Abstract
Repetitive retrograde contractions (RRCs) in response to sustained esophageal distension are a distinct contractility pattern observed with functional luminal imaging probe (FLIP) panometry that are common in type III (spastic) achalasia. RRCs are hypothesized to be indicative of either impaired inhibitory innervation or esophageal outflow obstruction. We aimed to apply FLIP panometry to patients with postfundoplication dysphagia (a model of esophageal obstruction) to explore mechanisms behind RRCs. Adult patients with dysphagia after Nissen fundoplication (n = 32) or type III achalasia (n = 25) were evaluated with high-resolution manometry (HRM) and upper endoscopy with FLIP. HRM studies were assessed for outflow obstruction and spastic features: premature contractility, hypercontractility, and impaired deglutitive inhibition during multiple-rapid swallows. FLIP studies were analyzed to determine the esophagogastric junction (EGJ)-distensibility index and contractility pattern, including RRCs. Barium esophagram was evaluated when available. RRCs were present in 8/32 (25%) fundoplication and 19/25 (76%) achalasia patients (P < 0.001). EGJ outflow obstruction was detected in 21 (67%) fundoplication patients by HRM, FLIP, or esophagram [6 (29%) had RRCs]. On HRM, none of the fundoplication patients had premature contractility, whereas 3/4 with defective inhibition on multiple-rapid swallows and 2/4 with hypercontractility had RRCs. Regression analysis demonstrated HRM with spastic features, but not esophageal outflow obstruction, as a predictor for RRCs. RRCs in response to sustained esophageal distension appear to be a manifestation of spastic esophageal motility. Although future study to further clarify the significance of RRCs is needed, RRCs on FLIP panometry should prompt evaluation for a major motor disorder.
NEW & NOTEWORTHY Repetitive retrograde contractions (RRCs) are a common response to sustained esophageal distension among spastic achalasia patients when evaluated with the functional luminal imaging probe. We evaluated patients with postfundoplication dysphagia, i.e., patients with suspected mechanical obstruction, and found that RRCs occasionally occurred among postfundoplication patients, but often in association with manometric features of esophageal neuromuscular imbalance. Thus, RRCs appear to be a manifestation of spastic esophageal dysmotility, likely from neural imbalance resulting in excess excitation.
Keywords: achalasia, EndoFLIP, functional lumen imaging probe, impedance, manometry
INTRODUCTION
The functional luminal imaging probe (FLIP) uses high-resolution impedance planimetry to measure luminal dimensions during controled volumetric distension. Distensive pressure is also measured to assess its relationship with luminal dimensions, i.e., distensibility. Esophageal contractility can also be elicited by FLIP distension, evident by occluding and nonoccluding contractions along the FLIP probe. Furthermore, when regional diameter changes along the FLIP probe are depicted as a function of time (FLIP panometry), patterns of contractility can be identified (5, 9). The pattern commonly observed among asymptomatic controls and patients with normal peristalsis is of repetitive antegrade contractions (RACs), which likely reflect a secondary peristaltic response to sustained esophageal distension (8, 9). Additionally, a unique distension-induced contractile pattern, repetitive retrograde contractions (RRCs), was commonly observed among patients with type III (spastic) achalasia, but not among 10 asymptomatic controls (8, 9). RRCs have also subsequently been reported among patients with high-resolution manometry (HRM)-motility diagnoses of nonspastic achalasia and jackhammer esophagus and also infrequently among patients with dysphagia and normal esophageal motility, eosinophilic esophagitis, and reflux symptoms (5–8). Hence, RRCs appear to be a pathologic finding in most cases. However, the underlying motility abnormality predisposing to RRCs remains unclear. Candidate mechanisms in spastic achalasia, the entity in which they were most commonly observed, are either an esophageal outflow obstruction or a neuromuscular imbalance between excitatory (cholinergic) and inhibitory (nitrergic) innervation (14).
There are a number of potential causes of dysphagia after fundoplication, but most commonly this is attributed to mechanical obstruction, e.g., a wrap that is too tight, disrupted, slipped, herniated, or some combination thereof. Thus, postfundoplication dysphagia can be a human model of structural esophageal outflow obstruction without features of impaired neural regulation.
Therefore, the aim of this study was to analyze patterns of distension-induced contractility in patients with postfundoplication dysphagia using FLIP panometry to gain insight into the causal mechanisms of RRCs.
METHODS
Subjects.
Patients presenting to the Esophageal Center of Northwestern for evaluation of dysphagia or chest pain that completed HRM and FLIP during upper endoscopy were prospectively included. Patients were specifically included in this study if they 1) had a previous Nissen fundoplication (evaluation between January 2015 and August 2017) and reported dysphagia or 2) had newly diagnosed, i.e., no previous treatment with pneumatic dilation or myotomy, type III achalasia on HRM (evaluation between November 2012 and August 2017) (15). Achalasia patients overlapped with cohorts from our previously published studies (5, 8). Patients were primarily identified by referral for manometry; thus, FLIP was included with the endoscopic evaluation when manometry was scheduled in temporal proximity to the endoscopy. Patients with previous upper gastrointestinal surgery other than Nissen fundoplication, significant medical comorbidities, eosinophilic esophagitis, severe reflux esophagitis [Los Angeles (LA)-classification C or D], or large hiatal hernia were excluded. The study protocol was approved by the Northwestern University Institutional Review Board. Patients provided written, informed consent.
