Emerging Treatments and Technologies ORIGINAL ARTICLE

The Treatment of Diabetic Gastroparesis With Botulinum Toxin Injection of the Pylorus

1 1 BRIAN E. LACY, PHD, MD CAROLE MATHIS, PHD though all of these medications have lim- 2 3 MICHAEL D. CROWELL, PHD PANKAJ J. PASRICHA, MD itations. Pylorospasm is thought to be a 2 ANN SCHETTLER-DUNCAN, RN contributing factor in the development of diabetic gastroparesis (9). Reports of in- trapyloric botulinum toxin injection to re- lieve symptoms of gastroparesis (10–14) prompted us to perform a trial in eight OBJECTIVE — Gastroparesis is a disorder of delayed gastric emptying that is often chronic in patients with severe diabetic gastroparesis nature. Up to 50% of type 1 diabetic subjects have symptoms of gastroparesis, which include who had failed standard therapy. nausea, vomiting, and early satiety. Elevated pyloric pressures may be responsible for delayed The hypothesis was that elevated py- gastric emptying in diabetic subjects. Botulinum toxin inhibits the release of acetylcholine and produces transient paralysis when injected into smooth muscle. The aim of this study was to loric pressures delay gastric emptying, determine whether injection of the pylorus with botulinum toxin in patients with diabetic and thus transient paralysis of the pylorus gastroparesis improves symptoms of gastroparesis, alters gastric emptying scan time, and/or should accelerate gastric emptying and changes weight and insulin use. improve symptoms of nausea and vomit- ing. Preliminary data from this study was RESEARCH DESIGN AND METHODS — This was an open-label trial with age- and presented in abstract form at the Ameri- sex-matched control subjects from a tertiary care referral center for patients with gastroparesis. can College of Gastroenterology meetings Eight type 1 diabetic subjects (six women and two men; mean age 41 years; mean years with in September 2000 (12). diabetes 25.3) who had failed standard therapy were enrolled. Intervention consisted of injection of the pylorus with 200 units of botulinum toxin during upper endoscopy. Symptoms, antro- pyloric manometry, gastric emptying scan times, weight, and insulin use were all recorded before intervention and during a 12-week follow-up period. RESEARCH DESIGN AND METHODS — Pylorospasm was first RESULTS — Seven of the eight patients completed the full 12-week follow-up period. No documented by comparing antropyloric complications were noted. Mean symptom scores declined from 27 to 12.1 (P Ͻ 0.01), whereas manometry findings between diabetic pa- the SF-36 physical functioning domain also improved (P Ͻ 0.05). Four patients noted an tients and age- and sex-matched healthy increase in insulin use of Ͼ5 units/day. Six of the seven patients gained weight (P ϭ 0.05). volunteers. Pylorospasm was not present Gastric emptying scan time improved in four patients. in any of the volunteers. Using a prospec- tive, open-label design, diabetic patients CONCLUSIONS — Botulinum toxin injection of the pylorus is safe and improves symptoms with severe gastroparesis were treated in patients with diabetic gastroparesis. These results warrant further investigation with a large, double-blind, placebo-controlled trial. with intrapyloric injections of botulinum toxin. Effectiveness was assessed by com- Diabetes Care 27:2341–2347, 2004 paring symptoms, weight, insulin use, gastric emptying, and antropyloric ma- nometry recordings at baseline and after botulinum toxin injection. astroparesis is a disorder of gastro- gastric pain. Gastroparesis is a common Eight patients with type 1 diabetes intestinal motility defined as a delay problem in type 1 diabetic subjects (1,2), (six women and two men) were enrolled in gastric emptying in the absence especially in the presence of hyperglyce- G in this study. The mean age was 41 years of mechanical obstruction. Common mia (3). Treatment options include eryth- (range 36–46), with a mean duration of symptoms include early satiety, nausea, romycin (4,5), metoclopramide (6), diabetes of 25.3 years (range 10–40) and vomiting, anorexia, weight loss, and epi- domperidone (7), and cisapride (8), al- mean