Author’s Accepted Manuscript

Achalasia

Saleem Islam

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PII: S1055-8586(17)30010-0
DOI: http://dx.doi.org/10.1053/j.sempedsurg.2017.02.001
Reference: YSPSU50665
To appear in: Seminars in Pediatric Surgery
Cite this article as: Saleem Islam, Achalasia, Seminars in Pediatric Surgery,
http://dx.doi.org/10.1053/j.sempedsurg.2017.02.001
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 Achalasia

Saleem Islam MD, MPH

Professor and Chief
Division of Pediatric Surgery
University of Florida, College of Medicine
Gainesville, FL, USA

Pediatric Surgery
1600 SW Archer Road
PO Box 100119
Gainesville, FL 32610

Phone: 352-273-8825
Fax: 352-273-8772

Email: Saleem.islam@surgery.ufl.edu

Abstract:

Achalasia is a rare neurogenic motility disorder of the esophagus, occurring in

approximately 0.11 cases per 100,000 children. The combination of problems

(aperistalsis, hypertensive lower esophageal sphincter (LES), and lack of receptive

LES relaxation) results in patients having symptoms of progressive dysphagia,

weight loss, and regurgitation. Treatment modalities have evolved over the past few

decades from balloon dilation and botulinum toxin injection to laparoscopic Heller

myotomy and endoscopic myotomy. Most data on achalasia management is

extrapolated to children from adult experience. This article describes understanding

 2

of the pathogenesis, discusses newer therapeutic techniques, as well as

controversies in management.

Key Words: esophageal achalasia, heller myotomy, fundoplication, manometry,

endoscopic therapy

Introduction and Pathophysiology:

Achalasia of the esophagus is a very rare condition, with an estimated annual

incidence of 1:100,000 cases overall, and less than 5% of those occurring in children

(0.11 per 100,000 pediatric patients)1,2. It is found to occur more frequently in

males. The condition was first described in 1672 by Sir Thomas Willis, and the term

achalasia (‘failure to relax’) was coined by Hurt and Rake in 19293. The neurogenic

disorder is characterized by three abnormal findings in esophageal motility –

absence of peristalsis, high resting pressure of the lower esophageal sphincter

(LES), and failure of receptive relaxation of the LES. As a result, patients develop

progressive dysphagia and regurgitation.

The etiology of achalasia is not fully understood, but is considered to be due to an

imbalance between the inhibitory and excitatory neurotransmitters in the distal

esophagus secondary to loss of ganglion cells4. The absence of nonadrenergic,

noncholinergic inhibitory ganglion cells leads to unopposed acetylycholine and

substance P action resulting in a non relaxing LES3. Deficiency in nitric oxide

releasing neurons in particular have been implicated in patients with achalasia3,5.

Autopsy and resected specimens have also noted an inflammatory response with
 3

CD3/CD8 positive cytotoxic T cells as well as eosinophils and mast cells in the area,

which may suggest an autoimmune phenomenon3,6,7. There are reports of

hereditary and familial cases of achalasia pointing to a possible genetic link. Patients

suffering from the “AAA” syndrome (achalasia, alacrima, ACTH insensitivity), or

Algood’s present with achalasia suggesting a potential genetic association in a small

number of cases4. Associations with trisomy 21, congenital hypoventilation

syndrome and glucocorticoid insufficiency have been reported8. Finally, there is an

association with an infectious etiology with the parasite trypanosoma cruzi causing

aganglionosis of the LES in Chagas disease, prevalent in South America. The clinical

findings in Chagas disease mirror that of typical idiopathic achalasia.

Achalasia is often discussed with other motility disorders of the esophagus such as

diffuse esophageal spasm, or nutcracker esophagus, as they share some clinical and

manometric features9,10. In some reports, it was suggested that diffuse spasm (DES)

may progress to achalasia, however this remains debated3,11. Some patients with

spinal cord injury (SCI) are noted to develop esophageal motility disorders such as

DES and achalasia, and these occur at a much higher rate than the non SCI

population11,12. Based on high resolution manometric studies, there has been a

division of achalasia into three subtypes based on the esophageal pressurization

generated9. This has been found in adults, and may have implications on the therapy

offered to some patients, however it remains unclear and its existence in children is

not known13.
 4

Untreated cases of achalasia lead to an extremely dilated esophagus forming a

tortuous, sigmoidal shape. This end stage condition is known as mega esophagus

and most treatment modalities are unsuccessful4.

