Abbreviations
GERD:
gastroesophageal reflux disease
LES:
lower esophageal sphincter
LHM:
laparoscopic Heller’s myotomy
POEM:
peroral endoscopic myotomy
D-POEM:
diverticular peroral endoscopic myotomy
Introduction
Most epiphrenic diverticula are pulsion diverticula and are associated with an underlying
esophageal motility disorder [1]
[2]
[3]
[4]
[5]. It is estimated that 58 % to 78 % of patients with an epiphrenic diverticulum have
an underlying esophageal motility disorder [1]
[2]
[3]. In patients diagnosed with achalasia, epiphrenic diverticula can occur due to stasis
of food and increased intraluminal pressure in the distal esophagus [6]. This pressure results in herniation of the mucosal and submucosal layer, resulting
in a so-called false diverticulum [7]. The prevalence of epiphrenic diverticula in achalasia ranges between 0.06 % to
4 % [8]. However, this may be an underestimation, as these estimates are derived from symptomatic
achalasia patients in which the diverticulum is presumed to contribute to the symptoms.
In the majority of cases, epiphrenic diverticula will remain asymptomatic [6]
[9].
The current standard treatment of epiphrenic diverticula is surgical diverticulectomy
often combined with laparoscopic Heller’s myotomy (LHM) and fundoplication. This procedure
is successful in around 80 % of cases, but is rather invasive and carries a significant
adverse event (AE) rate of 21 % to 27 % with an esophageal leakage rate of 7 % to
13 % [10]
[11]. Therefore, evolving surgical and endoscopic minimally invasive treatment approaches
are increasingly considered. Peroral endoscopic myotomy (POEM) appears to be effective
and safe for patients with achalasia and has mortality and morbidity rates of 0 %
and 3.2 % to 7.5 % respectively [12]
[13]. Previous studies have suggested that symptoms in patients with an epiphrenic diverticulum
are being caused by the underlying esophageal motility disorder rather than the epiphrenic
diverticulum itself [14]. Given the fact that esophageal motility disorders are mainly the underlying cause
of epiphrenic diverticula, the idea is to treat primarily the underlying cause by
myotomy without diverticulotomy to reduce symptoms as well as the chance of developing
new diverticula. In case of persistent symptoms after POEM, a second intervention
can be considered for additional diverticulotomy, diverticulectomy or resection of
the diverticular pouch [8]
[14]
[15]
[16].
To date, only a small number of studies have investigated the efficacy and safety
of POEM without diverticulotomy in patients with esophageal diverticula and they are
limited by the number of included patients [17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]. The largest study thus far with 14 patients showed a decrease in Eckardt score
after POEM. In total 20 patients have been reported in case series and case reports
and symptoms improved in all of them after POEM. The aim of this study was to examine
the efficacy and safety of POEM without diverticulotomy in reducing esophageal symptoms
in patients with esophageal diverticula.
Patients and methods
Study design
This retrospective cohort study was performed at the Amsterdam University Medical
Center. Data were collected from patients with an esophageal diverticulum who underwent
POEM between October 2014 and December 2021. Baseline characteristics and follow-up
variables were extracted from medical records. Patients who were included in the study
were contacted by telephone to complete a survey (appendix). Patients consented to
the use of their medical data for the purpose of this study.
Patient selection
Medical records of all consecutive patients who underwent POEM were screened for eligibility.
Barium esophagograms were used to confirm the esophageal diverticula. Inclusion criteria
were one or more esophageal diverticula diagnosed before POEM and an age > 18 years.
Also, POEM had to be carried out successfully and the diverticula had to be documented
during the procedure or during a previous gastroscopy. Patients with previous or current
malignancy of the esophagus, gastroesophageal surgery in the past or a Zenker diverticulum
were excluded.
POEM procedure
All POEM procedures were performed under general anesthesia with endotracheal intubation
and patients received perioperative intravenous antibiotics. The procedure was carried
out by two gastroenterologists with significant POEM experience (PF, BB) according
to the steps as follows: (1) a submucosal injection of saline and indigo carmine followed
by a mucosal incision of 2 cm approximately halfway down the esophageal body; (2)
creation of a submucosal tunnel up to the cardia to approximately 3 cm beyond the
LES; (3) myotomy of the circular muscular layer as well as part of the longitudinal
muscular layer; and (4) closure of the mucosal incision with multiple endoclips. The
length of the myotomy depended on the location of the diverticula and the type of
underlying esophageal motility disorder. Myotomy of the diverticular septum was not
performed.
