The concept of esophageal spastic disorders encompasses spastic achalasia, distal esophageal spasm, and jackhammer esophagus. These are conceptually distinct in that spastic achalasia and distal esophageal spasm are characterized by a loss of neural inhibition, whereas jackhammer esophagus is associated with hypercontractility. Hypercontractility may also occur as a result of esophagogastric junction outflow obstruction or inflammation. The diagnosis of jackhammer esophagus as a primary motility disorder is based on the characteristic manometric findings after ruling out mechanical obstruction and eosinophilic esophagitis. Despite the differences in pathophysiology among the esophageal spastic disorders, their management is similar.
Key points
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Largely as a consequence of refined classification made possible with high-resolution manometry (HRM) and esophageal pressure topography (EPT), the current concept of esophageal spastic disorders has evolved to encompass spastic achalasia, distal esophageal spasm (DES), and jackhammer esophagus.
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These esophageal spastic disorders are conceptually distinct in that spastic achalasia and DES are characterized by a loss of neural inhibition, whereas jackhammer esophagus is associated with hypercontractility, presumably by activation of the cholinergic pathway.
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Because the defining endoscopic features may also occur in the setting of esophagogastric junction (EGJ) obstruction, endoscopic examination is required when esophageal spastic disorders are suspected to evaluate for mechanical obstruction.
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Therapeutic management depends on the presence of EGJ outflow obstruction.
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Extensive myotomy using the POEM technique might have a role in cases of treatment failure.
Introduction
Although reflux disease is the most common cause of esophageal chest pain, esophageal manometry is often done in the course of its evaluation, and manometric abnormalities indicative of DES are often reported. The identified abnormalities, however, are rarely the cause of chest pain and most investigators would agree that the clinical diagnosis of DES is overused. It was that observation that led to a classic reappraisal of DES by Richter and Castell, conceived during the renaissance of esophageal manometry in the early 1980s. Arguing for a more restrictive use of the diagnosis, those investigators proposed 2 required manometric criteria for DES: (1) simultaneous contractions in greater than 10% of wet swallows and (2) intermittent normal peristalsis. Other associated features were also described and some minor modifications were subsequently made, but it was these 2 criteria that became part of the lore of (conventional) manometry.
A lot has changed with respect to esophageal motility testing since 1984. Clinical studies are now commonly done with high-resolution systems using in excess of 30 closely spaced pressure transducers, and esophageal contractile patterns are displayed and analyzed in terms of pressure topography rather than as line tracings. Merging these concepts, current motility studies are more accurately termed, HRM imaged with EPT . Although these innovations had their roots in the early 1990s with the pioneering studies of Clouse and colleagues, it was not until recently that commercial units became available, facilitating widespread adoption of EPT by the clinical community. The advantages of EPT compared with conventional manometry are several: (1) high-quality studies can be obtained that simultaneously image the entire esophagus, (2) standardized objective metrics have been developed for interpretation, and (3) topographic patterns of contractility are easily learned and recognized with great reproducibility. EPT also presented challenges, however, not the least of which was the need to reconsider the classification of esophageal motility developed for conventional manometric systems. That classification effort led to improved understanding of achalasia subtypes and hypomotility patterns. Headway has also been made in the domain of hypercontractile conditions, including DES. This work led to a conclusion, however, that the 2 essential criteria identified by Richter and Castell were suboptimal for defining DES as imaged in EPT and identified a heterogeneous group of patients, most of whom did not have DES. Hence, the aims of this synopsis are to update the understanding of esophageal spastic disorders in the era of EPT.
Introduction
Although reflux disease is the most common cause of esophageal chest pain, esophageal manometry is often done in the course of its evaluation, and manometric abnormalities indicative of DES are often reported. The identified abnormalities, however, are rarely the cause of chest pain and most investigators would agree that the clinical diagnosis of DES is overused. It was that observation that led to a classic reappraisal of DES by Richter and Castell, conceived during the renaissance of esophageal manometry in the early 1980s. Arguing for a more restrictive use of the diagnosis, those investigators proposed 2 required manometric criteria for DES: (1) simultaneous contractions in greater than 10% of wet swallows and (2) intermittent normal peristalsis. Other associated features were also described and some minor modifications were subsequently made, but it was these 2 criteria that became part of the lore of (conventional) manometry.