Clinical evaluation.
Symptoms were assessed by patient completion of written questionnaires at the time of high-resolution impedance manometry (HRIM). Dysphagia and chest pain were assessed via the Brief Esophageal Dysphagia Questionnaire, and reflux symptoms were assessed using the Gastresophageal Reflux Disease Questionnaire (13, 31).
Subjects underwent sedated upper endoscopy in the left lateral decubitus position using sedation with midazolam (2–15 mg) and fentanyl (0–300 µg). Propofol was used with anesthesiologist assistance in addition to midazolam and fentanyl at the discretion of the performing endoscopist in some cases. Endoscopy was reviewed to assess the integrity of the fundoplication, presence of hiatal hernia (axial or paraesophageal), and presence of reflux esophagitis according to the LA classification (23).
Barium esophagram was obtained if requested by the primary gastroenterologist. Available esophagrams were reviewed for the presence of delayed barium emptying or delayed passage of a 12.5-mm barium tablet, either of which was considered indicative of radiographic esophageal outflow obstruction.
High-resolution manometry.
After a minimum 6-h fast, HRIM studies were completed using a 4.2-mm-outer diameter solid-state assembly with 36 circumferential pressure sensors at 1-cm intervals and 18 impedance segments at 2-cm intervals (Medtronic, Shoreview, MN). The HRIM assembly was placed transnasally and positioned to record from the hypopharynx to the stomach with approximately three intragastric pressure sensors. The HRIM protocol included a 5-min baseline recording and 10 5-ml swallows in a supine position using 50% saline for test swallows at 20- to 30-s intervals. Additionally, a multiple-rapid swallow (MRS) sequence involving five 2-ml swallows at 2- to 3-s intervals was included to assess the integrity of deglutitive relaxation.
Manometry studies were analyzed using ManoView version 3.0 analysis software to measure basal EGJ pressure at end expiration, the integrated relaxation pressure (IRP), distal contractile integral (DCI), and distal latency (15, 26). Esophageal motility diagnoses were determined from the 10 supine swallows according to the Chicago Classification version 3.0, using a median IRP of 15 mmHg as the upper limit of normal (15). Thus, a median IRP >15 mmHg was considered manometric EGJ outflow obstruction. Although the Chicago Classification was designed and intended for patients without previous surgery, we also applied it to the postfundoplication cohort to describe their motility patterns. Premature contractility was considered if ≥20% of swallows had a distal latency of <4.5 s. Hypercontractility was considered if ≥20% of swallows had a DCI >8,000 mmHg·s·cm. The MRS sequence was analyzed for deglutitive inhibition. Impaired deglutitive inhibition was designated if a contraction segment with isobaric contour >20 mmHg, >3 cm in length, and DCI >100 mmHg·s·cm was present during the course of the MRS (4).
Functional lumen imaging probe.
The FLIP assembly consisted of a 240-cm-long 3-mm-outer diameter catheter with an infinitely compliant balloon (up to a distension volume of 60 ml) mounted on the distal 18 cm of the catheter (EndoFLIP; Crospon, Galway, Ireland). The balloon tapered at both ends to assume a 16-cm-long cylindrical shape in the center that housed 17 impedance planimetry ring electrodes spaced at 1-cm intervals and a solid-state pressure transducer positioned at the distal end to provide simultaneous measurement of 16 channels of luminal diameters (based on the assumption of circular lumen cross sections) and intraballoon pressure. Measurements from the impedance planimetry electrode pairs and the pressure transducer were sampled at 10 Hz with the data acquisition system and transmitted to the recording unit.
The endoscope was withdrawn before initiation of the FLIP panometry protocol. The FLIP was calibrated to atmospheric pressure before transoral probe placement. The FLIP was positioned within the esophagus such that one to three impedance sensors were beyond the EGJ as evidenced by a visible “waist” in the impedance planimetry segment at a balloon distension volume of 20–30 ml. FLIP assembly position was maintained by the endoscopist throughout the study. Simultaneous diameters and intraballoon pressure measurements were obtained during 10-ml stepwise distensions beginning with 20 ml and increasing to target volume of 70 ml. Each stepwise distension volume was maintained for 20–30 s during a single distension protocol for each patient.
FLIP data, including distension volume, intraballoon pressure, and 16 channels of luminal diameter for each subject, were subsequently exported to MATLAB (The Math Works, Natick, MA) for analysis using a customized MATLAB program (20). Interpolation between channels was applied to generate color-coded panometry plots. The program identified the EGJ-midline by searching for the minimal diameter of the distal impedance planimetry channels. The EGJ-distensibility index (EGJ-DI) was calculated by measuring the narrowest EGJ cross-sectional area (CSA) and intraballoon pressure at each data sample obtained during the time course at the 60-ml distension volume and then dividing median values (EGJ-DI = median CSA/median pressure; mm2/mmHg) (25). An EGJ-DI <2.8 mm2/mmHg was considered abnormal based on previously reported asymptomatic controls, indicative of a FLIP-EGJ outflow obstruction (5, 8).
