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

Abstract

Background and aims:

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.

Methods:

Patients with type I or II achalasia on baseline high-resolution manometry (HRM) who completed HRM, TBE, and functional lumen imaging probe (FLIP) after treatment were retrospectively identified. Contractility was defined on post-treatment HRM as presence of at least 1 supine swallow with DCI ≥100 mmHg∙s∙cm.

Results:

122 patients were included (mean age 48 ± 17 years, 50% female). At follow-up evaluation after treatment (54% peroral endoscopic myotomy, 24% pneumatic dilation, 22% laparoscopic Heller myotomy), 61 (50%) patients had contractility on HRM. Patients with contractility (compared to those without) more frequently had type II achalasia (84% vs 57%, p=0.001) and a post-treatment normal EGJ opening classification on FLIP (69% vs 49%; p<0.001). In the subgroup of patients with post-treatment integrated relaxation pressure <15mmHg and normal EGJ opening on FLIP (n=53), those with contractility had a lower median column height on TBE at 1 minute (4 vs 7 cm, p=0.002) and 5 minutes (0 vs 5 cm, p=0.001). In patients with ‘abnormal’ EGJ metrics, patients with contractility showed lower symptom scores (median Eckardt score 2 vs 3, p=0.03).

Conclusions:

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.

Graphical Abstract

In a study of 122 achalasia patients, we found post-treatment contractile activity in 50% cases, facilitated when adequate EGJ opening was achieved. Contractility was associated with improved esophageal emptying and, in cases with residual EGJ obstruction, it was associated with lower symptom scores. This study enlightens the role of esophageal body contractile function in achalasia as a potential determinant of treatment outcomes.

Introduction

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 contractility¹. Typical symptoms are dysphagia, regurgitation, chest pain and weight loss². 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 peristalsis³. The 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)^5,6.

While 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^1,7. This, 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 patients⁸. Moreover, previous studies have consistently shown that a varying degree of contractility can be exhibited after treatment^9–12. 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 treatment¹². No 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 recurrence¹³. We 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.

Methods

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, sub-group analysis of patients with both post-treatment IRP <15mmHg 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^14,15.

HRM protocol and analysis

HRM studies were completed after a 6-hour 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 3 intragastric sensors. After a 2-minute baseline recording, the HRM protocol was performed with ten, 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 criteria³. Additionally, 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 patterns³. All 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 1 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 > 5cm) 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 normal³.

The primary endpoint of contractile activity was defined on post-treatment HRM as presence of at least 1 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 described¹⁶. The 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 seconds.

The FLIP Panometry plots were created and analyzed using a customized program (available open source at http://www.wklytics.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^16,17. The contractile response (CR) pattern was assigned based on the patterns of contractility that occurred during the 50, 60, and 70ml fill volumes¹⁷. Normal 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 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 seconds of the study protocol at a 60ml fill volume was also assessed for analysis.

EGJ opening was assessed applying the EGJ distensibility index (EGJ-DI) at the 60ml FLIP fill volume and measuring the maximum EGJ diameter that was achieved at the 60ml or 70ml fill volume¹⁸. The classification of EGJ opening with FLIP Panometry used prespecified thresholds and classifications based on previous evaluation of asymptomatic volunteers and patients with achalasia^16,18,19; it was defined as normal (EGJ-DI ≥2.0 mm²/mm Hg and maximum EGJ diameter ≥16 mm), borderline normal (maximum EGJ diameter 14–16 mm or EGJ-DI <2.0 mm²/mm and maximum EGJ diameter ≥16 mm), borderline reduced (EGJ-DI <2.0 mm²/mm or maximum EGJ diameter <14 mm, but not normal or reduced EGJ opening) or reduced (EGJ-DI <2.0 mm²/mm Hg and maximum EGJ diameter <12 mm).

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 minutes. The height of the barium column was measured vertically from the EGJ. Patients without a barium column at 1 or 5 minutes were defined as having a height of 0 cm. Adequate esophageal emptying was defined as having a 5-minute column height <5 cm¹³. 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)²⁰. Because 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 categorical variables and ANOVA/t tests or Kruskal-Wallis/Mann-Whitney U for continuous variables, depending on the data distribution. Sub-group analysis was performed to stratify for the impact of EGJ pressure/opening on esophageal symptoms and symptoms with patients with both IRP <15mmHg (median supine) on HRM and normal EGJ opening on FLIP defined as “normal EGJ”. Patients with either a post-treatment IRP ≥15mmHg 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 minute column height < 5cm) 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.