insulin use of 24.4 years (range 10– ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● 40). All patients had been referred to the From the 1Marvin M. Schuster Center for Digestive and Motility Disorders, Johns Hopkins University, School Marvin M. Schuster Motility Center for of Medicine, Baltimore, Maryland; 2Novartis, East Hanover, New Jersey; and the 3University of Texas at further evaluation due to persistent symp- Galveston, Galveston, Texas. toms of gastroparesis despite the use of Address correspondence and reprint requests to Brian E. Lacy, PhD, MD, Dartmouth-Hitchcock Medical Center, Section of Gastroenterology, 1 Medical Center Dr., Lebanon, NH 03756. E-mail: standard medications. Mechanical ob- [email protected]. struction had been ruled out in all pa- Received for publication 26 March 2004 and accepted in revised form 28 June 2004. tients by the referring physicians using a P.J.P. is a paid consultant for Allergan. number of different tests (upper endos- Abbreviations: LES, lower esophageal sphincter. A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion copy [esophagogastroduodenoscopy], factors for many substances. small bowel follow-through, and com- © 2004 by the American Diabetes Association. puted scan of the abdomen

DIABETES CARE, VOLUME 27, NUMBER 10, OCTOBER 2004 2341 Botulinum toxin for diabetic gastroparesis and pelvis). A solid-phase gastric empty- Four side holes located at 0, 3, 6, and 9 Symptom questionnaires and ing scan was delayed in all eight patients. cm above the orad end of the sleeve re- weights The control group consisted of age- corded pressure events in the terminal Each patient filled out a symptom ques- and sex-matched control subjects with- and proximal antrum, respectively. The tionnaire (see APPENDIX). Each question out diabetes and without any complaints remaining side hole was located 1 cm dis- asked the patient to rate symptoms from referable to the gastrointestinal system. tal to the aboral end of the sleeve and re- none (0 points) to severe (3 points); the Exclusion criteria for both groups were as corded duodenal pressure events. The maximum score was 36. Patients com- follows: pregnancy; known allergy to manometry assembly was perfused with pleted two standardized questionnaires, eggs, botulinum toxin, or lidocaine; pre- distilled water using a low-compliance SF-36 and SCL-90, at the initiation and vious surgery to the stomach, pylorus, or pneumohydraulic pump (Mui Scientific, completion of the study. Questionnaires small bowel; previous Nissen fundoplica- Ontario, Canada) with a flow rate of 0.8 were included in this study because the tion or other antireflux surgery; known ml/min. After preamplification and low U.S. Food and Drug Administration now pyloric stricture; previous , tran- pass filtration (PC Polygraf HR; Synectics recommends that subjective measures be sient ischemic attack, or chronic diseases Medical, Stockholm, Sweden), pressure included as either primary or secondary involving the central nervous system; events were digitized at 16 Hz on a micro- end points in studies of gastrointestinal concurrent use of opiates or anticholin- computer (Polygram Upper GI Edition; disorders. Patients were asked to record ergics. Women of child-bearing age had Synectics Medical). daily insulin use and to monitor the need both urine and serum human chorionic After topical anesthesia (2% lidocaine for additional insulin. Weights were mea- gonadotropin checked to ensure that they HCl; AstraZeneca, Wilmington, DE) to sured at the initiation of the protocol and were not pregnant before testing and the nose, the catheter assembly was posi- at routine follow-up after treatment. treatment. Prokinetic and antiemetic tioned across the pylorus using fluoro- agents were continued during the trial; scopic guidance. Accommodation time of however, new medications were not initi- ϳ1 h occurred before obtaining3hof Laboratory studies ated during the trial. All patients stayed recordings in a fasting state. The patient A complete blood count, blood urea ni- on a gastroparesis diet (small frequent was then fed a standard liquid meal (Pul- trogen, creatinine, fasting glucose, HbA1c, meals low in both fat and fiber). This pro- mocare; Ross Products, Columbus, OH) albumin, and urinalysis were checked be- tocol was approved by the Institutional (837 ml; 355 kcal; 16.7% protein, 28.2% fore enrollment and again at 8 weeks after Review Board of Johns Hopkins Bayview fat, 55.1% carbohydrate), and recordings injection. Medical Center. were continued for another 2 h. To min- imize exacerbation of gastroparesis (2), Injection of the pylorus Gastric emptying scans blood glucose was monitored during the After informed consent, patients under- Gastric emptying scans were performed test, and insulin or glucose was provided went esophagogastroduodenoscopy to in an identical manner both before and 1 to maintain serum glucose between 80 rule out mechanical obstruction. All pro- week after botulinum toxin injection to and 150 mg/dl. Antropyloric manometry cedures were performed by one physician objectively measure changes in gastric was performed in an identical manner in (B.E.L.). Two hundred units of botulinum emptying. After an overnight fast, patients the week before and 1 week after injection toxin A (Botox; Allergan, Irvine, CA) were were given a standard meal consisting of of the pylorus with botulinum toxin. This dissolved in 4 ml of sterile normal saline two scrambled eggs mixed with one portion of the study provided an objective and injected into the pylorus using a stan- mCi-99 technetium sulfur colloid (15), measure of the response to botulinum dard sclerotherapy 25-gauge, 4-mm nee- two slices of white bread, and 300 ml of toxin injection. dle (Ballard, Draper, UT) (50 units of water (total of 270 kcal; 23% protein, Botulinum toxin A into each quadrant). 37% carbohydrate, 40% fat). Images were The patient was observed for 1–2hinthe taken every minute for a minimum of 120 Analysis of antropyloric manometry recovery area and then discharged home. min using a (Adak Com- Pyloric pressure activity was classified Telephone follow-up occurred at 24 h to pany, Militas, CA), and the t1/2 for gastric into one of three groups, according to the look for immediate side effects or compli- emptying was calculated (mean for nor- description by Mearin et al. (9). Baseline cations. Patients were seen in follow-up at mal patients in the De- elevation of the pyloric pressure wave Ͼ3 Ϯ Ͼ 1, 2, 4, 6, 8, and 12 weeks after the injec- partment is 90 15 min). Radiologists mmHg for 1 min was defined as a tonic tion therapy. who read the study were blinded to the pattern; antral-type phasic pressure activ- study protocol. ity mixed with duodenal phasic activity was categorized as a phasic pattern; and a Statistics Antropyloric manometry phasic pattern superimposed on tonic ac- Data were analyzed using the statistical Antral and pyloric intraluminal pressures tivity was categorized as a combined ton- software SPSS. Pre- and postinjection were recorded using a manometric as- ic-phasic pattern. Pylorospasm was weights, gastric emptying scan times, sembly (optical density 8 mm), which in- defined as prolonged (Ͼ3 min) or intense symptom scores, SF-36, and SCL-90 data corporated a 6-cm sleeve sensor and five (Ͼ10 mmHg) contractions above base- were compared using a paired sample side holes (Dentsleeve, Wayville, Austra- line. Each 15 min of pyloric recording was Student’s t test. Pyloric manometry was lia). The 6-cm sleeve sensor was posi- subjected to area under the curve analysis analyzed by comparing the area under the tioned across the pylorus and recorded to assess response to botulinum toxin curve in the pre- and postinjection period both pyloric tone and phasic activity. injection. using a paired sample Student’s t test.

2342 DIABETES CARE, VOLUME 27, NUMBER 10, OCTOBER 2004 Lacy and Associates

Figure 1—Symptom scores of patients at baseline (prebotox) and over the 12-week trial period. Symptom scores reflect all eight patients for baseline and 1-, 2-, 4-, and 8-week follow-up visits. Symptom scores for the week 12 follow-up visit reflect seven patients. Maximum symptom score was 36. The x-axis reflects time, and the y-axis reflects symptom score.

