral factors (Figure 2).²⁰

FIGURE 2.

Pathophysiology of ineffective esophageal motility (IEM). Neural control of esophageal smooth muscle contraction from the brain stem vagal nuclei is modulated by peripheral sensory data from the esophagus through vagal afferents, and by central inputs to the brain stem. Central and peripheral neural dysfunction can contribute to ineffective esophageal smooth muscle peristalsis. Muscle dysfunction can either be primary, a consequence of gastroesophageal reflux disease (GERD), or related to other factors influencing muscle function, including smooth muscle disorders and medications. However, IEM as currently defined is a manometric diagnosis and may be a normal variant without clinical consequences. Only severe IEM (with >70% ineffective swallows) has been implicated in abnormal esophageal reflux burden and dysphagia

3.2 |. Secondary peristalsis

Esophageal physiologic and pathophysiologic mechanisms are best understood as they pertain to primary esophageal peristalsis, but secondary peristalsis has important roles in normal esophageal physiology, and potentially in pathophysiologic states including IEM. Further, with the advent of functional luminal imaging probe (FLIP) technology, further study of secondary peristalsis may be relevant to FLIP interpretation.

Secondary peristalsis triggered by esophageal distention contributes to 90% of reflux clearance,²¹ particularly during sleep. Impaired esophageal muscle contractility, sensory and motor defects from abnormal vagal function, and central mechanisms influence failure of secondary peristalsis. Gastroesophageal reflux disease (GERD) patients, particularly those with IEM, have an attenuated secondary peristaltic response to air or water injection into the esophagus compared to age-matched normal subjects.^22,23 Finally, aging can impair secondary peristalsis and bolus clearance.^24,25

3.3 |. Mucosal integrity

Abnormal clearance of refluxed gastric content can result in prolonged esophageal acid exposure, and histologically, dilation of intercellular spaces (DIS).^26,27 Regulation of intercellular space diameter is accomplished by the intercellular junction complex,^28,29 under neural control as suggested by the human neural stem cell origin of tight junction proteins,³¹ panesophageal dilation of intercellular spaces in an animal stress model,^32,33 and identification of DIS proximally in response to distal esophageal acid perfusion.³² If neural injury mediated by GERD occurs at a central point that controls both esophageal intercellular space and motor function, then measurement of DIS or its consequences could correlate to IEM. Contrary to this, DIS represents a relatively rapid onset^34,35 and reversible phenomenon,³⁶ whereas IEM appears to correlate better with sustained acid exposure. Nevertheless, chronic DIS may be a prerequisite for IEM if it facilitates sustained exposure of esophageal neural and muscular elements to noxious gastric content. Although intuitive, there are no convincing data thus far to support this hypothesis, and further study is needed to define the role of evaluation of mucosal integrity in clinical esophagology. Finally, DIS is not specific to GERD and is well documented in other esophageal diseases, such as eosinophilic esophagitis.³⁷

4 |. SUPPLEMENTARY INVESTIGATION

Provocative maneuvers and supplementary physiologic testing can augment information acquired during HRM and characterize contraction reserve, bolus transit, and reflux burden (Figure 3). However, there are no well-designed prospective clinical trials evaluating these provocative maneuvers, and our understanding of these maneuvers is mostly from observational case series, case-control studies, or cohort studies. The following segment describes available data supporting use of provocative testing and provides direction on use of these provocative maneuvers in clinical care.

FIGURE 3.

Diagnosis of ineffective esophageal motility (IEM) is based on ≥50% ineffective supine primary swallows during high-resolution manometry (HRM) or high-resolution impedance manometry (HRIM). Supplementary evaluation can be personalized based on the clinical scenario being evaluated, using provocative tests. For instance, demonstration of contraction reserve during pre-operative HRM increases confidence in standard antireflux surgery (ARS) for the management of concurrent GERD. Secondary peristalsis can be evaluated during sedated endoscopy using functional lumen imaging probe (FLIP), but its role in clinical evaluation of IEM remains undefined

4.1 |. Provocative maneuvers

Multiple rapid swallows and rapid drink challenge are the most frequently used provocative tests¹ and are now recommended as part of routine HRM studies.^38,39 During repetitive swallowing, deglutitive inhibition blocks smooth muscle contraction and LES tone.⁴¹ When neural circuits and esophageal smooth muscle are intact, the final swallow of the sequence is followed by an augmented contraction sequence.^42,43 Edrophonium administration similarly augments esophageal smooth muscle contraction, but is not used as a provocative maneuver in clinical esophagology.⁹

