1. Introduction

Achalasia originates from the Greek word a-khalasis, meaning lack of relaxation. It is characterized by a spastic lower esophageal sphincter and a lack of esophageal peristalsis resulting in esophageal outflow obstruction ^[1][2]. Achalasia is a rare disease, with an estimated incidence of 0.03 to 1.63 per 100,000 persons per year and a prevalence of 10 per 100,000 ^[1]. Achalasia is generally diagnosed between the third and sixth decades and affects both males and females at equal rates without racial predominance ^[3][4]. The natural history of achalasia is characterized by a chronic, life-long, but rarely life-threatening disease that seriously affects patients’ morbidity and quality of life ^[5]. When successfully treated, the quality of life almost returns to near normal for a long time; on the other hand, when untreated, the course is usually progressive, leading to esophageal lumen dilatation, which, over time, leads to a burned-out, decompensated sigmoid esophagus with its clinical related consequences, including malnutrition ^[5][6]. Longstanding achalasia is a significant risk factor for esophageal adenocarcinoma (50 folds) and esophageal squamous cell carcinoma, even when achalasia is adequately managed ^[7]. Nonetheless, no formal practical guidelines recommend endoscopic surveillance in achalasia patients. However, an endoscopy every three years is considered an acceptable practical surveillance approach for esophageal cancer in longstanding achalasia. In a follow up prospective study that included 32 achalasia patients after surgical treatment for achalasia, Ota and colleagues ^[8] reported that six patients (18%) developed esophageal cancer in a period of approximately 14.3 years after surgery. Therefore, continuing endoscopic surveillance is required for the detection of malignancy at an early stage. Special clinical awareness is further required in patients with other risk factors for esophageal cancer such as smoking, Barrett’s esophagus, alcohol drinking, and family history of esophageal cancer ^[9].

The main clinical presentations of achalasia are dysphagia, chest pain, vomiting, and weight loss. Despite its chronic course, these profoundly disturb a patient’s quality of life ^[6]. Not uncommonly, the diagnosis of achalasia may not be made for a long time; thus, a high level of clinical suspicion is needed. Esophageal dilation and sigmoid esophagus are considered serious structural consequences of untreated achalasia and eventually may lead to severe nutritional difficulties. Thus far, all treatment options target lower esophageal sphincter (LES) tearing, consequently allowing a bolus to pass through the esophago-gastric junction (EGJ) ^[6].

2. Etiology

The etiology of achalasia is still vague, and the precise pathogenesis mechanism of achalasia has been ambiguous up to now. Nevertheless, research findings propose a theory of autoimmune origin, leading to a cascade of a destructive inflammatory processes resulting in destruction of the nitric oxide releasing neurons within the myenteric plexus and the vagus nerve fibers of the lower esophageal sphincter ^[7]. In end-stage disease, this affects the cholinergic neurons and subsequently progresses to the loss of inhibitory neurons containing nitric oxide synthase and vasoactive intestinal peptide A. This leads to an impaired relaxation of the lower esophageal sphincter ^[10]. Several patho-mechanisms were proposed as possible triggers of this immuno-destructive process, including underlying viral infection ^[11], idiopathic autoimmune trigger, and genetic predisposition ^[12]. Recent data have further addressed the role of autoimmunity and viral infection as the trigger for achalasia development. Innate immune system cells, including eosinophils and mast cells, have been increasingly observed in the esophageal tissue of achalasia patients ^{[13][14][15][16]}. These cells are already described as important mediators of immune-mediated inflammation and in degenerative neurological diseases ^[17]. Several studies have reported the involvement of the innate immune system in the pathogenesis of achalasia ^{[13][14][18][19][20]}. Moreover, the adaptive immune (B and T cells) system has recently been shown to play a major role in the development of achalasia. Previous studies using immunohistochemical analysis have shown a strong infiltration of CD3 + T lymphocytes within the esophageal mucosa of achalasia patients, thereby causing myenteric plexitis ^[21][22]. One recent study showed an increased expression of T lymphocytes ( Th22 , Th 17, Th 2, Th1, and T regulatory cells) in the lower esophageal sphincter tissue of achalasia patients ^[23][24]. Additionally, other studies have addressed the emerging role of proinflammatory cytokines (interleukin (IL)-22, IL-17, interferon-gamma, IL-6, and tumor necrosis factor alpha) that were overexpressed in achalasia patients compared with controls ^[23][25]. However, still more studies are needed to explore the dominant immune cells and cytokines that trigger the development of achalasia and to determine the underlying trigger for the activation of those immune cells and pathways ^[26]. Still, an underlying viral infection is an acknowledged and reported factor behind achalasia development ^[27][28]. Based on the existing evidence, the most known viral infections that are associated with achalasia are the herpes virus family (Herpes simplex virus, Epstein–Barr virus, Varicella Zoster virus, and Cytomegalovirus) ^[29][30], Paramyxoviruses ^[31], and human immunodeficiency virus (HIV) ^[32]. In the last few years, evolving new theories have been reported that attempt to address the etiological mechanisms of achalasia, starting from the involvement of the innate immune system. These include mast cells and eosinophils that reach the adaptive immune system and the cytokines that directly induce inhibitory neurons and damage the esophageal muscle layer. Furthermore, studies on the potential role of viral infection in achalasia cannot be ignored. All proofs lead to the conclusion that viruses may lay the foundation for autoimmune responses that attack inhibitory neurons.