Results

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%). Post-treatment motility evaluation was completed at a median (IQR) 13 (8–23) months after treatment.

Figure 1. Study flowchart.

IRP: integrated relaxation pressure; TBE: timed barium esophagram; HRM: high-resolution-manometry; FLIP: functional luminal imaging probe; REO: reduced esophagogastric junction opening; BrEO: borderline-reduced esophagogastric junction opening; BnEO: borderline-normal esophagogastric junction opening.

Table 1.

Baseline characteristics and contractile activity

	Total cohort	No contractility	Contractility present	P-value
N	122	61	61
Age, mean, years (SD)	48 (17)	49 (17)	48 (17)	0.784
Males, n (%)	61 (50)	25 (41)	36 (59)	0.046
Minimum PEP values, median, mmHg (IQR)	30 (23–40)	29 (22–40)	34 (27–39)	0.168
Maximum PEP values, median, mmHg (IQR)	46 (34–59)	42 (29–56)	52 (40–60)	0.054
Type I achalasia, n (%)	36 (30)	26 (43)	10 (16)	0.001
Type II achalasia, n (%)	86 (70)	35 (57)	51 (84)	0.001
Treatment, n (%)
POEM	66 (54)	30 (49)	36 (59)	0.276
PD	29 (24)	18 (30)	11 (18)	0.137
LHM	27 (22)	13 (21)	14 (23)	0.827
Follow-up time, median, months (IQR)	13 (8–23)	15 (9–29)	12 (8–17)	0.120

POEM: peroral endoscopic myotomy, PEP: panesophageal pressurization, PD: pneumatic dilation, LHM: laparoscopic Heller myotomy,

Contractile activity on HRM

Contractile activity was present after treatment in 61 patients (50%), with a median (IQR) DCI of 297 (183–545) mmHg∙s∙cm. In patients that had contractility on HRM, the median percentage of swallows with a DCI >100 mmHg∙s∙cm was 80% (50%−100%). Contractility pattern per CC v4.0 was ineffective in 42/61 patients (69%), premature in 14/61 (23%), and normal in 5/61 (8%). Patients with contractile activity were more frequently males (p=0.046) and more frequently 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 60ml 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.

Table 2.

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).

