Achalasia was one of the first gastrointestinal motility disorders to be characterized, both clinically and manometrically. Failure of relaxation of the lower esophag- eal sphincter (LES) is the cardinal feature of this disease, thought to result from a relatively selective degeneration of the inhibitory neurons in the surrounding myenteric plexus (Figure 1). This leads to a functional obstruction of the esophagus that, along with aperistalsis in the body of the esophagus, is responsible for the major symptoms of achalasia: dysphagia for solids and liquids, regurgitation of undigested food and chest pain. All current methods of treatment are essentially palliative in nature and are focused on reducing the LES pressure. The main focus of this review will be on the use of botulinum toxin (BTX) for this condition and how it compares with other available therapies.
BTX blocks the calcium-dependent release of acetylcholine from presynaptic cholinergic nerve terminals. It is a neuro- toxin produced by Clostridium botulinum. Although several serotypes are known, the one used clinically is BTX type A. Pasricha et al were the first to demonstrate the application of BTX for the treatment of achalasia in a double- blind, randomized, placebo controlled study. Since then, multiple studies and several reviews have been published. BTX causes a significant reduction in resting baseline LES pressure, esophageal clearance and symptoms (Figure 2). The efficacy ranges from 65% to 90% after a single injection, with the effect lasting anywhere from three months to more than one year. The main limitation to the use of BTX for achalasia is its lack of significant long term results with a single injection. With repeat injections at an average of every 10 months, Annese et al recently reported the highest long term efficacy rate to date (75% after a mean follow-up of 24±15 months).
Approximately 80 to 100 U of BTX are injected endo- scopically into the LES in four aliquots of 1.0 mL in each quadrant. Preliminary reports have thus far not shown a significant difference in efficacy with higher doses of BTX; more precise localization of the LES with the use of endoscopic ultrasound or injections over a wider area of the LES are similarly unproven in their effects on efficacy.
Figure 1) Lower esophageal sphincter (LES) regulation. Top Normal LES pressure can be viewed as a balance between the contractile effects of acetylcholine (ACh) and the relaxing effects of the neurotransmitters nitric oxide (NO) and vasoactive intestinal peptide (VIP) in the myenteric plexus. Bottom In achalasia, there is a selective loss of nitrinergic neurons in the myenteric plexus. This leads to an unopposed excitation of the LES by ACh, resulting in a hypertonic LES that fails to relax upon swallowing
Injection of BTX appears to be safe. The most commonly reported complications are periprocedural transient chest pain and heartburn. Esophageal wall injury and para- esophageal tissue inflammation have been reported in two patients. Caution needs to be exercised with regard to potential, yet unknown, late side effects. Antibodies may develop against the toxin, causing resistance.
Figure 2) Symptomatic improvement after botulinum toxin (BTX) injection. There is a statistically significant improvement in symptom score one week after BTX injection as compared to placebo. Data from reference 5
Given its low risk procedural profile, BTX injection is an attractive therapeutic option for high risk surgical patients and elderly patients, in whom conservative, albeit temporizing, management is preferred.
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