Multiple rapid swallows consists of five 2 mL swallows administered in rapid succession during HRM. Multiple rapid swallows DCI to mean single swallow DCI ratio >1 defines the presence of “contraction reserve”.⁴³ This ratio is inversely related to esophageal acid exposure and directly related to baseline impedance and effective chemical clearance at baseline⁴⁴ and following azithromycin administration.⁴⁵ Absence of contraction reserve on pre-operative HRM may identify patients with potential for persistent postoperative dysphagia following antireflux surgery,⁴³ and phenotypes of IEM that resolve, persist, or even develop over follow-up after antireflux surgery.⁴⁶ A minimum of three MRS sequences are needed for reliable demonstration of contraction reserve.⁴⁷

Rapid drink challenge consists of rapidly drinking 100–200 mL of water while upright.^48,49 RDC performs much less efficiently in demonstrating contraction reserve,^49,50 presumably because of the prolonged inhibitory stimulus of high volume drinking.⁵¹ Instead, RDC is a better test for demonstration of EGJ obstruction,⁵² which can correlate with severity of dysphagia.^48,49,52,53

As patients often report esophageal symptoms in relationship to meals, viscous or solid swallows,^54,55 test meals,^57,58 RDC,^48,49,51 and postprandial monitoring^60,61 have been utilized to provoke symptoms during manometry and to identify EGJ outflow obstruction (EGJOO).^55,59 Compared to liquid swallows, solid swallows improve peristaltic performance both in healthy individuals and those with endoscopy negative reflux disease,⁵⁴ and solid test meals may reproduce dysphagia symptoms.^57,59 Postprandial monitoring identifies mechanisms of postprandial symptoms, particularly supragastric or gastric belching and rumination.^61,62

The clinical situation being investigated dictates the rigor of evaluation necessary to characterize IEM. Thus, provocative testing assessing contraction reserve (MRS) could be preferentially utilized in GERD and prior to antireflux surgery.^43,48 Dysphagia syndromes are best assessed with RDC, solid swallows, and a standardized test meal, where adequacy of clearance of ingested bolus and symptom reproduction is assessed.^52,57,58 Postprandial syndromes are evaluated with HRIM studies that include a standardized test meal and prolonged postprandial monitoring.⁶¹

4.2 |. Functional luminal imaging probe

Functional luminal imaging probe measures luminal dimensions using serially spaced intra-balloon impedance planimetry channels during controlled, volumetric distension during upper endoscopy.⁶³ When combined with an intra-balloon (distensive) pressure measurement, luminal distensibility can be assessed.⁶⁴ Functional luminal imaging probe distension of the esophageal body can elicit secondary peristaltic responses measured as luminal diameter changes along the length of the balloon (Figure 4A).^63,65 Abnormalities in secondary peristalsis have been reported in conditions that may overlap with IEM, including non-obstructive dysphagia,^66,67 GERD,⁶⁸ and systemic sclerosis.⁶⁹

FIGURE 4.

Adjunctive evaluation of esophageal peristaltic performance using novel metrics and techniques. (A) Functional lumen imaging probe (FLIP) topography with lumen changes representing repetitive antegrade contractions as a response to luminal distension. These secondary peristaltic waves represent the ability of the esophagus to generate distension-induced secondary peristalsis. (B) A pH-impedance study demonstrating a reflux episode (upward arrow) followed by a postreflux swallow-induced peristaltic wave (PSPW) within 30 s of the end of the reflux episode. This represents the ability of esophageal neural connections to generate reflux-induced primary peristalsis, bringing salivary bicarbonate to neutralize esophageal mucosal acidification from the reflux episode

The normal contractile response to FLIP distension consists of ≥3 consecutive, repetitive antegrade contractions (RACs),⁶³ observed in 72% (21/29) of patients with normal motility⁶⁵ and 60% (3/5) with IEM.⁶⁵ Among patients undergoing wireless pH monitoring, the absence of a RAC pattern was associated with greater esophageal acid exposure, suggesting that the esophageal contractile response to distension may carry functional significance in GERD. Added characteristics of distension-induced contractility on FLIP, for example lumen occlusion, RAC pattern duration, or pressure changes associated with contractions, may enhance the evaluation of distension-induced contractile “vigor,” which could be applied to supplement the evaluation of IEM. Although FLIP has potential to detect an otherwise unappreciated EGJ outflow obstruction, experience remains limited in IEM.