	Entire cohort		Normal EGJ subgroup		Abnormal EGJ subgroup
	No contractility	Contractility present	No contractility	Contractility present	No contractility	Contractility present
N	61	61	20	33	41	28
Post-treatment HRM
IRP, mmHg, median (IQR)	13 (10–20)	12 (9–16)	11 (8–13)	10 (7–14)	17 (11–21)	17 (12–21)
DCI, mmHg∙s∙cm, median (IQR)	0 (0–0)	297 (183–545)	0 (0–0)	278 (180–471)	0 (0–0)	415 (196–697)
% swallows with DCI > 100, median (IQR)	0 (0–0)	80 (50–100)	-	-	-	-
Contractility pattern, n (%)
Normal	0	5 (8)	0	4 (6)	0	5 (18)
Ineffective	0	42 (69)	0	20 (67)	0	18 (64)
Absent	61 (100)	0	20 (100)	0	41 (100)	0
Premature	0	14 (23)	0	9 (27)	0	5 (18)
Post-treatment FLIP
60ml pressure, mmHg, median (IQR)	25 (21–31)	29 (24–33)	23 (20–28)	29 (25–32)	26 (21–33)	29 (24–36)
Max EGJ diameter, mm, median (IQR)	16 (13–18)	17 (16–19)	17 (17–19)	18 (17–20)	14 (13–16)	16 (14–18)
EGJ-DI, mm2/mmHg, median (IQR)	4.3 (2.6–6.6)	5.0 (3.5–6.1)	6.6 (4.5–7.1)	5.8 (4.8–6.8)	3.3 (2.3–4.7)	3.5 (2.4–5.0)
Contractile response pattern, n (%)
Normal	0	0	0	0	0	0
Borderline	0	3 (5)	0	1 (3)	0	2 (7)
Impaired-disordered	36 (59)	43 (70)	13 (65)	26 (79)	24 (59)	17 (61)
Absent	23 (38)	10 (16)	7 (35)	5 (15)	16 (39)	5 (18)
Spastic-reactive	1 (2)	5 (8)	0	1 (3)	1 (2)	4 (14)
EGJ opening classification, n (%)
Normal	30 (49)	42 (69)	20 (100)	33 (100)	10 (24)	9 (32)
Borderline-normal	10 (16)	14 (23)	-	-	10 (24)	14 (50)
Borderline-reduced	14 (23)	4 (7)	-	-	14 (35)	4 (14)
Reduced	7 (12)	1 (2)	-	-	7 (17)	1 (4)
Normal + Borderline-normal	40 (66)	56 (92)	-	-	20 (40)	25 (89)
Reduced + Borderline-reduced	21 (34)	5 (8)	-	-	21 (42)	5 (18)
Post-treatment TBE
1-minute column height, cm, median (IQR)	8 (5–12)	4 (0–8)	7 (5–10)	4 (0–7)	8 (5–13)	5 (0–12)
5-minute column height, cm, median (IQR)	6 (2–9)	0 (0–4)	5 (2–7)	0 (0–3)	7 (2–11)	0 (0–7)
5-minute column height <5cm, n (%)	25 (40)	48 (78)	10 (50)	28 (88)	15 (37)	20 (71)
Esophageal width, cm (IQR)	2.9 (2.0–3.5)	2.1 (1.7–2.7)	2.6 (1.6–3.1)	1.8 (1.7–2.3)	3.2 (2.3–3.9)	2.3 (1.8–3.0)
Symptoms	n=52	n=55	n=16	n=30	n=36	n=25
Eckardt score, median (IQR)	3 (1–4)	2 (1–3)	2 (1–4)	2 (1–4)	3 (2–4)	2 (1–3)
Eckardt score ≤3, n (%)	33 (63)	43 (78)	11 (68)	22 (73)	22 (61)	21 (84)

Comparisons with significant (p<0.05) differences are marked in bold.

IRP: integrated relaxation pressure, EGJ: esophagogastric junction; EGJ-DI: esophagogastric junction distensibility index, TBE: timed barium esophagram, HRM: high-resolution-manometry, DCI: distal contractile integral, FLIP: functional luminal imaging probe.

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 in the subgroup with normal EGJ metrics (Table 2).

Figure 2. Relationship between median DCI on post-treatment HRM and esophageal width.

The whole cohort, the subgroup with ‘normal EGJ’ metrics and the subgroup with ‘abnormal EGJ’ metrics were stratified based on maximum esophageal width on TBE (less than 3 cm, 3–5 cm, more than 5 cm). ‘Normal EGJ’ was defined by post-treatment IRP <15mmHg on HRM and normal EGJ opening on FLIP.

DCI: distal contractile integral; IRP: integrated relaxation pressure; EGJ: esophagogastric junction; TBE: timed barium esophagram; HRM: high-resolution-manometry; FLIP: functional luminal imaging probe

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 minute (p=0.002) and 5 minutes (p=0.001) than patients without contractility. They also more frequently showed a 5-minute column height <5cm (p=0.006) than patients without contractility (Figure 3, Table 2). Furthermore, patients without contractility had greater 1-minute (p=0.009) and 5-minute 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-treatment spastic contractile pattern (n=9) did not show significantly worse outcomes on median TBE column height at 1 minute (3 (0–6) vs 4 (0–7) cm, p=0.422) or 5 minutes (0 (0–2) vs 0 (0–3) cm, p=0.506) when compared to patients with non-spastic contractility.

Figure 3. Relationship between TBE column height at 1 minute (A, C) and 5 minutes (B, D) and contractility, stratified by ‘normal’ and ‘abnormal’ EGJ metrics.

‘Normal EGJ’ was defined by post-treatment IRP <15mmHg 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

Figure 4. Relationship between TBE column height at 1 minute (A, C) and 5 minutes (B, D) and median DCI, stratified by ‘normal’ and ‘abnormal’ EGJ metrics.

‘Normal EGJ’ was defined by post-treatment IRP <15mmHg on HRM and normal EGJ opening on FLIP.

