Treatment of Achalasia with Intrasphincteric Injection of Botulinum Toxin: A Pilot Trial

Methods

Ten symptomatic adult patients with achalasia were prospectively evaluated by barium video-esophagograms, esophageal scintigraphy, and manometry. Clinical response was evaluated by scoring three symptoms (dysphagia, regurgitation, and chest pain) on a scale ranging from 0 to 3 (0 = none, 1 = occasional, 2 = daily, and 3 = with each meal) [2]. At the time of upper endoscopy, 80 units of botulinum toxin was injected through a 5-mm sclerotherapy needle into the lower esophageal sphincter as estimated by endoscopy (1 mL of a 20 U/mL solution in each of the four quadrants). Patients were re-evaluated 1 week later. The study was approved by the Johns Hopkins Hospital Institutional Review Board. Statistical analysis was done using the student t-test. Unless otherwise stated, results are expressed as the mean ± SE.

Results

The study group consisted of 4 men and 6 women whose mean age was 51 years (range, 24 to 80 years). Patients had been symptomatic for an average of 4.7 years, during which time most patients had had esophageal dilatation at least once. One week after treatment, clinical scores for the 10 patients decreased from 5.3 ± 0.4 to 0.7 ± 0.3 (P < 0.001), and all three symptoms improved significantly. Seven patients became asymptomatic after one injection. Two patients with initially modest improvement required a second injection for a satisfactory response. One patient remained unsatisfied with the clinical response despite three injections; this treatment was thus considered a failure. All objective measurements of esophageal function improved. In 7 patients for whom results were available, lower esophageal sphincter pressure decreased from 46.0 ± 5.5 mm Hg to 26.0 ± 3.7 mm Hg (P = 0.007); in 9 patients, esophageal diameter decreased from 5.2 ± 0.7 cm to 4.3 ± 0.7 cm (P = 0.002); and in 9 patients, 5-minute esophageal retention decreased from 75% ± 8.9% to 56% ± 13% (P = 0.02).

Of the nine initial responders, three relapsed approximately 2 months later. The other six patients remained asymptomatic after a single injection of botulinum toxin for a median duration of about 12 months (range, 11 to 14 months). Most patients gained weight—in one case, as much as 16 kg. Clinical remission was accompanied by a sustained improvement in esophageal retention, as measured in two patients (the mean 5-minute retention at an average of 6 months after treatment was 26.3% compared with 38.5% before treatment; P = 0.01). The symptoms of three patients recurred approximately 1 year after treatment. Two of these patients have since been re-treated with botulinum toxin, and their symptoms completely resolved once again (Figure 1). No adverse effects were seen in any patient. No esophagitis was seen at follow-up endoscopy 1 week after injection.

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Figure 1. The four graphs show the percentage of ingested radioactivity (vertical axis) remaining in the esophagus at several points in time after ingestion of the test meal (horizontal axis). A. Baseline esophageal clearance was markedly abnormal, with a 5-minute retention of 56.1%. B. One week after botulinum toxin injection, the patient had normal esophageal clearance, with a 5-minute retention of 5%. The patient remained asymptomatic for about 1 year, then dysphagia gradually recurred. C. Esophageal clearance measured at this time was again grossly abnormal, with a 5-minute retention of 74.8%. This patient then had a second injection of botulinum toxin, and symptoms completely resolved. D. The patient's esophageal clearance then returned to normal, again with a 5-minute retention of 5.6%. The change in esophageal clearance in one patient in response to injections of botulinum toxin.

Discussion

Traditional treatment of achalasia consists of balloon dilatation or myotomy. Although these procedures may relieve symptoms, they carry a significant risk for complications, notably perforation and gastroesophageal reflux [3-5]. A need therefore exists for alternative ways to treat this condition. Our preliminary open-label trial of botulinum toxin in patients with achalasia did not use control injections. Nevertheless, our results are encouraging and suggest that this treatment is potentially safe and relatively simple. An initial response was seen in 9 of the 10 patients (90%); 60% had a satisfactory long-term response (defined arbitrarily as >6 months). This compares favorably to the response rates after a single pneumatic dilatation (approximately 60%) and surgery (64% to 95%) [2, 6, 7]. The response of symptoms in our patients was accompanied by significant improvement in all objective esophageal test results. Most importantly, lower esophageal sphincter pressure decreased by about 50%, a change equivalent to that reported after balloon dilatation (41% to 50%) [2, 8, 9].

Symptoms seem to recur in the long-term responders about 1 year after the initial injection. However, it appears that in these patients, further injections at this stage retain their efficacy. Pneumatic dilatation also has a high rate of relapse after the first dilatation [2]. This necessitates further dilatations, each with its own risk for perforation. Botulinum toxin therapy is therefore an attractive alternative to dilatation, even if repeated injections are required.

Although locally injected botulinum toxin has been used in several disorders of skeletal muscle spasm [10], this is the first report of its use in a disorder of gastrointestinal smooth muscle. Further studies are needed to confirm the initial promise of this new approach to treating achalasia.