Esophageal achalasia is an esophageal motility disorder of an unknown cause and is characterized by achalasia of the lower esophageal sphincter (LES) and impaired peristalsis of the esophageal body [1]. Conventionally, if pharmacological therapy fails to adequately control the symptoms of esophageal achalasia, endoscopic balloon dilation or Heller–Dor surgery are considered. However, with recent advances in endoscopic treatment techniques and devices, Inoue et al. [2] have developed peroral endoscopic myotomy (POEM), allowing adequate incision of the muscle layer alone without scarring the body surface, which has advanced treatment strategies for esophageal achalasia. Although there have been numerous reports regarding the efficacy and usefulness of POEM, very few studies have included over 100 cases [3–5]. We herein report the outcomes of POEM in 100 cases of esophageal achalasia at our hospital.

Methods

Patients

The data for our single-center POEM procedures were collected prospectively. The POEM procedure was approved by the Institutional Review Board of Fukuoka University Hospital, and written informed consent was obtained from all patients prior to enrolment in the study. The inclusion criterion was a confirmed diagnosis of achalasia.

Exclusion criteria were as follows: (1) patients unable to undergo general anesthesia and (2) patients who declined treatment with POEM.

Clinical assessment before POEM

Clinical achalasia symptoms were assessed using the Eckardt scores [6]. Patients were weighed, and preoperative tests, including manometry, endoscopy, barium swallow, and computed tomography, were performed.

Surgical preparation before POEM

Patients were admitted 1 day before the POEM procedure to perform esophagogastroduodenoscopy to ensure that all food remnants were removed from the esophagus prior to POEM.

POEM equipment

A forward-viewing endoscope with an outer diameter of 9.8 mm (GIF-H260, Olympus Medical Systems, Japan), which is routinely employed for upper gastrointestinal (GI) examinations, was used with a short ST hood (DH-28GR, Fujifilm, Japan). The main device was a triangle-tip knife (KD-640L, Olympus) that was used to create the submucosal tunnel as well as to divide circular muscle bundles. The coagulating forceps (FD-411QR Coagrasper, Olympus) were used to seal larger vessels prior to dissection and for hemostasis. Carbon dioxide (CO2) was used for insufflation during the procedure (UCR, Olympus), and the VIO 300D electrogenerator (ERBE, Tübingen, Germany) was used for electrosurgery. Finally, hemostatic clips (HX-610-90L EZ Clip and HX-610-90S EZ Clip Olympus) were used for closure of the mucosal entry site.

POEM procedure (Fig. 1)

The first case was performed by Haruhiro Inoue who pioneered the POEM technique for clinical practice, and the next 10 cases were operated upon under his supervision and as described by Inoue et al. [4] (Figs. 2, 3).

Fig. 1
figure 1

POEM procedure (anterior myotomy), A mucosal entry, B creating submucosal tunnel, C after creating submucosal tunnel, D myotomy, E after myotomy, F closure of mucosal entry

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Fig. 2
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Barium swallow examination before and after POEM

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Fig. 3
figure 3

High-resolution manometry before and after POEM

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POEM was performed under general anesthesia with CO2 insufflation. After injection of 7 mL of glycerol mixed with 0.3 % indigo carmine into the submucosal layer, a longitudinal mucosal incision was made in the mucosal surface to access the submucosal space. In the case of anterior myotomy, submucosal tunnel was created in the 1 o’clock to 2 o’clock position on the ventral aspect of the esophagus and then extended past the esophagogastric junction (EGJ) for 2–3 cm onto the gastric cardia.

For posterior myotomy, submucosal tunnel was created in the 5- to 6-o’clock position not to approach the aorta, and the submucosal tunnel was extended past the EGJ for 2–3 cm onto the gastric cardia, similar to anterior myotomy [7]. In cases of POEM for failed surgical myotomy, a new submucosal tunnel on the opposite side of the previous myotomy was created to avoid the fibrosis [8, 9].

