Pediatrics

Achalasia

OVERVIEW: What every practitioner needs to know

Are you sure your patient has achalasia? What are the typical findings for this disease?

Achalasia is a relatively rare motor disorder of the esophagus. Achalasia occurs because of loss of inhibitory neurons of the myenteric plexus in the esophageal wall resulting in: (1) impaired lower esophageal sphincter (LES) relaxation (absent or incomplete) and (2) dysregulation of esophageal peristalsis (inefficient or loss of peristalsis).

Impaired LES relaxation results in an overall increased lower esophageal sphincter pressure. This, along with dysregulation of esophageal peristalsis results in impaired esophageal emptying. In essence, the characteristic features of achalasia are incomplete LES relaxation and aperistalsis of the esophageal body.

The symptoms of achalasia often begin slowly and progress gradually. It is important to recognize that achalasia presents differently depending on the age of the child.

The key symptoms based on age groups are presented below;

Key symptoms of achalasia in infants:

Choking, cough, feeding aversion/poor-slow feeding, failure to thrive

Key symptoms of children and adolescents with achalasia:

Vomiting (particularly effortless)

Dysphagia (for solids and liquids)

Slow eating time

Weight loss

Key symptoms of the adult with achalasia:

Dysphagia (for solids and liquids)

Regurgitation of bland undigested food or saliva

Chest pain

Weight loss

Additional symptoms of achalasia:

Effortless vomiting (often of undigested food, liquid or saliva)

Slow eating

Noncardiac chest pain; suprasternal pain

Nocturnal awakening

Night time coughing

Nocturnal regurgitation and/or vomiting (often clear fluid)

Recurrent pneumonia

"Gurgling" sound of the chest

Food sticking, requiring liquids to wash down food or repeated swallowing

Diagnosis requires a carefully obtained history and physical examination as well as some of the following studies: plain chest radiography and barium swallow, radionucleotide testing, 24-hour pH monitoring, pH and multichannel intraluminal impedance monitoring, endoscopy and esophageal manometry.

Treatment can be successful in resolving the majority of the symptoms of achalasia in the short term. Treatment options include pneumatic dilation, Botulinum toxin injection, drug therapy, and/or surgery. Although few if any long-term studies of the natural history of childhood-acquired achalasia have been performed, most patients require regular monitoring and some require long-term regular esophageal dilation.

Historical background: Sir Thomas Willis first described achalasia in 1674. Sir Willis successfully treated a patient by dilating the LES with a cork-tipped whalebone. However, it was not until 1929 that Hurt and Rake first realized that the primary pathophysiology resulting in achalasia was a failure in LES relaxation.

What other disease/condition shares some of these symptoms?

There are a number of conditions and diseases that mimic or can masquerade as achalasia. Some reports state that between 20% and 50% of patients with achalasia are misdiagnosed initially. The presenting symptoms of the case may be vague or the physician may not appreciate the symptoms of functional esophageal disorders. Often, however, the typical findings of achalasia are misinterpreted and thought to be due to another condition.

In particular, the following conditions can masquerade as achalasia:

Gastroesophageal reflux disease (GERD)

Hiatal hernia (with and without GERD)

Eosinophilic esophagitis

Esophageal stricture

Leiomyomas

Rumination

Anorexia bullosa or bulemia

Infectious esophagitis (Candida, herpes, cytomegalovirus [CMV])

Globus phenomena

Scleroderma

Chagas disease (which can also have achalasia as a part of the disease process which is why it is included below)

In addition, there are certain conditions that also have achalasia as part of their symptom/disease complex. These conditions include the following:

Chagas disease

Sarcoidosis

Hirschsprung disease

Down syndrome

Hodgkin disease

Operative and nonoperative trauma to the mediastinum; common in complex congenital heart disease corrective surgery and motor vehicle accidents, respectively)

Rozycki syndrome

Triple-A or Allgrove syndrome

Insulin-dependent diabetes

Sjögren syndrome

Postvagotomy syndrome

Hereditary cerebellar ataxia

Autoimmune polyglandular syndrome type II

Normal Esophageal Motor Function

Striated muscle of the proximal esophagus is innervated by the somatic efferent fibers of the vagus nerve. Cell bodies for these fibers originate in the nucleus ambiguus and terminate on the motor end plate directly through via cholinergic receptors. Smooth muscle of the distal esophagus is innervated by the preganglionic vagus nerve fibers with cell bodies located in the dorsal motor nucleus (DMN). Preganglionic fibers first innervate the myenteric plexus via cholinergic fibers.

