IJGII Inernational Journal of Gastrointestinal Intervention

pISSN 2636-0004 eISSN 2636-0012
ESCI
scopus

Article

home All Articles View

Review Article

Int J Gastrointest Interv 2020; 9(2): 53-61

Published online April 30, 2020 https://doi.org/10.18528/ijgii200012

Copyright © International Journal of Gastrointestinal Intervention.

Management of achalasia in 2020: Per-oral endoscopic myotomy, Heller’s or dilatation?

Mohan Ramchandani * and Partha Pal

Department of Medical Gastroenterology, AIG Hospitals, Hyderabad, India

Correspondence to:* Department of Medical Gastroenterology, AIG Hospitals, Plot No 2/3/4/5, Survey No 136, 1 Mindspace Rd., Gachibowli, Hyderabad, Telangana 500032, India.
E-mail address: ramchandanimohan@gmail.com (M. Ramchandani).

Received: February 28, 2020; Revised: April 3, 2020; Accepted: April 3, 2020

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Go to

Achalasia cardia is a rare esophageal motility disorder. Although a primary neurological disorder, the treatment modalities of achalasia are primarily endoscopic or surgical. Pneumatic dilatation (PD) or laparoscopic Heller’s myotomy (LHM) have been the mainstay of achalasia management for several decades. With the introduction of third space endoscopy, the endoscopic management of achalasia has revolutionized. Randomized studies have concluded the superiority of per-oral endoscopic myotomy (POEM) over PD. In addition, the short-term outcomes of POEM are similar to LHM. POEM is a relatively new technique and long-term data is eagerly awaited. The main concern after POEM is a high incidence of gastroesophageal reflux disease (GERD) which is found in about half of the patients undergoing this procedure. GERD is higher after POEM when compared to PD and LHM with fundoplication. The management of achalasia should be individualized and based on factors like patient characteristics (age, sex, comorbidities), subtyping on high resolution manometry, patient/doctor preference, and surgical risk of the patient.

Keywords: Dilatation, Esophgeal achalasia, Heller myotomy, Per-oral endoscopic myotomy procedure

Introduction

Go to

Achalasia cardia is a primary esophageal motility disorder of unknown etiology. It is characterized by esophageal aperistalsis and insufficient relaxation of the lower esophageal sphincter (LES) in response to deglutition.1 The most widely accepted pathophysiological basis of achalasia is selective loss of inhibitory innervation from the myenteric plexus of the esophagus and LES due to genetics, infection, and autoimmune etiologies.1

The goal of achalasia treatment is to reduce the LES pressures, alleviate symptoms of dysphagia and regurgitation, improve esophageal emptying, and prevent the development of end stage achalasia.

Treatment modalities for achalasia include pharmacological therapy, endoscopic (botulinum toxin [BT] injection, pneumatic dilatation [PD], and per-oral endoscopic myotomy [POEM]), and surgical (laparoscopic Heller’s myotomy [LHM] and esophagectomy) (Table 1).2,3 Of these, pharmacotherapy and BT injection are primarily utilized in high risk patients who are not candidates for more durable treatment options like PD, LHM, and POEM.4,5

Table 1 . Advantages and Disadvantages of Different Modalities of Treatment of Achalasia Cardia.

TherapyAdvantageDisadvantage
Surgical myotomy (LHM)

Long-term durability.

Procedure time - 90 min.

Excellent response rate (90%–97% with 3%–10% recurrent dysphagia).

General anaesthesia required.

Higher recovery time - hospital stay for 2–3 days.

Cost.

GER (2%–26%): minimized with fundoplication.

PD

Most effective non-surgical option.

Durability range - 2–5 yr.

Short procedure.

Short recovery time.

Can be done on demand.

Risk of perforation (1%–5%).

Advised only in surgically fit candidates (who can be taken for surgery if complication occurs).

Response rate poor in young male (< 40 yr), type III and I achalasia (33% and 63%, respectively).

Relapse in 33%–50% patients.

POEM

Long-term durability comparable to LHM.

Minimally invasive - lesser hospital stay.

Longer myotomy - useful in type III achalasia and other motility disorders.

Limited availability and technically demanding.

High incidence of GER (20%–54%) - can be reduced by concurrent endoscopic fundoplication.

Medical therapy

Can be taken as on demand therapy.

Minimal risk for candidates with high surgical risk.

Least effective treatment option.

Short lasting effect and continuous treatment required.

High incidence of adverse effects of medications.

Esophagectomy

For end stage disease.

For treatment resistant achalasia.

High morbidity and mortality.

May develop anastomotic site strictures.

Chronic vomiting observed in some patients.

BT injection

Good option for high surgical risk candidates.

Short procedure time.

Durability of 6–12 mo.

Submucosal injection precludes future definitive therapy.

LHM, laparoscopic Heller’s myotomy; GER, gastroesophageal reflux; PD, pneumatic dilatation; POEM, per-oral endoscopic myotomy; BT, botulinum toxin..

In this review, we shall limit our discussion to the major modalities used for achalasia i.e., PD, POEM, and LHM.

PD

Go to

PD works by circumferential stretching and in some cases tearing of LES circular muscle fibres. PD is an effective and widely utilized endoscopic treatment for achalasia. The most widely used balloon dilator is the non-compliant, polyethylene balloon i.e., RIGIFLEX (Boston Scientific, Natick, MA, USA). Pneumatic balloons are available in three diameters (3.0, 3.5, and 4.0 cm) for graded dilatation (Fig. 1).6

Figure 1. Steps of pneumatic dilatation. (A) Fluoroscopy picture showing gastroesophageal junction marked (arrow) and guidewire inserted. (B) RIGIFLEX balloon inserted over the guidewire. (C) Balloon inflated and waist appears in the middle of the balloon. (D) Balloon fully inflated and waist disappeared.

