Ineffective esophageal motility: The impact of change of criteria in Chicago Classification version 4.0 on predicting outcome after magnetic sphincter augmentation

The most recent update of the Chicago Classification (CCv4.0) attempts to provide a more clinically relevant definition for ineffective esophageal motility (IEM). The impact of this new definition on predicting outcome after antireflux surgery is unknown. The aim of this study was to compare utility of IEM diagnosis based on CCv4.0 to CCv3.0 in predicting surgical outcome after magnetic sphincter augmentation (MSA) and to assess any additional parameters that hold value in future definitions.


| INTRODUC TI ON
Ineffective esophageal motility (IEM) is an esophageal motility disorder broadly characterized by impaired esophageal body peristalsis and hypocontractility. This diagnosis is commonly associated with gastroesophageal reflux disease (GERD), affecting up to 49.4% of reflux patients. 1 However, IEM poses a challenge for clinicians due to its unclear clinical significance and inconsistent association with antireflux surgery (ARS) outcomes. [2][3][4] Since its initial description almost 30 years ago, the specific criteria used to define IEM have evolved numerous times in attempts to create a more precise diagnosis with distinct clinical relevance. 5,6 Recently, the Chicago Classification of esophageal motility disorders on high-resolution manometry (HRM) was updated from Chicago Classification version 3.0 (CCv3.0) to Chicago Classification version 4.0 (CCv4.0). One of the major changes was a revised definition of IEM. 7,8 Specifically, the new definition increased the threshold of ineffective swallows for an IEM diagnosis and added fragmented swallows to the definition of an ineffective swallow. 9 However, this was a consensus driven change in definition, and its clinical ramifications remain untested.
Magnetic sphincter augmentation (MSA) is a safe and effective ARS. This procedure was introduced in 2008 and has been widely adopted in clinical practice since its FDA approval in 2012. 10 MSA implantation raises esophagogastric junction (EGJ) resistance, which the esophageal body contractions must be able to overcome in order to prevent dysphagia. 11 As a result, patients with impaired esophageal body peristalsis and hypocontractility are more likely to develop dysphagia, which is the most common complaint after MSA. 12,13 Therefore, HRM is considered the most crucial preoperative test to identify patients with impaired esophageal motor function and to determine their candidacy for MSA. The Chicago Classification is frequently referenced to aid in the interpretation of HRM findings during this process, 14 but the impact of the recent changes in the definition of IEM in the latest edition of this classification (CCv4.0) on surgical outcomes has yet to be studied. Therefore, we designed the current study to evaluate the impact of these new criteria on predicting dysphagia after MSA and to identify any additional manometric findings which may improve the accuracy of IEM in predicting postoperative dysphagia.

| Study population
Records of patients who underwent MSA at our institution from 2013 to 2020 were reviewed. A total of 707 patients were identified. Those who completed preoperative high-resolution impedance manometry (HRIM) at our institution and had at least 1 year postoperative follow-up were included. This study was evaluated and approved by the IRB at our institution (IRB No. 2021-259).