The esophageal wall and LES are subsequently innervated by the postganglionic neurons consisting of excitatory and inihibitory neurons. The postganglionic excitatory neurons release acetylcholine while the inhibitory neurons release nitric oxide (NO) and vasoactive intestinal peptide (VIP) resulting in esophageal and LES contractions and relaxations. In addition to tonic contraction and relaxation, the nitrinergic inihibitory neurons are also vital to normal esophageal peristalsis.

What caused this disease to develop at this time?

Mechanisms Resulting in Achalasia

The normal esophagus, at baseline, is in a contractile state; however with deglutition (i.e., swallowing), the inhibitory neurons result in esophageal relaxation. Esophageal peristalsis is the net result of the coordinated relaxation and contraction mediated by the inhibitory and excitatory myenteric plexus neurons along the length of the esophagus. In achalasia, there is a loss of nitric oxide (NO) and vasoactive intestinal peptide (VIP) inhibitory neurons. VIP is postulated as the major inihibitory transmitter released at the intramural postgangionic neurons of the lower esophageal sphincter (LES). The loss of inhibitory innervation in achalasia results in the manometric consequence of failure of LES relaxation as well as loss of esophageal peristalsis.

The loss of inhibitory innervation of the esophagus can be due to either extrinsic or intrinsic causes. Extrinsic causes may include central nervous system (CNS) lesions involving the DMN or the vagal nerve fibers. However, many studies demonstrated that extrinsic innervation abnormality is a rare finding in achalasia patients and thus is most likely not the primary mechanism of the disease. Intrinsic loss may be due to loss of inhibitory ganglion cells in the myenteric plexus. In particular, a number of studies demonstrated that the more likely neuronal abnormality in achalasia is the imbalance between excitatory and inhibitory neurons of the myenteric plexus.

In early disease, histologic changes may be minimal and confined to inflammation of the myenteric plexus with normal ganglion cell numbers. In the early stages of achalasia, the esophageal myenteric inflammation, caused by an unknown etiologic factor or factors, may cause neuritis and ganglionitis with no ganglion cell loss or fibrosis. Functional esophageal dysmotility such as vigorous achalasia may be the predominant manifestation.

As the disease progresses, reduced ganglion cell numbers, a decrease in varicose nerve fibers in the myenteric plexus of the esophagus, and degenerative changes of the vagus nerve may be seen. Progressive destruction of the myenteric ganglion cells and neural fibrosis occurs, resulting in classic achalasia.

Quantitative and qualitative changes of the DMN of the vagus as well as a decrease in VIP and neuropeptic Y have also been reported. Thus, loss of VIP may be responsible for the lack of LES relaxation during swallowing.

In addition, some human studies have demonstrated the absence of NO synthase, the enzyme responsible for NO production, and this further contributes to the lack of LES relaxation during swallowing in the patient with achalasia.

Etiology

The majority of cases of achalasia are sporadic and idiopathic. Early hypotheses proposed for development of chalasia were that chronic esophageal obstruction leads to irreversible manometric changes, and this hypothesis was supported by clinical and experimental evidence. Another suggested mechanism was neuronal degeneration. This hypothesis stemmed from the association of achalasia with various neurologic disorders such as Parkinson disease, hereditary cerebellar ataxia, and neurofibromatosis. Both esophageal obstruction and neuronal degeneration can lead to changes similar to achalasia; they represent a fraction of all achalasia cases.

The etiology of inflammatory processes leading to achalasia lies in three areas: familial, infectious, and autoimmune.

Familial: Numerous case reports provide compelling evidence for potential familial or genetic abnormalities leading to achalasia development with focus on cases occurring between siblings, and associations with diseases such as Down syndrome or HLA class II antigen association.

Infectious: This cause is supported by several observations ranging from Chagas disease to Guilliain-Barré syndrome, poliomyelitis, and varicella zoster virus. Overall, the current evidence is mixed without a clear association between viral infection and achalasia.

