Botulinum Toxin Type A for Poststroke Cricopharyngeal Muscle Dysfunction

Transcription

1 1346 ORIGINAL ARTICLE Botulinum Toxin Type A for Poststroke Cricopharyngeal Muscle Dysfunction Deog Young Kim, MD, PhD, Chang-il Park, MD, PhD, Suk Hoon Ohn, MD, Ja Young Moon, MD, Won Hyuk Chang, MD, MS, Seung-woo Park, MD, PhD ABSTRACT. Kim DY, Park C, Ohn SH, Moon JY, Chang WH, Park S. Botulinum toxin type A for poststroke cricopharyngeal muscle dysfunction. Arch Phys Med Rehabil 2006;87: Objective: To evaluate the therapeutic effectiveness of botulinum toxin type A (BTX-A) in poststroke patients with cricopharyngeal muscle dysfunction. Design: Before-after trial. Setting: University hospital. Participants: Eight poststroke patients. Intervention: BTX-A injection into the cricopharyngeal muscle under endoscope guidance for poststroke cricopharyngeal muscle dysfunction. Main Outcome Measures: Clinical symptom score, disability rating scale for swallowing impairment, videofluoroscopic swallowing study, and upper esophageal sphincter (UES) manometry. Results: Clinical symptom score, disability rating scale for swallowing impairment, residue in piriform sinus, and UES pressure were all significantly improved at 2 weeks after BTX-A injection compared with evaluations before injection (P.05). The effects on the clinical symptom score and disability rating scale for swallowing impairment continued to be significantly improved to 12 weeks after injection (P.05). However, the residue in piriform sinus and the UES pressure at 12 weeks postinjection were reduced compared with beforeinjection evaluations; these results were not significant. The pharyngeal transit time was not changed after injection. There were no side effects observed in the patients studied. Conclusions: The results of the present study suggest that BTX-A injection may be an effective and safe treatment in patients with poststroke cricopharyngeal muscle dysfunction. Key Words: Botulinum toxin type A; Dysphagia; Pharyngeal muscles; Rehabilitation; Stroke by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation THE PRESENCE OF DYSPHAGIA has been reported to be as high as 30% to 45% among poststroke patients. 1 Dysphagia is associated with increased mortality, increased length of hospital stay, and a decreased level of functional outcome. 1 From the Department and Research Institute of Rehabilitation Medicine (Kim, C Park, Ohn, Moon, Chang) and Department of Internal Medicine (S Park), Yonsei University College of Medicine, Seoul, South Korea. No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the author(s) or upon any organization with which the author(s) is/are associated. Reprint requests to Suk Hoon Ohn, MD, Rehabilitation Hospital, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemun-gu, Seoul, , South Korea, myeom@korea.com /06/ $32.00/0 doi: /j.apmr Common swallowing impairments associated with stroke are reduced lingual control, reduced pharyngeal peristalsis, delayed swallowing reflex, and cricopharyngeal muscle dysfunction. 2 The cricopharyngeal muscle acts as a muscular sling at the pharyngoesophageal junction, forming the upper esophageal sphincter (UES). The cricopharyngeal muscle normally remains in a contracted state and relaxes during swallowing. Incoordination or hypertonus of the cricopharyngeal muscle may lead to a range of symptoms including dysphagia and aspiration. Frequently, cricopharyngeal muscle dysfunction is caused by neuromuscular diseases or postoperative changes; however, the etiology remains unknown in a considerable number of cases. 3 Cricopharyngeal muscle dysfunction has been identified in 5.7% of patients with neurologic disorder, 4.9% of patients with head and neck or esophageal tumors, and 8.9% of patients with other medical problems. 4 Bougienage and endoscopic or transcervical cricopharyngeal myotomy have been suggested to lower the resting pressure of the cricopharyngeal muscle. However, the effect of these procedures has been debated, and they are associated with a variety of complications. 5,6 Botulinum toxin type A (BTX-A), synthesized from the bacillus Clostridium botulinum, is a neurotoxin that blocks neuromuscular transmission by inhibition of acetylcholine release at the presynaptic cholinergic nerve terminals. It has been found to have therapeutic value in patients with a variety of conditions characterized by muscle hyperactivity and spasticity For the treatment of cricopharyngeal muscle dysfunction, BTX-A was used for the first time by Schneider et al 11 in Since Schneider s report, there have been many studies reporting on BTX-A use to treat patients with cricopharyngeal muscle dysfunction Previous studies, however, included various etiologies of cricopharyngeal muscle dysfunction, including stroke. Haapaniemi et al 13 studied 2 stroke patients, 1 with lesions in the brainstem and the other with lesions in the middle cerebral artery. The stroke patient with brainstem lesions was able to eat quite normally for 10 months after the injection. The stroke patient with middle cerebral artery lesions was able to tolerate oral feeding for 2 months. Ahsan et al 14 studied 2 stroke patients; 1 patient was not improved after injection, and the other patient was improved for 2 months and then relapsed. Alberty et al 15 studied 1 brainstem stroke patient, whose dysphagia symptom was not improved after injection. Shaw and Searl 16 studied 2 stroke patients. In 1 patient, subjective symptom relief continued for 14 months; however, there was no objective measure of the improvement. Murry et al 17 studied 13 patients including 6 stroke patients and reported the efficacy of BTX-A. These studies focused on patients with a variety of causes of cricopharyngeal muscle dysfunction, and the effect of BTX-A in a sample of only stroke patients has not yet been established. Therefore, the aim of this study was to evaluate the therapeutic effect of BTX-A injection on the cricopharyngeal muscle for poststroke patients with cricopharyngeal muscle dysfunction.