RESULTS measured both before and after botuli- did not normalize (182–108 min; 351– num toxin injection of the pylorus. Two 148 min; 800–278 min). Three patients Symptoms patients did not completely fill out both did not have any significant change in The mean symptom score of all eight pa- sets of forms and thus were excluded from their gastric emptying scan half-times, tients before treatment was 27.0. Mean analysis. In the six patients who com- whereas one patient had an increase in symptom scores at weeks 1, 4, 6, and 8 pletely filled out both pre- and postinjec- gastric emptying scan half-time (78–146 were 14.5, 11.4, 12.1, and 12.2, respec- tion SF-36 questionnaires, total scores min). These latter four patients all noted tively, for all eight patients (Fig. 1). One did not change significantly. However, an objective improvement in their symp- patient (C.F.) developed severe nausea subscores for the physical functioning do- toms on the questionnaire. and vomiting at week 9 and underwent main did improve (P Ͻ 0.05). No signif- repeat endoscopy with a second injection icant differences were noted in SCL-90 Antropyloric manometry (200 units) of botulinum toxin without scores over the 12-week follow-up period. In eight healthy volunteers, there was no any complications. Symptoms of nausea evidence of pylorospasm during antropy- and vomiting completely resolved after Gastric emptying scans loric manometry. Pylorospasm was noted the second injection. This patient’s symp- Mean solid-phase gastric emptying scan in all eight diabetic patients, which con- tom scores are included for follow-up time (t1/2) before injection was 339.1 min firms the findings of Mearin et al. (9). Data weeks 1–8 but not week 12. Symptom (range 74–999). Gastric emptying time were available for complete analysis from scores of the seven patients who com- was reduced by one-third 1 week after only five patients. Data were excluded pleted all 12 weeks of follow-up after only injection to a mean of 227.3 min (range from two patients because the catheter one injection of botulinum toxin were not 74–906; P ϭ 0.11). One patient had a migrated during portions of the preinjec- significantly different from the scores normalization of gastric emptying scan tion period and because of persistent listed above for all eight patients and were time after injection (t1/2 of 142 min com- vomiting in one patient. After botulinum all significantly reduced compared with pared with 82 min). Three patients had toxin injection, area under the curve anal- baseline (P Ͻ 0.01 at all visits). significant improvement in their gastric ysis revealed that pylorospasm was signif- SF-36 scores and SCL-90 scores were emptying scan half-times, although they icantly reduced compared with baseline

DIABETES CARE, VOLUME 27, NUMBER 10, OCTOBER 2004 2343 Botulinum toxin for diabetic gastroparesis

(P ϭ 0.04). A reduction in tonic pyloric Complications greatest decline in symptom scores oc- pressures was also noted, although this Patients were questioned about possible curred in nausea and vomiting. Total was not significantly different compared side effects during the telephone inter- SF-36 scores did not significantly im- with the preinjection state (P ϭ 0.06) view 24 h after botulinum toxin injection prove in the six patients who completely (Fig. 2). and again at the 1-, 2-, 4-, 8-, and 12- filled out both pre- and postinjection week follow-up appointments. No com- questionnaires, although the physical plications were reported as a result of the functioning score did improve (P Ͻ Laboratory tests upper endoscopy or botulinum toxin in- 0.05). This may reflect an increased abil- Values for the complete blood count, blood jection of the pylorus. ity to function due to fewer episodes of urea nitrogen, creatinine, fasting glucose, nausea and vomiting. HbA1c, albumin, and urinalysis obtained at CONCLUSIONS — Several research Gastric emptying scan times were the 8-week follow-up visit were not signifi- studies have shown that achalasia, a dis- found to improve or normalize in four of cantly different from baseline. order of esophageal motility character- eight subjects. This confirms the findings ized by dysphagia and poor emptying of by Ezzeddine et al. (14). Although the the esophagus, can be effectively treated sample size is small, this improvement is Insulin use with botulinum toxin (16–18). Injection remarkable, as these patients had previ- No changes were noted in either regular of the lower esophageal sphincter (LES) ously failed all other standard therapy. In or NPH insulin use in any of the patients with botulinum toxin relaxes the LES, im- addition, nearly all previously published at the 1-, 2-, and 4-week follow-up ap- proves esophageal emptying, and im- studies that evaluated the efficacy of pro- pointments. At the 8-week follow-up proves complaints of dysphagia with kinetic agents failed to demonstrate an visit, four patients noted an increase in minimal side effects. improvement in gastric emptying scan NPH insulin