Outcomes

Initial response rates with PD is around 71% to 90%. However, relapse rates after initial remission are found in 30%–50% patients on follow-up.7–9 Graded and on demand dilatation is the accepted standard of care with respect to PD. With this approach, a long-term remission rate of up to 90% has been reported in recent trials.10,11 The median time to relapse after PD in long-term follow-up studies (> 10 years) is between 5–11 years.7,9,12,13

In ‘graded approach’ the smallest balloon (30 mm) is used for dilatation initially (35 kPa for 1 minute followed by 55 kPa for 1 minute). Subsequent dilatations are performed using incrementally larger balloons in those with persistent or recurrent symptoms (35 mm after 1–3 weeks, and 40 mm if Eckardt’s score > 3). In cases with late relapse (> 1 year) after completion of graded regimen, repeated dilatations have been shown to be effective in ameliorating the symptoms. In a large, retrospective study, long-term (10 years) response rates were superior with on demand dilatations as compared to single dilatation (90% vs 50%).8 However, in patients with persistent symptoms or early relapse (< 1 year) after graded PD alternative options like LHM or POEM should be considered. Some experts perform incremental dilatations on the same or consecutive days until pre-specified manometric (LES pressure < 15 mmHg) or radiographic goals are met.14 It is important to note that the technique of PD is not standardized making it difficult to compare the outcomes between different studies.

Predictors of response/failure

The predictors of good response after achalasia include type II achalasia and age > 40 years. The risk factors for non-response to PD include non-graded dilatation, age < 40 years, pre-existing daily chest pain, and pre-treatment width of the esophagus of < 4 cm.11,15 In addition, spastic esophageal motility disorders including type III achalasia, Jackhammer oesophagus, and distal esophageal spasm do not respond well to PD. Of the different symptoms of achalasia, chest pain responds in only about 50% of the patients.7,9,15,16

PD in special populations (children and prior treatment groups)

The data on the outcomes of PD in pediatric achalasia are limited. In few studies, good response (success 87%) has been found especially in older children.17 Of note, the currently available pneumatic balloons have not been specifically designed for use in small children (< 8 years).

The resonse rate to PD is lower (~50%) in patients with symptom relapse after Heller’s myotomy. Nevertheless, PD has been shown to be a safe procedure in patients with failed myotomy.18 Similarly, the response to PD is poor (0%–20%) in cases with recurrent symptoms after POEM.19

The data is limited regarding the outcomes of PD in pregnant patients. Few case reports have reported successful PD and BT injection in second trimester of pregnancy.20,21

Complications of PD

PD dilatation is a safe procedure and major complications are uncommon. The most feared complication associated with PD is perforation which has been reported in 1%–5% of patients. Lower rates of perforation have been reported in studies from high volume centres.22 The risk factors for perforation after PD include use of larger (> 35 mm) balloon for initial dilatation, old age, and unstable balloon position during PD.11,22–24

Tachycardia and chest pain persisting > 4 hours should alert the endoscopist about the possibility of perforation.25 Majority of the perforations after PD can be managed conservatively. However, larger perforations with free flow of barium into mediastinum require surgical repair.26 For the same reason, PD should be preferably avoided in high surgical risk patients. Other management options include endoscopic closure (over the scope clips, endoscopic suturing, and esophageal stents) and video-thoracoscopic repair.27–29

Gastroesophageal reflux disease (GERD) is uncommon after PD and has been reported in 4%–37% cases.8,30,31 Overall incidence of gastroesophageal reflux is low after PD.1,2,25

LHM

Go to

LHM is a widely performed surgical procedure for achalasia cardia. The main advantage of LHM over PD is durable response and reduced requirement of repeated interventions. The technique of Heller’s myotomy has undergone several critical modifications since its initial description by Heller in 1913.2,32 These modifications include the development of minimally invasive approach, addition of fundoplication procedure to reduce the incidence of GERD and performing an extended myotomy on gastric side to prevent future recurrences.33,34

Minimally invasive approaches are associated with shorter postoperative pain, and hospital stay as compared to open surgical myotomy.35 With the availability of minimally invasive surgical options, open surgical myotomy is performed only in exceptional circumstances like in cases with multiple prior surgeries or in those who cannot tolerate a pneumoperitoneum due to severe cardiopulmonary disease.35 Currently, a laparoscopic approach is preferred as it is associated with a shorter operating time, lower rate of conversion to an open myotomy and shorter hospital stay as compared with thoracoscopic approach.36,37

Anterior (Dor) or posterior (Toupet) fundoplication

Partial fundoplication is an essential component of LHM and can be performed anteriorly (Dor fundoplication, 180 degree) or posteriorly (Toupet fundoplication, 270 degree). Both the approaches are equivalent in terms of post-operative dysphagia and reduction in the incidence of GERD. In a randomized controlled trial (RCT), the incidence of GERD was lower in posterior fundoplication group. However, the difference was not statistically significant (21% vs 42%) (Table 2).38 Therefore, the choice of anterior or posterior fundoplication is largely operator dependent.

Table 2 . Summary of Landmark Randomized Clinical Trials in Achalasia Cardia Treatment by PD, LHM, and POEM.

StudyComparisonnSuccess (%)Follow-upAdverse events (%)GERD (%)Drawback
Ponds et al (2019)77POEM67922 yr041Only allowed PD up to 35 mm
vsConsidered re-dilatation as treatment failure
PD (30 and 35 mm)6654 (P < 0.001)37
Werner et al (2019)39POEM112832 yr2.744Length of myotomy was not standardized
vsPOEM was not accompanied by any anti-reflux procedure where LHM was done with for fundoplication
LHM + Dor fundoplication10981.7 (P = 0.007, non-inferiority)7.329
Boeckxstaens et al (2011)10PD9686 (2 yr)43 mo415Follow-up short as effect may decrease over time
vsRigorous PD protocol over 2 yr - only 3rd series of PD within 2 yr of 2nd series considered as failure
LHM + Dor Fundoplication10590 (2 yr) (P = 0.46)1223
Moonen et al (2016)11PD96825 yr512Re-dilatation required in 25% of PD patients - considered as treatment success
vs
LHM + Dor Fundoplication105841134
Khashab et al (2020)50Anterior73901 yr1149Single blinded
vsAbnormal acid exposure presented based on DeMeester score alone rather than percentage of time pH < 4
Posterior POEM7789942
Tan et al (2018)48Anterior3110015.5 mo12.926.7Small number
vsSingle centre
Posterior POEM321003.1 (P = NS)33.3 (pH study)Short follow-up
Mostly type II achalasia
Ramchandani et al (2018)49Anterior30100% technical success both groups6 mo2016Short follow-up
vsPilot study - small number
Posterior POEM30Similar reduction in LES pressure3.3 (mucosal perforation)37Single centre
Richards et al (2004)34LHM21Postoperative LES pressure comparable6 moNone47.6Small number
vsSingle centre
LHM + Dor Fundoplication22Primary outcome9 (P = 0.005)Very short follow-up (6 mo)
GERDConcern for incomplete myotomy
Rawlings et al (2012)38LHM + Dor36Similar symptoms relief of dysphagia6–12 mo5.542Small number
vsClinically significant GERD not measured
LHM + Toupet fundoplication24Primary outcome GERD8.321 (P = 0.152)

PD, pneumatic dilatation; LHM, laparoscopic Heller’s myotomy; POEM, per-oral endoscopic myotomy; LES, lower esophageal sphincter; GERD, gastroesophageal reflux disease; NS, not significant..

