Thomas R. Hendrix

Intrasphincteric Botulinum Toxin for the Treatment of Achalasia

BACKGROUNDnAchalasia is a disorder of swallowing in which the lower esophageal sphincter fails to relax. We report the use of botulinum toxin, a paralytic agent, for the treatment of this condition.nnnMETHODSnIn a double-blind trial, 21 patients with achalasia received either 80 units of botulinum toxin or placebo, injected endoscopically into the lower esophageal sphincter. One week later, the response to treatment was assessed on the basis of changes in the symptom scores (measured on a scale from 0 to 9), pharyngoesophagograms, and results of esophageal manometric and scintigraphic studies. Patients who received placebo initially were subsequently treated with botulinum toxin. After six months, esophageal scintigraphy was repeated.nnnRESULTSnOne week after treatment, the mean decrease in the symptom score was 5.4 points for the patients treated with botulinum toxin and 0.5 point for the placebo group (P = 0.001). The mean decrease in the pressure of the lower esophageal sphincter was 33 percent in the treatment group, as compared with a mean increase of 12 percent in the placebo group (P = 0.02), and the mean increase in the width of the opening of the lower esophageal sphincter was 204 percent in the treatment group, as compared with a mean decrease of 14 percent in the placebo group (P = 0.02). Nineteen of the 21 patients treated with botulinum toxin had symptomatic improvement initially; after six months 14 patients were still in remission. This improvement was accompanied by a decrease in esophageal retention that was sustained at six months (46 percent, as compared with a pretreatment value of 77 percent; P = 0.04). There were no serious adverse effects.nnnCONCLUSIONSnInjection of botulinum toxin into the lower esophageal sphincter is an effective, safe, and simple method of treatment for achalasia, with results that are sustained for several months.

Regulation of the gastric emptying of glucose

The gastric emptying characteristics of physiological saline (0.9% NaCl) and glucose solutions of three different concentrations (0.05, 0.125, 0.25 g/ml) were examined in order to identify distinctions in the control of the stomachs activity. Saline emptied rapidly and exponentially. Glucose assumed, soon after filling the stomach, a slow and calorie-constant emptying pattern such that 2.13 kcal of glucose were delivered per minute to the duodenum for all three concentrations of glucose. When, by means of a catheter passed beyond the pylorus, glucose was infused into the duodenum in amounts varying from 26.5 to 120 kcal, an inhibition on the gastric emptying of physiological saline of 0.46 min/kcal of intraduodenal glucose was demonstrated. Since 2.13 kcal/min and 0.46 min/kcal are reciprocals, it appeared that in emptying saline, the gastroduodenal system acts as an open-loop system passing liquids from the stomach at a rate primarily determined by the volume of gastric contents. With glucose, however, a closed-loop system is established that assumes a steady-state balance between the delivery of glucose to the duodenum and the inhibition of this delivery evoked from the duodenum by the glucose that enters it.

Selective Nonoperative Management of Contained Intrathoracic Esophageal Disruptions

Eight patients with intrathoracic esophageal disruptions were managed nonoperatively and without pleural drainage. Criteria for nonoperative treatment included the following: disruption contained in the mediastinum or between the mediastinum and visceral lung pleura; drainage of the cavity back into the esophagus; minimal symptoms; and minimal signs of clinical sepsis. Cause of the esophageal perforation was pneumostatic dilatation (1 patient), vomiting (2), and a leak following esophageal operation (5). Antibiotics were administered intravenously to all patients; hyperalimentation was accomplished intravenously in 5, and nasogastric suction was used in only 1. The cavities contracted and the esophageal leaks sealed in all instances. Time before oral intake was resumed ranged from 7 to 38 days (average, 18 days). Days until discharge ranged from 15 to 52 days (average, 28 days).

Treatment of achalasia with intrasphincteric injection of botulinum toxin. A pilot trial.

Achalasia is a disorder characterized by a failure of the lower esophageal sphincter to relax with swallowing and by a lack of esophageal peristalsis. The sphincteric abnormalities in achalasia are thought to be caused by a selective loss of inhibitory neurons in the myenteric plexus, resulting in the relatively unopposed excitation of the smooth muscle by acetylcholine and other mediators. Our previous studies in animals [1] have shown that locally injected botulinum toxin, a potent inhibitor of acetylcholine release, can reduce lower esophageal sphincter tone. We report our initial experience with this agent for the treatment of achalasia in humans. 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 weightin 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. Figure 1. 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.

Pharyngoesophageal interrelationships: observations and working concepts

Simultaneous disorders of the pharynx and esophagus are so frequent that the complete swallowing chain should be examined in all patients with dysphagia. Data are presented to support the concept that such simultaneous disorders represent related phenomena; the mechanism involves changes in cricopharyngeal function seen radiographically as cricopharyngeal prominence. If neurologic disease has been excluded, cricopharyngeal prominence may be the clue to esophageal disease. When cricopharyngeal prominence is found during dynamic imaging of the pharynx, intensive examination of the esophagus and a search for signs of compensation or decompensation in the pharynx should be undertaken.