Autoimmune: The autoimmune etiology of achalasia is supported by three groups of evidence: presence of circulating autoantibodies against the myenteric plexus, presence of inflammatory T-cell infiltrates in the myenteric plexus, and increased prevalence of HLA class II antigens.

Thus, idiopathic achalasia is an inflammatory disease with the loss of inhibitory neurons in the esophageal myenteric plexus of unknown cause. The initiating event has been postulated to be an environmental insult such as a viral infection resulting in inflammation of the myenteric plexus in the esophagus.

Not all affected individuals develop achalasia. Those who are more susceptible, possibly due to genetic predisposition, may develop an autoimmune response resulting in chronic inflammation. This high-risk population may have associated HLA class II antigens.

In the early stage, inflammation and ganglionitis with no neuronal cell loss may be the predominant finding. Patients at this stage may manifest esophageal dysmotility such as vigorous achalasia. Further destruction of the inhibitory ganglion cells and neural fibrosis by autoimmune processes continues as the disease progresses and results in classic achalasia.

Clearly, undertaking a thorough history and physical examination that not only focuses on current symptoms in the history of present illness but also addresses environmental exposures (i.e., infections) as well as family history, particularly of autoimmune diseases, can contribute to directing the workup of the patient with suspected achalasia.

After the thorough history and physical examination and before embarking on the stepwise process of radiography, pH impedance testing, endoscopy, and manometry to characterize the diagnosis, laboratory investigations designed at eliminating other diseases that can masquerade (see above) as achalasia are useful.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

There are no specific laboratory studies that can help make the diagnosis of achalasia. However, with the appropriate presenting signs and symptoms to suggest the diagnosis, other conditions that masquerade as achalasia can be excluded, or at least made less likely by appropriate laboratory investigations.

Failure to thrive is one of the presenting signs and symptoms of achalsia in infants. Therefore it is important to perform a 3-day calorie count to characterize the overall intake of the patient. Calorie intake is also important for the child and adolescent, particularly if there is poor weight gain and/or weight loss.

Stool studies that rule out malabsorption of fats (fecal fat, fatty acids), proteins (fecal elastase, fecal calprotectin), and carbohydrates (fecal pH and reducings substances) can assist the clinician in focusing on caloric intake or lack thereof resulting from esophageal dysfunction and then ordering subsequent studies.

A full hematology profile including white count, hemaglobin, and hematocrit as well as platelets and a comprehensive metabolic panel can determine whether there is active inflammation, a nutritional affect on iron stores and/or gastrointestinal bleeding, and the presence/absence of other metabolic processes such as liver and/or kidney disease.

Would imaging studies be helpful? If so, which ones?

Chest radiograph

The chest radiograph can show a widened mediastinum and an air-fluid level with an absent gastric air bubble.

Barium swallow (upper gastrointestinal series)

The upper gastrointestinal series demonstrates a dilatated esophagus with tapering at the distal end (See Figure 1, Figure 2, Figure 3). There will be an absence of peristalsis, and at times tertiary contractions. When barium fills the dilatated esophagus and the pressure generated by the barium column exceeds the LES pressure, partial emptying of the barium is seen.

Figure 1.

Barium swallow showing a dilatated esophagus with distal tapering.

Figure 2.

Barium swallow showing a dilatated esophagus with distal tapering.

Figure 3.

Barium swallow showing a dilatated esophagus with distal tapering.

The contrast study may also help to evaluate the response to therapy. Some studies have demonstrated that the height of the barium column approximately 5 minutes after barium ingestion in the upright position predicts outcome after therapeutic interventions.

Nuclear scintigraphy

A solid or liquid meal labeled with a radionucleotide, typically technitium-99m sulfur colloid, can be used to measure esophageal emptying.

Patients with achalasia retain the tracer longer in the upright position.

The test may help to differentiate achalasia from other conditions such as scleroderma, because of the differing retention pattern. However, the usefulness of nuclear scintigraphy to assess patient response to therapy is debatable, and head-to-head comparisons with other tests have not been performed in pediatric patients.

Confirming the diagnosis

Four major societies have published clinical practice guidelines on the diagnosis and management of achalasia:

American Gastroenterological Association, Society of American Gastrointestinal and Endoscopic Surgeons, Society for Surgery of the Alimentary Tract, and American College of Gastroenterology. It is important to note that these guidelines are primarily based on evidence collected in clinical trials, case reports, and retrospective studies in adults.

