Presence of esophageal contractility after achalasia treatment is associated with improved esophageal emptying

Some achalasia patients exhibit esophageal contractile activity on follow‐up after treatment, yet its importance remains unclear. We aimed to identify factors associated with presence of contractility after treatment and to assess its impact on timed barium esophagram (TBE) and clinical outcomes.


Conclusions & Inferences:
Occurring more frequently in type II achalasia, and if adequate EGJ opening is achieved after treatment, esophageal contractility may contribute to improved esophageal emptying and improved symptoms in non-spastic achalasia.Preservation of esophageal body muscle could improve outcomes in these patients.

| INTRODUC TI ON
Achalasia is a disease characterized by loss of function of esophageal myenteric plexus neurons, which ultimately leads to impaired relaxation of the lower esophageal sphincter (LES) and absent or spastic body contractility. 1 Typical symptoms are dysphagia, regurgitation, chest pain and weight loss. 2 Achalasia is typically diagnosed using high-resolution manometry (HRM) and applying the Chicago Classification (CC) with cardinal features being an abnormal integrated relaxation pressure (IRP) and the absence of normal body peristalsis. 3The CC further subtypes achalasia, which carries importance related to prognosis and response to achalasia treatments, based on contractility and pressurization patterns, specifically type I (absent contractility without pressurization), type II (absent contractility with panesophageal pressurization (PEP)), and type III (spastic contractions). 4 The goal of durable therapeutic interventions is the disruption of obstructive LES muscular fibers thereby facilitating bolus passage into the stomach.This can be achieved endoscopically with pneumatic dilation (PD) or peroral endoscopic myotomy (POEM), or surgically with laparoscopic Heller myotomy (LHM). 5,6ile impaired LES relaxation and spastic body contractions can be explained by loss of inhibitory nerve function, the pathophysiology of peristaltic dysfunction is still incompletely understood.
However, esophagogastric junction (EGJ) obstruction and esophageal dilatation are proposed to play a role. 1,7This, along with the observation that functional lumen imaging probe (FLIP) can detect contractility not evident on HRM in a significant number of cases, questions whether contractile function is permanently lost in all achalasia patients. 80][11][12] Excluding type III achalasia, wherein spastic contractility is already present yet in most cases intentionally abolished with a long myotomy, type II may be the subtype more likely to be associated with presence of contractile activity after treatment. 12 other physiological predictors are known to date and, most importantly, whether this phenomenon carries physiological and clinical significance also remains uncertain.It is also unclear to what degree primary and secondary contractility, as assessed on HRM and FLIP Panometry respectively, correlate with esophageal emptying on timed barium esophagram (TBE) after achalasia treatment, a clinically relevant endpoint which may also predict symptom recurrence. 13We hypothesized that contractile activity may benefit bolus clearance after LES-directed treatment in achalasia.
Therefore, aim of this study was to identify factors associated with the presence of contractile activity after achalasia treatment, and to assess its impact on clinical outcomes and esophageal emptying on TBE.

| ME THODS
We retrospectively interrogated a database of adult patients (ages 18-89 years) evaluated at the Esophageal Center of Northwestern from 2012 to 2022.Consecutive patients who had pre-treatment HRM and, after treatment, HRM, FLIP, and TBE were identify as eligible for inclusion.Treatment modalities could be PD, LHM, or POEM (only standard-length myotomy [9 cm total] was allowed).Patients in which the pre-treatment HRM achalasia subtype could not be determined (according to the available records), with type III achalasia, or treated with long myotomy were also excluded.As the focus of this study was on the impact of esophageal contractility after achalasia treatment, subgroup analysis of patients with both post-treatment IRP <15 mmHg on HRM and normal EGJ opening on FLIP was performed.
The standard follow-up after achalasia treatment was for patients to complete endoscopy with FLIP, HRM, TBE, and symptom scores at 6-12 months after treatment (or earlier if symptoms persist or recur).However, patients that completed testing outside of this window were also included (actual time to follow-up testing was assessed).