Barium esophagogram
A timed barium esophagogram was performed before POEM and between 3 and 18 months
after POEM. The patient had to swallow 200 mL of barium contrast within 15 to 20 seconds
while upright. Radiographs of the esophagus were made at baseline and after 1, 2 and
5 minutes [20]. The maximum size of the diverticula was measured in centimeters. In some patients,
more than one barium esophagogram was performed at different times of follow up. The
mean maximum size of the diverticula was used in case of multiple barium esophagograms
after POEM because in one patient, the maximum size of the diverticula on repeated
barium esophagogram after POEM did not differ significantly. The size of the diverticula
was measured independently by two observers. The mean size was used when the difference
between the values measured by the observers was < 0.5 cm. Otherwise, the size was
measured again until agreement was reached.
Outcome measures
The primary outcome was treatment success, defined as an Eckardt score < 4 with a
minimum decrease of 2 points after POEM [27]. The Eckardt score was used to quantify the esophageal symptoms and was calculated
just before POEM and at the time of the survey. Symptoms of weight loss, dysphagia,
retrosternal pain and regurgitation were scored from 0 to 3 indicating the severity
of the symptoms, resulting in a total maximum score of 12. The higher the score, the
higher the burden of symptoms. Secondary outcomes included retreatment after POEM,
self-reported improvement of esophageal complaints measured on a 6-point Likert scale,
symptoms of gastroesophageal reflux disease (GERD symptoms), reflux esophagitis observed
during gastroscopy 3 months after POEM, proton pump inhibitor (PPI) use and difference
in size of the diverticula at follow up. Some patients had more than one diverticulum
and these diverticula were analyzed separately. Therefore, the number of diverticula
was higher than the number of patients in this study. Secondary outcomes related to
the procedure were length and location of myotomy, number of days in hospital, procedure-related
events and AEs within 30 days after POEM.
Statistical analysis
Castor EDC was used for data management and all statistical analyses were performed
using SPSS version 26.0. The distribution of variables was assessed by plotting a
histogram and a quantile-quantile plot. Normally distributed outcomes were analyzed
using paired sample t-test. Non-parametric testing (the Sign test and Wilcoxon test) was used to compare
not normally distributed outcomes. P < 0.05 was considered to be statistically significant.
Results
Patient characteristics
After screening lists of 220 patients who underwent POEM and 327 patients with achalasia,
the charts of 54 patients mentioned possible presence of esophageal diverticula based
on reports of diagnostic tests and procedures or referral letters. Diverticula were
not confirmed on barium esophagogram in 23 of these patients. Of the 31 patients with
confirmed diverticula, 14 were excluded because they did not meet other eligibility
criteria. In six of the 14 patients, the diverticulum was not confirmed during gastroscopy,
four patients did not undergo POEM, one POEM was not successful, and in three patients,
the diverticulum was diagnosed after POEM. Of 17 included patients, one died for whom
no data were obtained on the survey. The cause of death was not related to the procedure
or the esophageal condition ([Fig. 1]).
Fig. 1 Flowchart. POEM, peroral endoscopic myotomy.
The variables age, body mass index and the maximum size of the diverticula were normally
distributed. As shown in [Table 1], the mean age was 71 years and 41.2 % of the patients were female. Achalasia was
confirmed in 13 patients (76.5 %), Jackhammer esophagus in two patients (11.8 %),
diffuse esophageal spasm in one patient (5.9 %) and one patient showed no evidence
of an esophageal motility disorder (5.9 %). About one-third of the patients underwent
pneumatic dilatation in the past (6/17, 35.3 %) of whom three also underwent a LHM
(17.6 %). The only patient without an esophageal motility disorder did have a surgical
thoracoscopic diverticulectomy in the past and one patient was treated with nifedipine
and isosorbide dinitrate because of diffuse esophageal spasm. Seven patients did not
have any treatment before POEM (41.2 %). Most patients had one diverticulum (13/17,
76.5 %). Three patients had two diverticula and one patient had three. Of all these
diverticula, 21 were epiphrenic and one was located in the lower part of the mid-esophagus.
The size of the diverticula ranged from 0.9 cm to 8.3 cm with a mean of 3.7 cm.
