Esophageal diverticulum, which is a pulsion-type false diverticulum, is a rare disease presenting with an outpouching of the esophagus. Most patients with an esophageal diverticulum do not require further treatment, as the condition does not usually cause any symptoms or other clinically relevant problems. However, a huge diverticulum (> 5 cm) or the coexistence of esophageal motility disorders can cause symptoms such as dysphagia, regurgitation, and chest pain.¹ Symptomatic esophageal diverticulum requires mechanical treatment to allow food materials to flow into the esophageal lumen without accumulating in the diverticulum and to improve the symptoms.² Moreover, surgery is considered the treatment of choice for an epiphrenic diverticulum. As 75-100% of patients with an epiphrenic diverticulum have accompanying esophageal motility disorders, a pathophysiologically directed treatment strategy including diverticulectomy and esophageal myotomy is required to address the functional obstruction caused by the underlying motor dysfunction and remains the basis for surgical treatment.^3-9

Diverticular peroral endoscopic myotomy (D-POEM) has been reported as a novel and feasible technique for the management of esophageal diverticular diseases.^10-15 During this procedure, the diverticular septum can be precisely exposed and completely excised using the peroral endoscopic myotomy (POEM) technique. In patients with accompanying esophageal motility disorders, extended myotomy below the esophagogastric junction (EGJ) can be additionally performed. However, as POEM through the EGJ may increase the risk of gastroesophageal reflux disease (GERD) after the procedure, selective cardiomyotomy should be considered in patients with evident esophageal motility disorders based on motility tests. The recently introduced endoluminal functional lumen imaging probe (EndoFLIP) impedance planimetry system enables evaluating the function of the EGJ through the real-time assessment of its distensibility, compliance, diameter, and cross-sectional area.¹⁶ The importance of this test is being increasingly recognized, as some patients with esophageal motility disorders show normal high-resolution manometry (HRM) results but abnormal EndoFLIP results.^17-19

Therefore, in this study, we aim to report our experience with D-POEM as a safe and effective treatment option for symptomatic esophageal diverticulum, as well as to investigate the usefulness of EndoFLIP for determining the need for additional cardiomyotomy with septotomy during D-POEM.

Study Population and Design

A total of 9 patients who underwent D-POEM for symptomatic epiphrenic diverticulum at Asan Medical Center, a tertiary university hospital in Seoul, Korea, between September 2019 and September 2021, were considered eligible for inclusion in this study. Esophageal diverticulum was diagnosed using imaging examinations (eg, barium esophagography or computed tomography) and was confirmed using esophagogastroduodenoscopy (EGD). Dysphagia was scored according to the Dakkak and Bennett grading system, as follows: 0, no dysphagia; 1, dysphagia to solids; 2, dysphagia to semi-solids; 3, dysphagia to liquids; and 4, complete dysphagia.²⁰ The clinical features and endoscopic outcomes were retrospectively reviewed from the patients’ medical records. Informed consent was obtained from all patients before the procedure. The institutional review board of Asan Medical Center approved this study (Approval No. 2021-1455).

Esophageal High-resolution Manometry and Endoluminal Functional Lumen Imaging Probe

Before the procedure, HRM with 32 circumferential sensors and 16 impedance sensors (InSight Ultima; Diversatek, Highlands Ranch, CO, USA) was performed to identify any coexisting motility disorders. One investigator (K.W.J.) analyzed the manometric data using Zvu Advanced GI Diagnostic Software (Diversatek), based on the Chicago classification (CC).²¹ The normal integrated relaxation pressure (IRP) was defined as < 15 mmHg based on CC version 3.0 (v3.0). After 2021, HRM was conducted according to CC v4.0, since the normal IRP values differ among different catheter and system manufacturers, 22 mmHg for supine and 15 mmHg for upright positions had been standardized in our institution using Diversatek’s products.²² The HRM protocol designed by CC v4.0 included additional positional change (upright position) and provocative testing, including rapid drink challenge in the upright position and multiple rapid swallows in the supine position. The rapid drink challenge test was performed by directing the patient to drink 200 mL of water in the upright position as fast as possible.²³ In the multiple rapid swallow test, 2 mL of water was swallowed 5 times separated by 2-3-second intervals.²⁴

The EndoFLIP system, which is composed of a 16-cm catheter with 16 sensors spaced 1 cm apart, was used to estimate the distensibility index (DI) of the lower esophageal sphincter (LES) before and after D-POEM. After the balloon has passed the LES, 2-3 sensors were placed distal to the LES. Distensibility was observed by filling the balloon with increasing volume of saline, from 50 mL to 60 mL and 70 mL, every 60 seconds. A DI value of > 3 mm²/mmHg was defined as normal.²⁵