4.3 |. Ambulatory reflux monitoring

Severe peristaltic dysfunction (>70% ineffective sequences) is associated with abnormal acid exposure and esophageal mucosal injury,^9,70,71 especially supine acid exposure.^72,73 However, despite the frequent association of IEM and abnormal reflux monitoring, IEM is not pathognomonic for the presence of GERD.³⁸ Based on these concepts, the primary indication for reflux monitoring in IEM is to establish or exclude the presence of GERD.^38,74

4.4 |. Postreflux swallow-induced peristaltic wave

Chemical reflux clearance requires neutralization of esophageal mucosal acidification with saliva, initiated by an esophago-salivary vagal reflex,⁷⁵ and delivered by reflux-induced primary peristalsis.⁷⁵ PSPW can be identified on pH-impedance monitoring as a distally migrating sequential impedance drop following a reflux episode, reaching the distal esophagus (Figure 4B).⁷⁶ PSPW index, the ratio of the PSPW count to number of reflux episodes,⁷⁷ records the efficiency of chemical clearance and predicts reflux-related heartburn responsive to PPIs.^78,79 The relationship of PSPW to contraction reserve deserves further study, as reflux-induced primary peristalsis, and potentially, RACs on FLIP topography will be influenced by the integrity of esophageal neural connections and smooth muscle function, which is the basis for contraction reserve.

4.5 |. Mucosal and baseline impedance

Esophageal mucosal impedance may be measured by one of four methods: using ambulatory pH/impedance monitoring during a quiescent nocturnal period when swallowing and reflux are ideally absent (mean nocturnal baseline impedance,Figure 5A & B),^80,81 with an endoscopically placed mucosal probe with two electrodes yielding a point impedance measurement^82,37,83 using impedance recordings during HRIM,⁸⁴ or with a esophageal balloon with 2–4 strips of longitudinally placed electrodes capable of measuring 9 impedance points per strip (Figure 5C).⁸⁵ Mucosal integrity is assessed by measurement of current flow, with reduced impedance to flow putatively reflecting dilation and/or increased electrolyte transfer through the epithelial intercellular spaces.³⁷

FIGURE 5.

Evaluation of reflux-induced mucosal integrity using baseline and mucosal impedance. (A) Normal mean nocturnal baseline impedance (MNBI) when baseline impedance is measured on an ambulatory pH-impedance study over a 10-min period during quiet sleep without swallows or other artifacts. Values above 2292 Ω in the distal esophagus are considered within normal range. (B) Low MNBI in a patient with GERD. (C) Mucosal impedance topograph using a second generation mucosal impedance probe with two strips of 9 impedance sensors mounted on a balloon to ensure adequate contact with the esophageal mucosa. Red colors indicate low mucosal impedance in the distal esophagus in this patient with GERD

Abnormal esophageal mucosal impedance and IEM are either derived from the same mechanism of injury, are interrelated, or each has an independent distinct pathophysiologic basis. Abnormal esophageal impedance may be an early marker for subsequent IEM with high sensitivity but likely low specificity. Consequently, testing using pH/impedance-based catheters or specific esophageal impedance directed devices does not establish IEM.

5 |. CLINICAL IMPLICATIONS

Potential implications of IEM relate to GERD severity, symptom reporting, and decision making prior to antireflux surgery. Ineffective esophageal motility has a higher prevalence in smooth muscle disorders, such as scleroderma, other connective tissue disorders⁸⁶ and gastroparesis,⁸⁷ but is not more common in diabetes mellitus, or hypothyroidism.⁸⁸ Ineffective esophageal motility has also been reported in Parkinson’s disease.⁸⁹ While phosphodiesterase inhibitors⁹⁰ and skeletal muscle relaxants⁸⁸ can reduce esophageal contraction vigor, use of calcium channel blockers, nitrates, opioid agents, and anticholinergic agents does not impact IEM diagnosis.⁸⁸

5.1 |. IEM and GERD

Ineffective esophageal motility impairs esophageal clearance and participates in the pathophysiology of GERD,^38,91,92 especially when profound.⁹ Esophageal body hypomotility is the most common motor disorder in pH-metry proven GERD,^74,93 increasing in prevalence with increasing severity of erosive esophagitis.⁹⁴ Conversely, erosive esophagitis,⁹⁵ increasing severity of GERD,⁹⁶ and Barrett’s esophagus^96,97 are consistently associated with a greater likelihood of IEM, in contrast to non-erosive reflux disease (NERD) and physiologic acid exposure, where IEM prevalence is low.⁹⁸ Patients with IEM and normal pH-metry are younger than those with abnormal pH testing or erosive esophagitis, suggesting that IEM could be an early primary event that subsequently leads to abnormal acid burden,⁷³ but no longitudinal studies exist. Patients with chronic cough have a higher likelihood of esophageal hypomotility, manifest as breaks in peristaltic integrity, lower contraction amplitude and vigor.^99,100 Identification of severe IEM (>70% ineffective peristalsis) provides supportive evidence for a more severe GERD phenotype marked by supine acid burden.^7,9,73