The diagnosis of achalsia should be confirmed by at least one of the following tests: esophageal manometry, pH multichannel intraluminal impedance (Figure 4), or endoscopy.

Figure 4.

Multichannel intraluminal impedance

Manometry (See Figure 5 and Figure 6)

Figure 5.

Esophageal manometry in achalasia

Figure 6.

Esophageal manometry

Esophageal manometry is considered by many to be the "gold" standard of diagnostic tests for achalasia. The characteristic manometry findings include the following:

Increased LES pressure.

Absent peristalsis usually involving the entire length of the esophagus.

Incomplete or absent LES relaxation.

Elevated intraesophageal pressure. As a result of distal obstruction, the esophageal luminal pressure may be higher than the gastric fundal pressure.

Additional findings include the following:

Low amplitude, simultaneous, mirror-image waves after water swallows.

Lack of bolus transit by impedance.

Simultaneous isobaric contour with high-resolution manometry.

Upper esophageal sphincter (UES) abnormalities may include:

Increased pressure.

A short duration of relaxation with swallows.

More rapid onset of pharyngeal contractions after UES relaxation (although the clinical relevance of this is not clear).

Manometric abnormalities have been reported in babies as young as 2 weeks of age.

Endoscopy

The esophagus appears dilated patulous and "wide open." Evidence of esophagitis secondary to food stasis and fermentation is often seen.The LES does not open with insufflation of air into the distal esophagus. Resistance is typically noted with the passage of the endoscope through the gastroesophageal junction, although this can yield to gentle pressure.

Particular attention should be paid by the endoscopist to the presence of a hiatal hernia. Presence of the hiatal hernia can increase the risk of perforation during dilation.

Endoscopy can also help exclude other esophageal diseases - mucosal infection (e.g., herpes, CMV, Epstein-Barr virus), carcinoma, leiyomyoma.

Timed barium swallow

Patient ingests 100-250 µL of low-density barium over 30-45 seconds in the upright position.

3-on-1 spot radiographs are obtained at 1, 2, and 5 minutes.

Healthy subjects empty this barium challenge completely over 1-2 minutes.

Most achalasia patients have residual barium in the esophagus at the end of 5 minutes.

Height of the residual barium column correlates with the severity of regurgitation and the slope of the esophageal emptying from 1-5 minutes with the degree of dysphagia.

Upright mucosal air contrast phase to detect mucosal details (esophagitis, masses), hernias, strictures, and a foreshortened esophagus.

Assessment of motility in the semiprone right anterior oblique position:

  • -Patients drink a small amount (5-10 mL) of low-density of barium, with each swallow separated by at least 25-30 seconds.

  • -Fluoroscopy and videotaping follows the barium column from the upper esophageal sphincter until it passes through the LES into the stomach.

  • -This assessment of motility, especially performed with at least 5 swallows of barium, correlates closely with esophageal manometry and impedance.

Distended single-contrast phase in the right anterior oblique position concentrating at the esophageal-gastric (EG) junction with fluoroscopy and videotaping:

  • -Small sliding hiatal hernias, vascular rings (e.g., aberrant left subclavian artery, aberrant innominate artery), and subtle strictures may be ellucidated by this technique.

  • -Sometimes these abnormalities can be augmented by rapid swallowing of barium or Valsalva maneuvers, both of which can distend the EG junction.

Solid food emptying phase in the upright position:

  • -This is typically performed with a 13-mm barium sulfate tablet, marshmallows, or foods that which the patient can bring to the examination.

If you are able to confirm that the patient has achalasia, what treatment should be initiated?

Initially, a determination of the patient's fluid balance is made and if necessary any fluid and/or electrolyte abnormalities are corrected. Typically this is not necessary as this disease evolves slowly and the majority of patients are well compensated from a hemodynamic and fluid status viewpoint.

After the patient is stabilized, the following approaches to therapeutic intervention are used:

Pharmacologic (i.e., drug) therapy

Botulinum toxin injection

Pneumatic dilation

Surgery

None of the available treatments restore normal peristaltic contractions in the esophagus of patients with achalasia. Symptom control and achievement of normal nutrition are realistic goals. A surgery consult should be obtained even if the decision is to proceed in a nonsurgical manner. Outcomes from the various treatment options are noted in Table I.

