What Is Known
- Achalasia is a disease caused by neuromuscular dysfunction in the esophagogastric junction and is mainly characterized by esophageal dysmotility and reduced relaxation during swallowing.
- Many studies show that peroral endoscopic myotomy promotes early recovery, thereby achieving favorable therapeutic effect in the treatment of adult achalasia.
What Is New
- Peroral endoscopic myotomy as a new endoscopic procedure for the treatment of achalasia was successfully applied in 21 children.
- This relatively long-term follow-up study shows that peroral endoscopic myotomy seems to be a promising new treatment for pediatric achalasia patients.
Achalasia is a disease caused by neuromuscular dysfunction in the esophagogastric junction (EGJ), and is mainly characterized by esophageal dysmotility, hypertensive lower esophageal sphincter (LES), and reduced relaxation during swallowing (1). The average incidence of achalasia among children is approximately 0.1/100,000 (0.03/100,000–0.21/100,000). Achalasia mainly manifests as dysphagia, gastroesophageal reflux, nausea, vomiting, and retrosternal pain or discomfort, and may lead to severe complications, such as recurrent or severe respiratory tract infection, malnutrition, and mental retardation. The symptoms of achalasia may proceed into adulthood and reduce the quality of life if not treated properly (2–4). The major treatment methods for achalasia currently include medications, endoscopy, and surgery. Peroral endoscopic myotomy (POEM) is a new minimally invasive procedure that involves muscle incision via tunneling endoscopy. POEM was first used in the treatment of adult achalasia in 2008. It was shown that POEM promotes early recovery, thereby achieving favorable therapeutic effect in the treatment of adult achalasia; nevertheless, POEM has not been widely applied to pediatric patients (5–7). This study aims to discuss the feasibility, safety and relatively long-term efficacy of POEM in the treatment of achalasia in children.
PATIENTS AND METHODS
The study protocol was reviewed and approved by our ethical committee of Children's Hospital of Fudan University (FDEK-N0. 147). We included children diagnosed as having achalasia and treated with POEM from October of 2014 to October of 2016 at the Center of Endoscopy, Children's Hospital of Fudan University. Inclusion criteria were as follows: age ≤18 years old; development of symptoms such as vomiting, dysphagia, gastroesophageal reflux, retrosternal discomfort, recurrent cough, aspiration pneumonia, and growth retardation with a Eckardt score ≥4; and diagnosis of achalasia confirmed by high-resolution esophageal manometry, upper gastrointestinal barium enema, and gastroscopy. Exclusion criteria were as follows: severe cardiopulmonary diseases or other diseases intolerant to general anesthesia or surgery; concomitant hiatal hernia; apparent esophageal dilatation; or ulcer at the lower esophagus.
Instruments and Agents of Peroral Endoscopic Myotomy
The system we used to conduct POEM in children are listed as follows: Host (Olympus, CV-260SL; Olympus Corp, Tokyo, Japan), endoscope (Olympus, GIF-Q260J), transparent cap (Olympus, D-201-11802), carbon dioxide insufflator (Olympus, UCR), hot biopsy forceps (Olympus, FD-410LR), handle of titanium clip (Olympus, HX-110LR), titanium clip (Olympus, HX-610-090, 90 degrees of opening angle), ERBE high-frequency system: host (ERBE 200D; ERBE GmbH, Tübingen, Germany), T-shaped electrotome (ERBE 20150-060), argon plasma coagulation unit (APC300; ERBE), insufflator (ERBE 20150-300), water jet scalpel, and the handle (ERBE JET2).