Table 1
Baseline characteristics.
|
Patient characteristics
|
N = 17
|
|
Age, years, mean (SD)
|
71 (9)
|
|
Sex
|
|
|
7 (41.2 %)
|
|
|
10 (58.8 %)
|
|
BMI, kg/m2, mean (SD)
|
25.3 (4)
|
|
EMD[1]
|
|
|
13 (76.5)
|
|
|
3 (17.6)
|
|
|
6 (35.3)
|
|
|
2 (11.8)
|
|
|
2 (11.8)
|
|
|
1 (5.9)
|
|
|
1 (5.9)
|
|
Time between EMD diagnosis and POEM, months, median (IQR)
|
10.5 (28.8)
|
|
Previous treatment
|
|
|
3 (17.6)
|
|
|
2 (11.8)
|
|
|
2 (11.8)
|
|
|
1 (5.9)
|
|
|
1 (5.9)
|
|
|
1 (5.9)
|
|
|
7 (41.2)
|
|
Number of diverticula
|
|
|
13 (76.5)
|
|
|
3 (17.6)
|
|
|
1 (5.9)
|
|
Diverticulum characteristics
|
N = 22
|
|
Location
|
|
|
1 (4.5)
|
|
|
21 (95.5)
|
|
Maximum size, cm, mean (SD)
|
3.9 (1.8)
|
|
Side
|
|
|
9 (40.9)
|
|
|
13 (59.1)
|
Results are presented as n (%) unless otherwise stated.
SD, standard deviation; BMI, body mass index; EMD, esophageal motility disorder; DES,
diffuse esophageal spasm; POEM, peroral endoscopic myotomy; IQR, interquartile range;
PD, pneumatic dilatation; BTI, botulinum toxin injection; LHM, laparoscopic Heller’s
myotomy.
1 Based on Chicago classification version 3.0.
Treatment outcomes
Treatment success was obtained in 68.8 % of patients. The median time between POEM
and the survey was 31 months with a range from 6 to 93 months. Eckardt scores were
not normally distributed. As shown in [Table 2], the Eckardt scores significantly decreased from a median of 7 (range 2–11) before
POEM to a median of 1 (range 0–9) after POEM (P < 0.001). From the graph in [Fig. 2], it can be seen that two patients had no difference in Eckardt score and the other
14 patients had a considerable decrease, of whom five patients had an Eckardt score
of 0 and four patients a score of 1 after POEM. A decrease in Eckardt symptom score
is seen for each symptom separately and is shown in Supplementary 1. Only one patient (6.3 %) had received retreatment after POEM, which was pneumatic
dilatation.
Table 2
Treatment outcomes.
|
Before POEM
|
After POEM
|
P value
|
|
Eckardt score, median (IQR)[1]
|
7 (3)
|
1 (5)
|
< 0.001
|
|
|
3 (0)
|
1 (2)
|
|
|
0 (2)
|
0 (0)
|
|
|
1 (3)
|
0 (1)
|
|
|
2 (2)
|
1 (1)
|
|
Maximum size diverticula, cm, mean (SD)[2]
|
3.6 (0.4)
|
2.9 (0.3)
|
< 0.001
|
|
Self-reported improvement[1]
|
|
|
|
|
|
7 (43.8)
|
|
|
3 (18.8)
|
|
|
3 (18.8)
|
|
|
0 (0)
|
|
|
1 (6.3)
|
|
|
2 (12.5)
|
|
Reflux esophagitis[1]
|
|
7 (43.8)
|
|
|
|
3 (18.8)
|
|
|
2 (12.5)
|
|
|
1 (6.3)
|
|
|
1 (6.3)
|
|
PPI use[1]
|
|
12 (75)
|
|
|
Retreatment[1]
|
|
1 (6.3)
|
|
|
PD
|
1 (6.3)
|
Results are presented as n (%) unless otherwise stated.
IQR, interquartile range; PD, pneumatic dilatation; POEM, peroral endoscopic myotomy;
SD, standard deviation; PPI, proton pump inhibitor.
1 n = 16.
2 n = 21.
Fig. 2 Eckardt scores before POEM and at follow up.
Four patients had more than one diverticulum and only one patient had no barium esophagogram
on follow up, so the difference in maximum size of the diverticula was analyzed for
21 diverticula. As can be seen in [Table 2], the mean maximum size of the diverticula significantly decreased from 3.6 cm before
POEM to 2.9 cm after POEM (mean difference 0.76 cm; 95 % CI 0.45–1.07; P < 0.001). [Fig. 3] shows an example of the effect of POEM on a large diverticulum. [Table 2] also provides the results of the self-reported improvement of esophageal complaints
after POEM. In total 13 patients noticed improvement, seven of whom had no complaints.