A lot has changed with respect to esophageal motility testing since 1984. Clinical studies are now commonly done with high-resolution systems using in excess of 30 closely spaced pressure transducers, and esophageal contractile patterns are displayed and analyzed in terms of pressure topography rather than as line tracings. Merging these concepts, current motility studies are more accurately termed, HRM imaged with EPT . Although these innovations had their roots in the early 1990s with the pioneering studies of Clouse and colleagues, it was not until recently that commercial units became available, facilitating widespread adoption of EPT by the clinical community. The advantages of EPT compared with conventional manometry are several: (1) high-quality studies can be obtained that simultaneously image the entire esophagus, (2) standardized objective metrics have been developed for interpretation, and (3) topographic patterns of contractility are easily learned and recognized with great reproducibility. EPT also presented challenges, however, not the least of which was the need to reconsider the classification of esophageal motility developed for conventional manometric systems. That classification effort led to improved understanding of achalasia subtypes and hypomotility patterns. Headway has also been made in the domain of hypercontractile conditions, including DES. This work led to a conclusion, however, that the 2 essential criteria identified by Richter and Castell were suboptimal for defining DES as imaged in EPT and identified a heterogeneous group of patients, most of whom did not have DES. Hence, the aims of this synopsis are to update the understanding of esophageal spastic disorders in the era of EPT.
What are the spastic disorders of the esophagus?
Spastic disorders of the esophagus might be conceived of as hyperactive conditions of the esophagus due to contractions of either abnormal propagation (premature contractions) or extreme vigor. In the current iteration of the Chicago classification of esophageal motility disorders, the relevant diagnoses are spastic (type III) achalasia, DES, and hypercontractile (jackhammer) esophagus. Despite differences in pathophysiology, which are discussed, these disorders share many similarities, including their clinical presentation: dysphagia, chest pain, regurgitation, and/or heartburn. The identification of these spastic disorders is based on the contractile pattern observed using HRM with EPT. The current Chicago classification criteria for identification of the spastic disorders are summarized in Tables 1 and 2 .
| Spastic Disorders | EGJ Relaxation | Esophageal Contractions |
|---|---|---|
| Distal esophageal spasm | Normal (mean IRP <15 mm Hg) | ≥20% Premature contractions (DL <4.5 s) |
| Spastic (type III) achalasia | Impaired (mean IRP ≥15 mm Hg) | ≥20% Premature contractions (DL <4.5 s) |
| Jackhammer esophagus | Normal or impaired a | At least 1 swallow with DCI >8000 mm Hg · s · cm |
a EGJ outflow obstruction (defined as mean IRP ≥15 mm Hg in association with some instances of peristalsis) may be associated with hypercontractile swallow.
| Abbreviation | Metric | Description | Normal |
|---|---|---|---|
| IRP | Integrated relaxation pressure | Mean EGJ pressure during the 4 s of maximal relaxation (contiguous or noncontiguous) in the 10-s window after UES relaxation | <15 mm Hg |
| DCI | Distal contractile integral | Amplitude × time × duration (mm Hg · s · cm) of the distal esophageal contraction >20 mm Hg from the proximal pressure through (transition zone) to the EGJ | <5000 mm Hg · s · cm |
| CDP | Contractile deceleration point | The inflection point along the 30–mm Hg isobaric contour where propagation velocity slows demarcating the tubular esophagus from the phrenic ampulla | — |
| CFV | Contractile front velocity | Slope of the tangent approximating the 30–mm Hg between the proximal pressure trough (transition zone) and the CDP | <9 cm/s |
| DL | Distal latency | Interval between UES relaxation and the CDP | >4.5 s |
Distal Esophageal Spasm and Spastic Achalasia
Definition
DES is an uncommon disorder characterized by an impairment of ganglionic inhibition in the distal esophagus. Using conventional manometry, DES was defined by the presence of simultaneous contractions. Using HRM with EPT, however, the higher-resolution recordings demonstrated that propagation velocity normally varies greatly along the length of the esophagus and finding regions of rapid propagation is common. A consequence of this finding is that the finding of rapidly propagated contractions is nonspecific for esophageal spasm. Alternatively, premature contractions, defined by reduced distal latency (DL), measured as the interval between upper sphincter relaxation and the onset of contraction in the distal esophagus, are more specific for spasm. Physiologically, the DL is likely a manifestation of inhibitory myenteric neuron activity that determines the timing of contraction in the distal esophagus. Premature contractions with normal EGJ relaxation define DES whereas premature contractions with impaired EGJ relaxation are defining criteria for spastic achalasia (also termed, type III achalasia ).