Peroral Endoscopic Myotomy Procedure
The children with achalasia were instructed to be fasted for 12 hours before their POEMs. After general anesthesia and endotracheal intubation, the endoscope was inserted perorally to reach the middle segment of the esophagus at 5 cm away from the cardia. Methylene blue-normal saline mixture was injected submucosally at the posterior wall of the esophagus. Then the mucosa was cut open for 1 to 1.5 cm to expose the submucosal layer and a transparent cap was used to shove the incised mucosa. Separation was made between the submucosal layer and lamina propria to establish a submucosal tunnel extending down to 1 to 1.5 cm below the cardia (8,9). A longitudinal incision of the circular muscle of 6 to 11 cm was then made at least 2 cm above the cardia. Electric coagulation hemostasis was applied to stop wound bleeding while making the incision. After the circular muscle was completely cut open, we suctioned the fluid inside the submucosal tunnel and esophageal lumen before the wound was rinsed and electric coagulation hemostasis was applied for excess bleeding. The endoscope was withdrawn and the incision of the mucosa was closed using 6 to 8 titanium clips (Fig. 1). Because of a narrow lumen and fragile mucosa in children, mucosal injury or even perforation may occur, especially as a consequence of tissue adhesions. This area often can be clipped with metal clips after myotomy.
Postoperative Management of Peroral Endoscopic Myotomy
All of the children were rested in a semisupine position after POEM and fasted further for 24 to 72 hours. Proton pump inhibitors (PPIs) and antibiotics were given for 3 to 5 days through intravenous infusion. Heart rate, respiration, and blood pressure were closely monitored. The presence of symptoms such as dyspnea, chest pain, abdominal pain or bloating was reviewed every 4 hours after POEM. Thoracoabdominal x-rays or computerized tomographic (CT) scans were conducted 24 hours after the POEMs. After postoperative fasting, we started liquid diet while no subcutaneous emphysema, mediastinal emphysema, pneumothorax, or other adverse events was observed. A semiliquid diet, such as porridge and noodles, was thereafter started at the second week after the POEM. The children were later gradually transitioned to soft diet within 1 month after POEM. In our study, we included 4 infant cases, whose body weights were <10 kg before the operation. Therefore, hypercaloric milk powder was added to their soft diet after POEM. All of the children continued to take PPIs orally for 2 to 3 months.
Follow-ups After Peroral Endoscopic Myotomy
The children were scheduled to visit our clinic at 1, 3, 6, and 12 months after POEMs and every 6 months afterward. During each visit, we examined Eckardt scores, conducted upper gastrointestinal barium enema and gastroscopy to review the dilatation of the esophagus and to check if the cardiac orifice was unobstructed. 99mTc diethylene triamine pentaacetic acid (DTPA) scintigraphic examinations and gastroscopy were conducted to monitor gastroesophageal reflux every 6 months from 6 months after the POEMs. For those who completed esophageal manometry before the POEMs, re-examinations were implemented within 1 year after the POEMs.
We used SPSS 19.0 software (Chicago, IL) package for statistical analysis. All of the measured values were expressed as mean, and t test or Fisher's exact test was used for data comparisons. A P < 0.05 was considered as statistically significant.
We included a total of 21 pediatric patients (9 boys) diagnosed as having achalasia in our hospital in this study (Table 1). Their age ranged from 0.9 to 18 years old, with a mean of 5.5 years. Disease duration of these children ranged from 0.3 to 2.5 years (mean of 1.5 years) and weight loss ranged from 0 to 8 kg (mean of 2.5 kg) before the POEMs. Among these children, 3 showed severe growth retardation (height and weight below the 3rd percentile of the standards). None of the children received drug therapy and only 1 case received balloon dilatation of the esophagus 5 times before POEM.
Peroral Endoscopic Myotomy Results
The POEM duration ranged from 30 to 55 minutes, with an average of 40 minutes. The length of the circular muscle endoscopical cut open was 6 to 11 cm, with a mean of 9 cm. The length of the submucosal tunnel was 8 to 15 cm, with a median of 10 cm. Seven titanium clips (on average) were used for each case.