Table I.

Predictors of treatment outcome in patients with achalasia

Pharmacologic Therapy

Drug therapy is the safest and least invasive option for achalasia treatment. Pharmacologic therapy is often recommended for younger patients who are not yet interested in mechanical treatments or may not be healthy enough, i.e., have mutliple comorbid conditions. It is important in the counseling process to educate both the parents and the patient that none of these medications can reverse the underlying loss of nerve cells in the esophagus.

Two classes of drugs are typically available for the treatment of achalasia; nitrates and calcium channel blockers, both of which have lower LES muscle-relaxing effects. The treatments are directed at weakening the LES muscle to the point that it no longer poses a barrier to the passage of food. These drugs can decrease symptoms in individuals with achalasia. The medications are typically administered by placing a pill under the tongue 10-30 minutes before meals.

Isosorbide dinitrate, is one of the agents that has been used in pediatric patients with achalasia. This agent is a smooth muscle relaxant, reduces LES pressure, and may improve esophageal emptying in achalasia. Hypotension, headache, and drug resistance have been described with medium- to long-term and even initial therapy.

Nifedipine, a calcium channel blocker, is another agent used for the pharmacologic treatment of achalasia. Limited data exists concerning this agent's use in pediatric patients.

Botulinum Toxin Injection

As described previously, the loss of inhibitory neurons in the myenteric plexus results in unopposed excitation of the smooth muscles of the LES. This excitatory effect is most likely mediated by acetylcholine. Botulinum toxin binds to the presynaptic cholinergic terminals, thereby inhibiting the release of acetylcholine at the neuromuscular junction and creating a chemical denervation.

In adults, botulinum toxin treatment of achalasia is described as a safe and simple therapeutic option. The toxin is injected into the LES through endoscopy. An initial favorable response has been reported in up to 90% of patients. However, a sustained response beyond 2-3 months was reported in only 64%, and subsequent therapy was not as effective.

Hurwitz et al treated 23 children with botulinum toxin; 19 responded to initial treatment for approximately 4.2 months. However, 74% of these patients ultimately required dilation and/or myotomy.

Khoshoo et al reported results of botulinum toxin treatment in three children, all of whom had an immediate response beyond 10 months, but no long-term follow-up has been published.

Thus the transient response makes botulinum toxin a temporizing measure rather than a definitive treatment of achalasia. A few reports suggest that previous treatment with botulinum toxin injection may increase the difficulty of subsequent surgical therapy.

Pneumatic Dilation

For this treatment procedure, the patient swallows a collapsed balloon that is positioned in the esophageal lumen at the level of the LES. The placement of the balloon is guided by either fluoroscopy or endoscopy. When the balloon is positioned at the LES, it is inflated abruptly to a larger size in order to dilate the muscle of the LES. The objective is to stretch and rupture enough of the LES muscle to allow the passage of solids and liquids. Obviously, care must be taken not to cause complete rupture of the esophagus or induce postdilation gastroesophageal reflux.

This procedure is effective for relieving the swallowing difficulty in approximately two thirds of patients with achalasia.

A single balloon dilation may relieve symptoms of achalasia in about 60% of individuals 1 year after the procedure and in about 25% of people up to 5 years after the initial procedure. The longest report has been an individual who has been asymptomatic up to 25 years after pneumatic dilation. Thus some patients with achalasia will require more than one balloon dilation treatment for adequate symptom relief.

Overall improvement has been reported in 58%; dysphagia persisted in 20% (one fifth) and 25% required surgical myotomy because of unsuccessful dilation. Children older than the age of 9 appear to respond better to the dilation than younger children.

Surgery

Surgical myotomy for achalsia was previously performed through a large (open) incision in the chest or abdomen. As such, surgery was reserved for those patients who developed perforation during dilation, had residual dysphagia after dilation, or were poor candidates for dilation. The contemporary approach for the surgical management of achalasia uses the laparascopic technique. Overall moribidity and adverse outcomes have been reduced significantly with laparoscopic techniques.