A proximal-to-distal circular myotomy was performed with care to preserve the longitudinal muscle layers of the esophagus and stomach. Preservation of the longitudinal muscle sheet potentially avoids unnecessary injury to the structures adjacent to the esophagus.

The secure incision of the LES was identified by the following points [10]:

  • length from incisor teeth to esophagogastric junction as a reference position for the scope.

  • narrowing of the esophageal lumen closer to the LES and then opening wide in the stomach when creating a submucosal tunnel.

  • change from palisade vessels (anatomically equivalent to the LES) to increased irregularity and augmentation of the vessels underlying the mucosa as viewed from the submucosal tunnel.

  • smooth endoscope passage through the LES inside the true esophageal lumen and mucosa of stomach is seen from the esophageal lumen after the myotomy.

  • in anterior myotomy, the branch of the left gastric artery and oblique muscle in the submucosal tunnel of the gastric side (sometimes, this cannot be confirmed).

  • in difficult cases, to identify the secure incision of the LES by above-mentioned points, using a small caliber transluminal scope inserted through the natural lumen to observe real-time dissection [11].

After spraying an antibiotic (80 mg gentamycin) into the tunnel, the mucosal entry was closed using endoscopic clips.

During the procedure, POEM was performed with CO2 insufflation every 30 min, and the upper abdomen was palpated to monitor severe pneumoperitoneum. In cases of excessive distention of the abdominal wall by severe pneumoperitoneum or poor ventilation reported by the anesthesiologist, the procedure was stopped and the abdomen was tapped, if necessary.

The operation time was defined from insertion of the scope to its removal.

Postprocedural management

Intravenous antibiotics were administered for 3 days after the procedure. Endoscopy was performed to confirm mucosal integrity on the first day after surgery, and barium swallow examination was performed to confirm the smooth passage of contrast media into the stomach without leakage or stasis on the second day. A liquid diet was started on the day after surgery, followed by soft diet on post-POEM day 3, with resumption of a normal diet on post-POEM day 4. On discharge, patients were prescribed a proton-pump inhibitor (PPI) for 1 month only after which they were asked to discontinue until the postoperative evaluation. Patients on anticoagulant therapy, however, were asked to continue the PPI treatment.

Investigation after POEM

To investigate the clinical effectiveness of POEM and to evaluate gastroesophageal reflux disease (GERD) after POEM, symptoms were quantified with the Eckardt scores and the frequency scale for the symptoms of GERD (FSSG) 3 months after POEM [12]. Patients were also weighed, and endoscopy and manometry were performed simultaneously with 24-h pH monitoring. Manometry was performed using the InSIGHT G3 System (Sandhill Scientific, USA), and 24-h pH monitoring was performed with the ZepHr® Impedance/pH Reflux Monitoring System (Sandhill Scientific, USA).

Evaluation of treatment effect

An Eckardt score of ≦3 three months post-POEM was deemed as a successful outcome.

Statistical analysis

All statistical analyses were conducted using the Statistical Package for the Social Sciences software version 22 (SPSS Inc, Chicago, IL). The data was analyzed by univariate Chi-square test and student’s t test. P values of <0.05 were considered as statistically significant.

Results

Patient characteristics

Between September 2011 and December 2014, 108 patients were diagnosed with achalasia at our hospital, and two patients with mild symptoms were treated with medication based on their choice (Fig. 4). Two additional patients, one with terminal pancreatic cancer and another 89-year-old female in American Society of Anesthesiologists physical status (ASA-PS) class IV, were treated by balloon dilatation. Further, another 89-year-old female in ASA-PS class IV was treated by botulinum toxin injection. Remaining 103 patients underwent POEM for achalasia and were followed up for 3 months after POEM. However, three patients did not return for follow-up appointments at their own discretion. Of the remaining 100 patients, including 42 men and 58 women with achalasia, the average age was 48.2 ± 18.8 (range 9–91) years (Table 1). Twenty-three patients had undergone balloon dilation, and four patients had undergone the Heller–Dor operation prior to enrolment in this study.