Esophageal body contractions were identified by a transient decrease of ≥5 mm in the luminal diameter in two or more adjacent impedance planimetry channels of the panometry plots and 16-channel-diameter tracing output (5, 8, 9). Contractions were categorized as antegrade or retrograde based on a tangent line placed at the onset of contraction. Contractions were considered repetitive (RACs or RRCs) when three or more occurred consecutively. The presence of RACs and RRCs was not mutually exclusive; thus, both could be present in a single patient over the course of the FLIP study.
Statistical analysis.
Values are expressed as median [interquartile range (IQR)], unless otherwise specified. Groups were compared using Χ2 or Mann-Whitney U-tests for categorical and continuous variables, respectively. Logistic regression was used to examine the relationships between RRCs and clinical variables, including esophageal outflow obstruction and spastic HRM features. Analyses assumed a 5% level of statistical significance.
RESULTS
Patients.
Thirty two patients with dysphagia after Nissen fundoplication (ages 19–77 yr; 59% female) and 25 patients with type III achalasia (ages 19–85 yr; 28% female) were included. An additional three patients were excluded for technical malfunctions (2 with FLIP, 1 with HRM). Fundoplication patients were more frequently female (P = 0.031) compared with achalasia patients (Table 1). Fundoplication patients were evaluated at a median (IQR) of 53 (15–125), range 2–235, mo after their most recent fundoplication; seven patients had undergone more than one Nissen fundoplication. Fundoplication was initially performed primarily for hiatal hernia repair in 12 (38%) patients and for reflux symptoms in 20 (62%) patients. Eight (25%) fundoplication patients had their most recent fundoplication performed at Northwestern; the remainder (75%) was performed externally.
Table 1.
Patient characteristics
| Characteristic | Postfundoplication | Type III Achalasia |
|---|---|---|
| n | 32 | 25 |
| Age, yr, mean ± SD | 53 ± 17 | 61 ± 15 |
| Sex, female, n (%) | 19 (59) | 7 (28)* |
| Primary indication for evaluation, n (%) | ||
| Dysphagia | 27 (84) | 22 (88) |
| Chest pain | 5 (16) | 3 (12) |
| Chronic opiate use, n (%) | 7 (22) | 7 (28) |
| Symptom scores | ||
| Completed questionnaires, n (%cohort) | 29 (91) | 19 (76) |
| BEDQ, median (IQR) | 18 (12–25) | 21 (10–28) |
| GERDQ, median (IQR) | 8 (5–12) | 8 (7–10) |
| Endoscopy | ||
| Midazolam, mg, median (IQR) | 6 (4–8) | 6 (4–8) |
| Fentanyl, µg, median (IQR) | 125 (100–175) | 125 (88–175) |
| Propofol, n (%) | 6 (19) | 4 (16) |
| High-resolution manometry | ||
| Basal EGJ pressure, mmHg, median (IQR) | 19 (8–28) | 25 (20–39)* |
| Median IRP, mmHg, median (IQR) | 14 (9–21) | 25 (20–39)* |
| Motility classification, n (%)* | ||
| Type III achalasia | 0 | 25 (100) |
| EGJ outflow obstruction | 11 (34) | |
| Hypercontractile esophagus | 1 (3) | |
| Absent contractility | 2 (6) | |
| Ineffective esophageal motility | 7 (22) | |
| Normal motility | 11 (34) |
n, No. of patients; BEDQ, Brief Esophageal Dysphagia Questionnaire; GERDQ, Gastresophageal Reflux Disease Questionnaire; IQR, interquartile range; EGJ, esophagogastric junction; IRP, integrated relaxation pressure.
P < 0.05 compared with fundoplication.
On endoscopy, the fundoplication was characterized as intact in 18 (56%) and at least partially disrupted in 14 (44%) patients. Hiatal hernia was observed in 10 (32%) fundoplication patients [axial in 6 (19%) and paraesophageal in 4 (13%)]. Two (8%) patients with achalasia had small hiatal hernias. Erosive esophagitis was observed in three fundoplication patients (two LA-A and one LA-B), and nondysplastic short-segment Barrett’s esophagus was observed in one fundoplication patient. None of the achalasia patients had erosive esophagitis or Barrett’s. Sedation dosages and utilization were similar between patients with fundoplication and achalasia (Table 1).
Esophagrams were available in 25 (78%) fundoplication patients and 21 (84%) patients with achalasia. Delayed barium clearance was observed in eight (32% of patients with esophagrams) fundoplication patients and a 12.5-mm barium tablet had delayed passage at the EGJ in 7/20 (35%) esophagrams in which a barium tablet was used. Thus, radiographic EGJ outflow obstruction was observed in 12/25 (48%) of the postfundoplication patients (38% of total fundoplication cohort). Delayed barium clearance was observed in 17 (81%) achalasia patients with esophagrams and delayed passage of a 12.5-mm barium tablet in 4/5 (80%) esophagrams in which a barium tablet was used, yielding an EGJ outflow obstruction in 18/21 (86%) patients with achalasia (72% of the total achalasia cohort).
High-resolution manometry.