The study protocol was approved by the Northwestern
University Institutional Review Board.There is partial overlap of this patient cohort with previous publications. 14,15E Y W O R D S achalasia, contractility, esophagram, manometry, outcome

Key points
• In a retrospective study of 122 treated patients with non-spastic achalasia, contractile activity, defined by a CC v4.0 criterion (≥10% swallow with DCI ≥100 mmHg s cm), was observed in 50% of patients during follow-up HRM.
• Baseline HRM diagnosis of type II achalasia and normal EGJ opening on follow-up FLIP were associated with contractility after treatment.Barium retention on posttreatment TBE was significantly less in patients with post-treatment contractility than without.In patients with residual physiological features of EGJ obstruction, contractility was also associated with significantly improved symptoms.
• Esophageal body contractile function emerges as relevant factor in determining achalasia treatment outcomes.Sparing of esophageal muscle with tailored myotomy may be beneficial.

| HRM protocol and analysis
HRM studies were completed after a 6-h fast using a 4.2-mm outer diameter solid-state assembly with 36 circumferential pressure sensors at 1-cm intervals (Medtronic, Shoreview, MN).The HRM assembly was placed transnasally and positioned to record from the hypopharynx to the stomach with approximately three intragastric sensors.After a 2-min baseline recording, the HRM protocol was performed with 10, 5-mL liquid swallows in a supine position and with five, 5-mL liquid swallows in an upright, seated position.
On pre-treatment HRM, diagnosis of type I or II achalasia was confirmed based on CC v4.0 criteria. 3Additionally, panesophageal pressurization (PEP) values were evaluated, namely assessing: (1)   minimum PEP pressure, defined as the pressure within the first break in the isobaric contour of the strongest PEP; (2) maximum PEP pressure, defined as the maximum pressure within the strongest PEP.
Although the CC was intended for patients without previous surgery, we utilized CC v4.0 criteria to facilitate standardized interpretation of post-treatment motility patterns. 3All exams were manually reviewed using a commercially available software (ManoView, Medtronic).The IRP was measured for the 10 supine swallows and the median values were applied.The distal contractile integral (DCI) was calculated for the 10 supine swallows using the smart box tool with the isobaric contour set at 20 mmHg.Median DCI was calculated if there was at least one swallow with DCI >100 mmHg s cm; failed swallows (DCI <100 mmHg s cm) were not included in the median DCI calculation.The median DCI was, by definition, 0 mmHg s cm in patients with absent contractility.Contractility in each swallow was defined as absent (DCI <100 mmHg s cm), weak (DCI 100-450 mmHg s cm), normal (DCI >450 mmHg s cm and evidence bolus propulsion on impedance if this was available), fragmented (DCI >450 mmHg s cm with large peristaltic break >5 cm) or premature (distal latency [DL] <4.5 s and DCI >450 mmHg s cm).The contractility pattern was defined as absent if 100% swallows were failed, ineffective if >70% swallows were ineffective (weak or fragmented) or ≥50% were failed, spastic if ≥20% swallows were premature, and otherwise as normal. 3e primary endpoint of contractile activity was defined on post-treatment HRM as presence of at least one swallow with DCI ≥100 mmHg s cm (i.e., <100% failed swallows) out of the 10 carried out in the supine part of the CC v4.0 protocol.

| FLIP protocol and analysis
The FLIP study using the 16-cm FLIP probe (EndoFLIP® EF-322N; Medtronic, Inc, Shoreview, MN) was performed during sedated endoscopy as previously described. 16The FLIP catheter was positioned across the EGJ with 2-3 channels maintained distal to the EGJ, while the FLIP study protocol was performed with stepwise 10-mL distensions up to 70 mL with each distension volume maintained for 60 sec.
The FLIP Panometry plots were created and analyzed using a customized program (available open source at http:// www.wklyt ics.com/ nmgi) and were interpreted while being blinded to the clinical history, associated HRM, and endoscopy results.FLIP Panometry motility parameters and classifications of contractile response patterns were defined as previously described. 16,17The contractile response (CR) pattern was assigned based on the patterns of contractility that occurred during the 50, 60, and 70 mL fill volumes. 17rmal contractile response (NCR) was defined as repetitive anterograde contractions (RACs) while borderline contractile response (BCR) demonstrated anterograde contractions not meeting criteria for RACs.Spastic-reactive contractile response (SRCR) was defined as presence of sustained occluding contractions (SOCs), and/or sustained lower esophageal sphincter contractions (sLESCs) and/ or repetitive retrograde contractions (RRCs).Impaired/disordered contractile response (IDCR) was defined as not having distinct anterograde contractions and without spastic features.Lastly, absent contractile response (ACR) was defined as no contractile activity.
The median FLIP pressure recorded during the 60 sec of the study protocol at a 60 mL fill volume was also assessed for analysis.