Fig. 4
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Recruitment of patients

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Table 1 Patient demographics and perioperative characteristics
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Results of POEM

The average total length of myotomy was 12.6 ± 3.9 cm (range 5–26 cm), and the average length of gastric myotomy was 2.5 ± 1.0 cm (range 1–5 cm; Table 1). The mean operation time was 150.8 ± 49.3 min. Pneumoperitoneum which affected anesthesia during the procedure occurred in 11 cases; all were treated with abdominal puncture by a long 16-gauge needle to release abdominal pressure. The mean preoperative and postoperative LES pressures were 43.6 ± 26.2 and 20.9 ± 12.7 mmHg, respectively, indicating a statistically significant decrease after POEM (P < 0.05). The mean preoperative and postoperative integrated relaxation pressure (IRP) values were 33.5 ± 15.2 and 15.3 ± 6.5 mmHg (P < 0.05). Furthermore, the Eckardt score significantly decreased from 5.9 ± 2.5 preoperatively to 0.8 ± 0.9 postoperatively (P < 0.05). In subgroup analysis, POEM outcomes were the same regardless of previous treatment (Table 2). One patient was diagnosed with incomplete myotomy of LES and underwent a second POEM procedure 1 year later and achieved symptomatic relief.

Table 2 Comparison of the therapeutic effect due to the presence or absence of previous treatment history
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Adverse events (Table 3)

We did not experience adverse events over Grade IIIb in the Clavien–Dindo classification (Table 3) [13]. Esophagitis due to mucosal injury occurred in six cases. Mediastinitis by late and extensive mucosal perforation occurred in one case; however, as the patient’s general condition was not severe, he was treated with fasting, antibiotics, and enteral nutrition. While inflammation improved, the recovery took about 50 days. Delayed bleeding from mucosal entry due to clip dislodgement on 7 days after POEM occurred in one case. Pneumothorax occurred in one case immediately after POEM, but no special treatment was needed. All cases, including above-mentioned cases with complications, were treated by conservative therapy.

Table 3 Adverse events (Clavien–Dindo classification)
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Incidence of GERD after POEM

Excluding seven patients who had been treated with anticoagulants, postoperative endoscopic findings led to the classification of grade N, A, B, and C reflux esophagitis in 32 % (30/93), 48 % (45/93), 13 % (12/93), and 7 % (6/93) of patients, respectively, as per the Los Angeles (LA) classification [14]. Twenty-four-hour pH monitoring was performed in these 93 patients, which indicated that the percent of monitoring time with a pH  < 4 was 25.6 % (22/86) in patients not on PPIs.

Of those seven patients on anticoagulant therapy, postoperative endoscopic findings led to the classification of grade N, A, and B reflux esophagitis in 57 % (4/7), 29 % (2/7), and 14 % (1/7) of patients, respectively, per the LA classification. Twenty-four-hour pH monitoring determined that the percent of monitoring time with a pH  <  4 was 28.5 (2/7) in patients on PPIs.

Nine patients were diagnosed with symptomatic GERD by FSSG [12]; however, PPI treatment in patients with simultaneous reflux esophagitis and symptomatic GERD resulted in clinical improvement.

Discussion

Esophageal achalasia is an esophageal motility disorder of an unknown origin and is characterized by achalasia of the LES with impaired peristalsis of the esophageal body [1]. Patients experience persistent difficulty in swallowing and chest pain and may also exhibit regurgitation into the oral cavity accompanied by pulmonary aspiration during sleep. Therefore, many achalasia patients presenting to medical institutions have markedly decreased quality of life. Surgical reduction in pressure on the LES is often required to eliminate, or at least reduce, the aforementioned symptoms due to the limited efficacy of pharmacological therapies. Previously, interventions commonly included either endoscopic balloon dilation or surgery [15, 16].