Outcomes of LHM

LHM has been extensively evaluated for the management of achalasia. In the European achalasia trial, the response rates to LHM at 1, 2, and 5-years are 93%, 90%, and 82%, respectively.10,11 In a more recent randomized trial, the clinical success at 2-years was 81.7%.39 Extended gastric myotomy (3 cm vs 1.5 cm) has been shown to improve success rates and reduce recurrences after LHM.33 In contrast to non-sigmoid achalasia, the outcomes of LHM in sigmoid achalasia are sub-optimal. The decision to add fundoplication in these cases should be carefully made.40

Adverse events

The most common complication following LHM is perforation (1%–7%) due to unrecognized mucosal injury during surgery.41 Some surgeons prefer an anterior fundoplication in these cases as it usually buttresses the repair.

GERD has been reported in 2%–26% of cases after LHM with fundoplication. In a meta-analysis, the pooled rate of post-procedure reflux symptoms, abnormal oesophageal acid exposure, and esophagitis were 8.8%, 16.8%, and 7.6%, respectively after LHM. The addition of fundoplication procedure to LHM reduces rate of pathological GERD from 47.6% to 9%. Similar reduction in esophageal acid exposure time has been reported after fundoplication (4.9% to 0.4%).34

Other adverse events are rare after LHM and include inadvertent division of vagus nerve (diarrhoea, bloating, early satiety or dumping syndrome) and splenic injury (1%–5%).42

POEM

Go to

POEM is a novel endoscopic procedure for achalasia based on the principles of submucosal endoscopy with mucosal flap safety valve technique. Since its introduction nearly a decade ago by Inoue et al,43 POEM is among the most widely performed procedures for achalasia.

Technique of POEM and variations

POEM is performed with the patient in supine position under general anaesthesia. Contraindications to POEM include coagulopathy, cirrhosis with portal hypertension, severe erosive esophagitis, esophageal submucosal fibrosis (e.g., radiation, endoscopic mucosal resection, radiofrequency ablation), and severe cardiopulmonary diseases.44,45

We have previously described the technique of POEM procedure.46 In brief, the steps of POEM procedure include mucosal incision, creation of a submucosal tunnel, myotomy, and closure of mucosal incision with multiple clips (Fig. 2). The length of esophageal myotomy is decided on the type of achalasia and manometry findings. Long esophageal myotomy is required in cases with type III achalasia. On the other hand, the length of gastric myotomy should be at least 2-cm in all the achalasia sub-types to avoid future recurrences. However, a long gastric myotomy (> 4 cm) should be avoided as it may lead to higher risk of severe erosive esophagitis.47

Figure 2. Steps of per-oral endoscopic myotomy. (A) Mucosal incision by needle knife. (B) Extension of incision. (C) Entry into submucosal plane. (D) Submucosal dissection. (E) Myotomy. (F) Closure of mucosal incision site by clips.

Several variations in the POEM technique have been described in the literature. These include orientation of myotomy (anterior, posterior or greater curvature), length of myotomy (short vs long), and thickness of myotomy (full thickness vs selective circular). All the approaches have similar efficacy with no clinically relevant difference in adverse events or incidence of GERD.48–52 Muscle fibres are cut in 1–2 o’clock and 5–6 o’clock position in anterior and posterior myotomy, respectively (Fig. 3). Currently, posterior approach is being increasingly used by endoscopists due to technical ease as accessories emerge from 6 o’clock position. Also, in patients with a history of prior Heller’s myotomy posterior orientation is preferred to avoid submucosal fibrosis during POEM.53 Therefore, the technique of POEM is largely operative dependent. However, greater curvature myotomy is not performed widely as it leads to disruption of ‘angle of His’ which may predispose to GERD.

Figure 3. Sites of myotomy. (A) Anterior myotomy (1–2 o’clock position). (B) Posterior myotomy (5–6 o’clock position).

A novel cautery device (Speedboat-RS2; Creo Medical Ltd., Chepstow, Wales, UK) which uses bipolar radiofrequency energy for cutting and microwave for coagulation has been described in creation of submucosal tunnel in POEM.54 The use of the device has been described recently for endoscopic submucosal dissection.55 The advantages of the device is that there is no need to change accessories for submucosal injection (has integrated injection needle) and coagulating vessels, capability of rotation to optimize cutting and coagulation, bipolar cutting and protective hull avoiding injury to muscle and mucosa.54,55

Outcomes of POEM

Over last decade, multiple studies with short- and medium-term follow-up have concluded the safety and efficacy of POEM for achalasia.56,57 The technical and clinical efficacy of POEM is > 90% and 80%–90%, respectively. POEM is also effective in patients with a history of prior treatment.58 The efficacy of POEM in patients with recurrent symptoms after LHM is 81% to 95% in different studies.59–61 Majority of the published data depicts the outcome of POEM on short-term follow-up. The efficacy of POEM in studies reporting long-term outcomes is between 80%–90%, suggesting that the response is durable after POEM.62–65 The long-term efficacy of POEM remains to be seen in large, prospective studies as these studies are mostly retrospective with only a proportion of patients completing entire follow-up.