Management in and After Procedure
All of the 21 children successfully received POEM. During the operation, one 11-month-old girl developed subcutaneous emphysema and pneumoperitoneum, which manifested as subcutaneous emphysema in the head, neck, anterior chest, and emphysema in the abdomen. This patient received abdominocentesis and her emphysema recovered. Another child developed subcutaneous and mediastinal emphysema, which spontaneously resolved as revealed by chest x-ray. None of the other children developed severe complications during the operations. All of the children received x-ray or CT scans postoperatively and 4 of them developed subcutaneous or mediastinal emphysema. One case developed fever and symptoms of pneumonia, however, recovered after antibiotics administration. All of the children were given PPIs after POEM intravenously until discharge. A liquid diet was started on the second day if there were no severe intra- or postoperative complications. The food intake was closely monitored and semiliquid diet was gradually started and continued for about 2 weeks if the children did not show discomfort. The length of the hospital stay was 7 to 14 days, and the children were discharged until vomiting or dysphagia was significantly alleviated with no significant complications. The mean length of the hospital stay was 10 days (Table 2).
The duration of follow-ups after POEM ranged from 3 to 24 months (with a mean of 13.2 months), only 1 child was followed for 3 months. During the follow-ups, none of the children developed severe adverse events, such as delayed hemorrhage, gastrointestinal fistulas, and secondary mediastinal or abdominal infections. In all of the 21 children, difficulty in feeding or swallowing was significantly alleviated or even resolved. The Eckardt scores were all under 3 at 1 month after the POEM and was 0.75 on average (0–2) at 6 months postoperatively, both were significantly less than the average score of 7.18 (5–10) before treatment (P < 0.001). Meanwhile, all of the children started weight gaining at 1 month postoperatively and an average weight gain of 2.7 kg was observed at 6 months after POEM. For children whose body weight were <10 kg before the POEMs and fed with hypercaloric milk, they had an average weight gain of 4.75 kg at 6 months after the POEMs.
In this study, there were 10 children older than 6 years and received esophageal manometry before POEM. The average pressure at the LES was 25.4 mmHg (18.5–40 mmHg). This value was significantly decreased to 10.7 mmHg (4.5–20 mmHg) at 6 months after POEM (P < 0.001).
The postoperative upper gastrointestinal barium enema (Fig. 2) and gastroscopy showed that the cardiac orifice was significantly improved and esophageal dilatation was reduced among these children after POEM. All of the titanium clips at the submucosal tunnel fell off at an average of 8 months (6–11 months) postoperatively and the mucosa covering the tunnel did not show visible lesions.
The incidence of gastroesophageal reflux was monitored 3 months after POEM. In consideration of the acceptance level and quality of life of these children, this study used gastroscopy and upper gastrointestinal barium enema combined with GER scintigraphy examination (99mTc-DTPA) to inspect the incidence of gastroesophageal reflux and reflux esophagitis. Among these 21 children, 6 developed postoperative symptoms, such as heartburn and regurgitation. Upper gastrointestinal barium enema and isotopic examination showed that 4 of them had gastroesophageal reflux, while the other 2 had gastroesophageal reflux concomitant with reflux esophagitis. Oral administration of PPIs was continued and conditions improved in the next 3 to 6 months.
Achalasia is an inflammatory disease with unknown causes. It has been deduced that there is chronic inflammation surrounding the neurons of individuals with hereditary susceptibility, damaging the inhibitory neurons in the muscular layer of the esophagus responsible for the synthesis of nitric oxide, and then leading to the lack of esophageal peristalsis and the inability of the LES to relax. The exact mechanism underlying the initiation of inflammation was, however, not fully understood (10,11).
It has been demonstrated that the expression of genes correlated to the contraction of smooth muscle, such as TPM2 and ITGA1, was significantly upregulated among patients with achalasia (12). TPM2 encodes β-tropomyosin, which is the component of the thin filament and plays a key role in calcium-dependent muscle contraction. ITGA1 encodes the α1 subunit of the integrin receptor for signal generated by integrin, which plays an important role in cellular adhesion, migration, survival, proliferation, and differentiation.