requirements of Ն5 units Investigations in our laboratory led us times. Three patients did not have an im- each day, whereas the remaining four pa- to believe that diabetic gastroparesis is provement in gastric emptying scan time, tients did not require an increase in NPH similar to achalasia. Both conditions in- although all noted an improvement in insulin use. At the 12-week follow-up volve smooth muscle sphincters that fail their symptoms. Interestingly, one pa- visit, three of the four patients still re- to relax appropriately and have elevated tient’s gastric emptying scan time in- quired at least 5 units more of NPH insu- tone. Elevated sphincter tone can prevent creased somewhat, although, subjectively, lin use per day, whereas the other four normal emptying of either the esophagus the patient felt better, and objectively, her patients did not have a change in their or the stomach. Modeling the therapeutic symptom scores declined. This discor- NPH insulin use compared with baseline. success in achalasia, two patients with se- dance might reflect a delayed response to No differences were noted for regular in- vere diabetic gastroparesis had a dramatic botulinum toxin, transient worsening of sulin use at either the 8- or 12-week fol- improvement in symptoms after botuli- pylorospasm, or day-to-day variation in low-up appointments. num toxin injection of the pylorus (10). gastric emptying. These preliminary results led us to initiate Several patients were surprised that, Medication use the current study involving eight patients after injection therapy, they were able to Four patients remained on the same dose with long-standing diabetes and mean in- gain weight and reverse a gradual trend of of domperidone (20 mg p.o. q.i.d.), two sulin use of 24.4 years. All patients had weight loss secondary to chronic nausea Ͼ patients stopped erythromycin, one pa- failed standard medical therapy (erythro- and vomiting. Three patients gained 10 tient remained on a stable dose of meto- mycin, metoclopramide, cisapride, dom- pounds each, and all three of these pa- Ն clopramide (20 mg p.o. q.i.d.), and one peridone) without improvement in tients required at least 5 units of NPH patient decreased their metoclopramide symptoms. When asked to objectively insulin each day over the course of the use (from 20 mg p.o. q.i.d. to 10 mg measure their symptoms of nausea, vom- study period. A reduction in early satiety, q.i.d.). Regarding antiemetic use, one pa- iting, and abdominal pain, mean pretreat- epigastric pain, nausea, and vomiting in tient decreased ondansetron use (from 8 ment scores were 27 of a maximum of 36. these patients may all have contributed to mg b.i.d. to q.d.), whereas one decreased Subjectively, all eight patients stated that an increased ability to eat. compazine use (from 10 mg p.o. t.i.d. to their symptoms greatly reduced their This study confirms the previous re- p.r.n.). quality of life on a daily basis. Botulinum port by Mearin et al. (9), which showed toxin injection of the pylorus was easily that patients with diabetic gastroparesis accomplished during routine endoscopy have pylorospasm. In the current study, Weight in all eight patients without any immedi- pylorospasm was reduced in all five pa- At the 8-week follow-up visit, one pa- ate or delayed side effects. tients who completed both antropyloric tient’s weight remained unchanged, three Individually, all eight patients noted manometries. This confirms and extends patients gained 1–4 pounds, one patient an improvement in symptom scores over the findings published in a recent case re- gained 5–9 pounds, and two patients the 12-week study period. Collectively, port (13). Symptom scores decreased in gained Ն10 pounds. At the 12-week fol- symptom scores decreased significantly at all five patients, whereas gastric emptying low-up visit, one patient’s weight was un- all follow-up visits when compared with scan times improved in three patients. changed, two patients had gained 1–4 baseline (P Ͻ 0.01). The greatest decrease In contrast to current medical ther- pounds, one patient had gained 5–9 occurred in the first week after botulinum apy, botulinum toxin injection of the py- pounds, and three patients had gained toxin injection, with a smaller drop dur- lorus has the unique advantage of treating Ն10 pounds (P ϭ 0.05). ing the second week. Individually, the a specific site within the stomach (the py-

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Figure 2—Antropyloric manometry using a Dentsleeve catheter. A and B: The first two panels reflect activity in the antrum (proximal and distal), the third panels reflect pyloric activity, and the last panels reflect duodenal activity. A: Baseline (preinjection). Area under the curve for the pylorus in this patient is 30,449.90 s. B: Postbotulinum toxin injection of the pylorus. In the same patient, a reduction in phasic activity in the pylorus can be visualized. Tonic-phasic activity, as measured by the area under the curve, decreased to 14,976.90 s.

