Address for Correspondence John Pandolfino MD, Department of Medicine, Division of Gastroenterology, Feinberg School of Medicine, Northwestern University, 676 St Clair St, Suite 1400, Chicago, IL 60611-2951, USA. Tel: +312 695 4729; fax: +312 695 3999; e-mail: firstname.lastname@example.org
Background High-resolution manometry and esophageal pressure topography have enhanced our ability to analyze esophageal motor disturbances by improving the detail and accuracy of measurements of peristaltic activity.This has been extremely helpful in the evaluation of disorders of rapid propagation as the technique is able to define important time points and physiologic landmarks that are crucial in defining peristaltic velocity and latency intervals.
Purpose The goal of the current review will be to assess how esophageal pressure topography has impacted our ability to define important phenotypes of rapid propagation. Additionally, this review will also be utilized to complement the description of the Chicago Classification of Esophageal Motor Disorders, which is presented in this supplement issue.
High resolution manometry (HRM), in and of itself, is an adaptation of conventional manometric hardware that basically incorporates an increased number of pressure sensors spaced closely together. The data generated by HRM would therefore be displayed as a tracing format similar to what would be utilized for conventional manometric interpretation. The real advance in terms of manometry is primarily focused on the analysis techniques that were derived to optimize the information from high resolution manometry. To better visualize the data, Clouse and Staiano1 incorporated a process of interpolation or averaging between sensors to display the information in the form of seamless isobaric color regions on esophageal pressure topography plots (EPT) (Fig. 1). The EPT or ‘Clouse Plots’ have the capacity to convert manometric information into distinct patterns that illustrate the physiology of contractile coordination and the mechanics associated with bolus transit evidenced on combined studies with fluoroscopy and impedance.
This new technique has benefitted our evaluation of esophageal body peristaltic function by improving both the detail and accuracy of measurements of peristaltic function. Firstly, important landmarks can be described that impact measurements of integrity of the wavefront and the pattern of propagation. These landmarks, coupled with the ability to define a space-time domain, greatly improve our ability to define the timing of contractile events and bolus transit through the esophagus and into the stomach. A disruption in the sequencing and order of contraction, as it relates to the timing of EGJ opening, will impair bolus transit and potentially lead to complications, such as discomfort and regurgitation/aspiration. The goal of this manuscript will be to detail how EPT has impacted our ability to measure important components of peristaltic function with a focus on contractile propagation and spastic disorders of the esophagus. Although we will discuss both the physiology and quantitative metrics utilized for assessing contractile vigor, the assessment of hypercontractility and weak peristalsis will be covered in greater detail in other sections of this supplement.
Esophageal Body Motility
Swallowing not only induces a contraction wave that progresses down the esophageal body but also triggers a wave of inhibition of the esophageal smooth muscle that precedes the arrival of the peristaltic contraction (deglutitive inhibition), resulting in relaxation of the lower esophageal sphincter and in preparation of the esophageal body to receive the oncoming bolus with minimal distal resistance.2,3 Experiments in vitro and in vivo have shown that a wave of muscle hyperpolarization spreads down the esophageal body preceding the occurrence of peristaltic contractions.4–7 The initial hyperpolarization of the muscle lasts progressively longer in progressively more distal segments; hence, it may play an important role in the normal propagation of primary peristalsis.4
The pattern of activation of the inhibitory and excitatory vagal pathways, the regional gradients of inhibitory and excitatory myenteric nerves, and the intrinsic properties of the smooth muscle all determine the latency between swallow and contractions and the velocity of peristalsis. The esophageal peristaltic contractions themselves are a blend of non-cholinergic and cholinergic components. As a consequence, cholinergic antagonists, such as atropine, increase the latency and decrease the amplitude of contraction in the proximal, but not the distal parts of the esophagus. In contrast, antagonists of nitric oxide synthase reduce the latency mainly in the distal segments and lead to simultaneous contractions.