Endoscopic Procedure and Follow-up

All patients underwent EGD for the evacuation of esophagogastric contents on the day before the procedure. The patients were placed in the left lateral decubitus position and underwent the D-POEM procedure after endotracheal intubation under general anesthesia in an operating room. Ampicillin/sulbactam (3 g, 4 times/day) was intravenously administered to the patients as a prophylactic antibiotic regimen from 2 hours pre-procedure until discharge. The procedure was performed by 2 experienced endoscopists (D.H.K. and H.Y.J.) (Fig. 1).

Figure 1. Diverticular peroral endoscopic myotomy for symptomatic epiphrenic diverticulum. (A) The proximal part of the septum between the true lumen and the diverticulum was observed. (B) Submucosal injection 2-3 cm proximal to the diverticular septum. (C) A submucosal bleb and mucosal opening were created. (D) Submucosal tunneling was started from the mucosal opening. (E) Submucosal tunneling was continued toward both the diverticulum side and the esophageal side. (F) The septum was exposed by dissecting the submucosal layer of both sides. (G) A complete septotomy was performed at the base of the diverticulum. (H) The height of the diverticular septum was significantly lower. (I) The mucosal opening was closed with hemoclips.

The proximal part of the septum between the true lumen and the diverticulum was evaluated using a forward-viewing endoscope (GIF-HQ290; Olympus, Tokyo, Japan), and the DI of the LES was measured using EndoFLIP before starting the procedure. Normal saline containing epinephrine and indigo carmine was submucosally injected 2-3 cm proximal to the diverticular septum. After creating a submucosal bleb, a mucosal opening serving as the tunnel entry was made using HookKnife J (KD-625LR; Olympus) in dry cut mode at 60 W on effect 5 (ERBE, Tuebingen, Germany). Submucosal tunneling was performed using the operator’s preferred knife, such as a HookKnife J or nano-IT knife (KD-612L; Olympus), set in spray coagulation mode at 80 W on effect 7. After confirming the proximal part of the septum by tunneling, submucosal tunneling was continued toward the bottom of the diverticulum. The septum was exposed by exfoliating the submucosal layer of the diverticular and esophageal sides of the septum. Thereafter, a complete septotomy was performed at the base of the septum using HookKnife J in spray coagulation mode at 80 W on effect 7. Patients who were determined to have decreased DI on EndoFLIP underwent cardiomyotomy extending distally to the gastric cardia. After cardiomyotomy, EndoFLIP was performed again to confirm whether the DI increased and normalized, and the height of the diverticular septum and any other mucosal injury were carefully examined. Finally, the mucosal opening was completely closed with hemoclips.

The patients were discharge after verifying no leakage from barium esophagography and were prescribed a proton pump inhibitor for 4-8 weeks. They visited the outpatient clinic at 2 weeks after discharge and then 6 months later to check for symptom recurrence. Thereafter, they were followed up annually with EGD.

Outcomes

The primary outcome was clinical success, defined as decreased symptoms (based on the Dakkak and Bennett scores before and after D-POEM) without the need for an additional endoscopic procedure or surgical intervention. The secondary outcomes were technical success, endoscopic outcomes, adverse events, and recurrence of symptoms during the follow-up. The risk of GERD after D-POEM was evaluated with GERDQ systems and EGD while patients were off proton pump inhibitor.²⁶ The follow-up period was defined as the interval from the day of the procedure to the last outpatient clinic visit or the last telephone interview to check for symptom recurrence.

Statistical Methods

Descriptive variables are summarized as medians (interquartile range [IQR]) or mean ± standard deviation. Wilcoxon’s signed-rank test was used to compare the dysphagia scores before and after the procedure. Statistical significance was set at P < 0.05. All statistical analyses were performed using SPSS (version 24; IBM Corporation, Somers, NY, USA).

Clinical Characteristics

The clinical characteristics of the study population are summarized in Table 1. The median age during the procedure was 58 (IQR, 56-77) years, and 66.7% of the patients were men. The chief complaints were dysphagia in all 9 patients (100.0%), and additionally regurgitation in 3 patients (33.3%) and foreign body sensation in 1 patient (11.1%). The median duration of symptoms was 2 (IQR, 1-8) years, and no patient had prior treatments for symptomatic epiphrenic diverticulum.

