Samuel Sostre

Intrasphincteric Botulinum Toxin for the Treatment of Achalasia

BACKGROUND Achalasia 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. METHODS In 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. RESULTS One 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. CONCLUSIONS Injection 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.

Erythromycin accelerates gastric emptying after pancreaticoduodenectomy. A prospective, randomized, placebo-controlled trial.

OBJECTIVE This study tested the hypothesis that erythromycin, a motilin agonist, reduces the incidence of early DGE after pancreaticoduodenectomy. SUMMARY BACKGROUND DATA Delayed gastric emptying (DGE) is a leading cause of morbidity after pancreaticoduodenectomy, occurring in up to 40% of patients. The pathogenesis of DGE has been speculated to involve factors such as peritonitis from anastomotic leaks, ischemia to the antropyloric muscles, and gastric atony in response to resection of the duodenal pacemaker or reduction in circulating motilin levels. METHODS Between November 1990 and January 1993, 118 patients undergoing pancreaticoduodenectomy completed this prospective, randomized, placebo-controlled trial. The patients received either 200 mg of intravenous erythromycin lactobionate every 6 hours (n = 58), or an identical volume of 0.9% saline (n = 60) from the third to tenth postoperative days. On the tenth postoperative day, a dual phase radionuclide gastric emptying study was performed. RESULTS The erythromycin and control groups were comparable regarding multiple preoperative, intraoperative, and postoperative factors. The erythromycin group had a 37% reduction in the incidence of DGE (19% vs. 30%), a significantly reduced (p < 0.05) need to reinsert a nasogastric tube for DGE (6 vs. 15 patients), and a significantly reduced (p < 0.01) per cent retention of liquids at 30 minutes and solids at 30, 60, 90, and 120 minutes. No major adverse reactions to erythromycin were observed. CONCLUSIONS Erythromycin is a safe, inexpensive drug that significantly accelerates gastric emptying after pancreaticoduodenectomy and reduces the incidence of DGE by 37%. These data support the use of erythromycin to decrease early DGE after pancreaticoduodenectomy.

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.

The Influence of Biological and Technical Factors on the Variability of Global and Regional Brain Metabolism of 2-[18F]Fluoro-2-Deoxy-D-Glucose:

This study investigated the influence of biological and technical factors on variations of global and regional cerebral metabolic rate of glucose (CMRglc) measured with 2-[18F]fluoro-2-deoxy-d-glucose ([18F]FDG). Twelve male volunteers (22–40 years) were investigated on three or four occasions for a total of 42 studies. We calculated the variance/covariance of the following parameters: CMRglc, six parameters of the blood clearance of [18F]FDG, hour of injection, peak time of blood radioactivity, and six components of the operational equation (nonradioactive blood glucose concentration, brain radioactivity, two integrals, numerator, and denominator). There was correlation among these six components, except for nonradioactive blood glucose. However, the correlation between the CMRglc and the individual components of the operational equation was poor. The inter- and intrapersonal CMRglc coefficients of variations were 13.8 and 7.1%, respectively. In contrast, coefficients of variations of the numerator and denominator of the operational equation were 34.6 and 32.6%, respectively, and were always in the same direction. No correlation was found between CMRglc and the technical factors in the numerator and denominator of the operational equation. Factor analysis disclosed that a single factor was responsible for 70% of the variance. This factor included caudate, putamen, thalamus, frontal cortex, temporal cortex, and cingulate gyrus. These structures are involved with multiple complex functions, from autonomic motor control to behavior and emotions. The intrinsic metabolic variability of these structures, along with the basal metabolic processes that are continuously going on in the brain, may be the best explanation for the variance encountered in our investigation.

Progesterone alters biliary flow dynamics

OBJECTIVE To test the hypothesis that progesterone alters sphincter of Oddi and gallbladder function and, therefore, bile flow dynamics. SUMMARY BACKGROUND DATA Although the effects of progesterone on the biliary tract have been implicated in the increased incidence of gallstones among women, the specific effects of prolonged elevation of progesterone levels, such as occurs with contraceptive progesterone implants and during pregnancy, on the sphincter of Oddi and biliary flow dynamics are still incompletely understood. METHODS Adult female prairie dogs were randomly assigned to receive subcutaneous implants containing either progesterone or inactive pellet matrix only. Hepatic bile partitioning and gallbladder emptying were determined 14 days later using 99mTc-Mebrofenin cholescintigraphy. RESULTS Significantly less hepatic bile partitioned into the gallbladder in progesterone-treated than in control animals. The gallbladder ejection fraction was significantly reduced from 73+/-6% in controls to 59+/-3% in the progesterone-treated animals. The rate of gallbladder emptying was significantly reduced from 3.6+/-0.3%/minute to 2.9+/-0.1%/minute. CONCLUSIONS Progesterone administered as subcutaneous implants alters partitioning of hepatic bile between gallbladder and small intestine and, therefore, gallbladder filling. Progesterone also significantly impairs gallbladder emptying in response to cholecystokinin. The effects of progesterone on the sphincter of Oddi and the gallbladder may contribute to the greater prevalence of gallstones and biliary motility disorders among women.

Gallbladder ejection fraction. Nondiagnostic for sphincter of Oddi dysfunction in patients with intact gallbladders.