5.2 |. IEM and esophageal symptoms

Several studies have shown no correlation between IEM and esophageal symptoms.^73,101.102 Even in patients with abnormal pH-metry, and those with or without contraction reserve, there is no difference in proportions of heartburn, regurgitation, dysphagia, chest pain, and belching reported by patients with and without IEM in observational studies.^73,102 Symptom reporting during water, viscous and solid swallows also does not correlate with HRM contraction metrics in the supine or upright position.¹⁰¹ Finally, perception of dysphagia with abnormal bolus transit from weak or absent peristalsis is also imperfect,^12,90 indicating that symptoms are not discriminative of IEM.

5.3 |. IEM and antireflux surgery

Complete (Nissen) fundoplication is the procedure performed most often in well-characterized GERD, except in extreme esophageal dysmotility including absent contractility.^103,104 Earlier concerns regarding postoperative dysphagia following Nissen fundoplication in conventional manometry-based IEM^103,105 have been refuted by four small randomized controlled trials^108,109 demonstrating similar overall outcomes after a partial (Toupet or Dor) fundoplication. Ineffective esophageal motility is a relative contraindication for magnetic sphincter augmentation (MSA), as peristalsis provides propulsive force to distend the magnetic band of the MSA device.^112,113 Statistically significant augmentation of proportions of intact peristaltic sequences and of distal esophageal amplitudes has been reported in IEM following fundoplication.^104,105,114 In contrast, Booth et al and Mello et al found that while some IEM patients exhibited improvement, others had a decline in peristalsis, and some with normal peristalsis pre-operatively developed IEM postoperatively.^46,111 Abnormal provocative testing (MRS) with a diagnosis of IEM could predict patients most likely to experience postoperative dysphagia⁴³ and therefore could influence procedure selection. Other provocative maneuvers, such as the RDC and solid meal test, are useful in evaluating symptomatic patients after fundoplication.⁵⁸

6 |. MANAGEMENT

There is no pharmacologic intervention that reliably restores esophageal smooth muscle contractility or improves symptoms.¹¹⁵ There is also no clear directive on when IEM needs management, as symptoms, and even GERD is not consistently identified with IEM. Therefore, unless GERD is identified, symptomatic patients with IEM are challenging to treat. Commonsense dietary intervention and lifestyle changes typically recommended to patients with GERD, and effective control of GERD remains the mainstay of clinical IEM management.⁹²

Dietary intervention benefits esophageal symptoms mainly by facilitating swallows, but may also impact esophageal contractility.¹¹⁶ With the hypothesis that dietary fiber binds nitric oxide (NO) contained in food, and could reduce the inhibitory effects of NO in the esophagus, psyllium (15 g/d) was reported to decrease esophageal symptoms and increase LES resting pressure in patients with GERD.¹¹⁶ However, effects on esophageal contractility were not reported in this open-label study. Transcranial direct current stimulation of the brain has been reported to improve esophageal contractility in NERD and functional heartburn in a randomized double-blind sham-controlled study.¹⁷

Alternative therapies are popular, as they decrease esophageal sensitivity and symptom perception, and may benefit esophageal contractility. A pilot study of patients with PPI-refractory GERD demonstrated significant increase in esophageal contraction vigor 10 minutes after an osteopathic intervention on the diaphragm, but long-term effects on esophageal symptoms are unknown.¹¹⁷ Prospective evaluation of the impact of these maneuvers is of interest, in addition to psychologist-assisted facilitation of coping mechanisms, cognitive and behavioral therapy, and hypnotherapy.¹¹⁸

Conventional prokinetic agents (metoclopramide, domperidone) are not beneficial in IEM. There are limited data on newer prokinetic agents. Mosapride, a 5HT-4 agonist, may facilitate secondary peristalsis induced by rapid air distension in patients with IEM¹¹⁹ and potentially improve GERD symptom scores,¹²⁰ but without improvement in primary and secondary esophageal contraction vigor.¹¹⁹ Prucalopride may enhance the amplitude of primary esophageal contractions in patients with GERD,¹²¹ while also decreasing esophageal acid exposure and accelerating gastric emptying in healthy controls.¹²² Buspirone, a mixed partial 5HT-1A agonist and dopamine D2 receptor antagonist, increased esophageal contraction amplitudes and decreased reflux symptoms in scleroderma patients,^123,124 but was not more effective than placebo in patients with IEM and dysphagia.¹²⁶ Azithromycin, a motilin receptor agonist, reduces esophageal reflux exposure in GERD¹²⁷ and following lung transplant,¹²⁸ without altering the total number of reflux episodes.