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Table 1—Symptom questionnaire with intractable nausea and vomiting who cannot tolerate oral medications and in Symptoms Response those with persistent symptoms despite maximal medical therapy. Although our Upper abdominal discomfort None Mild Moderate Severe study demonstrated that patients noted Regurgitation None Mild Moderate Severe an improvement in both nausea and vom- Bloating None Mild Moderate Severe iting, it is not likely that this therapy will Heartburn None Mild Moderate Severe replace the use of traditional antiemetic Loss of appetite None Mild Moderate Severe agents for gastroparetic patients with only Nausea (# days per week ) None Mild Moderate Severe mild nausea, given the expense of botuli- Vomiting (# times per week ) None Mild Moderate Severe num toxin and the need for endoscopy. Abdominal pain after eating None Mild Moderate Severe Future trials will need to evaluate the Abdominal pain between meals None Mild Moderate Severe long-term safety, efficacy, and cost of bot- Abdominal pain after drinking liquids None Mild Moderate Severe ulinum toxin therapy compared with bal- Early satiety (filling up very quickly) None Mild Moderate Severe loon dilation of the pylorus, Burning sensation in chest/upper abdomen None Mild Moderate Severe pyloromyotomy, and gastric electrical Symptom score ϭ ___. stimulation. lorus) that is dysfunctional. Targeted (24). Laparoscopic Heller myotomy is Summary therapy with botulinum toxin injection preferred by many gastroenterologists In this study, botulinum toxin injection of minimizes the likelihood of systemic side and surgeons given its long-term favor- the pylorus in eight patients with severe effects, which commonly occurs in pa- able outcome. diabetic gastroparesis was found to be safe tients treated with oral agents. The effi- Applying these lessons to the clinical and to improve symptoms of nausea, cacy of botulinum toxin provides insight scenario of pylorospasm in patients with vomiting, and abdominal pain. Pyloric into one of the underlying pathophysio- diabetic gastroparesis is difficult due to a tone and pressure was reduced after in- logical disorders of diabetic gastropare- lack of clinical studies. No well-designed trasphincteric injection with botulinum sis—pylorospasm. This may occur due to studies have been performed to assess the toxin. Gastric emptying scan half-times a relative imbalance between the excita- efficacy of balloon dilation of the pylorus improved in some, but not all, patients, tory neurotransmitter acetylcholine and in adults with gastroparesis. One study of whereas some patients gained weight and the inhibitory neurotransmitter nitric ox- 19 children demonstrated that balloon di- required higher doses of daily insulin. ide. A reduction in nitric oxide– lation of the pylorus led to complete res- Before botulinum toxin injection of containing neurons could lead to an olution of symptoms in 11 patients and the pylorus is adopted in clinical practice elevated tonic state in the pylorus and, transient improvement in symptoms of for the routine treatment of diabetic gas- thus, delay gastric emptying. A study per- up to 8 weeks in 5 patients (25). Pyloro- troparesis, we recommend that endosco- formed by Watkins et al. (19) demon- myotomy has been shown to improve pists interested in using this technique strated that nitric oxide plays a critical symptoms in patients with hypertrophic consider pooling both resources and pa- role in pyloric function and that loss of pyloric stenosis (26), although