| TBE protocol and analysis
During timed barium esophagram, patients were in the upright position and consumed 200 mL of low-density barium sulfate with images obtained at 1 and 5 min.The height of the barium column was measured vertically from the EGJ.Patients without a barium column at 1 or 5 min were defined as having a height of 0 cm.Adequate esophageal emptying was defined as having a 5-min column height <5 cm. 13 Esophageal body width was defined as the maximum esophageal transverse diameter as measured throughout the study protocol.

| Symptomatic outcomes
Most subjects completed validated self-reported symptom scores at the time of testing with FLIP and HRM, including the Eckardt score (ES). 20Because some patients chose not to complete the symptom questionnaires scores were not available for all subjects.The ES obtained at follow-up after treatment was applied as the measure of clinical treatment outcome.The ES includes four 4-point Likert scale questions (scored 0-3) that assess the frequency of dysphagia, chest pain, and regurgitation and the degree of weight loss, with items summed to yield a score of 0-12.Treatment success was defined as ES ≤3.

| Statistical analysis
Results were reported as mean (standard deviation; SD) or median (interquartile range; IQR) depending on the data distribution.
Groups were compared with the Chi-square/Fisher test for categori-

| Subjects
Of 198 patients who had post-treatment HRM, FLIP, and TBE available for evaluation, a total of 122 patients were included in the study (Figure 1) after exclusion of 14 patients with type III achalasia and 62 patients with unspecified HRM subtype.Mean age (SD) was 48 (17) years; 61 (50%) were males (Table 1).Pre-treatment subtype was type II achalasia in 86 (70%) patients.The most frequent treatment modality was POEM, utilized in 66 (54%) patients, while 29 patients were treated with PD (24%) and 27 with LHM (22%).Posttreatment motility evaluation was completed at a median (IQR) 13 (8-23) months after treatment.had a pre-treatment diagnosis of type II achalasia (p = 0.001) than patients without contractility (Table 1).Median panesophageal pressurization minimum (p = 0.168) and maximum (p = 0.054) values trended to be greater in patients with contractile activity.

| Contractile activity and FLIP results
In patients with post-treatment contractile activity on HRM, median 60 mL pressure was significantly greater (p = 0.026), while the frequency of patients with absent contractile response (ACR) was significantly less, than in patients without contractility (p = 0.007); Table 2.

| Relationship between EGJ obstruction, esophageal width, and contractile activity
Among the entire cohort (N = 122), median IRP did not differ (p = 0.157) between patients with or without post-treatment contractile activity (Table 2).However, patients with contractile activity (compared to those without contractility) more frequently had a normal/borderline-normal EGJ opening (p < 0.001) and less frequently had reduced/borderline-reduced EGJ opening (p < 0.001, Table 2).
To assess the impact of post-treatment contractile activity on clinical outcomes independently of EGJ obstruction, we performed subgroup analysis in patients with normal EGJ metrics (i.e., excluding 19 patients with IRP > 15 mmHg and 50 patients with reduced, borderline-reduced or borderline-normal EGJ opening (REO = 8, BrEO = 18, and BnEO = 24) on FLIP Panometry, Figure 1).In this subgroup with normal EGJ metrics (n = 53), 33 (62%) patients had contractile activity.Among the entire cohort, esophageal body was narrower in patients with contractile activity than without (p < 0.001), while there was a non-significant numeric difference in the subgroup with normal EGJ metrics (p < 0.282, Table 2).Furthermore, the median DCI differed between strata of esophageal body width, as patients with esophageal body diameter <3 cm showed greater DCI than patients with esophageal body width 3-5 cm or >5 cm (p = 0.004, Figure 2).
A similar trend, though not significant (p = 0.106), was found in the subgroup with normal EGJ metrics (Table 2).
In terms of FLIP contractile response patterns, patients without contractility on post-treatment HRM trended toward an ACR pattern (35% vs 15%, p = 0.094) which was also the case in the subgroup with normal EGJ metrics.