6.1 |. Prognosis and natural history

There is limited understanding of the natural history of IEM. The presence of muscle disorders, particularly connective tissue disorders, may imply progression of IEM to higher grades of hypomotility.⁸⁶ The presence of contraction reserve may suggest a better prognosis.⁴⁶ In most instances, however, IEM does not progress over time, and quality of life is not impacted.¹²⁹ It is important to emphasize that IEM is a manometric diagnosis that can be seen in healthy asymptomatic individuals, and does not necessarily imply symptom causation or illness.

7 |. CONCLUSIONS AND FUTURE DIRECTIONS

Ineffective esophageal motility is a heterogenous disorder, and not consistently related to disease states or symptoms. High-resolution manometry or HRIM is the currently accepted mode of diagnosis. Diet, lifestyle modifications, and GERD management remain the cornerstone of therapy. Medical management of IEM remains challenging, and there is no effective pharmacotherapy. Although newer prokinetic agents show promise, the endpoints of such therapy will need better definition, and it remains unclear which IEM patients need pharmacotherapy.

While central control of normal esophageal peristalsis has been well studied, the modulation of esophageal peristalsis by central and peripheral factors, and by esophageal stimuli, including distension and reflux needs further study. New precision prokinetic agents need to be developed to target esophageal smooth muscle contraction in IEM (Table 2).

TABLE 2.

Gaps in Current Understanding of Ineffective Esophageal Motility

Gaps in current understanding	Future directions
Etiology of IEM	Longitudinal studies following patients with and without IEM and GERD to determine if primary IEM leads to GERD vs. GERD causing IEM
Central and peripheral control of esophageal contractility	Evaluate physiologic and pharmacologic stimulants of esophageal peristalsis, and the value of central and peripheral stimulation in improving esophageal contractility
Heterogeneity within IEM	Longitudinal and cross-sectional studies
Diagnostic criteria for clinically relevant IEM	Diagnostic criteria may need to conform to the disease entity or symptoms being evaluated; bolus transit data from high-resolution impedance manometry may further refine IEM diagnostic criteria
Role of provocative testing	Prospective studies with provocative testing to determine impact on patient outcome
Role of novel esophageal physiologic tests	Cross-sectional studies evaluating mucosal impedance, other impedance-based metrics and functional lumen imaging probe in IEM
Impact on patient presentations and symptoms	Cross-sectional studies
Role of prokinetic therapy	Systematic study of prokinetics agents. Encourage pharmaceutical companies to develop new and novel prokinetic agents
Long-term impact of a diagnosis of IEM	Longitudinal studies evaluating outcome, complications, and impact on quality of life

IEM, ineffective esophageal motility; GERD, Gastroesophageal reflux disease.

The current Chicago Classification 3.0 definition of IEM can be further enhanced by characterizing failed swallows as distinct from weak swallows, and by defining a severe IEM category when >70% of sequences are ineffective, as there is consistent evidence implying that only severe IEM is clinically relevant. Characterizing IEM using MRS establishes presence or absence of contraction reserve, allowing confidence in standard fundoplication, and need for aggressive antireflux treatment or prokinetic therapy.

Ultimately, IEM is a manometric diagnosis that to some extent is artificial, based on minimum contraction required for “effective” bolus clearance. Current understanding indicates that mild IEM is of limited if any clinical significance, whereas severe IEM contributes to GERD pathophysiology.

Key Points.

• Ineffective esophageal motility is a heterogenous minor esophageal motility disorder not consistently associated with symptoms or esophageal disease, which can be seen in asymptomatic healthy individuals.

• Ineffective esophageal motility can be further characterized using provocative maneuvers during esophageal high resolution manometry, including multiple rapid swallows, rapid drink challenge, solid swallows and standardized test meal.

• No specific management is availble that reverses the motor pattern; instead, management focuses on improving patient symptoms, especially those related to reflux.

• Novel testing methodology (including baseline impedance measurements and functional lumen imaging probe) may help further define pathophysiology and segregate phenotypes of ineffective esophageal motility.