Of 16 patients who underwent gastroscopy after POEM, seven patients (41.2 %) had reflux
esophagitis, in whom three were grade A, two grade B, one grade C and one grade D.
Besides, GERD symptoms were reported as “sometimes” in 50 % and “often” in 6.3 % of
patients. PPIs, mainly omeprazole, were used by 75 % of the patients. Four patients
used PPIs once a day, seven patients twice a day and one patient only used a PPI when
experiencing GERD symptoms. GERD symptoms were well controlled with PPIs in all patients.
Fig. 3 Barium esophagogram of a patient with a large epiphrenic diverticulum. a before POEM. b after POEM.
Procedure-related outcomes
[Table 3] provides an overview of the procedure-related outcomes. Procedure time and the number
of days in hospital were normally distributed. Total length of myotomy and the time
between diagnosis of esophageal motility disorder and POEM did not follow a normal
distribution. The median time between date of diagnosis of esophageal motility disorder
and POEM was 10.5 months with a range from 0 to 53 months. The length of myotomy differed
from 7 cm to 16 cm with a mean length of 10.5 cm. Clinical admission for all patients
was one night. Mucosal injury occurred during one procedure, which was immediately
noticed and closed with four extra hemoclips. This procedure-related event had no
influence on patient outcome or hospital stay duration. Two AEs were reported within
30 days after POEM and were classified as grade II and grade IIIa according to the
AGREE classification [28].
Table 3
Procedure-related outcomes.
|
N = 17
|
|
Total length of myotomy, cm, median (IQR)
|
10 (4)
|
|
Location of myotomy
|
|
|
12 (70.6)
|
|
|
5 (29.4)
|
|
Procedure time, minutes, mean (SD)
|
88 (34)
|
|
Number of days in hospital, days, mean (SD)
|
2 (0)
|
|
Procedure-related events
|
1 (5.9)
|
|
Mucosal injury
|
1 (5.9)
|
|
Adverse events < 30 days after POEM[1]
|
2 (11.8)
|
|
|
1 (5.9)
|
|
|
1 (5.9)
|
Results are presented as n (%) unless otherwise stated.
1 Based on Classification for Adverse events Gastrointestinal Endoscopy (AGREE). IQR,
interquartile range; SD, standard deviation; POEM, peroral endoscopic myotomy.
Discussion
The results of this study suggest that POEM is an effective and safe treatment for
patients with an esophageal diverticulum. Of the 17 patients included, 16 had an underlying
esophageal motility disorder showing a large overall reduction in symptoms as well
as a reduction in diverticulum size. Only one patient required retreatment after POEM
and in the other 16 patients, the effect of POEM was sufficient that additional treatment
was deemed unnecessary. One patient had normal esophageal motility and did not benefit
from the POEM treatment. Thus, it seems imperative to carefully consider whether an
esophageal diverticulum in a patient without underlying esophageal motility disorder
is truly the cause of the symptoms.
There is a small number of series describing the effect of POEM without diverticulotomy
for esophageal diverticula. A retrospective study by Kinoshita et al (2020) concluded
that POEM alone for patients with an esophageal motility disorder and an epiphrenic
diverticulum was effective and safe. In their study with 14 patients, the median Eckardt
score significantly decreased from 5 (range 2–11) before POEM to 0 (range 0–2) after
POEM. No difference in perioperative complications in patients with and without epiphrenic
diverticula was observed [8]. Further, only small case series and case reports are published that concluded that
POEM without diverticulotomy was safe and effective as treatment for patients with
an esophageal diverticulum [17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26].
In a randomized controlled trial in which the effect of POEM was compared to pneumatic
dilatation in patients with achalasia, the treatment success rate of POEM was 92 %
after 2 years [29]. When comparing the effect of POEM to LHM, the treatment success rates for POEM
were 94.6 % and 83 % after 3 months and 2 years, respectively [30]. These treatment success rates differ from the findings in our current series. A
possible explanation for this difference might be that our series consisted of a more
heterogeneous group and only 77 % of the patients were diagnosed with achalasia.
POEM appeared to be safe for patients with esophageal diverticula and an underlying
motility disorder. In total, one procedure-related event was reported, which had no
influence on patient outcome or hospital stay duration. Two AEs within 30 days after
POEM occurred in our patients. Both patients were readmitted because of postoperative
retrosternal pain with need for non-opioid pain control in one patient and the other
patient received a duodenal feeding tube for 25 days because of partial dehiscence
of the mucosal incision that healed under conservative management.