| Impact of contractile activity on esophageal emptying and symptoms in the subgroup with normal EGJ metrics
On follow-up TBE, subgroup analysis showed that in the subgroup with normal EGJ metrics (n = 53), patients with contractility on HRM (33/53, 62%) had a lower column height both at 1 min (p = 0.002) and 5 min (p = 0.001) than patients without contractility.They also more frequently showed a 5-min column height <5 cm (p = 0.006) than patients without contractility (Figure 3, Table 2).Furthermore, patients without contractility had greater 1-min (p = 0.009) and 5-min column heights (p = 0.005) than patients with median DCI 100-450 mmHg s cm and DCI >450 mmHg s cm (Figure 4).Specifically, patients with a post-  2).

| Impact of contractile activity on esophageal emptying and symptoms in the subgroup with abnormal EGJ metrics
In the subgroup with abnormal EGJ metrics (n = 69), contractility on HRM (found in 28/69 patients, 41%) remained associated with a lower column height at 5 min (p = 0.004), but not at 1 min (p = 0.09) (Figure 4).Patients with contractility also more frequently showed a 5-min column height <5 cm (p = 0.006) than patients without (Table 2).
Conversely, in this subgroup patients with contractile activity showed a significantly lower median Eckardt score (p = 0.03) than those without, and also the percentage of patients with Eckardt score ≤3 was almost significantly higher (p = 0.054, Table 2).