A risk score (Zhongshan POEM score) has been proposed based on history of previous treatment, mucosal injury, and clinical reflux to predict risk of failure after POEM based on data from a large cohort (n = 1,538) from Shanghai, China. The patients in the high-risk group were 4 times more likely to encounter clinical failure on follow-up.66 Another study described high Eckardt score ≥ 9 as a predictive factor for POEM failure.67

Adverse events

POEM is a safe procedure with relatively uncommon serious adverse events. Different severity grading systems utilized in the published literature has resulted in considerable heterogeneity in the incidence of adverse events. The incidence of major adverse events in large studies ranges from 0.5% to 3.3%.62 Insufflation related events are common during POEM but usually do not translate into clinically significant adverse events. These include subcutaneous emphysema (7.5%), pneumothorax (1.2%), pneumomediastinum (1.1%), and pneumoperitoneum (6.8%).68 The use of CO2 which has a higher diffusion capacity than air has remarkably reduced the occurrence of insufflation related adverse events.69

Mucosal injuries are the second most common adverse events during POEM. Most of them can be identified and managed intra-operatively. A history of submucosal fibrosis, previous myotomy (Heller’s or POEM), mucosal edema, long tunnel (> 13 cm) are predisposing factors for mucosal injury.70 Other adverse events are rarer and include major bleeding, aspiration pneumonia, delayed mucosal barrier failure, mediastinitis, esophageal leaks, and pulmonary like pleural effusion.68 Most of them do not require major surgical intervention and can be managed intra-operatively.

POEM and gastroesophageal reflux

GERD is an important long-term adverse event of POEM procedure. Recent studies indicate a high incidence of GERD after POEM. In the published studies, the prevalence of symptoms, reflux esophagitis, and increased esophageal acid exposure after POEM ranges from 17% to 40%, 18% to 65%, and 13% to 58%, respectively.71 The predictors of post-POEM reflux include low integrated relaxation pressure after POEM, female sex, high body mass index (BMI), and the presence of hiatus hernia. However, these predictors need to be validated in large, prospective trials. On the contrary, the technical variations in POEM procedure have no significant impact on the incidence of GERD after POEM.71,72

Novel techniques to prevent reflux

Prevention of reflux is the one of the core concerns among the endoscopists performing POEM procedure. Several novel technical modifications have been proposed to reduce the incidence of post POEM GERD. These include avoidance of excess myotomy (> 4 cm) on the gastric side, preservation of sling or oblique fibers during posterior POEM (Fig. 4) and creating a fundoplication wrap during POEM NOTES-F (natural orifice transluminal endoscopic surgery-fundoplication) (Fig. 5).73–75 Of note, the double scope technique provides more accurate estimation of the extent of gastric myotomy and should utilized whenever feasible. Although appealing, the utility of these novel techniques remains to be seen in randomized trials.75

Figure 4. Showing technique of preservation of sling fibres by identifying two penetrating vessels (TPV). (A) The boundary between circular and oblique muscles, muscles of gastric cardia identified by TPV. (B) Preservation of sling fibres identifying TPV as the distal end of myotomy.
Figure 5. Steps of per-oral endoscopic myotomy with fundoplication. (A) Full-thickness myotomy done along the anterior wall of the submucosal tunnel. (B) Entry into peritoneal cavity. (C) The left lobe of liver and anterior side of stomach is seen. (D) Endoloop fixed with clips to anterior wall of stomach (distal anchor) (proximal anchor at distal end of myotomy site - not shown in picture). (E) By closing endoloop and approximating proximal and distal anchors fundoplication is completed. (F) Endoscopic view shows fundoplication wrap in funds of stomach.

Comparison of Different Treatment Modalities (Table 2)

Go to

PD vs LHM

LHM is a more durable treatment with less requirement of re-interventions as compared to PD. On the other hand, the efficacy of single session of PD is very low (50%) and re-dilatations are required in about a quarter of patients after graded dilatation. Graded and on demand PD have been found to provide similar efficacy to LHM in the landmark European achalasia trial.11 The efficacy of PD and LHM at 1 year (90% vs 93%), 2 years (86% vs 90%), and 5 years (82% vs 91%) was comparable with no difference in the objective parameters including LES pressure, quality of life, and esophageal acid exposure.10,11 The requirement for re-dilatation was higher in a subgroup of patient less than 40 years of age.10,31

PD vs POEM

In a large retrospective study, POEM was more effective than PD in all the sub-types of achalasia. The efficacy of POEM vs PD was 92% vs 51% in type I (P = 0.004), 92.3% vs 59.8% in type II (P = 0.007), and 91.7% vs 55.6% (P = 0.051) in type III achalasia.76 In a multi-center randomized trial comparing POEM with PD, treatment success was achieved in 92% of patients in POEM group as compared to 54% of patients in the PD group at two-years follow-up. On the other hand, reflux esophagitis was significantly more frequent after POEM as compared to PD (41% vs 7%).77 These studies suggest that POEM is more effective than PD at least in short-term follow-up. Of note, PD in the above RCT was limited to 1–2 dilatations (30-mm and 35-mm). The second dilatation was performed only if there was an inadequate symptom or physiologic response. This is in contrast to conventional graded dilatation protocol from 30 to 40 mm until symptom relief. Inclusion of 40 mm balloon may have improved the success rate from 54% to 76%. Also repeat dilatations due to recurrence of symptoms were considered as treatment failure. This might explain the lower success rates of PD in this study (85%–90% success rate at 2 to 5-year in earlier studies).77

POEM vs LHM

The comparison between LHM and POEM is limited to one randomized trial and multiple small nonrandomized studies. A meta-analysis consisting of 74 cohort studies with more than 7,000 patients concluded that POEM results in higher rate of dysphasia relief (93.5% vs 91% at 1 year and 92.7% vs 90% at 2 years, both statistically significant) than LHM. However, the follow-up was longer in the LHM group (41.5 vs 16.2 months).78 In the only published randomized trial, POEM (112 patients) was compared to LHM plus Dor’s fundoplication (109 patients). Clinical success at the 2-year follow-up was similar in both the groups (83.0% vs 81.7%). Serious adverse events occurred in 2.7% of patients in the POEM group and 7.3% of patients in the LHM group. Reflux esophagitis was higher in the POEM group (44% vs 29%).39 POEM and LHM appear comparable in efficacy with higher reflux rates after POEM.

