Achalasia is an esophageal motility disorder that leads to progressive dysphagia with solids and liquids. It is defined by aperistalsis and inability of relaxation at the lower esophageal sphincter [1, 2]. Its pathophysiology is hypothesized to involve damage to inhibitory neurons of the myenteric ganglion cells, leading to inability of the lower esophageal sphincter (LES) to relax or permit normal propagation of peristalsis in the esophageal body. In addition to idiopathic causes, proposed etiologies include infective destruction (e.g. Trypanosoma cruzi, Varicella zoster virus, Human papilloma virus infections), autoimmune destruction (e.g. Scleroderma, systemic lupus erythematosus, Sjögren disease, and Addison disease), or a combination of both [3, 4]. Regardless of etiology, there are three recognized phenotypes identified by high resolution manometry (HRM) and defined by the Chicago Classification [5, 6]. They have specific patterns on HRM that define them to their subtype: Type 1 has abnormal median integrated relaxation pressure and 100% failed peristalsis, Type 2 shows the same two features as Type 1 but includes ≥ 20% swallows with panesophageal pressurization, and Type 3 demonstrates abnormal median integrated relaxation pressure with premature/spastic contraction and no evidence of peristalsis [6].

Achalasia subtype has correlated with differing responses to available therapies in the past [7]. Treatment for achalasia includes medical management with nitrates or calcium channel blockers, endoscopic interventions with LES dilation, Botox injection, or surgical myotomy performed through open or laparoscopic Heller myotomy (LHM) or per-oral endoscopic myotomy (POEM). Multiple studies have shown that POEM is a safe and efficacious therapy for achalasia, and with clinical benefit comparable, and in some ways superior to, LHM [8].

The endoluminal functional lumen imaging probe (EndoFLIP® [Medtronic, Dublin, Ireland]) has emerged as a tool to evaluate and guide therapy for achalasia [9]. This catheter-based device can be deployed and inflated in the esophageal lumen, utilizing impedance planimetry to measure diameter, cross sectional area, and distensibility index (DI; defined as cross sectional area divided by balloon pressure) throughout the length of the esophagus. These metrics can assess extent and completeness of the myotomy intraoperatively. EndoFLIP® has been correlated with good clinical response and post-POEM reflux [9,10,11].

While esophagogastric junction (EGJ) distensibility has been demonstrated to help characterize subtypes of achalasia [12], no studies have investigated the effect of POEM on different achalasia subtypes as measured by pre- and post-POEM EndoFLIP® values. We hypothesized that achalasia Types 1, 2, and 3 would have differing pre-POEM DI and diameter but no differences in DI or diameter post-POEM. Direct comparisons of pre- and post-POEM EndoFLIP® values may help elucidate if a particular achalasia subtype responds differently to POEM and/or support if POEM is equally efficacious across all achalasia subtypes.

Materials and methods

Approval for this study was obtained by the Institutional Review Board of the University of Massachusetts Chan Medical School at Baystate Medical Center. This is a single-center retrospective review of consecutive POEM cases of patients ≥ 18 years old from June 10, 2011 to August 28, 2023. Inclusion criteria included POEM cases performed for achalasia and having both pre- and post-POEM measurements of diameter and DI as measured by impedance planimetry. Exclusion criteria included any cases without pre- or post-POEM impedance planimetry values or any cases performed for non-achalasia esophageal dysmotility disorders. All patients underwent pre-procedural high-resolution manometry. Patients were divided into achalasia subtype characterized according to the Third Edition of the Chicago Classification [5] and were reviewed and reclassified according to the Fourth Edition [6] when applicable.

Procedure

POEM was performed by a single surgeon-endoscopist team under general anesthesia. Full details of the procedure from our institution have been previously described [13, 14]. We perform an anterior approach to the myotomy in most cases unless the patient had undergone prior POEM or LHM that failed. We perform a myotomy on the esophagus of 10 cm plus 2 cm onto the stomach; however, we acknowledge that the extra 2 cm rarely goes far onto the stomach and serves more as a “margin for error”, which can occur from scope bowing, leading to inaccurate measurement. Completion of the myotomy was determined by assessment of the true lumen by finding blue dye through the mucosa on intra-gastric retroflexion as well as by EndoFLIP® data. It should be noted that, while the exact myotomy length for POEM and each achalasia subtype have not been fully elucidated, it has been suggested that that Type 3 may benefit from a longer myotomy [15, 16]. Based on results from these studies, our institution performs a longer myotomy for Type 3 achalasia compared to Types 1 and 2, tailoring to the length of the spastic segment as seen on HRM.

EndoFLIP® has additionally been described at our center [17]. In brief, we utilized a first-generation unit and an 8 cm catheter (EF-325) zeroed to atmospheric pressure and advanced under endoscopic guidance into the stomach. The scope is then removed and the balloon is filled to 40 mL, then slowly withdrawn until an hourglass shape is seen on the monitor. After measuring the distance from the incisors to the lower esophageal sphincter with the endoscope, the EndoFLIP catheter is placed at the same distance. The balloon is then filled, and an hourglass shape will begin to appear on the monitor. After allowing the readings to stabilize, minimum diameter, cross-sectional area, intra-bag pressure, and DI are recorded. The narrowest aspect of the hourglass depicts the lower esophageal sphincter, reflecting a high-pressure zone with the tightest diameter. The balloon is then deflated and the catheter removed. Following myotomy, measurements are repeated after endoscopic-guided insertion to prevent intubation of the submucosal tunnel.