| DISCUSS ION
In this retrospective study of 122 treated patients with non-spastic achalasia, we demonstrated that contractile activity, defined using a CC v4.0 criterion (i.e., <100% failed swallows) is found in 50% of patients on follow-up HRM.We also found that contractility after treatment is more likely to occur if treatment achieves adequate EGJ opening, while conversely, residual EGJ obstruction was associated with absence of body contractility.Most importantly, we found that post-treatment contractile activity was associated with improved esophageal emptying; column heights on follow-up TBE were signifi- These results suggest that esophageal body contractile function may be an underappreciated factor in determining achalasia treatment outcome (Figure 6).The present study, facilitated by a rigorous, comprehensive evaluation of esophageal function including HRM, FLIP, and TBE, is the first (to the best of our knowledge) to demonstrate a significant association between post-treatment contractile activity and the objective clinical outcome of esophageal emptying on TBE.Given the potentially disruptive impact of myotomy on esophageal contractility (especially extended myotomy with POEM), recognition of this aspect of function in achalasia could have significant implications for appropriate treatment planning in achalasia.
0][11][12] However, there is variability on how contractility is defined across studies.A recent study defined "peristaltic recovery" as presence of at least 3 cm isobaric contour integrity of 20 mmHg distal to the transition zone; a threshold of peristaltic vigor of uncertain relevance. 12,21In an attempt to quantify contractile strength, we used the CC v4.0 thresholds to define post-treatment contractility on HRM.These criteria are widely applied and based on thresholds for adequate bolus clearance. 22,23is approach enabled us to demonstrate associations with an important objective clinical outcome of retention on TBE, which is an independent outcome measure from HRM or FLIP.0][11][12] Our group previously showed that a subset of type II achalasia patients with high panesophageal pressurization values and FLIP pressures may exhibit post-treatment spasm, though the clinical outcomes did not seem worse in this subgroup. 15However, our novel findings demonstrate an association with improved esophageal emptying and, in patients with persistent EGJ obstruction, improved symptoms, thus suggesting that contractile activity may be a significant factor for treatment outcomes.Moreover, there may be potential for exploring the clinical relevance of secondary contractile activity measured on FLIP Panometry as we demonstrated a trend in terms of improved clinical outcomes in patients who showed some degree of contractile response (IDCR/BCR/SRCR) compared to those without (ACR).
Our findings also suggest that esophageal contractile function is not permanently lost in all achalasia patients.Indeed, some of these patients with achalasia without apparent contractility prior to treatment (i.e., type I and type II achalasia) may have preservation of some degree of esophageal body neuromuscular integrity, which may reflect an earlier stage of achalasia.This implies that if an unnecessarily extended myotomy was performed, it could carry the potential for harm if they disrupt functional esophageal muscle.In addition, there is added potential for harm as a result of longer myotomy creating a locus minoris resistentiae where esophageal wall strain can lead to structural deformations (i.e., blown-out-myotomy). 24,25It has been established that the high-pressure zone at the EGJ, as measured by HRM and FLIP, is typically only 3-4 cm in length, thus extending the myotomy more proximally up the esophagus may lack physiological rationale.The efficacy of short myotomy during POEM has been demonstrated in randomized trials and has been associated with lower rates of erosive esophagitis. 26,27Therefore, our study lends additional support to continue exploring tailored treatment in achalasia, including treatments that may preserve the potential for beneficial esophageal contractility after relief of obstruction from LES dysfunction.
This study also demonstrated the association of esophageal dilatation with contractile activity in treated achalasia given that patients with contractile activity had a significantly narrower esophageal body on follow-up esophagram (2.1 vs 2.9 cm, p < 0.001).This was more observed among patients that had residual post-treatment abnormal EGJ opening, but a trend was also observed trend was seen in the subgroup analysis of patients with normal EGJ metrics (Table 2).When controlling for esophageal dilation in multivariable analysis, post-treatment contractile vigor still remained an independent predictor for esophageal emptying (Table S1).Overall, the relationships between esophageal remodeling, peristaltic function, symptom generation, and esophageal clearance are complex and future studies investigating the mediation between these factors after achalasia treatment are needed.
While this study carries strengths related to its rigorous evaluation of a sizable cohort of patients with treated achalasia, there are also some limitations to this study.The observational design of the study is prone to potential inherent biases.Among these is the potential for a selection bias for patients treated at an achalasia referral center and/or that completed the recommended follow-up, thus potentially biasing this study cohort and limiting generalizability.
Moreover, the study was not designed to compare specific treatment modalities and thus factors that impacted initial treatment decisions could bias outcomes.As a result, we did not demonstrate that PD, certainly the most muscle-sparing intervention among those included, was associated with higher rates of contractile activity after treatment.However, adding to enthusiasm to evaluate the potential for POEM with short, LES-focused myotomy (which was not being utilized during this study period) could be beneficial in facilitating contractility after treatment and will be assessed in the future.
In conclusion, we demonstrated that presence of esophageal contractile activity after treatment in non-spastic achalasia appears to contribute to esophageal emptying.In patients with residual physiological features of EGJ obstruction, contractility was also associated with improved symptoms.We confirmed that contractility is associated with a pre-treatment diagnosis of type II achalasia and showed it more frequently occurs if adequate EGJ opening is achieved after treatment.These findings suggest that adoption of short, LES-tailored myotomy, sparing esophageal body muscle, could help preserve contractility in these patients and thus may improve their outcomes.

AUTH O R CO NTR I B UTI O N S
EV contributed to study concept and design, data analysis, data in- cal variables and ANOVA/t tests or Kruskal-Wallis/Mann-Whitney U for continuous variables, depending on the data distribution.Subgroup analysis was performed to stratify for the impact of EGJ pressure/opening on esophageal symptoms and symptoms with patients with both IRP <15 mmHg (median supine) on HRM and normal EGJ opening on FLIP defined as "normal EGJ." Patients with either a post-treatment IRP ≥15 mmHg or borderline or reduced EGJ opening on FLIP were considered as "abnormal EGJ." Logistic regression analysis with adequate esophageal emptying on TBE (i.e., 5 min column height <5 cm) as the dependent variable was performed.Additionally, the regression model included post-treatment DCI (HRM), IRP (HRM), EGJ opening classification (FLIP), and esophageal width on esophagram.Statistical tests were two-tailed and p-value <0.05 was considered statistically significant.