3. Diagnostic Approach to Dysphagia and Achalasia

Dysphagia is considered an alarm symptom that mandates the performance of esophago-gastro-duodenoscopy (EGD) as an initial diagnostic modality to exclude structural or mucosal lesions in the esophagus or the stomach cardia. Examples of these include tumors, inflammation, esophageal rings, strictures, and other pathologies that can mimic achalasia, a condition traditionally named pseudochalasia 4. A clinical suspicion of pseudo-achalasia should be sought in patients older than 55 years of age with a prompt onset of solid dysphagia that proceeds to liquid dysphagia and weight loss ^[33][34]. Classic endoscopic findings of achalasia present in about half of the cases include widening of the esophagus, residue in the esophageal lumen, and obstructed EGJ.

An additional important diagnosis is eosinophilic esophagitis (EoE), an immune-mediated/allergic disorder involving the esophagus causing dysphagia and diagnosed by eosinophils predominant inflammation ^[35]. Multiple biopsies are mandatory to confirm the diagnosis. Indicative endoscopic findings of EoE include mucosal thickening and edema, ring formation, and white patchy exudates and fibrosis in the late stage ^[35]. After the exclusion of anatomical, structural, and inflammatory conditions, HRM study is necessary to assess the esophageal motor function and the relaxation of the lower sphincter.

4. Treatment of Achalasia

The most fundamental goals of treating achalasia are to attain symptomatic relief and to improve patients’ quality of life and work capability. Since the repair and the rehabilitation of the defective contractility are impractical and unrealistic, the eventual target of treating achalasia is to release the resistance at the esophagogastric junction. This treatment choice is not straightforward, and a personalized approach should be adopted that takes into account factors including the demographics and medical background of the patient, the achalasia subtype, and the patient’s predilection ^[36]. Importantly, when describing treatment outcomes in achalasia, most previous trials relied on subjective symptom relief as reported by patients, generally by applying the EKARDT score. The EKARDT score includes the four main achalasia symptoms of dysphagia, regurgitation, weight loss, and chest pain. The score points relied on the frequency of each symptom reported by patients and ranges from 3 to 12 (worst symptoms) ^[37][38]. Nonetheless, despite the widespread implementation of the EKARDT score in clinical practice, it has not been validated yet for this purpose (I). Moreover, most trials considered an Eckardt score of >3 or a reduction in symptoms of <50% as treatment failure. However, several limitations exist with this instrument of assessing treatment outcomes, including using subjective symptoms that could be perceived differently between patients. It can be also be misleading, frequency and time intervals of applying the EKARDT core have yet to be defined, and the cardinal achalasia symptoms could be provoked by pathologies other than achalasia.

Botulinum toxin (Botox) is a well-known therapeutic option for achalasia that has been used for decades ^[39]. When injected into the distal esophagus and to the LES, the toxin inhibits the release of acetylcholine, which eventually leads to a transitory inhibition of the contractility of LES smooth muscle fibers. Despite the excellent safety profile of Botox injection, the key drawback of this therapeutic option is its short-term durability given a substantial decline in symptoms relief after 6 and 12 months ^[39]. Therefore, Botox use is restricted to special cases such as comorbid elderly patients or as a temporarily relief before surgery, POEM, or balloon dilation.

Pneumatic balloon dilation is a therapeutic option where a pneumatic balloon is placed in the LES under the guidance of fluoroscopy. The gradual inflation of the balloon leads to mechanical disruption of the LES and relieves the obstruction at the esophagogastric junction. Currently, the preferred protocol for dilation is using a graded attitude, where dilation starts with the 30 mm balloon but the balloon diameter increases in subsequent sessions to 35 mm and up to 40 mm. The gradual dilation approach has been shown to have greater efficacy and a higher safety profile ^[40]. Pneumatic balloon dilation is long-lasting, with a symptomatic relief over 80% after 2 and 5 years ^[41]. The long-standing clinical success of pneumatic balloon dilation after 2 and 5 years is satisfactory and similar to surgical outcomes ^[42]. Complications related to balloon dilation are rare and may include the development of esophageal reflux symptoms in 15–35% of patients. Esophageal perforation is rare and occurs in about 2% of cases and very rarely leads to bleeding ^[43].

Heller myotomy is an well-established procedure for achalasia treatment that has been performed for more than a century and involves the dissection of the LES smooth muscle fibers. The incidence of esophageal reflux symptoms and the development of erosive esophagitis after the myotomy have been significant; therefore, surgeons also complete a partial fundoplication wrap of the posterior (Toupet) or the anterior (Dor) to prevent reflux symptoms and complications. LHM is a safe and effective therapeutic modality with durable symptomatic relief, estimated to be over 85% after 5 years ^[42].