Presentation and Diagnosis:

While adults and children both present with progressive dysphagia initially to solids

and in some cases to liquids, the manifestations can be more protean and

challenging to diagnose in children. A majority of pediatric patients, especially those

younger than 6-7 years of age who present with difficulty in eating and progressive

weight loss will be treated for failure to thrive and gastroesophageal reflux disease

(GERD) due to the regurgitation, as those conditions are much more prevalent.

Proton pump inhibitors, histamine receptor blockers, and prokinetics are used and

the diagnosis may not be made for up to 6-10 years14. Some children are treated for

feeding aversion due to the inability to eat foods with certain textures from

progressive dysmotility and dysphagia8. Regurgitation of food in cases of achalasia,

is brought up without gastric contents or evidence of mixing, as opposed to severe

GERD. Nocturnal cough is an important presenting feature in children and occurs

due to chronic aspiration of esophageal contents when recumbent. Older children

may present with chest pain from the dilation or acid exposure. A chest x ray done

for chronic cough may reveal the outline of a dilated esophagus and air fluid level

which can clue in to the diagnosis.

The diagnostic work up is similar to that for adults, with the exception that

malignancy and pseudo achalasia is essentially nonexistent. Most clinicians start

 5

with an esophagram which would show a dilated esophagus tapering in to the LES

in a ‘bird-beak’ fashion (Figure 1). The degree of dilation is usually dependent on

the duration of symptoms. A timed barium esophagram, which looks at the time to

clear the esophagus, has been used as a definitive test by some authors, as it can

assess the peristaltic activity, and the degree of LES hypertension in how long it

takes to clear15,16. An upper endoscopy is a useful test to assess the mucosa and

estimate the degree of LES hypertension. Biopsies can be performed to rule out

other pathologies such as severe GERD. The gold standard test remains esophageal

manometry which involves placement of a catheter that measures the impedance

during the act of swallowing, and is able to assess all three critical components of

the diagnosis of achalasia – peristalsis, resting LES pressure, and receptive LES

relaxation. Some centers would still consider the diagnosis despite partial and a few

normal LES relaxations due to some heterogeneity in children8,17. Manometry can

also be performed to assess response to therapy, as well as in recurrent symptoms.

Additionally, intraoperative manometry has been utilized to help guide the length

and completeness of the myotomy18,19. High-resolution manometry and

intraluminal impedance monitoring are newer techniques that have been

introduced. With high-resolution manometry, pressure plots are generated for the

esophagus, which creates a topographical pressure map and helps to classify the

condition into the three subtypes. This recent understanding was summarized in the

Chicago classification of esophageal motility disorders, in which type I was defined

as minimal esophageal contractility, type II as intermittent compartmentalized

pressurizations with no peristalsis, and type III with spastic distal contractions10,20.
 6

High resolution manometry may also help in situations where standardized

manometry may not be completely diagnostic 21.

The Eckardt score has been used for the past decade or more in adults and grades

the symptom scores of dysphagia, regurgitation, chest pain, and weight loss on a 0-3

likert based scale22,23. Symptom scores can range from 0-12, and this score has been

useful in monitoring success of therapy as well as in standardizing outcomes.

Recently, this tool has been used in older children as well and has been useful16.

Medical Management:

Achalasia does not have a cure, and therefore all management principles are

palliative to help the patient be able to swallow with less dysphagia. The purpose of

any therapy for achalasia is improvement in esophageal emptying, usually achieved

by reducing the LES pressures. There are no mechanisms to induce peristalsis in the

esophagus; therefore reduction in LES pressure is usually accompanied with dietary

modification to allow gravity to assist esophageal clearance.

Calcium channel blockers have been used in adults with some success but less is

known about the effects in children. Nifedipine was used in a small report of 4

children who reported relief24. As reduced nitric oxide has been implicated in the

pathogenesis of failure of relaxation, nitrates such as nitroglycerin have also been

used, as has sildenafil, a nitric oxide potentiating agent25. The effects of all

medications are very limited and should be used as a bridge to more definitive

therapy, or in cases where any intervention would be considered too risky.