Manometric EGJ outflow obstruction was diagnosed among 34% of the fundoplication patients on HRM; none of the postfundoplication patients met manometric criteria for achalasia (Table 1). Peristaltic patterns observed among the fundoplication patients with EGJ outflow obstruction included hypercontractile esophagus in three (25%), ineffective esophageal motility in one (8%), and normal peristalsis in the remaining seven (58%). An MRS sequence was successfully completed in 23 (72%) fundoplication patients. Among these, impaired deglutitive inhibition was observed in four (17%) (Fig. 1). None of the fundoplication patients had premature contractility, but a total of eight (25%) had either impaired inhibition on MRS (n = 4) or hypercontractility (n = 4). Rapid contractions (defined by a contractile front velocity >9 cm/s in ≥20% of swallows) with normal distal latency were not observed among any patients with fundoplication (2, 27). HRM studies completed before fundoplication were available in six patients: motility diagnoses included normal contractility in five and ineffective esophageal motility in one (15).
Fig. 1.
Repetitive, retrograde contractions (RRCs). High-resolution manometry (left; 1 supine swallow and multiple-rapid swallow sequence) and functional luminal imaging probe (FLIP) topography (right) of a patient with postfundoplication dysphagia (A) and type III achalasia (B) are displayed. Premature contractility [i.e., distal latency (DL) <4.5 s] was only observed in the achalasia patient, but inhibition was impaired during multiple-rapid swallows (i.e., contraction present: within white dashed circles) on both patients. RRCs were present on both FLIP topographies, whereas the type III achalasia patient also had RRCs (B). Esophageal outflow obstruction was present on manometry and FLIP for both patients. EGJ-DI, esophagogastric junction distensibility index; IRP, integrated relaxation pressure. Figure used with permission from the Esophageal Center at Northwestern.
Consistent with diagnostic criteria, all 25 patients with type III achalasia had manometric EGJ outflow obstruction and premature contractility on HRM. Six (24%) also exhibited hypercontractility. An MRS sequence was successfully completed in 17 (68%) achalasia patients. Among these, impaired deglutitive inhibition was observed in seven (41%).
FLIP panometry.
Median (IQR) EGJ-DI was 3.5 (1.6–5.9) mm2/mmHg among the fundoplication patients; FLIP-EGJ outflow obstruction was observed in 12 (38%). Median EGJ-DI was less, 0.78 (0.42–1.0) mm2/mmHg, and FLIP-EGJ outflow obstruction was more frequent (100%) among type III achalasia patients than in postfundoplication patients (P < 0.001). Radiographic-, manometric-, or FLIP-defined EGJ outflow obstruction was observed in 21 (67%) fundoplication patients (P = 0.001 compared with achalasia).
RRCs were observed in 8 (25%) fundoplication patients and 19 (76%) type III achalasia patients (P < 0.001) (Fig. 1). RACs were observed in 19 (59%) fundoplication patients and 11 (44%) type III achalasia patients (P = 0.293). RRCs and RACs were both present in three (9%) fundoplication patients and nine (36%) achalasia patients. Contractility without repetitive contractions was observed in six (19%) fundoplication patients, whereas distension-induced contractility was absent in two (6%). The remaining four (16%) achalasia patients had contractility without repetitive contractions; none of the type III achalasia patients had absent contractility.
Predictors of RRCs.
RRCs were more commonly observed among type III achalasia patients than postfundoplication patients, i.e., groups uniformly with or without premature contractility. Fifteen postfundoplication patients (47% of the cohort) met our a priori concept, i.e., with EGJ outflow obstruction (by HRM, FLIP, or esophagram) but without impaired deglutitive inhibition or hypercontractility on HRM; only one (7%) had RRCs. Table 2 summarizes the clinical data among the eight fundoplication patients with RRCs. Of the 21 fundoplication patients with an EGJ outflow obstruction, 6 (29%) had RRCs. Hiatal hernia was present in 3/8 (38%) fundoplication patients with RRCs and 7/24 (29%) of fundoplication patients without RRCs (P = 0.681). Among the four fundoplication patients with impaired deglutitive inhibition on MRS, three exhibited RRCs; conversely, 3/6 fundoplication patients with RRCs that completed MRS had impaired deglutitive inhibition. Additionally, among the four fundoplication patients with hypercontractility, two had RRCs. Regression analysis found that features of impaired inhibition (impaired deglutitive inhibition on MRS ± hypercontractility) were the only factors associated with RRCs in the postfundoplication cohort (Table 3). Because alternate thresholds for outflow obstruction might be considered among patients following fundoplication, both IRP and EGJ-DI were also evaluated as continuous variables without significant associations with RRC presence detected. Furthermore, an IRP threshold of 24.4 mmHg was previously reported as the 95th percentile among asymptomatic postfundoplication patients (33). Five (16%) postfundoplication patients had a median IRP >24.4 mmHg, but, with the use of this threshold, neither HRM-EGJ outflow obstruction, odds ratios (95% confidence intervals) 1.4 (0.13–14.7), nor EGJ outflow obstruction defined by any method, 2.5 (0.42–15.2), were significantly associated with RRC presence.
Table 2.