Individualized Approach to Achalasia: One Size Does Not Fit All

Go to

Achalasia cannot be cured with the currently available treatment options which are directed at reducing LES pressures. A finite proportion of cases do relapse on follow-up irrespective of the treatment modality used. Presently, there are three effective treatment options for achalasia cardia i.e., PD, POEM, and LHM. The choice between these three is based on patient characteristics like age and co-morbidities, type of achalasia, available expertise and patient’s preference (Fig. 6). The best candidates for PD are those older than 40 years and those with type II achalasia. Type I and III achalasia do not respond well as compared to type II achalasia (63% vs 33% vs 90%). The possible requirement of repeated dilatations and small risk of perforation (1%–3%) should be conveyed to the patients. Graded dilatation followed by on demand dilatation is the standard of care and anything less is likely to give sub-optimal results with PD. Both LHM and POEM are effective modalities with fewer requirement for re-interventions (Table 3).79–82 LHM and POEM should be preferred over PD in young patients (< 40 years) and those with spastic esophageal motility disorders. Since there is no difference in efficacy (type I and II achalasia), the choice between these two is largely determined by the available expertise and the treating physician or surgeon’s preference. POEM may be preferred over LHM in type III or spastic achalasia and in those with spastic esophageal motility disorders. The ability to perform long esophageal myotomy is the reason for better response rates with POEM as compared to LHM in spastic esophageal motility disorders. Similarly, POEM is more efficacious than PD in patients with prior Heller’s myotomy. In patients with relapse of symptoms after POEM, re-do POEM and LHM may be superior to PD. The major drawback of POEM is limited data on outcomes during long-term follow-up and a high incidence of GERD. LHM should be preferred to POEM in patients with high risk of post-POEM reflux like those with concomitant hiatal hernia and high BMI. On the contrary, LHM has been shown to effective in long-term and the incidence of reflux is significantly lower than POEM. The risk of GERD and possible need to stay on proton pump inhibitors for long-term should be discussed with the patient while contemplating POEM procedure. At this point, POEM may be avoided in pediatric age group as they may be exposed to acid exposure for more years of which the consequences are not well-known.

Table 3 . Comparison of Efficacy according to Achalasia Subtype.

PDLHMPOEM
Type I AC (%)63–8579,81818191.346
Type II AC (%)90–9379,8193–1008196.346
Type III AC (%)33–4079,8180–8680,8188–9846,79
Overall efficacy (%)44–841157–89.311,31,3975–9746,56,69
Follow-up (yr)≥ 5≥ 51–3
GERD (%)4312–3334,38,8220–5456,71,72

PD, pneumatic dilatation; LHM, laparoscopic Heller’s myotomy; POEM, per-oral endoscopic myotomy; AC, achalasia cardia; GERD, gastroesophageal reflux disease..
Figure 6. Current management algorithm of achalasia cardia (AC). AC is divided into 3 types based on high resolution manometry. High surgical risk cases can be considered for botulinum toxin (BT) injection. For young and type I achalasia patients, either POEM or LHM are initial choices due to suboptimal results with PD. For type II AC, either of PD or LHM or POEM can be done. For type III AC, POEM with long myotomy followed by LHM should be the initial choices. On failing therapy, re-do PD/POEM/LHM can be done. Resistant cases can be subject to esophagectomy. CT, computed tomography; EUS, endoscopic ultrasonography; POEM, per-oral endoscopic myotomy; LHM, laparoscopic Heller’s myotomy; PD, pneumatic dilatation.