Statistical analyses

Numeric values are represented as n (%). Continuous variables with non-normal distribution are presented as median [interquartile range (IQR)]. Pearson’s Chi-Square test was utilized for categorical comparisons, Kruskal–Wallis rank sum test was utilized for continuous, non-normally distributed comparisons. Multivariable linear regression was utilized to analyze the DI and diameter by EndoFLIP® while adjusting for potentially confounding factors. Factors found to be significant on univariate analysis and/or considered clinically relevant were included in the model, with no more than one factor per 10 data points to prevent overfitting of the model. All variables in the model were assessed for collinearity. All tests were two-tailed and p < 0.05 was considered significant. Statistical analyses were performed using R [18].

Results

Patient population and baseline characteristics

There were 64 patients who underwent POEM for achalasia with pre- and post-POEM EndoFLIP® data (Table 1). Of these, 29 (45%) were female, median body mass index was 29.7 [IQR: 24.3–34.7]. Patient histories prior to POEM included 1 (2%) who had previously undergone Botox injection and 16 (25%) who had previously undergone endoscopic dilation. Stratified by achalasia subtype, there were 9 (14%) Type 1 patients, 36 (56%) Type 2 patients, and 19 (30%) Type 3 patients. There were no intraoperative conversions from POEM to LHM.

Table 1 Baseline patient characteristics and univariate comparisons of achalasia subtypes
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Univariate analysis of achalasia subtypes

There were no differences between subtypes in sex, body mass index, pre-POEM or post-POEM Eckardt scores, previous Botox injection, previous endoscopic dilations, intraoperative duration of POEM procedure in minutes, EGJ location, anterior vs posterior approach to the myotomy, post-POEM DI or diameter by EndoFLIP® between Types 1, 2, and 3 (Table 1).

There was variability in pre-POEM DI between subtypes (Type 1 = 1.8 [1.3–3.2] vs. Type 2 = 0.9 [0.6–1.6] vs. Type 3 = 0.6 [0.5–0.8] cm, p = 0.003), pre-POEM diameter between subtypes (Type 1 = 6.9 [6–8.5] vs. Type 2 = 5.5 [5–6.8] vs. Type 3 = 5 [5–6.1] cm, p = 0.025), and length of myotomy performed during POEM (Type 1 = 12 [11, 12] vs. Type 2 = 12 [11, 12] vs. Type 3 = 16 [13.5–18] cm, p < 0.001).

Multivariable linear regression analysis

To adjust for potentially confounding factors, a multivariable linear regression was performed including significant factors from the univariate analysis as well as clinically relevant factors; achalasia Type 2 was selected as the Referend as it had the greatest number of patients. For pre-POEM DI, there was a 1% decrease in DI as one’s age increased (0.99 (95% CI 0.98–1)) as well as a 45% higher DI among females (1.45 (95% CI 1.03–2.04)). The remainder of pre-POEM DI values were similar as well as all post-POEM DI, pre-POEM diameter, and post-POEM diameter (Table 2).

Table 2 Multivariable linear regression of pre- and post-POEM impedance planimetry
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When specifically looking at achalasia subtypes, the previously significant factors of pre-POEM diameter and DI did not persist, with similar pre-POEM and post-POEM DI and diameters with reference of Type 2 to Types 1 and 3 (Table 2).

Discussion

We present a retrospective study investigating the direct effects of POEM on different achalasia subtypes by comparing intraoperative EndoFLIP® parameters before and after myotomy. To the authors’ knowledge, this is the first work to directly investigate the effect of POEM on different achalasia subtypes using intraoperative EndoFLIP® to measure DI and diameter, seeing the direct effect of POEM in real time on achalasia subtypes. We originally hypothesized that the achalasia subtypes would demonstrate variability in pre-POEM EndoFLIP® values, which was seen in univariate analysis. However, multivariable regression analysis did not maintain statistically significant differences in pre- or post-POEM DI or diameter between subtypes. We do demonstrate increased pre-POEM DI among females and decreasing pre-POEM DI as one ages. With no differences in post-POEM DI, diameter, or Eckardt scores, this work helps support the use of POEM in all subtypes of achalasia with assurance that the effect should be similar.