F I G U R E 3
Relationship between TBE column height at 1 min (A, C) and 5 min (B, D) and contractility, stratified by "normal" and "abnormal" EGJ metrics."Normal EGJ" was defined by post-treatment IRP <15 mmHg on HRM and normal EGJ opening on FLIP.IRP: integrated relaxation pressure; EGJ: esophagogastric junction; TBE: timed barium esophagram; HRM: high-resolution manometry; FLIP: functional luminal imaging probe.
less in patients with contractility versus patients without contractility.Post-treatment contractility was associated with improved esophageal emptying both among patients with normal and abnormal post-treatment EGJ opening (though slightly more consistent among patients with normal EGJ metrics, applying both HRM IRP <15 mmHg and FLIP criteria), and thus supporting the importance of contractility independent of the role of EGJ obstruction.Moreover, in the subgroup of patients with residual EGJ obstruction as demonstrated on HRM and FLIP Panometry (IRP >15 and/or borderlinenormal, borderline-reduced or reduced EGJ opening), contractility was associated with improved symptoms based on Eckardt score.

F I G U R E 5
FLIP contractile response patterns and TBE column height at 1 min (A) and 5 min (B), esophageal width, (C) and Eckardt score (D) in "normal EGJ" metrics subgroup."Normal EGJ" was defined by post-treatment IRP <15 mmHg on HRM and normal EGJ opening on FLIP.IRP: integrated relaxation pressure; EGJ: esophagogastric junction; TBE: timed barium esophagram; HRM: high-resolution manometry; FLIP: functional luminal imaging probe.
terpretation, drafting of the manuscript and approval of the final version.DAF, PJK, and AHK contributed to data interpretation, editing the manuscript critically, approval of the final version.JEP contributed to obtaining funding, editing the manuscript critically and approval of the final version.DAC contributed to study concept and design, data interpretation, editing the manuscript critically, and approval of the final version.FU N D I N G I N FO R M ATI O NThis work was supported by Public Health service grant P01 DK117824(Pandolfino).CO N FLI C T O F I NTE R E S T S TATE M E NTJohn E. Pandolfino and Peter J. Kahrilas (with Northwestern University) hold shared intellectual property rights and ownership surrounding FLIP Panometry systems, methods, and apparatus with Medtronic, Inc; Dustin A. Carlson is a speaker for Medtronic, and a consultant for Medtronic and Phathom Pharmaceuticals, and shares a licensing agreement with Medtronic.Peter J. Kahrilas F I G U R E 6 Contractility after treatment and impact on esophageal emptying.In the first patient (A), baseline HRM was consistent with type II achalasia (median supine IRP 29 mmHg, >20% panesophageal pressurizations).After standard-length (9 cm) POEM, follow-up HRM showed an IRP of 10 mmHg and body contractile activity (median DCI 703 mmHg s cm, 90% swallows with DCI >450).FLIP showed normal EGJ opening (EGJ-DI 3.36 mm 2 /mmHg, maximum EGJ diameter 19.7 mm).Post-treatment ES was 1. TBE showed no barium column at 2 min.In another patient (B), baseline HRM was consistent with type I achalasia (median supine IRP 17 mmHg, no panesophageal pressurizations).After laparoscopic Heller myotomy, follow-up HRM showed an IRP of 12 mmHg and no contractility.FLIP showed normal EGJ opening (EGJ-DI 6.11 mm 2 /mmHg, maximum EGJ diameter 16.3 mm).Post-treatment ES was 3. TBE showed a 10 cm barium column at 5 min.IRP: integrated relaxation pressure, EGJ: esophagogastric junction; EGJ-DI: esophagogastric junction distensibility index, TBE: timed barium esophagram, POEM: peroral endoscopic myotomy, HRM: high-resolution manometry, DCI: distal contractile integral, LES: lower esophageal sphincter, FLIP: functional luminal imaging probe, LHM: laparoscopic Heller myotomy; ES: Eckardt Score.

cohort Normal EGJ subgroup Abnormal EGJ subgroup No contractility Contractility present No contractility Contractility present No contractility Contractility present
Contractile activity after treatment and relationship with HRM and FLIP EGJ opening parameters in the entire cohort, in the subgroup with "normal EGJ" metrics and with "abnormal EGJ" metrics (IRP <15 mmHg and normal EGJ opening classification on FLIP).