Postfundoplication patients with repetitive retrograde contractions
| Age, yr | Sex | Hiatal Hernia | Months Since Fundoplication | Median IRP, mmHg | EGJ-DI, mm2/mmHg | Radiographic Outflow Obstruction* | Any Outflow Obstruction? | HRM Hypercontractile | MRS-Inhibition | Spastic HRM Features?† |
|---|---|---|---|---|---|---|---|---|---|---|
| 21 | M | Yes | 27 | 8 | 2.9 | No | No | No | Defective | Yes |
| 51 | M | Yes | 91 | 14 | 2.9 | Yes | Yes | No | Defective | Yes |
| 72 | M | No | 194 | 23 | 1.1 | NA | Yes | No | Defective | Yes |
| 60 | F | No | 179 | 15 | 0.6 | Yes | Yes | Yes | Intact | Yes |
| 70 | F | No | 15 | 30 | 1.6 | No | Yes | Yes | NA | Yes |
| 75 | F | Yes | 186 | 18 | 3.8 | No | Yes | No | NA | No |
| 44 | F | No | 3 | 15 | 2.2 | No | Yes | No | Intact | No |
| 38 | M | No | 26 | 8 | 4.6 | NA | No | No | Intact | No |
M, male; F, female; EGJ-DI, esophagogastric junction-distensibility index; HRM, high-resolution manometry; MRS, multiple-rapid swallows; NA, not available.
Esophagram with delayed passage of liquid barium or 12.5 mm barium tablet.
HRM with defective inhibition on MRS or hypercontractility.
Table 3.
Regression analysis of factors associated with RRCs among postfundoplication patients
| Univariate |
||
|---|---|---|
| Predictor of RRCs | OR | 95% CI |
| Age | 1.00 | 0.96–1.1 |
| Sex, male | 1.7 | 0.33–8.4 |
| Opiate use | 0 | 0 |
| Midazolam dosage | 0.99 | 0.77–1.3 |
| Fentanyl dosage | 1.01 | 0.99–1.02 |
| Propofol use | 1.7 | 0.24–11.4 |
| Hiatal hernia | 1.5 | 0.27–7.8 |
| Integrated relaxation pressure† | 1.04 | 0.94–1.16 |
| EGJ distensibility index† | 0.67 | 0.43–1.05 |
| EGJ outflow obstruction | ||
| HRM | 1.5 | 0.27–7.8 |
| FLIP | 0.50 | 0.10–2.5 |
| Esophagram‡ | 0.45 | 0.07–3.1 |
| Any method | 1.8 | 0.30–10.9 |
| Impaired inhibition* | ||
| a) Impaired inhibition on MRS§ | 16.0 | 1.2–210 |
| b) Hypercontractility | 3.7 | 0.42–32 |
| a or b | 11.7 | 1.8–76 |
RRC, repetitive retrograde contraction; OR, odds ratio; CI, confidence interval; FLIP, functional lumen imaging probe.
n = 25.
n = 23.
Premature contractility was not observed in any of the postfundoplication patients.
Included as continuous variable.
None of the fundoplication patients with RRCs were on chronic opiates, and endoscopic sedation dosing or propofol use did not appear related to RRC presence (Table 3). Five of 19 (26%) achalasia patients with RRCs and 2/6 (33%) achalasia patients without RRCs were on opiates, P = 0.99. Endoscopic sedation dosing or propofol use did not appear related to RRC presence among the achalasia patients with odds ratios (95% confidence intervals) of 0.70 (0.46–1.1) for midazolam dosage, 0.98 (0.97–1.00) for fentanyl dosage, and 0.94 (0.08 –11.2) for propofol use.
DISCUSSION
RRCs elicited in response to volumetric distension of the distal esophagus during FLIP panometry represent a novel esophageal motility pattern. The observation that RRCs most frequently occurred in type III achalasia suggested that they were a manifestation of either the associated esophageal outflow obstruction or premature contractions (i.e., impaired deglutitive inhibition) defining that entity (5, 8). In this investigation, we applied FLIP panometry to another model of esophageal outflow obstruction, patients with postfundoplication dysphagia, to ascertain whether or not RRCs occurred with outflow obstruction not associated with premature contractions. Our major findings were that RRCs did, indeed, occur in postfundoplication patients but that they were rarely observed in these individuals without an associated HRM finding indicative of neural imbalance favoring excitation.
The aboral propagation of esophageal peristalsis is thought to result from a neural gradient in the myenteric plexus with inhibitory (nitrergic) innervation progressively dominant over excitatory (cholinergic) innervation in the more distal esophagus (12). Inhibitory innervation delays the onset of smooth muscle contraction during peristalsis, and impaired inhibitory innervation alters the timing of peristalsis, resulting in more rapidly propagated contractions with reduced latency in the distal esophagus (1). That seminal observation of Behar and Biancani was incorporated in the interpretation of HRM studies by using the metric of distal latency to define premature (spastic) contractions, a required criterion for type III achalasia and distal esophageal spasm (1, 15, 27). However, in the current study, none of the postfundoplication patients exhibited premature contractions. Hence, although the observation that RRCs occurred more frequently in type III achalasia than in postfundoplication dysphagia patients supports the hypothesis of impaired inhibitory innervation as an underlying mechanism, the occurrence of RRCs in a substantial subset of postfundoplication patients suggests additional mechanisms.