DCI: distal contractile integral; IRP: integrated relaxation pressure; EGJ: esophagogastric junction; TBE: timed barium esophagram; HRM: high-resolution-manometry; FLIP: functional luminal imaging probe

Symptomatically, patients with contractile activity did not differ from patients without contractility by Eckardt score (p=0.528), nor by percentage of patients with Eckardt score ≤3 (p=0.742, Table 2). Patients with a post-treatment spastic contractile pattern (n=9) numerically had worse symptomatic outcomes based on median Eckardt score (3 (3–5) vs 2 (1–3) cm, when compared to patients with non-spastic contractility, but this difference was not statistically significant (p=0.263).

We also explored the impact of contractile activity as measured with FLIP on clinical outcomes. Patients with ACR showed a trend towards worse clinical outcomes with greater median 5-minute column height (5 (0–7) vs 1 (0–4) cm, p=0.096) and esophageal width (2.7 (1.8–3.1) vs 1.9 (1.6–2.4), p=0.081) on TBE and higher median Eckardt scores (3 (2–4) vs 2 (1–3), p=0.183) when compared to patients with IDCR/BCR/SRCR (Figure 5).

Figure 5. FLIP contractile response patterns and TBE column height at 1 minute (A) and 5 minutes (B), esophageal width (C) and Eckardt score (D) in ‘normal EGJ’ metrics subgroup.

‘Normal EGJ’ was defined by post-treatment IRP <15mmHg 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

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 minutes (p=0.004), but not at 1 minute (p=0.09) (Figure 4). Patients with contractility also more frequently showed a 5-minute column height <5cm (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).

In this subgroup, 13/53 (24%) patients with type II achalasia showed persistent (≥20%) panesophageal pressurizations (30-mmHg) after treatment: of these, 6 (46%) had contractility on HRM. Similar rates of contractility were detected in patients without persistent panesophageal pressurizations (18/40, 45%; p=0.94).

Finally, on multivariable logistic regression analysis (which included the entire patient cohort), we found that presence of contractility on HRM (OR 2.8, 95%CI 1.15–6.79; p=0.023) and esophageal width <3cm (were associated with adequate esophageal emptying (column <5 cm on TBE). While having normal EGJ opening on FLIP nearly significantly predicted adequate emptying (p=0.067), IRP <15 mmHg did not (p=0.217) (Supplementary table 1).

Discussion

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 significantly 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 borderline-normal, borderline-reduced or reduced EGJ opening), contractility was associated with improved symptoms based on Eckardt score. 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.

Figure 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 mm²/mmHg, maximum EGJ diameter 19.7 mm). Post-treatment ES was 1. TBE showed no barium column at 2 minutes. 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 mm²/mmHg, maximum EGJ diameter 16.3 mm). Post-treatment ES was 3. TBE showed a 10 cm barium column at 5 minutes.

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

Contractile activity after achalasia treatment has been described in several studies, with rates ranging from 27% to 57% (similar to the presently described cohort)^9–12. 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^12,21. In 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^22,23. This 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. Previous studies have suggested that contractile activity after treatment has minimal or no impact on physiological and clinical outcomes^9–12. 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 subgroup¹⁵. However, 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).^24,25 It has been established that the high-pressure zone at the EGJ, as measured by HRM and FLIP, is typically only 3–4 centimeters 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.^26,27 Therefore, 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.

Abbreviations:

ACR

absent contractile response

BnEO

borderline-normal esophagogastric junction opening

BCR

borderline contractile response

BrEO

borderline-reduced esophagogastric junction opening

CC

Chicago Classification

DCI

distal contractile integral

EGJ

esophagogastric junction

EGJ-DI

esophagogastric junction distensibility index

ES

Eckardt Score

FLIP

functional luminal imaging probe

HRM

high-resolution-manometry

IRP

integrated relaxation pressure

IDCR

impaired/disordered contractile response

LES

lower esophageal sphincter

LHM

laparoscopic Heller myotomy

POEM

peroral endoscopic myotomy

PEP

panesophageal pressurization

PD

pneumatic dilation

REO

reduced esophagogastric junction opening

SRCR

spastic-reactive contractile response

TBE

timed barium esophagram

Data availability statement:

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.