there are tients to conduct a blinded, placebo- nitric oxide impedes gastric emptying. no controlled studies of pyloromyotomy controlled trial to confirm the efficacy of As noted previously, our trial was in patients with diabetic gastroparesis. In this treatment. Funding agencies such as modeled on the therapeutic success of addition, the underlying pathophysiology the National Institutes of Health or the botulinum toxin for the treatment of of hypertrophic pyloric stenosis is likely American Diabetes Association should achalasia, a spastic smooth muscle disor- quite different quantitatively than dia- strongly consider support of such re- der of the LES. Historically, therapeutic betic pylorospasm. search, which has the potential to bring options to treat achalasia were limited to Our results point out that botulinum relief to diabetic patients suffering from balloon dilation and surgery (myotomy). toxin injection of the pylorus can provide gastroparesis. Botulinum toxin injection of the LES was significant relief of symptoms over several enthusiastically greeted as a therapeutic months. The dose of botulinum toxin option given initial reports describing sig- used in our study (200 units) was higher Acknowledgments— This study was funded nificant success in relieving symptoms than that used to typically treat achalasia by donations to the Marvin M. Schuster Center (16,17). Over the last several years, how- (100 units), as the mass of the pylorus is for Digestive and Motility Disorders and by unrestricted educational grants (to B.E.L. ever, an accumulating body of evidence believed to be greater than that of the LES. [CERT grant from Johns Hopkins and has demonstrated that botulinum toxin Botulinum toxin injection of the pylorus Allergan]). injection provides long-term benefits may earn a place in our armamentarium (Ͼ12 months) in only a minority of pa- of therapeutic agents for patients with tients (20) and is often ineffective in mild-to-moderate diabetic gastroparesis APPENDIX younger patients (21,22). Balloon dila- who have failed traditional prokinetic Please rate any symptoms that you cur- tion of the LES is generally more effica- agents (metoclopramide, erythromycin, rently have. If the symptoms were given cious at providing long-term relief of cisapride). This therapy may prove to be as numbers, then no symptoms would symptoms (23) and is more cost-effective most valuable in those diabetic patients equal 0, mild symptoms would equal 1,

2346 DIABETES CARE, VOLUME 27, NUMBER 10, OCTOBER 2004 Lacy and Associates moderate symptoms would equal 2, and open-label study. J Int Med Res 25:182– Gastroenterol 91:1724–1730, 1996 severe symptoms would equal 3 (Table 1). 189, 1997 18. NIH Consensus Development Confer- 9. Mearin F, Camilleri M, Malagelada JR: ence Statement: Clinical use of botulinum Pyloric dysfunction in diabetics with toxin. Arch Neurol 48:1294–1298, 1991 recurrent nausea and vomiting. Gastroen- 19. Watkins CC, Sawa A, Jaffrey S: Insulin References terology 90:1919–1925, 1986 restores neuronal nitric oxide synthase 1. Koch K: Gastroparesis: diagnosis and 10. Lacy BE, Zayat EN, Crowell MD, Schuster expression and function that is lost in di- management. Practical Gastroenterol 32: MM: Botulinum toxin for the treatment of abetic gastropathy. J Clin Invest 106:373– 30–43, 1987 gastroparesis (Abstract). Gastroenterology 384, 2000 2. Horowitz M, Harding PE, Maddox A, 118:A624, 2000 20. Martinek J, Siroky M, Plottova Z, Bures J, Maddern GJ, Collins PJ, Chatterton BE, 11. Lacy BE, Zayat EN, Crowell MD, Schuster