Most of the techniques are variations of the Heller myotomy method, which was initially performed in 1914 in which the surgeon cuts part of the muscles at the end of the esophagus and the top of the stomach. The length of the myotomy required is a matter of judgement. The aim of the surgery is to relieve the obstruction without inducing gastroesophageal reflux. Use of intraoperative manometry to document a complete reduction in LES pressure may be useful. Typically the surgeon will also perform a fundoplication, an antireflux surgery in which the proximal portion of the stomach is wrapped around the esophagus to minimize the reflux of stomach contents.

Surgery relieves symptoms of achalsia acutely in up to 90% of patients. Symptom relief has been described in approximately 85% of individuals 10 years after surgery and in about 20% of individual patients 20 years after surgery.

What are the adverse effects associated with each treatment option?

Pharmacotherapy:

Headache

Hypotension; low blood pressure

Dizziness

Reflux

Botulinum toxin injection:

Chest pain

Gastroesophageal reflux disease

Heart burn

Pneumatic dilation:

Primary complications: esophageal perforation, fever, and plueral effusion.

Esophageal perforation: severe chest pain, fever, dysphagia, mediastinal and subcutaneous emphysema, or plueral effusion.

After dilation water-soluble contrast studies can identify perforation, and some centers perform this routinely.

Asymptomatic linear tears require no therapy.

If there are symptoms, conservative therapy with intravenous antibiotics and nothing by mouth is usually adequate.

Immediate surgery and drainage are recommendations for free perforation; however medical treatment with intravenous antibiotics and parenteral nutrition also has been used unsuccessfully.

Rare complications include persistent esophageal pain, aspiration pneumonia, and bleeding.

GERD can be a late complication ranging from 5%-12%.

Surgery

Postoperative pain

Gastroesophageal reflux and further esophageal damage

Postfundoplication complications: difficulty swallowing, bloating, flatulence, dumping, and diarrhea

What are the possible outcomes of this disease?

Typically, families are told that there is a long-term risk of esophageal adenocarcinoma in untreated achalasia and that esophageal cancer risk is still higher but dramatically reduced in the patient who had successful therapy. Families are also told that there is risk for other types of esophageal injury including strictures.

Patients need to be monitored closely long term by the pediatric gastroenterologist. The goal of therapy is to recognize and treat those symptoms or complications of treatment early (e.g., gastroesophageal reflux), and to prevent long-term complications.

Megaesophagus and esophageal cancer are possible.

As mentioned previously, families are counseled about the risks and benefits of the following:

Drug therapy

Botulinum toxin injection

Pneumatic dilation

Surgery

A decision will then be made between the family and the physician regarding the approach, with consensus agreement on the right approach for the right patient.

What causes this disease and how frequent is it?

Epidemiology

Achalasia can be either congenital or acquired, with the majority being idiopathic. It is still a relatively rare disease. The overall estimated incidence is 0.4-1.1/100,000, approximately 1/100,000 overall. Achalasia develops in about 3000 individuals in the United States each year. It typically is diagnosed in adults but can occur in children as well. About 5% of all patients with achalasia present with childhood symptoms.

Overall, achalasia can occur at any age; however, most patients are diagnosed between 25 and 60 years, with some incidence peaks in individuals older than the age of 60 to 70 years. There appears to be an equal predilection (i.e., distribution) for men and women. There are several series that have observed a female predominance, but this observation may be confounded because of a greater prevalence of older women than men.

In British studies, the incidence ranges between 0.4 and 1/100,000, rising to 3/100,000 for individuals older than 70 years of age. The overall prevalence in most European reports is approximately 8/100,000. Incidence rates in New Zealand and Israel are similar, at around 1/100,000, but achalasia seems less common among Asian and African populations. For example, in Singapore, the prevalence is 0.3/100,000 and in Zimbabwe only 0.03/100,000.

In these examples, case identification can be a factor, i.e., lack of appropriate technology to accurately make the diagnosis. The annual incidence of achalasia in the United States is approximately 0.6/100,000 and has remained stable in recent decades.

There is no particular racial or ethnic group that appears to be affected and there are no reports of this condition having a familial predilection or running in families. Racial differences have been highlighted in some studies, with a New Zealand study showing a higher incidence of achalasia in Pacific Islanders and individuals of Maori descent than in white individuals. In Singapore, achalasia was more common in Chinese and Indian individuals compared with Malaysians. In the United States, achalasia occurs equally frequently in white and nonwhite populations. These regional and ethnic variations in the incidence of achalasia suggest a role for both environmental and genetic factors in its etiology.