References

Go to
  1. Reynolds JC, Parkman HP. Achalasia. Gastroenterol Clin North Am. 1989;18:223-55.
    Pubmed
  2. Spiess AE, Kahrilas PJ. Treating achalasia: from whalebone to laparoscope. JAMA. 1998;280:638-42.
    Pubmed CrossRef
  3. Boeckxstaens GE, Zaninotto G, Richter JE. Achalasia. Lancet. 2014;383:83-93.
    Pubmed CrossRef
  4. Wang L, Li YM, Li L. Meta-analysis of randomized and controlled treatment trials for achalasia. Dig Dis Sci. 2009;54:2303-11.
    Pubmed CrossRef
  5. Bassotti G, Annese V. Review article: pharmacological options in achalasia. Aliment Pharmacol Ther. 1999;13:1391-6.
    Pubmed CrossRef
  6. Kadakia SC, Wong RK. Graded pneumatic dilation using Rigiflex achalasia dilators in patients with primary esophageal achalasia. Am J Gastroenterol. 1993;88:34-8.
    Pubmed
  7. Ghoshal UC, Kumar S, Saraswat VA, Aggarwal R, Misra A, Choudhuri G. Long-term follow-up after pneumatic dilation for achalasia cardia: factors associated with treatment failure and recurrence. Am J Gastroenterol. 2004;99:2304-10.
    Pubmed CrossRef
  8. Zerbib F, Thétiot V, Richy F, Benajah DA, Message L, Lamouliatte H. Repeated pneumatic dilations as long-term maintenance therapy for esophageal achalasia. Am J Gastroenterol. 2006;101:692-7.
    Pubmed CrossRef
  9. Eckardt VF, Gockel I, Bernhard G. Pneumatic dilation for achalasia: late results of a prospective follow up investigation. Gut. 2004;53:629-33.
    Pubmed KoreaMed CrossRef
  10. Boeckxstaens GE, Annese V, des Varannes SB SB, Chaussade S, Costantini M, Cuttitta A, et al. Pneumatic dilation versus laparoscopic Heller's myotomy for idiopathic achalasia. N Engl J Med. 2011;364:1807-16.
    Pubmed CrossRef
  11. Moonen A, Annese V, Belmans A, Bredenoord AJ, Bruley des Varannes S S, Costantini M, et al. Long-term results of the European achalasia trial: a multicentre randomised controlled trial comparing pneumatic dilation versus laparoscopic Heller myotomy. Gut. 2016;65:732-9.
    Pubmed CrossRef
  12. Karamanolis G, Sgouros S, Karatzias G, Papadopoulou E, Vasiliadis K, Stefanidis G, et al. Long-term outcome of pneumatic dilation in the treatment of achalasia. Am J Gastroenterol. 2005;100:270-4.
    Pubmed CrossRef
  13. Elliott TR, Wu PI, Fuentealba S, Szczesniak M, de Carle DJ DJ, Cook IJ. Long-term outcome following pneumatic dilatation as initial therapy for idiopathic achalasia: an 18-year single-centre experience. Aliment Pharmacol Ther. 2013;37:1210-9.
    Pubmed CrossRef
  14. Hulselmans M, Vanuytsel T, Degreef T, Sifrim D, Coosemans W, Lerut T, et al. Long-term outcome of pneumatic dilation in the treatment of achalasia. Clin Gastroenterol Hepatol. 2010;8:30-5.
    Pubmed CrossRef
  15. Csendes A, Braghetto I, Henríquez A, Cortés C. Late results of a prospective randomised study comparing forceful dilatation and oesophagomyotomy in patients with achalasia. Gut. 1989;30:299-304.
    Pubmed KoreaMed CrossRef
  16. Eckardt VF, Aignherr C, Bernhard G. Predictors of outcome in patients with achalasia treated by pneumatic dilation. Gastroenterology. 1992;103:1732-8.
    Pubmed CrossRef
  17. Di Nardo G G, Rossi P, Oliva S, Aloi M, Cozzi DA, Frediani S, et al. Pneumatic balloon dilation in pediatric achalasia: efficacy and factors predicting outcome at a single tertiary pediatric gastroenterology center. Gastrointest Endosc. 2012;76:927-32.
    Pubmed CrossRef
  18. Kumbhari V, Behary J, Szczesniak M, Zhang T, Cook IJ. Efficacy and safety of pneumatic dilatation for achalasia in the treatment of post-myotomy symptom relapse. Am J Gastroenterol. 2013;108:1076-81.
    Pubmed CrossRef
  19. van Hoeij FB FB, Ponds FA, Werner Y, Sternbach JM, Fockens P, Bastiaansen BA, et al. Management of recurrent symptoms after per-oral endoscopic myotomy in achalasia. Gastrointest Endosc. 2018;87:95-101.
    Pubmed CrossRef
  20. Fiest TC, Foong A, Chokhavatia S. Successful balloon dilation of achalasia during pregnancy. Gastrointest Endosc. 1993;39:810-2.
    Pubmed CrossRef
  21. Neubert ZS, Stickle ET. Bridging therapy for achalasia in a second trimester pregnant patient. J Family Med Prim Care. 2019;8:289-97.
    Pubmed KoreaMed CrossRef
  22. Lynch KL, Pandolfino JE, Howden CW, Kahrilas PJ. Major complications of pneumatic dilation and Heller myotomy for achalasia: single-center experience and systematic review of the literature. Am J Gastroenterol. 2012;107:1817-25.
    Pubmed KoreaMed CrossRef
  23. Borotto E, Gaudric M, Danel B, Samama J, Quartier G, Chaussade S, et al. Risk factors of oesophageal perforation during pneumatic dilatation for achalasia. Gut. 1996;39:9-12.
    Pubmed KoreaMed CrossRef
  24. Metman EH, Lagasse JP, d'Alteroche L, Picon L, Scotto B, Barbieux JP. Risk factors for immediate complications after progressive pneumatic dilation for achalasia. Am J Gastroenterol. 1999;94:1179-85.
    Pubmed CrossRef
  25. Nair LA, Reynolds JC, Parkman HP, Ouyang A, Strom BL, Rosato EF, et al. Complications during pneumatic dilation for achalasia or diffuse esophageal spasm. Analysis of risk factors, early clinical characteristics, and outcome. Dig Dis Sci. 1993;38:1893-904.
    Pubmed CrossRef
  26. Lo AY, Surick B, Ghazi A. Nonoperative management of esophageal perforation secondary to balloon dilatation. Surg Endosc. 1993;7:529-32.
    Pubmed CrossRef
  27. Elhanafi S, Othman M, Sunny J, Said S, Cooper CJ, Alkhateeb H, et al. Esophageal perforation post pneumatic dilatation for achalasia managed by esophageal stenting. Am J Case Rep. 2013;14:532-5.
    Pubmed KoreaMed CrossRef
  28. Sanaka MR, Raja S, Thota PN. Esophageal perforation after pneumatic dilation for achalasia: successful closure with an over-the-scope clip. J Clin Gastroenterol. 2016;50:267-8.
    Pubmed CrossRef
  29. Nathanson LK, Gotley D, Smithers M, Branicki F. Videothoracoscopic primary repair of early distal oesophageal perforation. Aust N Z J Surg. 1993;63:399-403.
    Pubmed CrossRef
  30. Novais PA, Lemme EM. 24-h pH monitoring patterns and clinical response after achalasia treatment with pneumatic dilation or laparoscopic Heller myotomy. Aliment Pharmacol Ther. 2010;32:1257-65.