Achalasia subtypes and response to treatment

Achalasia is rare and its exact etiology remains unknown. Manometric differences between subtypes have been well described [6] and there have been different proposed etiologies. Therefore, we hypothesized that there would be a difference pre-POEM impedance planimetry values between subtypes. Univariate analysis originally supported this hypothesis, with decreasing pre-POEM DI and diameter as one progresses from Type 1 to Type 2 to Type 3 (median 1.8–0.9–0.6 and median 6.9–5.5–5 cm, respectively). These pre-procedure data, while representing a small sample size and would require further study, support some observations that, rather than three distinct subtypes, achalasia may be a progression of disease, with Type 3 being early stage and having less distensibility with Type 1 acting as the “final” stage of achalasia as the esophageal contraction mechanisms fail and the esophagus dilates [19, 20]. However, these statistical differences on univariate analysis did not persist after multivariable regression. We believe these differences may lie in that all subtypes share a common manometric endpoint with a non-relaxing LES that is seen on EndoFLIP® moreso than the characterizations seen by HRM. The clinical presentations of patients with achalasia remains relatively similar regardless of subtype: dysphagia, weight loss, gastroesophageal reflux, and regurgitation [21], so the findings in this study may reflect the clinical manifestation of the disease and reflect the common manometric endpoint seen on HRM.

While there are many treatment options available, including Botox injection, calcium channel blocker administration, endoscopic pneumatic dilation of the LES, LHM, and POEM, achalasia subtypes may respond differently depending on subtype. It has been suggested that Types 2 and 3 respond better to Botox injection than Type 1, perhaps because it addresses the entire esophagus rather than just the LES [22]. Type 2 patients as well as females have been shown to respond better to pneumatic dilation [23]. Type 3 patients may benefit from POEM because one can utilize a longer myotomy to address more proximal disease that a LHM cannot reach via a trans-abdominal approach [15, 24, 25]. For POEM specifically, this study demonstrates that there were no differences in DI, diameter, or Eckardt scores with respect to subtype, suggesting that, once a patient is deemed a surgical candidate, one can expect similar durable clinical results and symptom relief regardless of subtype from POEM, including those individuals who have undergone previous intervention with pneumatic dilation. While exact myotomy length for POEM and each subtype has yet to be fully elucidated, it has been suggested that Type 3 may benefit from a longer myotomy [15, 16]. As mentioned in our Methods, our institution performs a longer myotomy for Type 3 (median 16 cm in this study, compared to median 12 cm for Types 1 and 2), and similar to others uses EndoFLIP® as a means for measuring the endpoint of the myotomy during POEM [26]. We did adjust for this practice in the regression model, but this study did not demonstrate differences in DI or diameter, strengthening the assertion that clinical results pre-to-post-POEM can be expected regardless of subtype.

HRM may be seen as an important tool in the diagnosis and treatment of achalasia, supported by the use of EndoFLIP® [24]. HRM helps to diagnose achalasia subtypes and may help guide non-surgical (e.g. Botox selection for specific subtypes) and surgical treatment (e.g. longer myotomy for Type 3). Impedance planimetry, a more recent tool used during POEM, may help inform response to treatment and help address the extent of myotomy needed. It also provides confirmatory anatomic information that might help prevent an inadequately placed myotomy, leading to treatment failure. However, this study supports that patients benefit from POEM regardless of subtype and that, once deemed a surgical candidate, POEM should continue to be entertained as a safe, effective treatment modality.

Effect of age and sex on Pre-POEM distensibility index

A novel finding identified in this study is an increased pre-POEM DI among females after multivariable analysis. The clinical characteristics between sexes in achalasia have been investigated before, with females having increased chest pain symptoms compared to males [27] and less esophageal dilation [28]. While these results would require further inquiry, this study supports that there are differences between sexes, either reflective of different anatomic manifestations of achalasia or of time to presentation as females with increased pain may present sooner for evaluation and treatment. The increased DI among females appears to contradict the findings by Tsuboi and colleagues [28] of decreased esophageal dilation among females, but our study took into account potentially confounding factors in the analysis. This would be an interesting avenue for future inquiry.

Another unique finding was that there was a decreasing pre-POEM DI as one ages. Previous studies have suggested that age is inversely correlated with frequency and severity of symptoms in achalasia patients, but did not influence post-LHM resolution of symptoms [29]. Additionally, a meta-analysis demonstrated that increasing age was associated with improved clinical response to treatment [30]. This study supports these notions in that decreasing DI as one ages would suggest decreased non-relaxation of the LES and potentially fewer symptoms.

Limitations

We present a retrospective series by a single surgeon-endoscopist team, potentially limiting its generalizability, especially considering the variability in practice among physicians performing POEM, such as length of myotomy performed, targeted myotomies, where to start the myotomy proximally or end distally, etc. While performed at a high-volume tertiary center, given that not all patients had pre- and post-POEM EndoFLIP® values, the sample size is relatively small, especially among Type 1 achalasia patients, potentially limiting the generalizability of our conclusions.

Conclusion

Impedance planimetry is a useful tool to help guide the myotomy in POEM. Achalasia, while having three described subtypes via HRM, does not demonstrate differences in pre- or post-POEM DI or diameter as measured by EndoFLIP® between achalasia subtypes. This, combined with similar pre- and post-POEM Eckardt scores with robust clinical response, further support that POEM is an effective treatment in the treatment of achalasia and one can expect similar excellent clinical outcomes regardless of achalasia subtype.