| Preoperative assessment
All patients underwent a standardized workup consisting of esophagogastroduodenoscopy, esophageal pH monitoring HRIM, and esophagram. Patients also completed the gastroesophageal reflux disease-health related quality of life (GERD-HRQL) questionnaire, which contains questions that evaluate severity of dysphagia, odynophagia, and heartburn on a scale of 0 (best) to 5 (worst). A value of 3 or greater on question 7 "difficulty swallowing" was used to define significant dysphagia.
HRIM was performed in all participants using a solid-state assembly with 36 circumferential sensors spaced at 1-cm intervals and 19 metal rings spaced 2-cm apart to facilitate 18 impedance readings (Manoscan ESO Z Catheter; Medtronic). Patients fasted for at least 6 h prior to testing. The manometric catheter was introduced transnasally and positioned to record from hypopharynx to stomach with at least three intragastric sensors. The participant was placed in a reclined position to start the recording. Standard HRM protocol was followed, with 10 5-mL 50% saline solution swallows at 30-s intervals.
Manometric data were analyzed using the ManoView analysis software (ManoView 3.0; Medtronic). All tracings were re-analyzed for the purpose of this study by two investigators using the same procedure. Data obtained during the standard HRM protocol were analyzed in accordance with the Chicago consensus, 7,8 and patients were diagnosed accordingly. Each individual swallow was evaluated and classified as failed if DCI was <100 mm Hg or weak if DCI was between 100 and 450 mm Hg. Fragmented swallows were defined by a DCI >450 mm Hg with breaks larger than 5 cm.
Patients were classified with CCv3.0 IEM if they met a minimum threshold of 50% ineffective swallows, defined as weak or failed. 8 Patients were classified with CCv4.0 IEM if they met a threshold of 50% failed or 80% ineffective swallows, defined as weak, failed or fragmented. 7
• High-resolution manometry is used prior to antireflux surgery to identify patients with esophageal motility disorders. Bolus clearance (BC) was assessed for each individual swallow using both colored contour function of the Manoview software and impedance tracings. To determine baseline impedance, the color contrast was adjusted so that the contour showed an empty esophagus before the swallow with a peak of 0.7 kΩ. After color adjustment, BC was considered complete if colorization was followed by color disappearance and incomplete if this was not the case.

| Surgical procedure.
All procedures were performed laparoscopically with a standardized procedure. The key components of the operation were circumferential dissection of the gastroesophageal junction with mobilization of the posterior vagus nerve, assessment of the hiatus and closure if appropriate, sizing of the device, and implantation of the device at or just above the gastroesophageal junction. Device size was determined using a standardized protocol based on the manufacturer provided sizing device, which measures esophageal circumference in number of MSA beads.

| Postoperative outcomes
Postoperative outcomes were assessed at 2-week, 6-week, 6-month, and 1-year visits. Immediate dysphagia was defined as any difficulty swallowing within the first 6 weeks after surgery. Persistent dysphagia was defined as a score of 3 or more for the dysphagiaspecific item within the GERD-HRQL at 1 year following surgery.
Additional outcomes included GERD-HRQL total score, 50% reduction in GERD-HRQL score, postoperative PPI use, postoperative DeMeester score, and patient satisfaction.

| Statistical analysis
Values for continuous variables were expressed as mean and standard deviation. Values for categorical variables were presented as frequency and percentage. Descriptive analysis was applied to preoperative parameters and postoperative outcomes. Wilcoxon signed-rank test was performed to assess the change in the GERD-HRQL total score. Accuracy of CCv3.0 IEM, CCv4.0 IEM, individual esophageal body characteristics and BC in predicting postoperative immediate and persistent dysphagia was assessed in terms of sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV), respectively. Area under the ROC curve was used to assess overall predictive accuracy for immediate and persistent dysphagia with respect to each of selected predictors in a fitted logistic model. Chi-square test with one degree of freedom was performed to exam difference of area under the ROC curve among two selected predictors in predicting a dysphagia outcome. A p-value < 0.05 was considered to be statistically significant.
All statistical analyses were performed using SAS software (version 9.4, SAS Institute).

| Study population and outcome
The final study population consisted of 336 patients (63.1% female) with a mean (SD) age of 56.1 (13.3) years and mean BMI of 29.2 The accuracy tests for immediate and persistent dysphagia are compared between CCv3.0 and CCv4.0 definitions of IEM in Table 1.

| Individual manometric feature's predictive utility for postoperative dysphagia
The utility of the individual components of CCv4.0 IEM and abnormal percent BC thresholds (50% to 80%) in predicting persistent dysphagia are shown in Table 2. The individual components of CCv4.0 IEM were found to be similarly highly specific, but poorly sensitive predictors of dysphagia (p = 0.7008). For abnormal complete BC, each 10% increase in the abnormal threshold resulted in a stepwise decrease in accuracy and specificity, but an increase in sensitivity for predicting persistent dysphagia. However, the difference in accuracy tests between different thresholds of abnormal complete BC was comparable (p = 0.4371). Abnormal BC was added to the criteria that defines IEM under CCv4.0. The predicted probabilities of persistent dysphagia for both definitions of IEM, the abnormal BC thresholds, as well as the combined criteria of CCv4.0 IEM and abnormal BC at various thresholds are shown in Figure 2. When abnormal percent BC was added to the CCv4.0 criteria for IEM, there was an additive effect in the combined criteria's predicted probability.
Among abnormal BC thresholds, <70% was noted to have the highest predicted probability (17.4%), which was also higher than both definitions of IEM. Area under the ROC curve analysis showed that the addition of <70% complete BC to the criteria that define IEM   was a significant predictor of dysphagia on univariate analysis (Table 3).