Impairment of neural inhibition?
DES and spastic achalasia share a common pathophysiology characterized by loss of inhibitory ganglionic neuron function in the distal esophagus. The impairment of inhibitory innervation leads to both premature, rapidly propagated, or simultaneous contractions in the distal esophagus and to incomplete deglutitive EGJ relaxation. Unlike the proximal esophagus, where sequencing of the peristaltic contraction is directly programmed from motor neurons in the medulla, the timing of peristalsis in the distal smooth muscle esophagus is mediated via excitatory (cholinergic) and inhibitory (nitric oxide [NO]) myenteric plexus neurons. Furthermore, a neural gradient exists such that there is an increasing proportion of inhibitory ganglionic neurons progressing distally to the lower esophageal sphincter. The deglutitive response begins with a period of quiescence (deglutitive inhibition) in the distal esophagus that is progressively prolonged approaching the EGJ as a consequence of that neural gradient. Behar and Biancani qualified this period of quiescence as contractile latency and suggested that patients with spasm could be characterized by a reduction in contractile latency. Thus, distal contractile latency, measured from the onset of the pharyngeal swallow to the onset of the contraction in the distal esophagus, was shorter in patients with simultaneous contractions than in those with normal peristaltic propagation. NO is the dominant inhibitory neurotransmitter in the esophageal myenteric plexus. Experimentally scavenging NO with free hemoglobin in control subjects induces simultaneous esophageal contraction and inhibits deglutitive EGJ relaxation. This demonstrates the role of inhibitory innervation in the genesis of DES and impaired EGJ relaxation.
Some structural changes have been observed in the esophageal muscularis propria of patients with DES. These are inconsistent and nonspecific, however. Recent observations by Pehlivanov and colleagues using high-frequency intraluminal ultrasound suggest increased esophageal smooth muscle thickness in DES patients. Even in the absence of esophageal contractions, the muscularis propria in DES patients was thicker than in controls or patients with nonspecific motor disorders. Finally, a study in knockout mice suggested that lack of inhibitory innervation might result in increased muscularis propria thickness.
Jackhammer Esophagus
Definition
The term, nutcracker esophagus , was coined in conventional manometry for a novel disorder associated with noncardiac chest pain and characterized by hypertensive but normally propagated peristaltic contractions. Unlike the case of spasm, there were no characteristic fluoroscopic abnormalities. The manometric criterion for nutcracker esophagus were initially an average peristaltic amplitude of greater than 180 mm Hg in the distal esophagus. Subsequently, this threshold value was increased to 220 mm Hg in hopes of improving specificity. With the era of HRM and EPT, peristaltic amplitude was replaced by the distal contractile integral (DCI) as the summary metric of the vigor of the distal esophageal contraction. If the entire distal esophageal contraction is envisioned as a solid with the height of the peaks corresponding to peristaltic amplitude and the footprint corresponding to the length of the involved esophagus and the duration of the contraction, the DCI, expressed as mm Hg · s · cm, is the volume of that solid above a 20–mm Hg minimum. A DCI mean value of 5000 mm Hg (hypertensive peristalsis in the Chicago classification) approximately corresponds to nutcracker esophagus in conventional manometry. Even that value is seen in up to 5% of normal subjects, however, making it inherently nonspecific. Alternatively, an extreme phenotype of hypertensive contractions was described based on the occurrence of at least one contraction with a DCI greater than 8000 mm Hg · s · cm, a value never observed in controls. This was termed, esophageal hypercontractility or the jackhammer esophagus . Although still somewhat heterogeneous (the pattern is sometimes seen with EGJ outflow obstruction), this extreme phenotype is likely more clinically relevant than hypertensive peristalsis (nutcracker esophagus). Hypercontractility is commonly associated with multipeaked contractions, sometimes resulting in DCI values in excess of 50,000 mm Hg · s · cm.
Excess of cholinergic stimulation?