Hep A, Spicak J: Treatments of patients Wishart J, Shearman DJC: Gastric and oe- MM: Botulinum toxin for the treatment of with achalasia with botulinum toxin: a sophageal emptying in insulin-dependent gastroparesis: a preliminary report. Am J multicenter prospective cohort study. Dis diabetes mellitus. J Gastroenterol Hepatol Gastroenterol 97:1548–1552, 2002 Esophagus 16:204–209, 2003 1:97–113, 1986 12. Lacy BE, Schettler-Duncan VA, Crowell 21. D’Onofrio V, Miletto P, Leandro G, Ia- 3. Rayner CK, Su YC, Doran SM, Jones KL, MD: The treatment of diabetic gastropa- quinto G: Long-term follow-up of achla- Malbert CH, Horowitz M: The stimulation resis with botulinum toxin (Abstract). sia patients treated with botulinum toxin. of antral motility by erythromycin is at- Am J Gastroenterol 95:2455, 2000 Dig Liver Dis 34:105–110, 2002 tenuated by hyperglycemia. Am J Gastro- 13. Gupta P, Rao SSC: Attenuation of isolated 22. Neubrand M, Scheurlen C, Schepke M, enterol 95:2233–2241, 2000 pyloric pressure waves in gastroparesis in Sauerbruch T: Long-term results and 4. Peeters T, Matthijs G, Depoortere I, Ca- response to botulinum toxin injection: a prognostic factors in the treatment of chet T, Hoogmartens J, Vantrappen G: case report. Gastrointest Endosc 56:104– achalasia with botulinum toxin. Endos- Erythromycin is a motilin receptor ago- 107, 2002 copy 34:519–523, 2002 nist. Am J Physiol 257:G470–G474, 1989 14. Ezzeddine D, Jit R, Katz N, Gopalswamy 23. Bansal R, Nostrant TT, Scheiman JM, Ko- 5. Anese V, Janssens J, Vantrappen G, Tack N, Bhutani MS: Pyloric injection of botu- shy S, Barnett JL, Elta GH, Chey WD: In- J, Peeters TL, Willemse P, Van Cutsem E: linum toxin for treatment of diabetic gas- trasphincteric botulinum toxin versus Erythromycin accelerates gastric empty- troparesis. Gastrointest Endosc 55:920– pneumatic balloon dilation for treatment ing by inducing antral contractions and 923, 2002 of primary achalasia. J Clin Gastroenterol improved gastroduodenal coordination. 15. Camilleri M, Hasler WL, Parkman HP, 36:209–214, 2003 Gastroenterology 102:823–828, 1992 Quigley EMM, Soffer E: Measurement of 24. Richter JE: Comparison and cost analysis 6. Albibi R, McCallum RW: Metoclopra- gastrointestinal motility in the GI labora- of different treatment strategies in achala- mide: pharmacology and clinical applica- tory. Gastroenterology 115:747–762, 1998 sia. Gastrointest Endosc Clin N Am 11: tion. Ann Int Med 98:86–95, 1983 16. Pasricha PJ, Ravich WJ, Hendrix TR, 359–370, 2001 7. Soykan I, Sarosiek I, McCallum RW: The Sostre S, Jones B, Kaloo AN: Intrasphinc- 25. Israel DM, Mahdi G, Hassall E: Pyloric effect of chronic oral domperidone ther- teric botulinum toxin for the treatment of balloon dilation for delayed gastric emp- apy on gastrointestinal symptoms, gastric achalasia. N Engl J Med 332:774–778, tying in children. Can J Gastroenterol 15: emptying, and quality of life in patients 1995 723–727, 2001 with gastroparesis. Am J Gastroenterol 92: 17. Fishman VM, Parkman HP, Schiano TD, 26. Sun WM, Doran SM, Jones KL, Davidson 976–980, 1997 Hills C, Dabezies MA, Cohen S, Fisher RS, G, Dent J, Horowitz M: Long-term effects 8. Kendall BJ, Kendall ET, Soykan I, McCal- Miller LS: Symptomatic improvement in of pyloromyotomy on pyloric motility lum RW: Cisapride in the long-term treat- achalasia after botulinum toxin injection and gastric emptying in humans. Am J ment of chronic gastroparesis: a 2-year of the lower esophageal sphincter. Am J Gastroenterol 95:92–100, 2000

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