Achalasia

Achalasia is a primary esophageal motility disorder that develops from the degeneration of the myenteric plexus. This condition results in impaired lower esophageal sphincter relaxation and absence of normal esophageal peristalsis. Patients typically present with dysphagia to solids and liquids along with regurgitation. Diagnosis is established by high-resolution manometry. To rule out malignancy as a cause of achalasia, upper endoscopy is performed. Barium swallow study helps evaluate the esophageal morphology. Management options include pneumatic balloon dilation, surgical myotomy, and botulinum toxin injection. Choice of treatment is dependent on the type of achalasia and surgical risk. Medications are available for those who fail initial intervention; however, they provide the least benefit.

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Overview

Definition

  • Primary esophageal motility disorder due to degeneration of the myenteric plexus  
  • Condition is characterized by:
    • Impaired relaxation of the lower esophageal sphincter (LES)
    • Absence of normal esophageal peristalsis

Anatomy and physiology

  • Esophagus:
    • Made up of an outer longitudinal muscle layer and an inner circular muscle layer 
    • Circular muscle fibers: allow peristalsis
    • Upper ⅓ of esophagus: predominantly skeletal muscles
    • Lower ⅔ of esophagus: Smooth muscles become more dominant from the middle to the distal esophagus.
  • Myenteric plexus (Auerbach’s plexus):
    • Group of ganglia between the circular and longitudinal muscle layers
    • Part of the enteric nervous system 
    • Function: controls the peristalsis of the gastrointestinal tract
  • Type of neurons or ganglion cells in the myenteric plexus:
    • Excitatory: secrete acetylcholine → muscle contraction
    • Inhibitory: secrete nitrous oxide and vasoactive peptide → muscle relaxation

Epidemiology

  • Incidence: 12 cases per 100,000 individuals
  • Prevalence: 10 cases per 100,000 individuals
  • Seen mostly in adults between 25 and 60 years of age
  • Men and women are equally affected.

Etiology

  • Primary: idiopathic
  • Secondary (also called pseudo-achalasia): 
    • Caused by diseases that lead to esophageal abnormalities, similar to primary achalasia
    • Malignancy (esophageal, gastric, or other extraesophageal cancers) by mass effect or as part of paraneoplastic syndrome
    • Chagas disease
      • Infection with a parasite, Trypanosoma cruzi
      • Commonly found in South and Central America
    • Infiltrative disorders: amyloidosis, sarcoidosis 
    • Genetic diseases: neurofibromatosis, multiple endocrine neoplasia type 2B, Fabry’s disease
    • Others: eosinophilic esophagitis, juvenile Sjögren’s syndrome, chronic idiopathic intestinal pseudo-obstruction

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Pathophysiology

Pathologic process

  • Degeneration of Auerbach’s plexus, where there is selective loss of inhibitory ganglion cells in the distal esophagus 
  • Unopposed excitatory activity → failure of smooth muscle relaxation at LES → increase in LES pressure → progressive loss of peristaltic function

Proposed factors that contribute to the pathogenesis

  • Genetic predisposition
    • Achalasia is associated with genetic mutation (Allgrove’s syndrome).
    • Familial cases point to a possible inherited pattern.
  • Viral infection
    • Varicella zoster, measles, and Herpes simplex (type 1) virus antibodies have been noted in affected patients. 
    • A causal relationship, however, has not been established.
  • Inflammation and autoimmune process
    • Autoantibodies to enteric neurons have been found in patients with achalasia.
    • In affected esophagus: Inflammatory T-cell infiltrates surround the inhibitory neurons, with relative sparing of the excitatory neurons.