Table 1 . Clinical Characteristics of Patients

Characteristics	n = 9
Age during the procedure (yr)	58 (56-77)
Male sex	6 (66.7)
Presenting symptoms
Dysphagia	9 (100.0)
Regurgitation	3 (33.3)
Foreign body sensation	1 (11.1)
Comorbidity
HTN	4 (44.4)
DM	2 (22.2)
CAD	2 (22.2)
Other malignancy	1 (11.1)
Charlson comorbidity index	2 (1-3)
Prior treatments	0 (0.0)
Duration of symptom (yr)	2 (1-8)
Follow-up (mo)	7 (2-19)

IQR, interquartile range; HTN, hypertension; DM, diabetes mellitus; CAD, coronary artery disease.

Data are expressed as median (interquartile range) or n (%).

Endoscopic Treatment Outcomes

The median size of the diverticulum and septum was 50 (IQR, 48-80) mm and 20 (IQR, 20-30) mm, respectively (Table 2). Submucosal tunneling and complete septotomy or additional cardiomyotomy were successfully achieved in all (9 of 9, 100%) patients, with a median procedure time of 60 (IQR, 46-100) minutes. The median hospitalization duration was 3 (IQR, 3-7) days. One patient was hospitalized for 20 days for the treatment of underlying pneumonia. Pneumoperitoneum with free air was detected on chest radiography in 2 patients, who recovered after conservative management including antibiotics administration. No serious adverse events that required surgical intervention or delayed discharge were documented.

Table 2 . Endoscopic Treatment Outcomes

Outcomes	n = 9
Size of the diverticulum (mm)	50 (48-80)
Length of the septum (mm)	20 (20-30)
Procedure time (min)	60 (46-100)
Technical success	9 (100)
Clinical success	9 (100)
Dysphagia score
Pre-procedure	2.0 ± 1.0
Post-procedure	0.4 ± 0.7
Adverse events
Pneumoperitoneum	2 (22.2)
Post-procedure bleeding	0 (0.0)
Duration of hospital stay (day)	3 (3-7)

Data are expressed as median (interquartile range), n (%), or mean ± standard deviation.

After D-POEM, the depth of the diverticulum was observed to be markedly shallow on follow-up EGD and barium esophagography (Fig. 2). After D-POEM, the depth of the diverticulum was observed to be markedly shallow on follow-up EGD and barium esophagography (Fig. 2). The mean dysphagia score decreased from 2.0 ± 1.0 before the procedure to 0.4 ± 0.7 (P = 0.001) during a median follow up period of 11 (IQR, 4-21) months after the procedure. Three patients (1 of septotomy and 2 of septotomy with cardiomyotomy) had symptomatic or asymptomatic GERD after procedure that did not require medication. Further, none of the patients experienced recurrence of dysphagia symptoms.

Figure 2. Comparison of esophagogastroduodenoscopy (EGD) and esophagography before and 5 months after diverticular peroral endoscopic myotomy (D-POEM). (A) The diverticular septum had nearly disappeared on EGD after D-POEM. (B) The depth of the diverticulum was estimated to be shallow, and the diverticular neck was widening. The passage of barium was improved on esophagography after D-POEM.

Outcomes of Septotomy With Cardiomyotomy

The endoscopic outcomes of all enrolled patients and the results of HRM or EndoFLIP are summarized in Table 3. A total of 8 patients underwent HRM before D-POEM, 6 of them showed normal IRP value, and the other 2 patients had elevated IRP. Five patients were confirmed to have decreased DI on pre-procedure EndoFLIP. All of them underwent cardiomyotomy extending to the gastric cardia along with septotomy based on the EndoFLIP results, although 3 patients showed normal IRP on HRM. After D-POEM, all patients except 1, in whom DI could not be measured owing to mechanical failure, showed improved and normalized DI of the LES on post-procedure EndoFLIP (Fig. 3). Technical success and clinical success were achieved in all patients. During the follow-up period of 11 months, 1 patient showed asymptomatic mucosal break on EGD, and other one was complained of heartburn under once a week (GERDQ score 1), however, all of them were not significant to require medical treatment.