Balloon dilation is a simple and effective treatment method and is one of the widely used endoscopic treatments [17, 18]. However, it is extremely difficult to apply an appropriate amount of pressure during this procedure as the inner circular muscle cannot be visualized. Too little pressure makes the procedure ineffective, whereas too much pressure may cause esophageal perforation. Therefore single dilation often provides varied and inconsistent results, repeated dilation is required. Moreover, as it is impossible to reach the inner circular muscle of the esophageal body even in cases where the area around the LES can be effectively tightened, it is not suitable for Chicago classification III achalasia cases in which strong spasms of the esophageal body also contribute to symptoms [19]. On the other hand, although surgery is a superior alternative to balloon dilation as it offers reliable and permanent results, it is only suggested for achalasia patients in whom balloon dilation has been unsuccessful. This is because achalasia is a benign disease, and even for small incisions, surgery requires either laparotomy or thoracotomy.

POEM, devised by Inoue et al., is a groundbreaking treatment method, in which the principles of endoscopic treatment are applied to Heller myotomy; thus, it can otherwise be described as “scarless Heller myotomy” [2, 20]. POEM has been previously reported as less invasive with greater treatment efficacy than conventional treatment methods. In the near future, POEM is expected to be established as the global standard treatment for esophageal motility disorders including esophageal achalasia.

The usefulness of POEM for esophageal achalasia and related diseases has already been reported [21–30]; however, as esophageal achalasia is a rare disease, few reports involve patient series of over 100. Here, we report our experience on POEM in 100 cases [3–5].

In this study, statistically significant improvements were observed in both clinical symptoms and LES pressure. Further, short-term outcomes after POEM were extremely good independent of age, type of achalasia, and previous therapy. In addition, subgroup analysis to determine the effect of previous therapeutic history on POEM outcomes showed that improvements in the LES pressure and Eckardt scores were independent of previous treatments (Table 2). Furthermore, there were no statistical differences in the length of myotomy, procedure time, or rate of adverse events related to POEM. Thus, this subgroup analysis revealed POEM as a safe and effective approach for achalasia regardless of previous treatment.

Posterior myotomy rate was high in patients with a history of previous therapy. This is expected as posterior myotomy was performed during rescue POEM on the opposite side of previous myotomy to avoid the fibrotic area.

Procedural complications of Grade IIIa and below, according to the Clavien–Dindo classification, were observed in 10 % of the patients (Table 3); however, no procedural complications requiring surgery (Clavien–Dindo classification of Grade IIIb or higher) occurred.

Incomplete myotomy occurred in one patient.

Until 3 months after first POEM, symptom (regurgitation and dysphagia) and weight improved better than that before treatment. However, the symptom and weight loss gradually recurred and finally attained the same value at the time of first POEM.

Barium swallow examination showed the stasis in the esophagus.

Endoscopic examination showed resistance in the LES part and no improvement in esophagitis in the esophageal body. Twenty-four-hour pH monitoring showed no reflux. Furthermore, manometry showed that high-pressure zone remained in the distal side of LES. We diagnosed incomplete myotomy in the first POEM, and redo POEM was performed 1 year after first POEM. The patient was relieved from symptoms after redo POEM. First POEM of this patient is the 64th case in our institution. POEM procedure was stable. At the time of first POEM, the secure incision of LES was identified by the described points except the insertion of second scope [10, 11]. Despite the incomplete resection of LES anatomically, there was no resistance in the LES part during procedure. However, 2 days after POEM, endoscopic examination revealed that the LES part became narrow and showed resistance. It is considered that temporary relaxation of muscles may have occurred because of electrical stimulation, but the details are unknown. After this event, we routinely insert a second scope (GIF-N260) on the stomach side and release the LES after confirming that the main scope has reached the stomach side using the light transmitted through the mucous membrane [11]. This method allowed for the prevention of unreliable LES incision, and we could subsequently prevent incomplete myotomy.