Clinical Presentation and Complications

Clinical presentation

  • Insidious onset
  • Dysphagia to solids and liquids 
  • Regurgitation of bland undigested food 
  • Difficulty belching
  • Heartburn
  • Nocturnal cough
  • Hiccups
  • Weight loss

Complications

  • Aspiration pneumonia: from regurgitation
  • Megaesophagus in 10% of cases
  • Increased risk of esophageal cancer
Grade IV megaesophagus

Image of megaesophagus (loss of esophageal motility and diffuse esophageal dilation)
A: Posteroanterior X-ray showing widening of the superior mediastinum (arrows)
B: Barium swallow study demonstrating a dilated and tortuous esophagus (arrowheads)

Image: “Grade IV megaesophagus” by US National Library of Medicine. License: CC BY 4.0

Diagnosis

Diagnostic approach

  • Achalasia suspected in:
    • Dysphagia to solids and liquids
    • Heartburn unresponsive to proton pump inhibitor
  • Upper endoscopy is performed → suggestive findings or equivocal but with high suspicion → proceed with esophageal manometry:
    • If manometry is consistent with achalasia: Rule out malignancy (endoscopic ultrasound with fine needle aspiration).
    • If with equivocal manometry findings: barium swallow study
    • If with normal manometry: Achalasia is ruled out.

Esophageal manometry

  • Establishes the diagnosis of achalasia
  • High-resolution manometry (HRM) with esophageal pressure topography (EPT):
    • Gold standard test 
    • More sensors than conventional manometry
    • Pressure: represented by color (↑ intensity of color = ↑ pressure)
    • Demonstrates the following:
      • Resting pressure of the esophagogastric junction
      • Swallowing-triggered esophageal activity
    • Classifies the types of achalasia (which guide treatment):
      • Type I classic achalasia: 
        • Minimal contractility or 100% failed peristalsis in the esophageal body 
        • Due to aganglionosis
      • Type II achalasia: 
        • Intermittent periods of pressurization 
        • Magnitude of aganglionosis is lower.
      • Type III spastic achalasia: 
        • Premature or spastic distal contractions 
        • Imbalance of excitatory and inhibitory influence, mostly intact ganglion cells
  • Conventional manometry:
    • Findings:
      • Aperistalsis in lower ⅔ of esophagus 
      • Incomplete LES relaxation after swallow
      • High LES resting pressure
Achalasia types

Types of achalasia

All types exhibit impaired esophagogastric junction relaxation.
Type I: On swallow, the upper esophageal sphincter relaxed, but is followed by 100% failed contractions and no esophageal pressurization (absent peristalsis).
Type II has panesophageal pressurization in at least 20% of swallows.
Type III is defined by the presence of preserved fragments of distal peristalsis or premature contractions for at least 20% of the swallows (spastic).

Image: “Achalasia types” by US National Library of Medicine. License: CC BY 4.0, edited by Lecturio.

Other diagnostic tests

  • Esophagoduodenoscopy (EGD): 
    • Findings: 
      • Retained food in esophagus
      • Increased resistance to passage of the endoscope through the esophagogastric junction
    • Can have normal or equivocal results
    • Necessary to rule out malignancy as the cause of achalasia
  • Barium swallow study: 
    • Performed in equivocal manometric findings
    • Evaluates esophagogastric junction morphology
    • “Bird’s beak”: pathognomonic barium swallow finding (dilated esophagus due to lack of peristalsis, which terminates in narrowing at LES)
  • Endoscopic ultrasound:
    • Evaluates esophageal wall thickness
    • Significant and asymmetric wall thickening: suspicious for malignancy
  • EndoFLIP (functional lumen imaging probe):
    • FLIP catheter passes through esophagus and displays diameter of esophageal segments.
    • Helps assess esophageal emptying by the distensibility of the esophagogastric junction
    • Achalasia: low distensibility

Management

Approach to management

  • The loss of ganglion cells cannot be reversed.
  • Goal of intervention is to improve the passage of ingested material.
  • Among the types of achalasia:
    • Type II: has the best response to treatment options
    • Type III: the most difficult to manage