Any condition in the gastrointestinal tract which impairs neural inhibitory activity will probably result in a discoordinated motor behavior. In the esophagus, the classical example of degenerative loss of neurons and impairment of inhibitory activity is achalasia of the LES. In 1970, Christensen8 suggested that a system of local inhibitory innervation was crucial to the understanding of the pathogenesis of diffuse esophageal spasm and achalasia. Evidence of inhibitory dysfunction associated with abnormal peristalsis and/or incomplete LES relaxation has been found both in animal experiments9,10 and in patients with achalasia.11–14 Since then, many investigators proposed that the spectrum of primary esophageal motility disorders may be due to different degrees of inhibitory dysfunction.8,15–18
Given the fact that deglutitive inhibition and latency intervals are crucial in determining propagation of contractile activity in the esophagus, new metrics focused on defining latency, and contractile velocity have been devised using EPT. The clear description of the timing of important events with EPT, such as the onset of swallowing and the contractile deceleration point, have allowed a more uniform description of latency and velocity. These new measurements have been integrated with other measurements focused on the integrity and vigor of contraction to determine phenotypes of rapid propagation that may be both clinically relevant and physiologically distinct.
Esophageal Pressure Topography
Anatomy and landmarks
Fig. 1 depicts the typical pressure topography of both sphincters and the intervening esophagus during a normal swallow. Clouse19 originally described three types of pressure troughs in the topography of peristalsis, labeled P (proximal), M (middle), and D (distal). Although the clinical relevance and neuromuscular control of these segments remains unclear, swallows may also exhibit exaggerated troughs with defects in the 20 mmHg isobaric contour. Defects within the proximal trough had previously been labeled a transition zone defect based on the hypothesis that this area represented a transition in the neuromuscular control of the esophagus from extrinsically controlled striated muscle to intrinsically dominated smooth muscle. Defects in this particular location, which are >2 cm using a 20 mmHg isobaric contour can be associated with impaired bolus transit and proximal stasis.20–22 In contrast, defects associated with the middle and distal pressure troughs are more in line with what would be defined as ineffective esophageal motility, given the proximity of the middle and distal trough with the 3–8 cm domain above the LES utilized in defining this entity.
In addition to the segmental architecture displayed by the Clouse Plots, another important landmark becomes apparent, which has important implications in the context of assessing propagation. The contractile deceleration point (CDP) is defined as the point where the most abrupt deceleration in velocity occurs within the distal esophagus.23 This landmark defines a transition from esophageal peristaltic clearance to emptying of the phrenic ampulla on fluoroscopy, where the mechanism of emptying is dominated by compartmentalized pressurization, re-elongation and recoil of the phrenoesophageal ligament rather than peristaltic propagation.23 The CDP location is determined by defining the intersection point between two tangent lines of the 30 mmHg isobaric contour: one extending distally from the transition zone and the other extending proximal from the EGJ when it reestablishes its normal postdeglutitive position (Fig. 1). The distance of the CDP above the proximal margin of the EGJ typically ranges from 1.5 to 2 cm and thus, the previous landmarks to assess peristalsis using 3 and 8 cm above the LES, were in fact a reasonable estimate of peristaltic function.
Assessing propagation using esophageal pressure topography metrics
The assessment of peristaltic integrity should always be the first step in the evaluation of peristaltic function as the integrity of the contraction will determine whether other measurements are feasible or worthwhile (Table 1). The integrity of the contraction using a 20 mmHg isobaric contour associated with each swallow describes how completely that contraction spans from the upper sphincter to the EGJ, irrespective of the vigor or velocity of the contraction. Qualifying measures of Distal Latency (DL) and Contractile Front Velocity (CFV) can only be measured accurately when there is sufficient contractile integrity to allow proper landmark identification and measurement.
Table 1. Esophageal pressure topography metrics utilized in assessing propagation
Defects or breaks in peristaltic activity can be severe to the point where no propagating contractile activity is present or only a short segment of contraction defined by a 20 mmHg isobaric contour <3 cm is noted.24,25 These swallows are defined as failed and therefore, DL or CFV should not be measured. Defects are further defined based on size of the breaks [large >5 cm but not failed, small 2–5 cm].25 Large defects noted in the distal esophagus will potentially conceal the CDP and thus, DL and CFV may be difficult to interpret. These swallows are more akin to swallows labeled as ineffective esophageal motility (IEM) as they will have peristaltic amplitudes below 30 mmHg in a pressure sensor placed 3–8 cm above the EGJ. Therefore, one would define these swallows based on the defect in integrity as a weak swallow, and a determination of abnormal propagation will not be possible.