Surgical diverticulectomy is successful in reducing symptoms of esophageal diverticula
but carries a relatively high AE rate of 21 % to 27 % with suture leakage as the most
frequently recorded complication with rates up to 13 % [10]
[11]. The potential benefit of an intervention for the esophageal diverticula must always
be weighed against the complication risk. Zaninotto et al (2008) compared the outcomes
of patients with esophageal diverticula after surgical diverticulectomy and after
a conservative approach. They concluded that surgical diverticulectomy was effective
in reducing esophageal symptoms. On the other hand, it was also safe to treat asymptomatic
or mildly symptomatic patients conservatively [31]. To date, no study has been performed comparing the outcome of patients with esophageal
diverticula undergoing POEM and a conservative approach. From our results, it seems
that the size of the diverticulum is not related to complaints or complication risk,
and therefore, it is questionable whether the size of the diverticulum should play
a role in determining the indication for intervention [14].
The main disadvantage of POEM is the risk of post-procedure gastroesophageal reflux.
In this study, the GERD symptoms did not correspond with the presence of reflux esophagitis.
Three of seven patients with reflux esophagitis had no GERD symptoms. In addition,
six of nine patients without reflux esophagitis did have GERD symptoms. GERD symptoms
were well controlled with PPIs, but the dose varied among patients. Previous studies
reporting the risk of reflux esophagitis and GERD symptoms after POEM are not conclusive.
Usually, GERD symptoms are less frequent after POEM than reflux esophagitis [32]. As compared to LHM, fundoplication is usually not performed during POEM, and therefore,
the risk of reflux esophagitis is higher after POEM. However, transoral incisionless
fundoplication is an emerging minimally invasive endoscopic fundoplication technique
but the long-term efficacy and safety is unknown [33]. With longer follow up, the difference in prevalence of reflux esophagitis between
POEM and LHM becomes smaller.
There are a few limitations of this study. Because esophageal diverticula are rare
and POEM is not a standard intervention, the sample size was relatively small. Nonetheless,
together with the study by Kinoshita et al (2020), this was the largest study evaluating
the effect of POEM in patients with esophageal diverticula [8]. Another limitation is that the time between POEM and the survey varied and ranged
from 6 to 93 months after POEM. From the survey, however, it can be concluded that
there is a considerable improvement with a decrease in Eckardt scores in most patients,
even after a long period of follow up. In view of the retrospective study design,
no control group was included in this study. Treatment effect and AEs, therefore,
could not be compared with standard care or other treatment.
POEM may reduce the resistance in the distal esophagus that makes food pass more easily,
and thus, reduce intraluminal pressure. The underlying esophageal motility disorder
is treated with POEM as well. This will contribute to reduction in symptoms and prevent
development of new diverticula. When a patient has an esophageal diverticulum, a diverticular
peroral endoscopic myotomy (D-POEM) can be performed in which septum division is carried
out in addition to the esophageal myotomy [34]. This treatment appeared to be effective and safe for patients with esophageal diverticula,
although samples sizes of reported studies are small [35]
[36]
[37]
[38]
[39]
[40]. Some authors suggest that D-POEM is preferred because septotomy is relatively easy
to perform and additional diverticulotomy after a previous POEM can be difficult [37]. Our data suggest that additional diverticulotomy might not be necessary to achieve
satisfactory treatment results. However, not all patients were asymptomatic after
POEM and therefore, treatment can be further optimized. Persistent symptoms might
be explained by the remaining diverticular pouch or sometimes the diverticulum may
not be the cause of all symptoms after all. Further research is required to compare
effect and safety of D-POEM versus POEM without diverticulotomy, to establish the
long-term effects of POEM in patients with esophageal diverticula and to compare the
effect with other treatments. Also, questions about the timing of intervention remain
to be elucidated.
Conclusions
In conclusion, our data provide further evidence that POEM is feasible, safe and effective
as treatment for patients with esophageal diverticula and an underlying esophageal
motility disorder.
Contributorʼs statement
EMW, JMS and AJB designed the study. JMS and AJB supervised the project. EMW collected
the data and was responsible for project administration. EMW performed the data and
statistical analysis. All authors contributed to the interpretation of the results.
EMW wrote the manuscript with input from all authors. All authors had full access
to the data and approved the final manuscript.