    Pubmed CrossRef
  31. Vela MF, Richter JE, Khandwala F, Blackstone EH, Wachsberger D, Baker ME, et al. The long-term efficacy of pneumatic dilatation and Heller myotomy for the treatment of achalasia. Clin Gastroenterol Hepatol. 2006;4:580-7.
    Pubmed CrossRef
  32. Heller E. Extra mucous cardioplasty in chronic cardiospasm with dilatation of the esophagus (extramukose cardiaplastik mit dilatation des oesophagus). Mitt Grenzgels Med Chir. 1913;27:141-8.
  33. Oelschlager BK, Chang L, Pellegrini CA. Improved outcome after extended gastric myotomy for achalasia. Arch Surg. 2003;138:490-5.
    Pubmed CrossRef
  34. Richards WO, Torquati A, Holzman MD, Khaitan L, Byrne D, Lutfi R, et al. Heller myotomy versus Heller myotomy with Dor fundoplication for achalasia: a prospective randomized double-blind clinical trial. Ann Surg. 2004;240:405-12.
    Pubmed KoreaMed CrossRef
  35. Patti MG, Pellegrini CA, Horgan S, Arcerito M, Omelanczuk P, Tamburini A, et al. Minimally invasive surgery for achalasia: an 8-year experience with 168 patients. Ann Surg. 1999;230:587-93.
    Pubmed KoreaMed CrossRef
  36. Patti MG, Arcerito M, De Pinto M M, Feo CV, Tong J, Gantert W, et al. Comparison of thoracoscopic and laparoscopic Heller myotomy for achalasia. J Gastrointest Surg. 1998;2:561-6.
    Pubmed CrossRef
  37. Stewart KC, Finley RJ, Clifton JC, Graham AJ, Storseth C, Inculet R. Thoracoscopic versus laparoscopic modified Heller Myotomy for achalasia: efficacy and safety in 87 patients. J Am Coll Surg. 1999;189:164-9.
    Pubmed CrossRef
  38. Rawlings A, Soper NJ, Oelschlager B, Swanstrom L, Matthews BD, Pellegrini C, et al. Laparoscopic Dor versus Toupet fundoplication following Heller myotomy for achalasia: results of a multicenter, prospective, randomized-controlled trial. Surg Endosc. 2012;26:18-26.
    Pubmed CrossRef
  39. Werner YB, Hakanson B, Martinek J, Repici A, von Rahden BHA BHA, Bredenoord AJ, et al. Endoscopic or surgical myotomy in patients with idiopathic achalasia. N Engl J Med. 2019;381:2219-29.
    Pubmed CrossRef
  40. Mineo TC, Pompeo E. Long-term outcome of Heller myotomy in achalasic sigmoid esophagus. J Thorac Cardiovasc Surg. 2004;128:402-7.
    Pubmed CrossRef
  41. Zaninotto G, Costantini M, Rizzetto C, Zanatta L, Guirroli E, Portale G, et al. Four hundred laparoscopic myotomies for esophageal achalasia: a single centre experience. Ann Surg. 2008;248:986-93.
    Pubmed CrossRef
  42. Wohler A, Evans SRT. Laparoscopic esophagomyotomy with dor fundoplication. In: Evans SRT, editor. Surgical pitfalls: an evidence-based approach to prevention and management. Philadelphia: Saunders; 2009, p. 187-95.
    CrossRef
  43. Inoue H, Kudo SE. Per-oral endoscopic myotomy (POEM) for 43 consecutive cases of esophageal achalasia. Nihon Rinsho. 2010;68:1749-52.
    Pubmed
  44. Kahrilas PJ, Katzka D, Richter JE. Clinical practice update: the use of per-oral endoscopic myotomy in achalasia: expert review and best practice advice from the AGA Institute. Gastroenterology. 2017;153:1205-11.
    Pubmed KoreaMed CrossRef
  45. Zaninotto G, Bennett C, Boeckxstaens G, Costantini M, Ferguson MK, Pandolfino JE, et al. The 2018 ISDE achalasia guidelines. Dis Esophagus. 2018;31:doy071.
    Pubmed CrossRef
  46. Nabi Z, Ramchandani M, Chavan R, Kalapala R, Darisetty S, Rao GV, et al. Per-oral endoscopic myotomy for achalasia cardia: outcomes in over 400 consecutive patients. Endosc Int Open. 2017;5:E331-9.
    Pubmed KoreaMed CrossRef
  47. Inoue H, Shiwaku H, Kobayashi Y, Chiu PWY, Hawes RH, Neuhaus H, et al. Statement for gastroesophageal reflux disease after peroral endoscopic myotomy from an international multicenter experience. Esophagus. 2020;17:3-10.
    Pubmed KoreaMed CrossRef
  48. Tan Y, Lv L, Wang X, Zhu H, Chu Y, Luo M, et al. Efficacy of anterior versus posterior per-oral endoscopic myotomy for treating achalasia: a randomized, prospective study. Gastrointest Endosc. 2018;88:46-54.
    Pubmed CrossRef
  49. Ramchandani M, Nabi Z, Reddy DN, Talele R, Darisetty S, Kotla R, et al. Outcomes of anterior myotomy versus posterior myotomy during POEM: a randomized pilot study. Endosc Int Open. 2018;6:E190-8.
    Pubmed KoreaMed CrossRef
  50. Khashab MA, Sanaei O, Rivory J, Eleftheriadis N, Chiu PWY, Shiwaku H, et al. Peroral endoscopic myotomy: anterior versus posterior approach: a randomized single-blinded clinical trial. Gastrointest Endosc. 2020;91:288-97.e7.
    Pubmed CrossRef
  51. Rodríguez de Santiago E E, Mohammed N, Manolakis A, Shimamura Y, Onimaru M, Inoue H. Anterior versus posterior myotomy during poem for the treatment of achalasia: systematic review and meta-analysis of randomized clinical trials. J Gastrointestin Liver Dis. 2019;28:107-15.
    Pubmed CrossRef
  52. Mohan BP, Ofosu A, Chandan S, Ramai D, Khan SR, Ponnada S, et al. Anterior versus posterior approach in peroral endoscopic myotomy (POEM): a systematic review and meta-analysis. Endoscopy. 2020;52:251-8.
    Pubmed CrossRef
  53. Khashab MA, Sethi A, Rosch T, Repici A. How to perform a high-quality peroral endoscopic myotomy? Gastroenterology. 2019;157:1184-9.
    Pubmed CrossRef
  54. Nabi Z, Chavan R, Ramachandani M, Darisetty S, Reddy DN. Peroral endoscopic myotomy in a patient with failed Heller’s myotomy by use of a novel bipolar radiofrequency device. VideoGIE. 2020;5:138-40.
    Pubmed KoreaMed CrossRef
  55. Tsiamoulos ZP, Sebastian J, Bagla N, Hancock C, Saunders BP. A new approach to endoscopic submucosal tunneling dissection: the "Speedboat-RS2" device. Endoscopy. 2019;51:E185-6.
    Pubmed CrossRef
  56. Inoue H, Sato H, Ikeda H, Onimaru M, Sato C, Minami H, et al. Per-oral endoscopic myotomy: a series of 500 patients. J Am Coll Surg. 2015;221:256-64.
    Pubmed CrossRef
  57. Shiwaku H, Inoue H, Onimaru M, Minami H, Sato H, Sato C, et al. Multicenter collaborative retrospective evaluation of peroral endoscopic myotomy for esophageal achalasia: analysis of data from more than 1300 patients at eight facilities in Japan. Surg Endosc. 2020;34:464-8.