The pathophysiology of esophageal hypercontractility likely involves an excess of cholinergic drive. Temporal asynchrony between the contractions of circular and longitudinal muscle layers of the muscularis propria have been observed with high-frequency intraluminal ultrasound in patients with nutcracker esophagus. This asynchrony was reversed with atropine. The observations of Loo and colleagues in diabetics with autonomic neuropathy are also an indirect argument for an excess of cholinergic stimulation. Multipeaked contractions occurred more frequently in diabetics with neuropathy than in control subjects or diabetics without neuropathy. Multipeaked contractions became single-peak contraction after atropine injection. Multipeaked contractions are also a common finding in jackhammer esophagus. It remains to be determined if atropine may change the multipeaked pattern in such patients. Finally, as with DES, increased muscle thickness has been observed in patients with nutcracker esophagus and with esophageal hypercontractility (Kahrilas, 2011, unpublished observations).
Esophageal Spastic Disorders: A Consequence of EGJ Obstruction?
Both DES and jackhammer esophagus can be associated with EGJ outflow obstruction, an association supported by experimental models. For instance, Mittal and colleagues observed esophageal muscle hypertrophy and hyperexcitability by placing calibrated ligatures around the EGJ in cats. In humans, esophageal hypercontractility has been observed with mechanical EGJ obstruction induced by fundoplication or gastric lap band. Gyawali and Kushnir expanded on this observation, reporting that patients with EGJ outflow obstruction exhibited a motor pattern characterized by multipeaked contractions, high distal esophageal amplitude, and prolonged contraction duration. Finally, as previously defined, impaired EGJ relaxation in association with premature contractions constitutes spastic achalasia.
Given the relationship between EGJ outflow obstruction and hypercontractility, some investigators have speculated that esophageal spastic disorders can progress to achalasia. Supporting this contention, among a series of 35 patients diagnosed with DES on conventional manometry, 5 (14%) progressed to achalasia, 4 (12%) reverted to normal manometry, and 26 (74%) had persistent DES at a mean follow-up of 2.1 years. Progression from nutcracker esophagus to achalasia also was observed. The number of patients reported to undergo such progression, however, is extremely limited (only case reports of nutcracker esophagus), leaving open the possibility that the type of spastic disorder might have been misdiagnosed with either the initial or the follow-up conventional manometry study. EGJ pseudorelaxation secondary to esophageal shortening commonly leads to an erroneous diagnosis of DES instead of spastic achalasia.
Association with Other Conditions: Gastroesophageal Reflux Disease and Eosinophilic Esophagitis
Manometric findings consistent with primary spastic motility disorders can also occur in conjunction with, or as a consequence of, other conditions, notably gastroesophageal reflux disease (GERD). In a series of 108 patients with DES, GERD was documented by either pH-metry or endoscopy in 38%. Furthermore, in some instances, esophageal acid perfusion can induce spasm. In a series of 45 patients with nutcracker esophagus (conventional manometry), 47% had abnormal acid exposure time on pH-metry, 4% had endoscopic esophagitis, and 16% positive symptom index. Finally, reflux esophagitis has also been observed in patients with jackhammer esophagus and the hypercontractile pattern can resolve with of proton pump inhibitor (PPI) therapy.
Similar overlap exists between spastic disorders and eosinophilic esophagitis. In a retrospective study of patients who underwent Heller myotomy for achalasia, mucosal eosinophilia was reported in 8%. A case of achalasia with eosinophilic infiltrate responding to steroid therapy has been reported. Jackhammer esophagus was also associated with eosinophilic esophagitis in 3 of 41 patients (7%) who underwent endoscopy with mucosal biopsies.
Diagnosis of esophageal spastic disorders
Dysphagia, chest pain, regurgitation, and heartburn are all symptoms potentially associated with esophageal spastic disorders. All of these are nonspecific, however, and esophageal spastic disorders are rare. Hence, the clinical evaluation needs to prioritize identifying more morbid conditions and more prevalent conditions before pursuing these rare, nonfatal conditions. When chest pain is among the presenting symptoms, the evaluation should first prioritize excluding cardiovascular disease owing to its potentially life-threatening nature. Even within the realm of esophageal chest pain, reflux is a more common cause than spastic disorders. Using the liberal definitions put forth by Richter and Castell, DES accounted for fewer than 5% of patients referred for dysphagia or chest pain in a motility laboratory. With the more refined criteria of the Chicago classification, the combined prevalence of DES, spastic achalasia, and jackhammer is even lower, approximately 2%. Consequently, evaluation of suspected esophageal spastic disorders requires a thorough evaluation to first identify or exclude other potential causes of esophageal chest pain.