Small breaks in the peristaltic wavefront may not obscure measurement of the CDP, and thus DL and CFV can be measured when these defects are not localized at the middle or distal trough. Defects occurring at the proximal trough or transition zone should not complicate the determination of the CDP and will not alter the accuracy of measuring DL and CFV.26
Velocity The measurement of peristaltic velocity is the primary criterion for diagnosing spasm using conventional manometry based on the concept that a velocity >7.5–8 cm s−1 is synonymous with a simultaneous contraction.27 However, esophageal pressure topography has revealed that velocity along the contractile wavefront is dependent on contractile morphology and regional changes in distal propagation. This is most notable in the description of the CDP, which describes a clear demarcation of two distinct areas of functional activity focused on changes in velocity along the propagating wavefront. Propagation of the contractile wavefront beyond the CDP is not peristaltic as it represents emptying of the phrenic ampulla. Therefore, a more accurate assessment of peristaltic velocity is made by taking the best-fit tangent between the transition zone and CDP. This is in contrast to the arbitrary utilization of 3 and 8 cm above the EGJ, where the assessment of peristaltic velocity may extend into the phrenic ampulla.
The CFV is calculated by taking the best-fit tangent between the transition zone and CDP (Fig. 1). In instances of increased intrabolus pressure, trapped between the distal esophageal contraction and the EGJ, the CFV should be determined at an isobaric contour pressure exceeding EGJ pressure so as not to mistake esophageal pressurization for a simultaneous contraction.28 The upper limit of normal for the CFV is >9 cm s−1 based on 95th percentile values of data in 75 normal subjects.23
Latency The DL is a measure that is reflective of peristaltic timing and the period of deglutitive inhibition rather than the late phase of esophageal emptying. The measurement is made by taking the time from the start of upper esophageal sphincter (UES) relaxation to the CDP and represents a means for quantifying the latency of the distal contraction as a surrogate for inhibitory ganglionic integrity29 (Fig. 1). A computer simulation using normalized measurements of esophageal length determined that the median DL was 6.0 s (95% CI 4.8–7.6 s).30 A manual analysis of the same data found that the median time for propagation from the start of UES relaxation to the CDP was 6.2 s with a minimal value observed of 4.6 s in the control group. Given these findings, a cut-off of 4.5 s was established as the lower limit of normal for the DL. This threshold is also similar to the values previously described by Behar and Biancani29 with a small shift to account for the difference in landmarks for the beginning of the swallow. Although DL can be measured with conventional manometry, it is difficult to standardize because of gaps in pressure sensor spacing and poor identification of the segmental boundaries of the contraction.
Contractile vigor Although contractile vigor is an important measure of overall peristaltic function, it does not have a significant impact on defining the timing and coordination of the contractile wavefront. That being said, abnormalities of contractile vigor may represent an imbalance in the neurologic input of the smooth muscle esophagus and thus, could potentially define relevant pathology. The EPT metric devised to characterize the vigor of the distal esophageal contraction is the Distal Contractile Integral (DCI), measured for the segment spanning from the proximal to distal pressure troughs.31 To exclude the effects of intrabolus pressure in the DCI computation, the first 20 mmHg is ignored.31 The upper limit of normal defined by the 95th percentile in a normal population is 5000 mmHg-s-cm.31
The conventional criteria of distal esophageal spasm utilized a cut-off threshold value of 30 mmHg to distinguish contractile activity from non-contractile pressure events in the esophageal body.27 Similarly, EPT does require a minimum contractile activity that is defined by assessing the peristaltic integrity using the 20 mmHg isobaric contour. The DCI was devised primarily to identify swallows of excessive contractile vigor and thus, there is no lower limit for DCI to use as a criterion for determining whether a swallow has sufficient vigor to be potentially classified as spastic. The fall back has been to utilize the peristaltic integrity as an inclusion criterion and a diagnosis of spasm cannot be made in the presence of failed swallows, swallows with large breaks in the distal trough or when pan-esophageal pressurization is present.
Pressurization preclude measuring DL and CFV as the accuracy and relevance of these measures remains unclear in these swallow types.
In contrast to defining threshold contractile levels to define inclusion criteria for disorders of rapid propagation, DCI measurements above normal values may have clinical relevance. This is most apparent in the instances where the DCI value is >8000 mmHg-s-cm where contractions are typically associated with repetitive contractions that may extend beyond the timing of the normal deglutitive swallow window.28 These swallows may represent a disorder of altered neurogenic input as the termination of the contraction is abnormal. These patterns of hypercontractility can be seen in patients with and without abnormal propagation of the contractile wavefront and the clinical relevance of these contractile patterns will be covered in another review in this supplement.