Table 3 . Clinical Characteristics and Endoscopic Outcomes of Patients Who Underwent High-resolution Manometry or Endoscopic Functional Luminal Imaging Probe

Patient No.	HRM	IRP	Esophagography	EndoFLIP DI (pre→post)	Procedure type	Dysphagia score (pre→post)
1	N/A	N/A	N/S	N/A	Septotomy	1→0
2	Normal	Normal	Tertiary movement in the entire esophagus	0.8→7.4	Septotomy + cardiomyotomy	3→1
3	Normal	Normal	Gastroesophageal reflux	N/A	Septotomy	1→0
4	Distal esophageal pressurization	High normal	N/S	N/A	Septotomy	4→2
5	Distal esophageal pressurization	Normal	N/S	N/A	Septotomy	2→0
6	Ineffective esophageal motility	Normal	N/S	1.8→N/A	Septotomy + cardiomyotomy	2→0
7	Jackhammer esophagus	Increased	N/S	1.4→7.1	Septotomy + cardiomyotomy	2→1
8	Normal	Normal	Prominent tertiary contraction	3.0→5.1	Septotomy + cardiomyotomy	1→0
9	Normal	Normal	Distal passage disturbance	2.1→4.5	Septotomy + cardiomyotomy	2→0

HRM, high-resolution esophageal manometry; IRP, integrated relaxation pressure; EndoFLIP, endoscopic functional luminal imaging probe; DI, distensibility index; N/A, not applicable; N/S, non-specific.

Figure 3. Change in distensibility index (DI) of the lower esophageal sphincter (LES) measured with EndoFLIP before and after the procedure (patient no. 9). (A) High-resolution manometry showed normal results. (B) Although the integrated relaxation pressure (IRP) was normal, the DI of the LES before D-POEM was determined to be lower than normal (1.4 mm²/mmHg at 50 mL, 2.4 mm²/mmHg at 60 mL, and 2.1 mm²/mmHg at 70 mL). (C) After D-POEM, the DI of the LES improved and normalized (2.0 mm²/mmHg at 50 mL, 4.7 mm²/mmHg at 60 mL, and 4.5 mm²/mmHg at 70 mL).

D-POEM is a safe and effective procedure for the treatment of symptomatic esophageal epiphrenic diverticulum, and EndoFLIP is a clinically useful diagnostic tool that can determine the need for cardiomyotomy with septotomy and predict the outcomes after D-POEM. To our best knowledge, this is the first study to demonstrate the usefulness of EndoFLIP in the management of symptomatic epiphrenic diverticulum by measuring the distensibility of the EGJ.

An epiphrenic diverticulum is a pulsion-type diverticulum within 10 cm of the EGJ that appears as a pseudodiverticulum lacking a muscle layer. In early studies based on barium esophagography, an epiphrenic diverticulum has been suspected to have a strong correlation with esophageal motility disorders, including incoordination between the LES and distal esophagus, achalasia, or distal esophageal spasm, which contribute to its development.^27-29 Therefore, when treating an esophageal epiphrenic diverticulum, the functional obstruction caused by the underlying motor dysfunction should be addressed. A pathophysiologically directed therapeutic strategy including myotomy in addition to septotomy has been the basis for the modern treatment of an epiphrenic diverticulum.³⁰ Surgical treatment including septotomy with myotomy is the standard therapy for symptomatic epiphrenic diverticulum.

D-POEM has been recently introduced, and other studies have reported that myotomy alone is sufficient to control symptomatic epiphrenic diverticulum.^31,32 This is based on the assumption that the diverticulum might disappear spontaneously when the underlying motility disorder is resolved. However, many patients with symptomatic epipherenic diverticulum have not shown abnormal findings in manometry, and the diverticulum may not be effectively improved by myotomy alone if it is quite large. In other words, it is essential to comprehensively review the presence of the underlying motility disorder and the size and location of the diverticulum. There is no one-size-fits-all solution, and it is necessary to determine whether the procedure should be performed and the extent of treatment for each individual based on a comprehensive evaluation and multidisciplinary approach. However, it is difficult to draw conclusions from the existing studies because they are usually experimental or have a small sample size.

Few studies have consistently proved the correlation between motility disorders and anepiphrenic diverticulum based on manometry.⁶ Manometry cannot show pressure signals merely through the insertion of a catheter, and active swallowing of the examinee during the test is always required to visualize the pressure signals. Moreover, it is often difficult to perform manometry in patients with large epiphrenic diverticulum, including successful insertion of the manometry catheter and subsequent swallowing tests. Indeed, previous studies have reported that > 75% of epiphrenic diverticulum cases concomitantly occur with esophageal motility disorders even if the manometry results are normal.²