Hypercontractility, i.e., overly vigorous peristalsis as defined in HRM by a DCI >8,000 mmHg·s·cm, is hypothesized to result from an imbalance in esophageal innervation with excitatory (cholinergic) excess (16, 18, 28). Hypercontractility can occur as a primary disorder (jackhammer esophagus) or secondary to mechanical outflow obstruction (3, 15, 21, 26). We previously reported RRCs in three out of three patients with jackhammer esophagus (5). However, hypercontractility in the postfundoplication cohort more closely resembles the experimental model of induced esophageal outflow obstruction by ligature or compression ring, which also resulted in simultaneous contractions and radiographically observed retrograde contractions (3, 21, 22, 24, 30). Retrograde contractions are occasionally observed on manometry in patients with and without achalasia; however, retrograde esophageal contractions are infrequently reported in previous studies, and their significance, if any, is not well delineated. Retrograde contractions (or components of the contractile pressure wave) were reported among patients with spastic and nonspastic achalasia and among patients with esophageal hypercontractility (10, 17, 32). Overall, the clinical or functional significance of these retrograde contractile features on manometry was not clear, although the authors postulated that these retrograde contractions were related to an impairment of esophageal innervation (e.g., inhibitory and excitatory imbalance). Yet another HRM finding potentially indicative of a neural imbalance with excitatory excess is of impaired deglutitive inhibition during MRS. Presumably, the cholinergic excess overwhelms the nitrergic inhibition, stimulating contraction in what should be a refractory period. Such impaired deglutitive inhibition was observed in three of eight postfundoplication patients with RRCs. Hence, in total five out of eight postfundoplication patients with RRCs had HRM evidence of an imbalance in ganglionic input with excitatory excess.
Among the 32 postfundoplication patients studied, 15 fulfilled our conceptual model of outflow obstruction without associated HRM motility abnormalities indicative of neuromuscular imbalance. Notable, only one (7%) of these had RRCs. In regression analysis, HRM findings associated with neuromuscular imbalance (i.e., impaired deglutitive inhibition and hypercontractility), but not EGJ outflow obstruction, were associated with RRCs. Therefore, the emerging picture is that RRCs are associated with “spastic-type” motility of the distal esophagus manifest either as impaired nitrergic input with premature contractions as in type III achalasia or with augmented cholinergic input with hypercontractility and/or impaired deglutitive inhibition as in jackhammer esophagus. Thus, although RRCs have been observed infrequently among other patient cohorts, ultimately, RRCs appear to be an abnormal finding indicative of either a primary motor disorder or a secondary response to other stimuli (5–8).
Whereas our study supports the role of ganglionic neural imbalance as the primary underlying mechanism of RRCs, it has important limitations. First and foremost, we infer pathophysiology from HRM findings, which is necessarily speculative, as is often the case in the evaluation of esophageal disease, given the rarity of having the necessary tissue for direct neurohistology. Second, although abnormal distal latency is considered a specific finding for impaired deglutitive inhibition (1, 27), we complemented our manometric evaluation by also assessing for deglutitive inhibition during MRS (11, 19, 29). However, although abnormal inhibition on MRS was not consistently observed among type III achalasia as expected (41% of our cohort), it was observed at a similar frequency as a previous study evaluating MRS in type III achalasia (31% of 16 patients) (19). Distal esophageal spasm is another esophageal motility disorder defined by abnormal distal latency on HRM; however, sufficient FLIP evaluation of patients with distal esophageal spasm is presently limited by the rarity of this disorder (27). Furthermore, the potential of esophageal motility changes related to the sedation agents used for endoscopy, particularly the opioid fentanyl, is worth acknowledging. Although future study is warranted to better address the effects of sedating agents on FLIP parameters, sedation dosages or agents were not associated with differences in FLIP contractile patterns observed in this or our previous studies using similar methods (5). Finally, esophageal manometry completed before fundoplication was not uniformly available, often because of the external or remote completion of an initial fundoplication, which limits our ability to assess potential preexistence of spastic motility features, as opposed to the more likely secondary effect of a chronic obstruction associated with the fundoplication.
In conclusion, RRCs are a distinct contractile pattern observed on FLIP panometry that appear to be a manifestation of spastic-type esophageal dysmotility, i.e., impaired deglutitive inhibitory inhibition or a neural imbalance resulting in excess excitation. Further research will be needed to clarify the specific mechanisms involved, including gauging RRC response to pharmacological (i.e., nitrergic and cholinergic) manipulation. The clinical significance of RRCs across esophageal disease states also warrants additional study; however, their identification on FLIP panometry should prompt further evaluation for a major motility disorder.
GRANTS
This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant R01-DK-079902 (to J. E. Pandolfino).
DISCLOSURES
John E. Pandolfino: Crospon, Inc. (stock options), Given Imaging (Consultant, Grant, Speaking), Sandhill Scientific (Consulting, Speaking), Takeda (Speaking), Astra Zeneca (Speaking).
AUTHOR CONTRIBUTIONS
D.A.C. conceived and designed research; D.A.C. performed experiments; D.A.C., K.R., and Z.L. analyzed data; D.A.C. interpreted results of experiments; D.A.C. prepared figures; D.A.C. drafted manuscript; D.A.C., P.J.K., and J.E.P. edited and revised manuscript; D.A.C., P.J.K., K.R., Z.L., and J.E.P. approved final version of manuscript.