Pharyngeal Findings in 21 Patients with Achalasia of the Esophagus

Dynamic imaging of the pharynx revealed unsuspected pharyngeal findings in 11 of 21 consecutive patients with achalasia of the esophagus. Findings included cricopharyngeal prominence, asymmetry of pharyngeal contraction or epiglottic tilt, and lateral pharyngel pouches, many of which emptied postswallow into the pyriform sinus, resulting in retention of contrast. Two patients had a Zenkers diverticulum; a Zenkers diverticulum had been resected 10 years previously in a third. There may be a causal relationship between these pharyngeal findings and the esophageal disease. In achalasia, it is important to examine the pharynx in addition to the esophagus, so that pharyngeal findings will not be overlooked.

Failure of oxethazaine to alter acid-induced esophageal pain

SummaryFifty patients with positive responses to acid perfusion tests were studied to determine the effectiveness of oxethazaine, a topical anesthetic, in preventing acid-induced esophageal pain. Oxethazaine was tested in concentrations ranging from 0.2% to 2.4% and acid-induced esophageal pain was not altered in 48 of 50 patients studied.

Granular small bowel mucosa: a reflection of villous abnormality

Diffuse mucosal granularity was reported recently in small bowel Crohns disease. The radiographic appearance corresponded on histopathologic examination to villous hypertrophy, fusion, or epithelial bridge formation. We have observed similar granularity in Crohns disease but also in several other conditions, including radiation enteritis, pancreatic glucagonoma, protein-losing enteropathy, and small bowel ischemia. Histopathologic examination demonstrated various alterations in villous morphology, such as edema, hyperplasia, clubbing, or fusion. In Crohns disease, this appearance was sometimes an indication of early inflammatory disease but was also seen following extensive small bowel resection, possibly due to villous enlargement resulting from intestinal adaptation. These findings suggest that granular mucosa in the small bowel is a nonspecific finding reflecting an alteration in villous structure.

DIAGNOSIS OF CAMPYLOBACTER PYLORI GASTRITIS

Campylobacter pylori is a bacterium that inhabits gastric mucosa. It causes chronic active gastritis and is highly associated with duodenal ulcer.Campylobacter pylori has a urease enzyme (not present in man), which allows diagnosis by a [14C]urea breath test. We compared two noninvasive tests, the breath test and serum ELISA, to biopsy and histologic diagnosis. Twenty-two patients who underwent gastroduodenoscopy for evaluation of possible peptic ulcer disease entered the study. The breath test detected the organism in eight of eight patients biopsy-positive for the organism (sensitivity 100%). The breath test was negative in 12 of the 14 patients who were biopsy-negative (specificity 86%). The ELISA was performed in 14 patients. It was positive in 5 of 5 patients biopsy-positive for the organism (sensitivity 100%) and negative in 7 of 9 patients who were biopsy-negative (specificity 78%). We conclude that both the ELISA and the [14C]urea breath test are excellent noninvasive methods to detectCampylobacter pylori. However, only the breath test is suitable for following the response to treatment, as it detects the presence of the organism rather than an immune response to it.

Commentary on the determination of the evaluation of dysphagia

Sharing views with colleagues on clinical issues and comparing approaches to the diagnosis and management of these disorders is always stimulating and enlightening. The recent joint meeting of the faculties of the Arbeitgemeinschaft ffir Schluckstrrungen, Munich, Germany and the Johns Hopkins Swallowing Center, Maryland, USA was no exception. In this issue of Dysphagia, Dr. Reinhard Lorenz and associates in the Department of Internal Medicine of The Technical University of Munich present their approach to dysphagia. Their inquiry is limited to esophageal disorders with reliance placed on colleagues in other specialties to deal with structural and functional disorders of the oropharynx. As a consequence, endoscopy is their primary diagnostic intervention with radiographic examination playing a secondary role. In the process, dysphagia is characterized by the company it keeps. For example, dysphagia is discussed as it is found in association with clinical disorders, e.g., esophageal reflux disease, non-reflux related esophagitis, systemic diseases and angina-like chest pain. The approach used in The Johns Hopkins Swallowing Center is somewhat different in that we approach dysphagia from a pathophysiological point of view. Thus, dysphagia is an indication that some step in the swallowing process is abnormal. By analyzing the history, we attempt to localize the defect to one of the three stages of swallowing (oral, pharyngeal, or esophageal) and to characterize the responsible disorder as a structural (anatomical) or a motility disorder. In keeping with the belief that swallowing is a continuum beginning with the propulsion of the bolus from the mouth to the pharynx and is completed by its passage through the lower esophageal sphincter into the stomach, a cine or video study of the entire swallowing sequence is our initial diagnostic study. This examination consists of a double contrast examination for mucosal detail of the oral cavity, pharynx and esophagus and a dynamic imaging study evaluating the function or motility of the same structures [1]. This examination often incorporates multiple bolus consistencies in an attempt to provoke or initiate the patients symptoms. The radiologist then tests the clinical hypotheses that have been generated from the patients history as to the cause of the dysphagia by following the passage of the bolus from mouth to stomach. The findings indicate what the subsequent diagnostic and therapeutic steps should be, e.g., upper gastrointestinal endoscopy for biopsy confirmation of the presumptive diagnosis or endoscopic therapy such as dilation of a stricture, pneumostatic dilatation for achalasia, a 24 h monitoring of intraesophageal pH, esophageal motility or consultation with colleagues in neurology or otolaryngology. Thus, dynamic imaging of the swallowing process, first with liquid