With the introduction of the POEM procedure, EndoFLIP has been applied to assess luminal distensibility. This technology was introduced to screen for various esophageal motility disorders that are difficult to diagnose with esophageal manometry by exactly measuring the EGJ distensibility even without active swallowing of the examinee during the test.²⁵ Some patients with esophageal motility disorders show normal esophageal manometry results but abnormal EndoFLIP results, and the superior diagnostic accuracy of EndoFLIP over manometry has been proved by many studies.^17,18,33-35 We used EndoFLIP to measure the EGJ distensibility for diagnosing disorders with impaired LES relaxation or functional obstruction due to a diverticulum. As a result, although the median IRP on HRM was normal, 4 patients showed decreased DI on pre-procedure EndoFLIP, accompanied by resistance during the passage of the endoscope through the EGJ. Three of the 4 patients also showed prominent tertiary contraction or distal passage disturbance on barium esophagography. Post-procedure EndoFLIP showed normalized DI after the additional cardiomyotomy, and all patients showed improvement in symptoms. This suggests that not only HRM but also barium esophagography and EndoFLIP are important for determining the need for additional cardiomyotomy with septotomy. Among these techniques, EndoFLIP can objectively evaluate the EGJ distensibility. A large-scale randomized prospective study is needed to prove the feasibility of EndoFLIP during D-POEM.

Selective cardiomyotomy through prediction of EGJ distensibility with EndoFLIP is helpful for pathophysiological treatment in patients with epiphrenic diverticulum, but there is a possibility of GERD due to cardiomyotomy like POEM for achalasia. As for surgical treatment of epiphrenic diverticulum, diverticulectomy and myotomy are performed in all patients, an antireflux fundoplication is additionally performed to prevent GERD. In our study, 2 of 5 patients who underwent cardiomyotomy had symptomatic or asymptomatic GERD that did not require medication.^9,36,37 This may be similar to potential adverse events that may inevitably occur in the POEM procedure for the treatment of achalasia.^38,39 Since the follow-up period is short in our study, mid- to long-term follow-up will be necessary further to identify the development of GERD.

In most previous studies about D-POEM, the symptom was graded using the Dakkak and Bennett scoring system, which is used for evaluating the severity of dysphagia. A new symptomatic scoring system combining the Dakkak and Bennett score and the Eckardt score has also been reported.¹⁵ In our study, dysphagia was graded according to the Dakkak and Bennett score. However, this scoring system has a limitation in that it cannot exactly evaluate symptoms in patients with a diverticulum because some patients have symptoms other than dysphagia. In this study, 4 of the 9 patients additionally complained of foreign body sensation or regurgitation in addition to dysphagia. Several symptoms associated with an epiphrenic diverticulum are accompanied by underlying motility disorders. Furthermore, diverticular inflammation and ulceration may cause retrosternal chest pain, and retention of food in the diverticulum can cause fullness during eating, regurgitation, or vomiting.^29,40 Therefore, a new symptomatic scoring system should be established to accurately assess the symptoms arising from an esophageal diverticulum.

This study had several limitations. First, it was inherently limited by the retrospective study design. Second, only 5 of the 9 (55.6%) patients underwent EndoFLIP, as 4 patients refused the test. Third, the sample size was small and patients were enrolled from a single tertiary referral center. Further, there was no comparative group. The epiphrenic diverticulum is a rare disease and only a limited number of patients complain of symptoms and undergo endoscopic myotomy even in tertiary hospitals. Fourth, the follow-up period was short and insufficient to thoroughly exclude the possibility of long-term symptom recurrence or complications such as reflux disease. Despite these limitations, this study showed the favorable outcomes of D-POEM, similar to previous reports. To support our suggestion regarding the role of EndoFLIP, further investigation about the influence of cardiomyotomy and septotomy for EGJ metrics via sequential measurement of EndoFLIP may be useful. To our knowledge, this is the first study to investigate the feasibility of EndoFLIP for determining the need for complete cardiomyotomy during D-POEM.

In conclusion, EndoFLIP may help decide whether cardiomyotomy with septotomy should be performed and predict outcomes after D-POEM for an epiphrenic diverticulum. Further large-scale randomized prospective studies are needed to validate our suggestion.

This work was supported by grants from the Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea (2017-03-041).

None.

Conception and design: Do Hoon Kim and Jin Hee Noh; analysis and interpretation of the data: Jin Hee Noh, Do Hoon Kim, Kee Wook Jung, Hee Kyong Na, Ji Yong Ahn, Jeong Hoon Lee, Kee Don Choi, Ho June Song, Gin Hyug Lee, and Hwoon-Yong Jung; drafting of the article: Jin Hee Noh, Do Hoon Kim, and Kee Wook Jung; and critical revision of the article for intellectual content: Jin Hee Noh, Do Hoon Kim, and Kee Wook Jung.