Phenotypes of Rapid Propagation
The classification of esophageal motor disorders associated with rapid peristaltic propagation has been refined to include a measure focused on deglutitive inhibition in addition to the standard definition focused on peristaltic velocity. The diagnosis of distal esophageal spasm using conventional criteria utilized a peristaltic velocity threshold of >7.5–8.0 cm s−1 as criteria for spasm with the caveat that the contractile activity was >30 mmHg at the level of 3 and 8 cm above the EGJ.27 However, this definition of DES identifies a very heterogeneous population as evidenced on an assessment of bolus transit in 71 such patients with combined manometry and impedance.32 Thus, new criteria utilizing EPT metrics focused on CFV and DL have been proposed to improve the categorization of disorders of rapid propagation.
Although quantifying DL is not unique to EPT,33,34 the technique simplifies and potentially standardizes this measurement. The EPT provides the detail required to define the segmental architecture of peristalsis necessary to differentiate regional variations in contraction velocity. In addition, it allows one to define the onset of the swallow and the point where esophageal contraction shifts from peristalsis to ampullary emptying. These landmarks are crucial for accurate measurement of the CFV and DL.
A recent study applied carefully standardized metrics for CFV and DL to a large series (1070 consecutive studies) of clinical high resolution EPT studies in an attempt to refine the diagnosis of DES.26 The results defined three distinct subtypes of rapid propagation: (i) rapid premature contraction, (ii) premature contraction and (iii) rapid contraction with normal latency (Fig. 2). Only 2% subjects (n = 24) in that series were defined as having premature contractions [reduced DL]. This categorization is important because it is never encountered in asymptomatic control populations and these swallows will also have impaired deglutitive inhibition during multiple rapid swallows. These patients are classified as having Distal Esophageal Spasm in the Chicago Classification if there is evidence of normal EGJ relaxation (Mean Integrated Relaxation Pressure <15 mmHg). Only six patients (0.5%) in this series were classified as true DES based on the criteria of reduced DL and a rapid CFV in 20% or more swallows highlighting the fact that this disorder is extremely rare. Patients with reduced DL and rapid CFV in the context of abnormal EGJ relaxation (Mean Integrated Relaxation Pressure <15 mmHg) are classified as having Type III achalasia.
Rapid contractions with normal latency is a much more common entity compared to premature contractions.26 In the same series of 1070 patients, 67 patients (6%) fulfilled criteria for rapid contraction with normal latency in 20% or more swallows using the Chicago Classification definition. The majority of these patients were ultimately classified as having either weak peristalsis (61%) with a proximal defect or otherwise normal/borderline normal peristalsis with normal transit mechanics. The clinical implication of rapid contraction with normal latency remains unclear and probably rests within the confines of a normal variant or weak peristalsis. Interesting physiologic studies using low doses of atropine reveal that rapid contractions can be shifted to the right suggesting a potential neural cholinergic issue at the transition zone and future studies should focus on assessing the effects of atropine and nitric oxide inhibitors on these subtypes of rapid propagation.
Incorporating the measurement of DL into the diagnostic algorithm for assessing esophageal motor disorders has helped define distinct pathophysiologic phenotypes of rapid propagation.26 Disorders of rapid propagation are now defined into categories based on this measurement using the Chicago Classification system. Distal Esophageal Spasm and Type III achalasia are associated with premature contractions characterized by functionally impaired inhibition in the distal esophagus [reduced DL]. In contrast, rapid contraction with normal latency is a separate diagnosis highlighting preserved deglutitive inhibition and the overlap with normal and weak peristalsis. Although this classification is based on definitions extrapolated from prior physiologic investigations and the assessment of simulations in normal asymptomatic controls, the clinical relevance of this classification scheme needs to be tested in long-term natural history studies and outcome trials. We theorize that this distinction may have clinical relevance in directing therapy in that patients with reduced latency should respond better to agents that target smooth muscle relaxation (calcium channel blockers, nitrates, phosphodiesterase type five inhibitors). On the contrary, patients with rapid contraction and normal latency would probably do poorly with treatment focused on inducing smooth muscle relaxation and would be more suitable with a management approach similar to weak peristalsis or functional dysphagia. Further work will also require a focus on defining physiologic responses to various pharmacologic interventions and provocative swallows to determine the appropriate threshold levels and targets for treatment.
This work was supported by R01 DK079902 (JEP) from the Public Health Service and Daniel Sifrim research work is supported by MRC (UK) (89495); FWO (Belgium) G.0682.08 and Sandhill Scientific, USA.
Conflict of Interest
John Pandolfino [Given Imaging (Consulting, Educational), Sandhill (Consulting)]. Daniel Sifrim [Sandhill (Research Grant)].