Dietary modifications are usually part of the natural adaptive process that occurs in

each patient as the dysphagia progressively increases. These include a mostly liquid
 7

diet and frequent smaller meals with small bites. However, dietary modifications

alone are not sufficient for achalasia, but are recommended in addition to more

definitive treatments.

Endoscopic Interventions:

Pneumatic dilation of the LES is one of the oldest therapies for achalasia and

works by stretching the circular muscle fibers and causing tears which result in

relative LES incompetence and reduction in resting pressure4. Pneumatic dilation

has been used extensively in children, with 30-35 mm diameter balloons

recommended in patients older than 8 years8,26. Multiple studies have documented

the efficacy of one or multiple pneumatic dilations in effectively improving

dysphagia symptoms in children26-28. The reduced dysphagia is typically immediate,

and Pastor et al reported that 17% did not require any further interventions, while

53% needed further dilations and did not require surgical intervention in long term

follow up29. While the complications include possible perforation, chest pain, and

GERD, the reported incidence of these were low in children8,27-30. A landmark study

from the European Achalasia Trial Investigators randomized 201 adults to either

pneumatic dilation or laparoscopic Heller myotomy (LHM), and noted that dilation

was equally efficacious at 2 years using Eckardt scores for evaluation23. They did

make note that the dilation strategy may have less durability for patients less than

40 years of age in whom LHM may be a better choice, and this was considered to be

the case by other authors as well23,31,32. The same cohort was reported after 5 year

follow up, and while the beneficial effects were maintained at 84% for LHM and
 8

82% for dilation, the dilation group had a 25% incidence of re dilation

requirement33.

Botulinum toxin injection in the LES results in relaxation of the muscles by

inhibition of acetylcholine release, and good initial relief of symptoms has been

reported, however this has been shown to be only effective for 3-4 months, and

therefore multiple treatments per year would be necessary8,30,34,35. The optimal

dosing has not been well studied in children, and the incidence of permanent relief

or cure is unknown, whereas in adults up to 10-40% of cases have reported long

term results8. Definitive surgical care can potentially become more challenging in

cases where botulinum toxin has been used due to the development of some degree

of fibrosis, with a higher perforation rate reported by some authors36-38. This

therapy has been used much less in children recently as both dilation and Heller

myotomy are considered superior with more durable symptom improvement8.

Surgical Management:

In 1913, Heller described the myotomy that bears his name – his approach utilized

both an anterior and posterior incision in the muscle, which was later modified to

the currently performed anterior one alone39,40. The key components of the

procedure are an esophageal myotomy, which extends 5-6 cm above the

gastroesophageal junction, as well as between 1-3 cm below onto the cardia of the

stomach. The incision on the cardia is considered critical in the alleviation of

dysphagia, however the exact length of the incision is controversial40,41. In the

1990’s, the Heller myotomy was first performed using minimally invasive
 9

techniques (laparoscopically and thoracoscopically), which improved post-

operative recuperation and became rapidly accepted41,42. The laparoscopic Heller

myotomy (LHM) is currently considered the gold standard to which other therapies

are compared8,41. In most cases, the operation is performed with 5 ports, and the

myotomy is done with either shears, an energy device (ultrasonic scalpel or

bipolar), or monopolar cautery. There are reports of single port LHM as well43. The

procedure has been described with or without concurrent endoscopy to ensure

completeness of the myotomy, as well as to assure the integrity of the mucosa. Some

surgeons prefer to use intraoperative manometry to prevent an incomplete

myotomy8,18. As mentioned previously, a RCT comparing pneumatic dilation to LHM

showed no significant difference in adults at 2 year follow up23. However, a later

meta-analysis of RCT’s in adults noted that LHM was superior to dilation 44. The 5

year data of the European Achalasia group also noted a 25% rate of secondary

interventions in the dilation group33. Given the rarity of this condition in children

there are no randomized studies in achalasia, however there are multiple single

center reports that noted the safety and higher efficacy of LHM over dilation,

especially in the medium to long term outcomes 18,29,30,45-50. Few of these studies

reported standardized scores however and therefore comparisons may be

challenging. A variable number of children who underwent pneumatic dilation

required additional procedures for recurrent dysphagia (50-100%), and up to 30-

75% underwent a surgical myotomy18,29,30,45,48,49. A systematic review of the

pediatric literature was attempted by Sharp and St Peter, comparing dilation with

HM, however they were unable to clearly elucidate a treatment algorithm, despite
 10

acknowledging that dilation had a higher failure rate in younger ages 28. In

summary, for children it would appear that there has been a clear transition to

preferring surgical treatment of achalasia, however offering a pneumatic dilation

would be an appropriate first option as long as the family understood the higher

rate of secondary procedures.