Management options

  • Pneumatic balloon dilation of LES
    • Circumferential stretching of the LES
    • Patients referred to surgery if no improvement after 3 consecutive dilations
    • Risk of esophageal perforation
    • For type I or type II achalasia
  • Surgical myotomy
    • Lower esophageal sphincter muscle fibers are surgically cut to relieve pressure.
    • Heller myotomy (laparoscopic option)
    • Risk of esophageal and gastric perforation
    • Risk of gastroesophageal reflux (fundoplication performed at the same time to reduce this risk)
  • Peroral endoscopic myotomy (POEM):
    • Longer myotomy
    • Procedure of choice for type III achalasia
    • Can result in severe gastroesophageal reflux
  • Botulinum toxin injection into LES
    • Botulinum toxin is injected to block the release of acetylcholine from excitatory ganglions → ↓ LES tone
    • Good short-term results; requires retreatment within 612 months
    • Reserved for poor surgical candidates
  • Pharmacologic options:
    • Least benefit
    • Considered for poor surgical candidates and for those who fail botulinum injections
    • Mechanism of medications: Reduce LES pressure.
    • Medications: nitrates, calcium channel blockers

Differential Diagnosis

  • Esophageal spasm: also presents with dysphagia to solids and liquids but is associated with sudden onset of chest pain that is not exertion-related. There are 2 types of this condition: distal esophageal spasm and hypercontractile esophagus. Manometry shows characteristic esophageal contractions with normal relaxation of the esophagogastric junction. 
  • Gastroesophageal reflux disease (GERD): symptoms of heartburn and regurgitation caused by the reflux of stomach contents. Patients usually complain of a burning epigastric pain radiating up the chest, with a sour or metallic taste in the mouth. Gastroesophageal reflux disease is due to inappropriate relaxation of the LES. Proton pump inhibitors are used to control symptoms of GERD.
  • Scleroderma: also called systemic sclerosis, this condition presents with dysphagia to solids and liquids at the onset, accompanied by findings of skin thickening and hardening (sclerosis) and specific serum autoantibodies. Lower esophageal sphincter is weak or incompetent in scleroderma, so manometry shows low or absent LES pressure.
  • Esophageal stricture: narrowing of the esophagus that is frequently a sequelae of gastroesophageal reflux. This narrowing can also result from malignancies. Esophageal stricture presents with dysphagia to solids, progressing to liquids. Barium swallow study shows a narrowed luminal diameter. Upper endoscopy is performed for dual purposes, as it aids in diagnosis through visualization and biopsy and also allows dilation when necessary for treatment. 
  • Esophageal ring and web: thin structures that produce partial occlusion of the esophageal lumen. Plummer-Vinson syndrome consists of iron deficiency anemia, dysphagia, and a cervical esophageal web. Presentation includes dysphagia to solids. Schatzki’s ring, the most common type of esophageal ring, is also associated with intermittent dysphagia to solids. Diagnosis is by barium swallow study and upper endoscopy.

References

  1. Allaix, M., Patti, M., Roy, P. (2017) Achalasia. Medscape. Retrieved 2 Oct 2020, from https://reference.medscape.com/article/169974-overview#a1
  2. Ates, F., Vaezi, M. (2015) The Pathogenesis and Management of Achalasia: Current Status and Future Directions. Gut Liver. 9(4): 449–463. doi: 10.5009/gnl14446
  3. Desai, J., Moustarah, F. (2020). Esophageal Stricture. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK542209/
  4. Furuzawa-Carballeda, J. et al. (2016). New insights into the pathophysiology of achalasia and implications for future treatment. World J Gastroenterol. 22(35):7892-7907. doi: 10.3748/wjg.v22.i35.7892
  5. O’Neill, O., Johnston, B., Coleman, H. (2013). Achalasia: A review of clinical diagnosis, epidemiology, treatment and outcomes. World Journal of Gastroenterology 19(35):5806-5812. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3793135/
  6. Rogers, A., Rogers, B., Gyawali, P. (2020) Pathophysiology of achalasia. Annals of Esophagus 3. https://doi.org/10.21037/AOE-2019-ACH-07
  7. Shahrestani, J., Das, J. (2020). Neuroanatomy, Auerbach Plexus. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK551559/
  8. Spechler, S., Talley, N., Robson, K. (2020) Achalasia: Pathogenesis, clinical manifestations, and diagnosis. UpToDate. Retrieved 1 Oct 2020, from https://www.uptodate.com/contents/achalasia-pathogenesis-clinical-manifestations-and-diagnosis

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