One potential consequence of spastic contractions is an impairment of esophageal bolus transit that may explain the perception of dysphagia. As evident by the fluoroscopic appearance of DES as a corkscrew or rosary bead esophagus, long segments of simultaneous contractions might occur. In such instances, the bolus becomes trapped in the spastic segment because the distal portion contracts prematurely with insufficient time to allow for bolus transit. Paradoxically, Tutuian and Castell reported that 55% of patients with DES defined with conventional manometry and 97% of patients with nutcracker esophagus exhibited complete bolus transit when tested with multichannel intraluminal impedance. Although their findings with respect to nutcracker are consistent with understanding of its physiology, the observation regarding DES are not and speak to the overdiagnosis of the condition using conventional manometry and diagnostic criteria. DES patients with dysphagia exhibited more frequently abnormal bolus transit than DES patients with chest pain.
The mechanism by which spastic disorders induce chest pain is not well understood. The amplitude of contractions might be relevant. Tutuian and colleagues demonstrated that DES patients with chest pain had greater amplitude esophageal contractions than DES patients with dysphagia or GERD. Hypersensitivity might also play a role. Using stepwise balloon distension, Mujica and colleagues observed a lower chest pain threshold in patients with nutcracker esophagus compared with controls. Hypersensitivity might also explain the perception of heartburn in patients without demonstrable evidence of reflux.
Finally, epiphrenic diverticula might occur as a consequence of spastic disorders. The majority of patients with epiphrenic diverticula are found to have an esophageal motility disorder. In a surgical series of 21 patients with epiphrenic diverticula, 24% were diagnosed as DES before surgery, 24% as nutcracker esophagus, and 9% as achalasia. The presence of a diverticulum might also explain the symptoms of dysphagia or regurgitation.
Upper Endoscopy
Upper endoscopy should be performed as initial evaluation of esophageal symptoms consistent with spastic disorders. It allows exclusion of mechanical obstruction, esophageal stenosis, or esophagitis. Systematic esophageal biopsies should be obtained to rule out eosinophilic esophagitis, especially when dysphagia is a prominent symptom. Usually no specific endoscopic abnormality is revealed, but disordered esophageal contractions might be observed by the endoscopist. In some cases of achalasia, increased resistance at the EGJ might be perceived.
Esophageal Manometry
The diagnosis of spastic disorders is established by esophageal manometry and recent developments suggest that HRM with EPT is superior to conventional manometry for several reasons. First, the diagnosis of EGJ relaxation is more reliable with HRM compared with conventional manometry, which is essential in distinguishing DES from spastic achalasia. A major factor leading to the failure to detect impaired EGJ relaxation with conventional manometry is esophageal shortening that occurs during peristalsis that may be accentuated with spasm. Correct evaluation of EGJ relaxation is of cardinal importance because spastic contractions with normal EGJ relaxation constitute DES but spastic contractions with impaired EGJ relaxation diagnose spastic achalasia, and treatment then focuses on alleviating EGJ obstruction. Moreover, the use of the integrated relaxation pressure (IRP), DL, and DCI measurements in HRM (see Table 2 ) more accurately diagnose spastic disorders than the metrics used in conventional manometry. The EPT definitions of spastic disorders are summarized in Table 1 .
DES was initially defined using conventional manometry by the presence of at least 20% simultaneous contractions with minimum amplitude of 30 mm Hg. A simultaneous contraction was defined by a propagation velocity greater than 8 cm/s measured between 3 cm and 8 cm above the EGJ. Associated, but not essential, criteria for DES were spontaneous, repetitive, or multipeaked contractions and intermittent normal peristalsis. With HRM and EPT, DES is defined as at least 20% premature contractions in the context of normal EGJ relaxation. Premature contractions exhibit a reduced (<4.5 s) DL defined as the interval between upper esophageal sphincter (UES) relaxation and onset of the contraction at the contractile deceleration point (CDP) ( Fig. 1 ). Recently, Pandolfino and colleagues demonstrated that DL was much more specific than the contractile front velocity (CFV) for detecting spastic disorders. Among 1070 patients, 91 exhibited rapid contractions (defined as CFV >9 cm/s). In 24 of them, these contractions were also premature. All of the patients with premature contractions were ultimately managed as either DES or spastic achalasia. In contrast, the 67 patients with rapid contractions but normal DL were more likely to have nonspastic disorders, in particular, weak peristalsis. Finally, in the Chicago classification, there is no requirement of any normal contractions in the diagnosis of DES.