There does not appear to be any knowledge regarding the overall incidence of achalasia, and even prevalence studies have been fraught with difficulty. There also does not appear to be any seasonal variation; the age distribution is demonstrated above.

There does not appear to be any infectious cause, but the condition is inflammatory and thus an infectious trigger or triggers are likely plausible. Since no infectious agent has been identifiied, there is no known mode of transmission. In addition, there do not appear to be any predisposing exposures (zoonoses, environmental, toxin, activities).

How do these pathogens/genes/exposures cause the disease?

The underlying mechanisms for disease are outlined below.

The etiology of the inflammatory processes leading to achalasia is unknown but is hypothesized to involve familial, infectious, and/or autoimmune factors.

Familial: Numerous case reports provide compelling evidence for potential familial or genetic abnormalities leading to achalasia development, with focus on cases occurring between siblings, and associations with diseases such as Down syndrome or HLA class II antigen association.

Infectious: This etiology is supported by several observations ranging from Chagas disease to Guilliain-Barré syndrome, poliomyelitis, and varicella zoster virus. Overall, the current evidence is mixed without a clear association between viral infection and achalasia.

Autoimmune: The autoimmune etiology of achalasia is supported by three groups of evidence: presence of circulating autoantibodies against the myenteric plexus, presence of inflammatory T-cell infiltrates in the myenteric plexus, and increased prevalence of HLA class II antigens.

Mechanisms Resulting in Achalasia

In achalasia, there is a loss of NO- and VIP-releasing inhibitory neurons. VIP is postulated as the major inihibitory transmitter released at the intramural postgangionic neurons of the LES. The loss of inihibitory innervation in achalasia results in the manometric consequence of failure of LES relaxation as well as loss of esophageal peristalsis. The loss of inhibitory innervation of the esophagus can be due to either extrinsic or intrinsic causes.

Extrinsic causes may include CNS lesions involving the DMN or the vagal nerve fibers. However, many studies demonstrated that extrinsic innervation abnormality is a rare finding in achalasia patients and thus is most likely not the primary mechanism of the disease.

Intrinsic loss may be due to loss of inhibitory ganglion cells in the myenteric plexus. In particular, a number of studies demonstrated that the more likely neuronal abnormality in achalasia is the imbalance between excitatory and inhibitory neurons of the myenteric plexus.

In early disease, histologic changes may be minimal and confined to inflammation of the myenteric plexus with normal ganglion cell numbers.

In the early stages of achalasia, the esophageal myenteric inflammation, caused by an unknown etiologic factor or factors, may cause neuritis and ganglionitis with no ganglion cell loss or fibrosis. Functional esophageal dysmotility such as vigorous achalasia may be the predominant manifestation.

As the disease progresses, reduced ganglion cell numbers, a decrease in varicose nerve fibers in the myenteric plexus of the esophagus and degenerative changes of the vagus nerve may be seen. Progressive destruction of the myenteric ganglion cells and neural fibrosis occurs, resulting in classic achalasia.

Quantitative and qualitative changes of the DMN of the vagus as well as decreases in VIP and neuropeptic Y have also been reported. Thus, loss of VIP may be responsible for the lack of LES relaxation during swallowing.

In addition, some human studies have demonstrated the absence of NO synthase, the enzyme responsible for NO production, and this further contributes to the lack of LES relaxation during swallowing in the patient with achalasia.

Idiopathic achalasia is an inflammatory disease with the loss of inhibitory neurons in the esophageal neurons in the esophageal myenteric plexus of unknown etiology. However, based on the current evidence, a possible mechanism of the disease can be postulated.

The initiating event may be an environmental insult such as a viral infeciton resulting in inflammation of the myenteric plexus in the esophagus. Not all affected individuals develop achalasia. Those who are more susceptible, possibly because of a genetic predisposition, may develop an autoimmune response resulting in chronic inflammation. Autoimmune destruction of the inhibitory gangion cells and neural fibrosis continues as the disease progresses and results in classic achalasia.

What complications might you expect from the disease or treatment of the disease?