Thirty consecutive patients with intact gallbladders and biliary pain were evaluated to determine whether gallbladder ejection fraction could identify sphincter of Oddi dysfunction. The mean gallbladder ejection fraction was 45% in patients with abdominal pain and 72% in normal controls. Gallbladder ejection fractions were then correlated with endoscopically measured sphincter of Oddi pressures in patients with abdominal pain. The mean gallbladder ejection fraction was 41% in 7 patients with elevated sphincter pressures and 46% in 23 patients with normal pressures (P = NS). Thirty-six percent of patients with elevated pressures and 33% of patients with normal pressures had abnormal gallbladder ejection fractions. Gallbladder ejection fraction had a sensitivity of 33%, a specificity of 63%, and a positive predictive value of 25% for detection of elevated pressures. Regression analysis revealed a poor correlation between sphincter pressure and gallbladder ejection fraction (r2 = 0.02). These findings suggest that gallbladder ejection fraction cannot be used to diagnose sphincter of Oddi dysfunction in patients before they undergo cholecystectomy.

Gallbladder response to a second dose of cholecystokinin during the same imaging study

Patients on total parenteral nutrition or after prolonged fasting may require treatment with cholecystokinin (CCK) prior to hepatobiliary imaging. Some may also require evaluation of gallbladder (GB) contractility, and the need for a second dose of CCK may arise. It is not clear whether gallbladder function can be adequately evaluated with CCK when a previous CCK dose had already been administered. We studied ten normal subjects to evaluate GB response to a second CCK injection. The subjects received 20 μg/kg sincalide in a 3-min infusion prior to administration of technetium-99m disofenin. They then received an identical sincalide dose at 60 min postinjection, and imaging was continued for another 30 min to quantify GB contraction. Gallbladder ejection fraction (GBEF) values ranged from 42–98% (mean: 71.5±19%). Pretreatment with CCK does not preclude GB contraction evaluation with a second dose of CCK. Expected GBEF values are similar to those obtained with single CCK injections.

Factor analysis of regional cerebral glucose metabolic rates in healthy men

Cerebral glucose utilization measured with fluorine-18-fluoro-2-deoxy-D-glucose is characterized by considerable variability both among different persons and for the same person examined on different occasions. The goal of this study was to explore whether some regions of the brain were more variable than others with respect to glucose utilization and whether there was a pattern in their covariance. The global and regional cerebral utilization of glucose was measured in 12 healthy young volunteers on 3 or 4 occasions. In all, 24 regions were examined. The interrelation of the glucose utilization rates of the brain regions was investigated by factor analysis of the metabolic rates. Some 70% of the total variance was attributable to only 1 factor, while 80% of the total variance could be attributed to 2 factors. Regions making up the first factor were the frontal and temporal cortex, cingulate gyrus, caudate nucleus, thalamus and putamen. These regions are functionally related to the limbic system. Regions of the second factor were the parietal cortex, occipital cortex and cerebellum, regions more clearly related to sensory and motor functions. The 2-factor pattern was highly reproducible, being found with different algorithms for factor extraction and rotation. Under resting conditions, the variance of cerebral metabolism seems to be primarily related to regions which are closely involved with the limbic system. Cortical regions involved primarily in motor and sensory functions have less influence on the variance.

Failure of perchlorate to inhibit Tc-99m isonitrile binding by the thyroid during myocardial perfusion studies

The thyroid gland receives an average radiation dose of 3 rads during two Tc-99m isonitrile (MIBI) myocardial perfusion studies, if 20 mCi is administered both at rest and at peak exercise. In patients with coronary artery disease, multiple myocardial perfusion studies may be required, resulting in a high level of thyroid radiation. We attempted to reduce this radiation exposure by blocking thyroidal Tc-99m MIBI uptake with oral potassium perchlorate (KCIO4). Fourteen normal subjects received 0.6g to 0.8g KCIO4 20-25 minutes before tracer injection. Subjects who received KCIO4 at rest (n=11) did not receive KCIO4 at their stress study, and vice versa (n=3). Thyroid uptake values were obtained with a thyroid probe 20 minutes after injection for both rest and stress studies and were corrected for saturation effects. There was no difference between fractional thyroid uptake values with and without preceding perchlorate administration: 1.9 ± 0.5% and 1.8 ± 0.3% (mean ± SD), respectively. Failure to block Tc-99m MIBI uptake after intravenous (IV) injection is probably due to high thyroidal blood flow and nonspecific tracer accumulation. The concentration of this radioisotope in adjacent muscles also contributes to the high thyroid radiation dose. In summary, administration of KCIO4 before Tc-99m MIBI studies does not reduce the thyroidal radiation dose or uptake of this tracer, suggesting that thyroidal uptake of this tracer is not mediated by the iodine trapping mechanism.

Bowel visualization during indium-111-labelled diethylene triamine penta-acetic acid cisternography due to massive cerebrospinal fluid leak - Case report and review of the literature

We report a case of massive cerebrospinal fluid (CSF) leakage where the tracer injected intra-thecally for radionuclide cisternography was later visualized in the bowel as well as the nasopharynx. We discuss the potential implications of this finding in patients with CSF leaks. A brief review of the diagnosis of CSF leaks is included.