REFERENCES
- 1.Behar J, Biancani P. Pathogenesis of simultaneous esophageal contractions in patients with motility disorders. Gastroenterology 105: 111–118, 1993. doi: 10.1016/0016-5085(93)90016-6. [DOI] [PubMed] [Google Scholar]
- 2.Bredenoord AJ, Fox M, Kahrilas PJ, Pandolfino JE, Schwizer W, Smout AJ; International High Resolution Manometry Working Group . Chicago classification criteria of esophageal motility disorders defined in high resolution esophageal pressure topography. Neurogastroenterol Motil 24, Suppl 1: 57–65, 2012. doi: 10.1111/j.1365-2982.2011.01834.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Burton PR, Brown W, Laurie C, Richards M, Afkari S, Yap K, Korin A, Hebbard G, O’Brien PE. The effect of laparoscopic adjustable gastric bands on esophageal motility and the gastroesophageal junction: analysis using high-resolution video manometry. Obes Surg 19: 905–914, 2009. doi: 10.1007/s11695-009-9845-3. [DOI] [PubMed] [Google Scholar]
- 4.Carlson DA, Crowell MD, Kimmel JN, Patel A, Gyawali CP, Hinchcliff M, Griffing WL, Pandolfino JE, Vela MF. Loss of peristaltic reserve, determined by multiple rapid swallows, is the most frequent esophageal motility abnormality in patients with systemic sclerosis. Clin Gastroenterol Hepatol 14: 1502–1506, 2016. doi: 10.1016/j.cgh.2016.03.039. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Carlson DA, Kahrilas PJ, Lin Z, Hirano I, Gonsalves N, Listernick Z, Ritter K, Tye M, Ponds FA, Wong I, Pandolfino JE. Evaluation of Esophageal Motility Utilizing the Functional Lumen Imaging Probe. Am J Gastroenterol 111: 1726–1735, 2016. doi: 10.1038/ajg.2016.454. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Carlson DA, Kathpalia P, Craft J, Tye M, Lin Z, Kahrilas PJ, Pandolfino JE. The relationship between esophageal acid exposure and the esophageal response to volumetric distention. Neurogastroenterol Motil 2017 Dec 21. doi: 10.1152/ajpgi.00368.2017 [Epub ahead of print]. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Carlson DA, Lin Z, Hirano I, Gonsalves N, Zalewski A, Pandolfino JE. Evaluation of esophageal distensibility in eosinophilic esophagitis: an update and comparison of functional lumen imaging probe analytic methods. Neurogastroenterol Motil 28: 1844–1853, 2016. doi: 10.1111/nmo.12888. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Carlson DA, Lin Z, Kahrilas PJ, Sternbach J, Donnan EN, Friesen L, Listernick Z, Mogni B, Pandolfino JE. The Functional Lumen Imaging Probe Detects Esophageal Contractility Not Observed With Manometry in Patients With Achalasia. Gastroenterology 149: 1742–1751, 2015. doi: 10.1053/j.gastro.2015.08.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Carlson DA, Lin Z, Rogers MC, Lin CY, Kahrilas PJ, Pandolfino JE. Utilizing functional lumen imaging probe topography to evaluate esophageal contractility during volumetric distention: a pilot study. Neurogastroenterol Motil 27: 981–989, 2015. doi: 10.1111/nmo.12572. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Clouse RE, Staiano A, Alrakawi A. Topographic analysis of esophageal double-peaked waves. Gastroenterology 118: 469–476, 2000. doi: 10.1016/S0016-5085(00)70252-6. [DOI] [PubMed] [Google Scholar]
- 11.Fornari F, Bravi I, Penagini R, Tack J, Sifrim D. Multiple rapid swallowing: a complementary test during standard oesophageal manometry. Neurogastroenterol Motil 21: 718–e41, 2009. doi: 10.1111/j.1365-2982.2009.01273.x. [DOI] [PubMed] [Google Scholar]
- 12.Goyal RK, Chaudhury A. Physiology of normal esophageal motility. J Clin Gastroenterol 42: 610–619, 2008. doi: 10.1097/MCG.0b013e31816b444d. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Jonasson C, Wernersson B, Hoff DA, Hatlebakk JG. Validation of the GerdQ questionnaire for the diagnosis of gastro-oesophageal reflux disease. Aliment Pharmacol Ther 37: 564–572, 2013. doi: 10.1111/apt.12204. [DOI] [PubMed] [Google Scholar]
- 14.Kahrilas PJ, Boeckxstaens G. The spectrum of achalasia: lessons from studies of pathophysiology and high-resolution manometry. Gastroenterology 145: 954–965, 2013. doi: 10.1053/j.gastro.2013.08.038. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Kahrilas PJ, Bredenoord AJ, Fox M, Gyawali CP, Roman S, Smout AJ, Pandolfino JE; International High Resolution Manometry Working Group . The Chicago Classification of esophageal motility disorders, v3.0. Neurogastroenterol Motil 27: 160–174, 2015. doi: 10.1111/nmo.12477. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Kim HS, Park H, Lim JH, Choi SH, Park C, Lee SI, Conklin JL. Morphometric evaluation of oesophageal wall in patients with nutcracker oesophagus and ineffective oesophageal motility. Neurogastroenterol Motil 20: 869–876, 2008. doi: 10.1111/j.1365-2982.2008.01128.x. [DOI] [PubMed] [Google Scholar]