LHM with or without Fundoplication:

The aim of a Heller myotomy is to reduce LES tone, thus facilitating esophageal

clearance. Therefore, gastro esophageal reflux (GER) is a very common

complication, noted in 5-50% of cases in adults51,52. The use of an anti reflux

procedure with LHM is controversial and has been subjected to many studies51. The

choice of the type of fundoplication has been studied extensively in adults, and the

most common operations are a Dor (anterior fundoplication), a Toupet (posterior

270 degree fundoplication), or a Nissen (360 degree fundoplication)53. There is no

prospective data on its use in children, with a majority of series’ having some form

of concurrent antireflux procedure8,29,30,45,50,54. Corda et al reported on a series of 20

patients without any fundoplication and stated low rates of GER, with no formal

testing done30,46. A survey of members of the International Pediatric Endosurgery

group showed that 95% of the responding surgeons performed a concurrent

antireflux operation, 79% of which were a Dor55. Richards, et al published a RCT of

42 patients comparing a LHM and Dor to LHM alone, and noted that pathologic GER

occurred in 9% vs. 48%, and recommended using a Dor in addition to the LHM56.

Two other studies compared the use of a Dor vs. a Nissen and a Dor vs. a Toupet in

addition to a LHM57 52. They found that a Nissen was effective, but had a higher rate
 11

of dysphagia, whereas the Dor and Toupet were similar in effectiveness and

dysphagia. Most studies, including pediatric, have a preponderance of the Dor

fundoplication.

Per Oral Endoscopic Myotomy (POEM)

Since 2004, investigators have been working to create a working space inside the

submucosal plane58. Multiple animal studies conformed the feasibility as well as

safety of creating a plane after a 2 cm mucosal incision and subsequent flap, and

performance of a myotomy59. The technique represented another innovation in the

minimally invasive approach to achalasia. Inoue first described the technique in

adult humans in 2010, and this was rapidly and widely adopted, with very large

series’ being reported within a few years58,60,61.

Early comparisons with LHM noted favorable results with low Eckardt scores in

short and mid-term follow up61-63. POEM has been used in cases deemed either too

advanced for LHM, such as sigmoid esophagus, or in high risk patients for surgery59.

It has also been advocated for failures of other modalities of treatment such as

dilation or LHM63,64. The procedure has been used in children as well, with the first

report in 201265. Li from China and Caldaro from Italy both published series of 9

cases of POEM for achalasia in children with excellent results, while Nabi et al

reported on 15 cases with resolution of symptoms at 1 year66-68. Others have

subsequently reported smaller experiences, indicating the increasing adoption in

 12

pediatric providers as well16,69. To date, there has not been a randomized trial

comparing POEM to LHM or to dilation.

Esophagectomy: Despite the effectiveness of currently available therapies for

achalasia, 2-5% of patients are noted to develop what is called ‘end stage’ disease

with a massively dilated esophagus and recurrent symptoms. In this group of

patients, esophagectomy with reconstruction (gastric transposition, colon or jejunal

interposition) has been performed with reasonable outcomes. This is unlikely to

occur in the pediatric age group, however may happen with long term follow up of

patients treated as children.

Future treatments: While existing therapies aim at palliation through destruction of

the LES, future treatment might aim to preserve this while addressing the main

issue of absence of the myenteric ganglion cells4. There has been one case report of

using steroids in achalasia to arrest the loss of ganglion cells, however, in most

patients the cells are already gone at the time of diagnosis70. Stem cell based

treatments for achalasia may hold promise in the future as research has shown the

development of gut differentiated neural cells71.

Conclusions: Despite achalasia being a rare condition in children, advances in care

have been rapidly adapted. The LHM is the current treatment of choice with

excellent long term outcomes, and pneumatic dilation is also an acceptable first line

therapy. POEM has been used in children and may become an alternative to LHM.
 13

Further studies into the understanding of extended outcomes will help in

determining the best management strategy.

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 17

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Figure 1: Esophagram with typical bird beak appearance of distal esophagus