Pharmacotherapy:

Headache

Hypotension; low blood pressure

Dizziness

Reflux

Botulinum Toxin Injection:

Chest pain

Gastroesophageal reflux disease

Heart burn

Pneumatic Dilation:

The primary complication is esophageal perforation with severe chest pain, fever, dysphagia, mediastinal and subcutaneous emphysema or a pleural effusion. Postdilation radiographic studies with water-soluble contrast can identify perforation, and some centers perform this routinely. Asymptomatic linear tears usually require no therapy. If there are symptoms, conservative therapy with intravenous antibiotics and nothing by mouth is usually adequate. Immediate surgery and drainage may be required for significant perforations with free air leaks.

Rare complications include persistent esophageal pain, aspiration pneumonia, and bleeding. GERD can be a late complication, ranging from 5%-12%.

Surgery:

Postoperative pain

Gastroesophageal reflux and further esophageal damage

Postfundoplication complications: difficulty swallowing, bloating, flatulence, dumping, and diarrhea

Are additional laboratory studies available; even some that are not widely available?

There are no additional laboratory studies or noninvasive tests that can identify those with achalasia.

How can achalasia be prevented?

This disease cannot be prevented. There are no known prophylactic drugs or vaccines available. There are no known behavior factors that can prevent the disease, but behavioral changes can help with outcomes. There is no ability to do genetic counseling, since the genetic basis remains unclear.

What is the evidence?

Furness, JB. "The enteric nervous system and neurogastroenterology". Nat Rev Gastroenterol Hepatol 2012 Mar. vol. 9(5). 6. pp. 286-94.

Kessing, B F, Smout, AJ, Bredenoord, AJ. "Clinical applications of esophageal impedance monitoring and high-resolution manometry". Curr Gastroenterol Rep. vol. 14. 2012. pp. 197-205.

Bredenoord, AJ, Fox, M, Kahrilas, PJ. "Chicago classification criteria of esophageal motility disorders defined in high resolution esophageal pressure topography". Neurogastroenterol Motil. vol. 24 Suppl 1. 2012. pp. 57-65.

Fovos, A, Jarral, O, Patel, V. "Does Heller's myotomy provide superior clinical outcome in comparison to botulinum toxin injection for treatment of achalasia?: Best evidence topic (BET)". Int J Surg. vol. 10. 2012. pp. 120-3.

Boeckxstaens, G, Zaninotto, G. "Achalasia and esophago-gastric junction outflow obstruction: focus on the subtypes". Neurogastroenterol Motil. vol. 24 Suppl 1. 2012. pp. 27-31.

Popoff, AM, Myers, JA, Zelhart, M. "Long-term symptom relief and patient satisfaction after Heller myotomy and Toupet fundoplication for achalasia". Am J Surg. vol. 203. 2012. pp. 339-42.

Castell, DO. "The evolution of achalasia". Dig Dis Sci. vol. 57. 2012. pp. 597-8.

Patti, MG, Pellegrini, CA. "Esophageal achalasia 2011: pneumatic dilatation or laparoscopic myotomy". J Gastrointest Surg. vol. 16. 2012. pp. 870-3.

Morera, C, Nurko, S. "Heterogeneity of lower esophageal sphincter function in children with achalasia". J Pediatr Gastroenterol Nutr. vol. 54. 2012. pp. 34-40.

Wang, L, Li, YM. "Meta-analysis of randomized and controlled treatment trials for achalasia". Digestive Diseases and Sciences. vol. 54. 2009. pp. 2303-2311.

Barnes, MA, Ho, AS, Malhotra, PS. "The use of botulinum toxin for pediatric cricopharyngeal achalasia". Int J Pediatr Otorhinolaryngol. vol. 75. 2011. pp. 1210-4.

Parise, P, Santi, S, Solito, B. "Laparoscopic Heller myotomy plus Dor fundoplication in 137 achalasic patients: results on symptoms relief and successful outcome predictors". Updates Surg. vol. 63. 2011. pp. 11-5.

Marlais, M, Fishman, Fell, JM. "Health-related quality of life in children with achalasia". J Paediatr Child Health. vol. 47. 2011. pp. 18-21.

Marlais, M, Fishman, JR, Fell, JM. "UK incidence of achalasia: an 11-year national epidemiological study". Arch Dis Child. vol. 96. 2011. pp. 192-4.

Ongoing controversies regarding etiology, diagnosis, treatment

The overall controversies surround etiopathogenesis and long-term natural history.

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