- 17.Kim TH, Patel N, Ledgerwood-Lee M, Mittal RK. Esophageal contractions in type 3 achalasia esophagus: simultaneous or peristaltic? Am J Physiol Gastrointest Liver Physiol 310: G689–G695, 2016. doi: 10.1152/ajpgi.00459.2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Korsapati H, Bhargava V, Mittal RK. Reversal of asynchrony between circular and longitudinal muscle contraction in nutcracker esophagus by atropine. Gastroenterology 135: 796–802, 2008. doi: 10.1053/j.gastro.2008.05.082. [DOI] [PubMed] [Google Scholar]
- 19.Kushnir V, Sayuk GS, Gyawali CP. Multiple rapid swallow responses segregate achalasia subtypes on high-resolution manometry. Neurogastroenterol Motil 24: 1069–e561, 2012. doi: 10.1111/j.1365-2982.2012.01971.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Lin Z, Nicodème F, Boris L, Lin CY, Kahrilas PJ, Pandolfino JE. Regional variation in distal esophagus distensibility assessed using the functional luminal imaging probe (FLIP). Neurogastroenterol Motil 25: e765–e771, 2013. doi: 10.1111/nmo.12205. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Little AG, Correnti FS, Calleja IJ, Montag AG, Chow YC, Ferguson MK, Skinner DB. Effect of incomplete obstruction on feline esophageal function with a clinical correlation. Surgery 100: 430–436, 1986. [PubMed] [Google Scholar]
- 22.Lu C, Schulze-Delrieu K, Shirazi S, Cram M, Raab J. Dynamic imaging of obstructed opossum esophagus. From altered load to altered contractility. Dig Dis Sci 39: 1377–1388, 1994. doi: 10.1007/BF02088037. [DOI] [PubMed] [Google Scholar]
- 23.Lundell LR, Dent J, Bennett JR, Blum AL, Armstrong D, Galmiche JP, Johnson F, Hongo M, Richter JE, Spechler SJ, Tytgat GN, Wallin L. Endoscopic assessment of oesophagitis: clinical and functional correlates and further validation of the Los Angeles classification. Gut 45: 172–180, 1999. doi: 10.1136/gut.45.2.172. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Mittal RK, Ren J, McCallum RW, Shaffer HA Jr, Sluss J. Modulation of feline esophageal contractions by bolus volume and outflow obstruction. Am J Physiol 258: G208–G215, 1990. doi: 10.1152/ajpgi.1990.258.2.G208. [DOI] [PubMed] [Google Scholar]
- 25.Pandolfino JE, de Ruigh A, Nicodème F, Xiao Y, Boris L, Kahrilas PJ. Distensibility of the esophagogastric junction assessed with the functional lumen imaging probe (FLIP™) in achalasia patients. Neurogastroenterol Motil 25: 496–501, 2013. doi: 10.1111/nmo.12097. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Pandolfino JE, Ghosh SK, Rice J, Clarke JO, Kwiatek MA, Kahrilas PJ. Classifying esophageal motility by pressure topography characteristics: a study of 400 patients and 75 controls. Am J Gastroenterol 103: 27–37, 2008. doi: 10.1111/j.1572-0241.2007.01532.x. [DOI] [PubMed] [Google Scholar]
- 27.Pandolfino JE, Roman S, Carlson D, Luger D, Bidari K, Boris L, Kwiatek MA, Kahrilas PJ. Distal esophageal spasm in high-resolution esophageal pressure topography: defining clinical phenotypes. Gastroenterology 141: 469–475, 2011. doi: 10.1053/j.gastro.2011.04.058. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Roman S, Kahrilas PJ. Management of spastic disorders of the esophagus. Gastroenterol Clin North Am 42: 27–43, 2013. doi: 10.1016/j.gtc.2012.11.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Savojardo D, Mangano M, Cantù P, Penagini R. Multiple rapid swallowing in idiopathic achalasia: evidence for patients’ heterogeneity. Neurogastroenterol Motil 19: 263–269, 2007. doi: 10.1111/j.1365-2982.2006.00886.x. [DOI] [PubMed] [Google Scholar]
- 30.Shirazi S, Schulze-Delrieu K. Role of altered responsiveness of hypertrophic smooth muscle in manometric abnormalities of the obstructed opossum oesophagus. Neurogastroenterol Motil 8: 111–119, 1996. doi: 10.1111/j.1365-2982.1996.tb00251.x. [DOI] [PubMed] [Google Scholar]
- 31.Taft TH, Riehl M, Sodikoff JB, Kahrilas PJ, Keefer L, Doerfler B, Pandolfino JE. Development and validation of the brief esophageal dysphagia questionnaire. Neurogastroenterol Motil 28: 1854–1860, 2016. doi: 10.1111/nmo.12889. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.van Herwaarden MA, Samsom M, Smout AJ. Prolonged manometric recordings of oesophagus and lower oesophageal sphincter in achalasia patients. Gut 49: 813–821, 2001. doi: 10.1136/gut.49.6.813. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Weijenborg PW, Savarino E, Kessing BF, Roman S, Costantini M, Oors JM, Smout AJ, Bredenoord AJ. Normal values of esophageal motility after antireflux surgery; a study using high-resolution manometry. Neurogastroenterol Motil 27: 929–935, 2015. doi: 10.1111/nmo.12554. [DOI] [PubMed] [Google Scholar]