| Other outcomes
The comparison of antireflux outcomes and need for additional procedures between CCv4.0 IEM and CCv3.0 IEM are shown in

| DISCUSS ION
The first definition of IEM was introduced in 1997, sparking a controversy in the diagnosis and management of this clinical entity that has continued to the present day. 15 Since the Chicago Classification with IEM and ARS is whether the patient's esophageal body will be able generate enough force to overcome the increased resistance at the EGJ. Early tenets of ARS suggested that a diagnosis of IEM should prompt a tailored fundoplication to mitigate postoperative dysphagia. 17 However, in recent years multiple studies have shown similar rates of dysphagia after partial or complete fundoplication in patients with IEM, calling into question the utility of the definition once again. 18,19 The CCv4.0 released in November 2020 included major revisions to the definition of IEM. 9 The new more stringent definition aims to better correlate with clinical symptoms. Therefore, we    26 This finding suggests that a greater contractility is required to overcome the forces at the EGJ following MSA and should be considered in preoperative planning.
Similarly, we found that a DCI <750 was a more accurate predictor of postoperative dysphagia than DCI <450, although not significant.
The 450 mmHg threshold for weak swallows was selected be-  impedance data is illustrated in Figure 3B, which demonstrates complete clearance followed by a reflux event. When there are reflux events and incomplete clearance, the residual contents affect BC in subsequent swallows. For that reason, using HRIM in preoperative planning and assessing individual swallows for both pressure and impedance data is critical in surgical planning. 32,33 To determine whether BC would improve the IEM definition, we compared ability to predict postoperative dysphagia between CCv4.0 IEM to IEM redefined as BC <70% + CCv4.0 criteria. We found that neither definition was particularly accurate in predicting postoperative dysphagia, but there was a significant improvement in accuracy when BC was included. Tutuian and Castell found similar results in their study evaluating impedance in 70 patients with IEM. 30 They found that 68% of patients had a BC >70%, suggesting an overestimation of the patients with esophageal dysfunction. 30 These findings suggest that the addition of impedance data to the criteria for IEM would narrow the definition to more precisely identify those unable to effectively transport a swallowed bolus.  HRM is a crucial test before MSA to identify patients whose esophageal body motility is inadequate to overcome the augmented LES resistance and is therefore at risk for postoperative dysphagia.
However, current and previous Chicago Classification definitions of IEM do not predict postoperative dysphagia. The addition of abnormal BC to current criteria does increase the accuracy and should be considered in future iterations of the Chicago Classification to provide a more clinically relevant diagnosis. The current definition of IEM is not significantly associated with different ARS outcomes.
Therefore, it is imperative to evaluate HRIM data as a whole and consider all aspects of contractility and BC in the surgical patient.

AUTH O R CO NTR I B UTI O N S
Margaret Riccardi involved in planning and conducting the study, collecting and interpreting data, and drafting the manuscript. This author has approved this manuscript. Sven Eriksson involved in planning and conducting the study, interpreting data, and drafting the manuscript. This author has approved this manuscript. Steven Tamesis involved in planning and conducting the study, and collecting and interpreting data. This author has approved this manuscript.
Ping Zheng involved in interpreting data and drafting the manu-

script. This author approves this manuscript. Blair Jobe and Shahin
Ayazi involved in planning and conducting the study, and drafting the manuscript. These authors have approved this manuscript.

FU N D I N G I N FO R M ATI O N
None.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.