With regards to GERD onset following POEM, no intractable symptoms or ulceration were observed, and all cases were controlled with oral PPI administration.

Twenty-four-hour pH monitoring documented that percent total time pH  <  4 was 25.6 % (22/86) of patients without PPI prescription.

These results indicate a higher incidence of postoperative GER than that observed after Heller myotomy with fundoplication and a lower incidence than that after Heller myotomy without fundoplication [16].

Antireflux mechanisms involve the inner circular muscles, oblique muscle, crus of diaphragm, and the phrenicoesophageal ligament [31].

Simić et al. [32] reported that preservation of the phrenicoesophageal ligament during Heller myotomy can suppress the development of GERD, regardless of whether fundoplication is performed.

Preservation of the phrenicoesophageal ligament is believed to hold the key to the development of postoperative GERD [33].

POEM preserves the adjacent structures surrounding the distal esophagus, and the phrenoesophageal ligament remains intact.

In other words, in terms of preserving the antireflux mechanism, POEM is equally or more effective than Heller myotomy without fundoplication in that it preserves the phrenoesophageal ligament partially. Therefore, it is natural that the rate of GERD after POEM is low.

The reason for high rate (28.5 %) of GERD occurrence in patients with PPI prescription is considered that the patients who were on anti-coagulant therapy, which needed PPI prescription, tend to be elder.

And the two patients who were diagnosed with GERD by 24-h pH monitoring had round shoulders.

We performed long myotomy from the upper thoracic esophagus to the stomach side in the cases of Chicago classification type III achalasia accompanied by spasms of the esophageal body. For 12 cases of Chicago classification type III achalasia, myotomy involving lateral wall–anterior wall incision was performed. In remaining 2 cases, muscle layer incision of the posterior wall was performed.

When performing long myotomy, careful selection of the strategy used for muscular incision of the upper thoracic esophagus is required, as theoretically esophagotracheal fistula can result when the trachea and esophagus are in contact.

The first method we used involved performing myotomy on the lateral wall (3 o’clock direction) in the upper thoracic esophagus, where the trachea and esophagus are in contact, before shifting to the 2 o’clock direction to preserve the oblique muscles below the tracheal bifurcation. We were able to perform POEM without complications using this method, but it had the disadvantage of being technically demanding and had the possibility of esophageal diverticulum. However, long myotomy on the posterior wall side is not technically as challenging except that the area is submerged. Anatomically, this procedure is relatively safe when the aorta can be avoided, and the risk of esophagotracheal fistula onset during anterior wall incision can be eliminated. Moreover, as the vertebral bodies are posterior to the esophagus, this procedure could also help prevent postoperative hernia. Accordingly, when performing long myotomy from the upper thoracic esophagus to the stomach side, we believe that posterior wall myotomy is particularly useful.

We were able to perform four cases of POEM for failed surgical myotomy.

Symptoms remained after previous surgery because of insufficient myotomy in all cases (two cases: LES part, two cases: esophageal body).

Scar of previous myotomy exist in anterior wall in all cases.

Therefore, we make a new submucosal tunnel on posterior wall to avoid the fibrosis and perform redo myotomy including responsible part.

In all cases, symptoms were improved.

Redo Heller myotomy is more technically demanding because of the presence of adhesions and fibrosis resulting from the previous surgery.

However, in rescue POEM (POEM after previous surgery for achalasia), we are able to make a new submucosal tunnel on opposite side of previous myotomy to avoid the fibrosis.

There is no adhesion and easy access to the responsible part. Rescue POEM is also an effective method for failed surgical myotomy instead of redo surgical Heller myotomy in this study.

The following are the limitations of this study: It was conducted at a single center, and only one surgeon performed all procedures and long-term outcomes were not evaluated.

Further research works, including long-term results of multiple centers, are awaited.

In conclusion, our results confirm the efficacy of POEM in a large series of patients. POEM will become one of the first-line therapies of achalasia in the near future.