    Pubmed CrossRef
  58. Nabi Z, Ramchandani M, Chavan R, Tandan M, Kalapala R, Darisetty S, et al. Peroral endoscopic myotomy in treatment-naïve achalasia patients versus prior treatment failure cases. Endoscopy. 2018;50:358-70.
    Pubmed CrossRef
  59. Ngamruengphong S, Inoue H, Ujiki MB, Patel LY, Bapaye A, Desai PN, et al. Efficacy and safety of peroral endoscopic myotomy for treatment of achalasia after failed Heller myotomy. Clin Gastroenterol Hepatol. 2017;15:1531-7.e3.
    Pubmed CrossRef
  60. Tyberg A, Sharaiha RZ, Familiari P, Costamagna G, Casas F, Kumta NA, et al. Peroral endoscopic myotomy as salvation technique post-Heller: international experience. Dig Endosc. 2018;30:52-6.
    Pubmed CrossRef
  61. Zhang X, Modayil RJ, Friedel D, Gurram KC, Brathwaite CE, Taylor SI, et al. Per-oral endoscopic myotomy in patients with or without prior Heller's myotomy: comparing long-term outcomes in a large U.S. single-center cohort (with videos). Gastrointest Endosc. 2018;87:972-85.
    Pubmed CrossRef
  62. Li QL, Wu QN, Zhang XC, Xu MD, Zhang W, Chen SY, et al. Outcomes of per-oral endoscopic myotomy for treatment of esophageal achalasia with a median follow-up of 49 months. Gastrointest Endosc. 2018;87:1405-12.e3.
    Pubmed CrossRef
  63. Guo H, Yang H, Zhang X, Wang L, Lv Y, Zou X, et al. Long-term outcomes of peroral endoscopic myotomy for patients with achalasia: a retrospective single-center study. Dis Esophagus. 2017;30:1-6.
    Pubmed CrossRef
  64. Teitelbaum EN, Dunst CM, Reavis KM, Sharata AM, Ward MA, DeMeester SR, et al. Clinical outcomes five years after POEM for treatment of primary esophageal motility disorders. Surg Endosc. 2018;32:421-7.
    Pubmed CrossRef
  65. He C, Li M, Lu B, Ying X, Gao C, Wang S, et al. Long-term efficacy of peroral endoscopic myotomy for patients with achalasia: outcomes with a median follow-up of 36 months. Dig Dis Sci. 2019;64:803-10.
    Pubmed CrossRef
  66. Liu XY, Cheng J, Chen WF, Liu ZQ, Wang Y, Xu MD, et al. A risk-scoring system to predict clinical failure for patients with achalasia after peroral endoscopic myotomy. Gastrointest Endosc. 2020;91:33-40.e1.
    Pubmed CrossRef
  67. Ren Y, Tang X, Chen Y, Chen F, Zou Y, Deng Z, et al. Pre-treatment Eckardt score is a simple factor for predicting one-year peroral endoscopic myotomy failure in patients with achalasia. Surg Endosc. 2017;31:3234-41.
    Pubmed CrossRef
  68. Nabi Z, Reddy DN, Ramchandani M. Adverse events during and after per-oral endoscopic myotomy: prevention, diagnosis, and management. Gastrointest Endosc. 2018;87:4-17.
    Pubmed CrossRef
  69. Ramchandani M, Nageshwar Reddy D D, Darisetty S, Kotla R, Chavan R, Kalpala R, et al. Peroral endoscopic myotomy for achalasia cardia: treatment analysis and follow up of over 200 consecutive patients at a single center. Dig Endosc. 2016;28:19-26.
    Pubmed CrossRef
  70. Wang Y, Liu ZQ, Xu MD, Chen SY, Zhong YS, Zhang YQ, et al. Clinical and endoscopic predictors for intraprocedural mucosal injury during per-oral endoscopic myotomy. Gastrointest Endosc. 2019;89:769-78.
    Pubmed CrossRef
  71. Nabi Z, Ramchandani M, Reddy DN. Per-oral endoscopic myotomy and gastroesophageal reflux: where do we stand after a decade of "POETRY"? Indian J Gastroenterol. 2019;38:287-94.
    Pubmed CrossRef
  72. Shiwaku H, Inoue H, Sasaki T, Yamashita K, Ohmiya T, Takeno S, et al. A prospective analysis of GERD after POEM on anterior myotomy. Surg Endosc. 2016;30:2496-504.
    Pubmed KoreaMed CrossRef
  73. Inoue H, Ueno A, Shimamura Y, Manolakis A, Sharma A, Kono S, et al. Peroral endoscopic myotomy and fundoplication: a novel NOTES procedure. Endoscopy. 2019;51:161-4.
    Pubmed CrossRef
  74. Nabi Z, Ramchandani M, Darisetty S, Kotla R, Reddy DN. Peroral endoscopic myotomy with endoscopic fundoplication in a patient with idiopathic achalasia. Endoscopy. 2020;52:74-5.
    Pubmed CrossRef
  75. Tanaka S, Toyonaga T, Kawara F, Watanabe D, Hoshi N, Abe H, et al. Novel per-oral endoscopic myotomy method preserving oblique muscle using two penetrating vessels as anatomic landmarks reduces postoperative gastroesophageal reflux. J Gastroenterol Hepatol. 2019;34:2158-63.
    Pubmed CrossRef
  76. Kim GH, Jung KW, Jung HY, Kim MJ, Na HK, Ahn JY, et al. Superior clinical outcomes of peroral endoscopic myotomy compared with balloon dilation in all achalasia subtypes. J Gastroenterol Hepatol. 2019;34:659-65.
    Pubmed CrossRef
  77. Ponds FA, Fockens P, Lei A, Neuhaus H, Beyna T, Kandler J, et al. Effect of peroral endoscopic myotomy vs pneumatic dilation on symptom severity and treatment outcomes among treatment-naive patients with achalasia: a randomized clinical trial. JAMA. 2019;322:134-44.
    Pubmed KoreaMed CrossRef
  78. Schlottmann F, Luckett DJ, Fine J, Shaheen NJ, Patti MG. Laparoscopic heller myotomy versus peroral endoscopic myotomy (poem) for achalasia: a systematic review and meta-analysis. Ann Surg. 2018;267:451-60.
    Pubmed CrossRef
  79. Pratap N, Kalapala R, Darisetty S, Joshi N, Ramchandani M, Banerjee R, et al. Achalasia cardia subtyping by high-resolution manometry predicts the therapeutic outcome of pneumatic balloon dilatation. J Neurogastroenterol Motil. 2011;17:48-53.
    Pubmed KoreaMed CrossRef
  80. Kumbhari V, Tieu AH, Onimaru M, El Zein MH MH, Teitelbaum EN, Ujiki MB, et al. Peroral endoscopic myotomy (POEM) vs laparoscopic Heller myotomy (LHM) for the treatment of type III achalasia in 75 patients: a multicenter comparative study. Endosc Int Open. 2015;3:E195-201.
    Pubmed KoreaMed CrossRef
  81. Rohof WO, Salvador R, Annese V, Bruley des Varannes S S, Chaussade S, Costantini M, et al. Outcomes of treatment for achalasia depend on manometric subtype. Gastroenterology. 2013;144:718-25.
    Pubmed CrossRef
  82. Campos GM, Vittinghoff E, Rabl C, Takata M, Gadenstätter M, Lin F, et al. Endoscopic and surgical treatments for achalasia: a systematic review and meta-analysis. Ann Surg. 2009;249:45-57.
    Pubmed CrossRef

Stats or Metrics

Share this article on :

Related articles in IJGII

more