The main therapies for achalasia in children include medications, therapeutic endoscopy, and surgery (13). Medications might be effective for children with milder conditions, but the long-term efficiency is relatively poor. Therapeutic endoscopy mainly includes esophageal botulinum toxin injection and endoscopic balloon dilation. Botulinum toxin injection or endoscopic balloon dilation should replace calcium channel blockers and isosorbide dinitrate for use in patients who may not tolerate more invasive procedures. The short efficacy of botulinum toxin injection or endoscopic balloon dilation is favorable, but the efficacy decreases over time with significantly higher rates of symptoms recurrence and additional intervention. As pediatric patients assume a long life expectancy, the benefits of botulinum toxin injection or endoscopic balloon dilation is controversial (14,15). Available data suggest that laparoscopic Heller myotomy (LHM) is safe and effective in children. Nevertheless, the widely used LHM is rather traumatic and requires a long recovery period. In addition, there are increased risks for complications, such as infection, longer length of hospital stay, addition expenses, and thus the acceptance was relatively low (16–18).
In 2010, Inoue et al reported the application of POEM in the treatment of 17 cases for achalasia (8). Because it was shown to be well tolerated, effective in the short term, and less traumatic, POEM began to develop vigorously in the treatment for achalasia. Compared with other therapies, POEM has the following advantages: POEM is incision-free and performed through a natural orifice; the integrity of esophageal mucosa is preserved, and there is little distance between the entry to the tunnel and the location of myotomy, thus reducing the incidence of perforation and infection; compared with LHM, POEM is a scar-free procedure for achalasia with comparable safety and efficacy, but it has a shorter hospitalization, causes less pain and discomfort, and is relatively less expensive (19–21); and though the short-term efficacy of POEM and endoscopic balloon dilation were comparable, but POEM could lead to a better intermediate and long-term efficacy (22). POEM, however, has the following adverse effects: a skilled endoscopic team is mandatory to safely perform the procedure, and postoperative gastroesophageal reflux disease (GERD) is a major concern after POEM because of the absence of a concomitant antireflux procedure. There are several advantages of POEM for pediatric patients with achalasia: POEM is as effective and safe as LHM, but POEM is a mini-invasive technique with an inferior execution timing compared to LHM (6); and POEM at early stage of achalasia can effectively prevent the incidence of long-term complications of the disease such as dysphagia or vomiting therefore improve growth, development, and quality of life (23).
It has been shown that there were several key points for a successful POEM in children with achalasia. First, the surgery should be performed as early as possible when the disease is too short to cause obvious esophageal dilatation. Secondly, the longitudinal incision at the entry to the tunnel should be as small and short as possible. Thirdly, complete incision of the circular muscle is basically therapeutic for pediatric patients therefore the success rate of POEM would highly depend on the accuracy in the determination of the gastroesophageal junction location. Fourthly, sustaining the integrity of mucosa intraoperatively helps healing and decreases the risk of pleuroperitoneal infection therefore intraoperative establishment of the tunnel should be close to the muscular layer to avoid mucosal injuries. Metal clips would be necessary if there are mucosal injuries or perforations during the POEMs.
Owing to the inevitable cardiac sphincter injury, the major postoperative complication of POEM is GERD (5,24). Therefore, myotomy should be confined to the esophageal hiatus during the POEM to prevent the loss of the anti-reflux function produced by gastroesophageal junction (8,18,25). In our study, considering the acceptability of children, we employed 99mTc DTPA scintigraphic examinations to monitor the incidence of gastroesophageal reflux and gastroscopy to detect esophagitis. Postoperative gastroesophageal reflux could be kept under control with PPIs. The better way to monitor the incidence of gastroesophageal reflux and reflux esophagitis is, however, the regular postoperative testing of 24-hour pH values at the lower esophagus, which is also the major drawback of this study. Nevertheless, long-term gastroesophageal reflux of children could lead to the risk of esophageal stenosis, Barrett esophagus, and even malignancy. Although the incidence of postoperative reflux is relatively low, a long-term follow-up study is still needed.
