Achalasia: From New Insights in Pathophysiology to Treatment

Abstract

Achalasia is the best characterized esophageal motor disorder. It is a rare disorder with an estimated prevalence of 0.5-1 per 100.000 per year without a clear age predilection (1). In children, it is part of the Triple A syndrome, characterized by achalasia, alacrima and adrenocorticotrophic hormone resistant adrenal insufficiency, and has been suggested to be part of Alport´s syndrome in some patients. Recent observations also suggest that achalasia is more frequent in Down´s syndrome. Besides idiopathic achalasia, Chagasic achalasia may lead to a clinically similar picture. This infectious disease is endemic in South-America as a consequence of an infection with the parasite Trypanosoma cruzi. Pseudo-achalasia, occurring in approximately 5% of patients, is usually due to in growth of a tumor in the distal esophagus or the cardia. Pseudo-achalasia is generally seen in older patients with rapidly progressive symptomatology and with prominent weight loss. Diagnosing pseudo-achalasia is usually difficult and requires meticulous endoscopic inspection, and in some cases additional endoscopic ultrasound examination to diagnose an infiltrating submucous or pancreatic tumor. Manometry typically shows an incomplete relaxation of the LOS upon deglutition. In addition, esophageal peristalsis is absent and resting tone of the LOS will often be elevated (1). The net result of these motor abnormalities is that saliva and food will be retained in the esophagus leading to the typical symptoms of achalasia: dysphagia for both solids and liquids, regurgitation of undigested food, respiratory complications (nocturnal cough and aspiration), chest pain and weight loss. In clinical practice, the diagnosis is made preferably by manometry, after exclusion of organic causes of dysphagia. Endoscopy is diagnostic in about 1/3 and radiology in about 2/3 of the patients; diagnostic certainty is provided by manometry in over 90% of cases. The pathogenesis of achalasia is still incompletely elucidated. Histological examination reveals a significant decrease in the number of myenteric neurons, especially inhibitory NO releasing neurons in the distal esophagus and at the level of the LOS. Also in children with achalasia, a decrease in NO synthase containing neurons has been described (2). Detailed examination of resection specimens shows infiltration of myenteric ganglia with CD3/CD8 positive lymphocytes. In addition, IgM antibodies and evidence of complement activation was shown within myenteric ganglia. Finally, antibodies against myenteric neurons have been repeatedly shown in serum of achalasia patients, especially in patients with a specific HLA genotype, namely those carrying the DQA1 * 0103 and DQB1 * 0603 alleles (3). These findings all point towards an auto-immune origin of the myenteric ganglionitis. The exact stimulus initiating this auto-immune response or the antigen targeted remain however to be identified. Some studies suggest a previous viral infection as possible trigger, however others fail to confirm this. Other investigators however have also demonstrated antineuronal antibodies in serum from GORD patients, suggesting that the antineuronal antibodies are generated in response to tissue damage and thus rather represent an epiphenomenon and not a causative factor. The loss of the nitrergic neurons results in the absence of relaxation of the LOS in response to various stimuli both in vitro and in vivo. Muscle strips taken from the LOS of patients with achalasia fail to relax in response to electrical field stimulation (4). In addition, infusion of cholecystokinin, known to relax the LOS in healthy volunteers, contracts the LOS in patients with achalasia and LOS relaxation to esophageal distension is reduced. Finally, gastric distension fails to induce transient lower esophageal sphincter relaxations in achalasics, further illustrating the absence of inhibitory innervation to the LOS. The treatment of children with achalasia is largely comparable to that of adults. It is aimed at improving bolus transport across the LOS by reducing the pressure at the LOS. At present, treatment options in achalasia are pharmacotherapy, pneumatic dilation, surgery or injection of botulinum toxin. Although several studies have reported some degrees of success using calcium channel blockers or nitrates, these types of treatment are only useful in less severe types of achalasia. They are associated with cardiovascular side-effects and they are generally less efficacious. Pneumatic dilatation aims at disruption of the LOS by forceful dilatation using an air-filled balloon. Follow-up studies in adults have indicated that the best predictor for a long-term remission is a residual sphincter pressure below 10 mmHg (5). Pneumatic dilatation yields good to excellent results in 70-80% of patients, especially in patients over 45 years old, in patients with a longer standing history (>5 years of symptoms) and in patients with a slightly dilated esophagus. It should be emphasized though that the success rates significantly drop in time to only 40% after 15 years or more of follow up (6). In children, only small series have been reported with similar success rates ranging between 70 and 90%. An alternative to pneumatic dilatation is per-endoscopic injection of botulinum toxin in the LOS, an easy and patient-friendly procedure (7). The mechanism of action consists of a temporarily blockade of release of acetylcholine from excitatory motor neurons at the level of the LOS. Although the initial rate of symptomatic benefit may be comparable to that of pneumatic dilatations, the effect wears off quickly in many patients, making this treatment less attractive. Also in children, botulinum toxin has been used to treat achalasia. A relatively large series of 23 patients was reported by Hurwitz et al. (8). Nineteen children responded to this treatment, but the mean duration of the effect was only 4 months. A meta-analysis showed that the need for re-treatment in children with achalasia is comparable to that of adult patients receiving botulinum toxin. Based on their results, the authors recommend that botulinum toxin should be used only in children who are poor candidates for either pneumatic dilation or surgery. Surgical myotomy, now performed via a laparoscopic approach, is increasingly performed and has become the treatment of choice in many centers. Via laparoscopic route, a myotomy combined with an anti-reflux procedure is applied leading to reported success rates of 80-90% (9). Mattioli et al. (10) reported similar positive results in a series of 20 children with achalasia treated with a single longitudinal anterior esophageal myotomy and a 180 degrees anterior gastropexy according to Dor. Whether this rather new approach is superior to pneumatic dilatation is still unclear and is currently studied in a large European prospective study. Unfortunately, none of these therapies corrects the underlying abnormality. Recent studies in mice however suggest that transplantation of neuronal stem cells may be a therapeutical option. Indeed, neuronal stem cells injected in the pylorus survived and even expressed NO synthase (11). The advantage of such a technique would be that not only sphincter function will be restored, but perhaps even peristalsis. Clearly, a lot of research remains to be done further exploring this approach.