All children with achalasia present dysphagia or recurrent vomiting, which leaves them to consume a liquid diet only. The patients suffered from growth retardation, weakened immune system, and respiratory diseases such as pneumonia and atelectasis. Therefore, preoperative nutritional support and perioperative management are crucial. For those children whose <5 years of age height/weight were <2SD to 3SD of the standard at 4 weeks before admission, or children with mild growth retardation/underweight however presented severe lower respiratory tract infection or electrolyte disturbance, we introduced nutritional support and perioperative management. Our center of endoscopy adopted enteral nutrition-dominant nutritional support added with parenteral nutrition. For children under 3 years of age, enteral nutrition was implemented through an indwelling nasogastric tube and intake of hypercaloric milk powder (100 kcal/100 mL). Nasogastric feeding could bypass the stenotic esophageal-cardiac segment and hypercaloric milk powder provides more energy based on the normal quantity demanded. Altogether these helped build up body weight, increased surgical tolerance, corrected the water and electrolyte disturbance, and eliminated pulmonary infections. For children over 3 years of age, hypercaloric milk powder was fed orally to ensure the quality of life. If the daily enteral nutritional intake of children did not meet 120% of the physiological nutritional demand, or there was an obvious water and electrolyte disturbance, or the nasogastric tube could not be tolerated due to respiratory tract infections, parenteral nutrition would be added. Hence, in the meantime, the treatment of respiratory tract infections and the correction of the water and electrolyte disturbances were also important processes before POEM.
A 11-month-old girl with achalasia successfully underwent POEM in December 2014 (26). She was the youngest patient received POEM. She began to vomit after eating 5 months after birth. Conditions gradually worsened afterward and only a liquid diet, such as milk, was allowed, leading to her inability to gain weight and malnutrition. POEM was scheduled when she was 11 months old. Her body weight was, however, only 7.3 kg, and she also had pneumonia and atelectasis, making POEM and anesthesia rather risky. Comprehensive supportive treatment, such as enteral nutrition, parenteral nutrition, and anti-infection therapy, was implemented 4 weeks before the POEM. Our center of endoscopy used a long-term (6 weeks maximally) indwelling nasogastric tube and hypercaloric milk (Infatrini, NUTRICIA, Zoetermeer, the Netherlands) was given every 6 hours. The process of feeding took up 1 hours each time and the milk was pumped in at the rate of 1 mL/kg per minute via an infusion pump (Flocare Infinity Enteral Feeding pump, NUTRICIA). Three days before the POEM, her body weight increased to 7.42 kg and the pulmonary infection was obviously alleviated, which was favorable to surgery and anesthesia. Although she developed pneumoperitoneum in POEM procedure, conditions improved after abdominocentesis. She went through a thoracoabdominal CT scan 24 hours postoperatively and subcutaneous emphysema, mediastinal emphysema, or pneumoperitoneum was not detected. After 5 days of fasting and complete parenteral nutrition, she gradually turned to a liquid diet, such as water and milk. A semiliquid diet, such as porridge, was started afterward and the amount was increased. She did not develop vomiting at any point. One month after the POEM, she began to eat a soft diet at a relatively slow speed with no vomiting. Re-examinations of gastroscopy and upper gastrointestinal barium enema showed that the cardiac orifice was significantly dilated and unobstructed compared with before the POEM. Pulmonary infection was completely gone and her body weight increased to 7.6 kg.
In summary, although Heller myotomy is still widely accepted as the standard treatment for achalasia in children (27), POEM, as a minimally invasive endoscopic technique, may provide a better treatment for achalasia in children due to less hospitalization expenses, less trauma, faster recovery, easier manipulation, and long-term efficiency. POEM is a safe, highly efficient, and feasible method. Although POEM is not complication-free, the complications could be properly managed. Our study with long-term follow-ups, determined that POEM can be the preferred treatment for achalasia in children.
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