2 BOTULINUM TOXIN FOR CRICOPHARYNGEAL MUSCLE DYSFUNCTION, Kim 1347 Patient No. Table 1: General Characteristics of Subjects Age (y) Sex Diagnosis METHODS Duration From Onset (mo) Feeding Method 1 66 M Cerebellar infarction 8 NG tube 2 56 M Cerebellar infarction 3 NG tube 3 68 F Pontine hemorrhage 2 NG tube 4 53 M Lateral medullary 7 NG tube infarction 5 65 M Cerebellar infarction 8 Oral 6 46 F Posterior cerebral 5 Oral artery infarction 7 65 M Lateral medullary 4 PEG tube infarction 8 64 F Pontine hemorrhage 3 NG tube Abbreviations: F, female; M, male; NG tube, nasogastric tube; PEG tube, percutaneous endoscopic gastrostomy tube. Participants Eight stroke patients (5 men, 3 women) with cricopharyngeal muscle dysfunction were recruited for this study after we obtained informed consent (table 1). This study was approved by the institutional review board of our institute. The mean duration from stroke onset was 5.0 months (range, 2 8mo). The diagnosis of stroke in all participants was confirmed by magnetic resonance imaging, and the following abnormalities were found: cerebellar infarction (n 3), pontine hemorrhage (n 2), lateral medullary infarction (n 2), and posterior cerebral artery infarction (n 1). Cricopharyngeal muscle dysfunction was confirmed by a videofluoroscopic swallowing study (VFSS). The severity of dysphagia was classified by the clinical symptom score. 15 Clinical symptom scores for all patients were equal to or more than 7; therefore, all patients were classified as severe. Five patients were being nourished by a nasogastric tube and 1 patient by a percutaneous endoscopic gastrostomy tube. Two patients were eating by mouth. Before the BTX-A injection, we followed up with all patients; they did not have improved dysphagia symptoms, even after intensive interventions including the Mendelsohn maneuver, neck rotation to the affected side, and bougienage for at least 2 weeks. One of the 8 patients, a 65-year-old man with a cerebellar infarct, was withdrawn because of another cerebral infarct at 3 weeks after the BTX-A injection; however, his dysphagia was improved (table 2). Therefore, 7 patients were available for the remainder of the study. Procedure A standard medical history and physical, neurologic, and otolaryngologic examination were provided for each patient. The clinical symptom score and disability rating scale for swallowing impairment 11 were assessed to determine the severity of dysphagia before the injection and at the 2nd, 4th, and 12th weeks after injection. The clinical symptom score consisted of 4 categories: tolerated food consistency (score, 0 3), relative duration of food intake (score, 0 2), requirement of additional swallows for emptying the hypopharynx (score, 0 2), and clinical signs of aspiration (score, 0 3). According to the sum of each category, dysphagia was classified as mild (score, 1 3), moderate (score, 4 6), or severe (score, 7 10). 15 In addition, we used the disability rating scale for swallowing impairment. The severity of dysphagia was rated on a scale of 0 to 4. The disability rating scale for swallowing impairment includes a score of 0 for normal function and a patient without complaint, a score of 1 for no functional impairment but subjective dysphagia when swallowing solid and/or liquid foods, a score of 2 for mild functional impairment for solid and/or liquid foods, a score of 3 for marked disability with moderate aspiration, and a score of 4 for severe functional impairment with complete inability to swallow, a consideration of aspiration or pneumonia. In addition, body weight was recorded before injection and at the 2nd, 4th, and 12th weeks after injection. VFSS and UES manometry were performed before injection and at the 2nd and 12th weeks after injection. After the VFSS was completed, 2 physiatrists analyzed the results. For the VFSS, the test liquid was prepared from 200mL of water and 40mL of gastrograffin. a The patients were positioned upright for an anteroposterior view, and the amount of piriform sinus residue was measured by 15mL of test liquid 8 times. Next, the patients were positioned upright for a lateral view, and the pharyngeal transit time was measured 8 times. The residue from the piriform sinus was assessed by the remaining amount of liquid in the piriform sinus that did not pass through the cricopharyngeal muscle. In addition, the pharyngeal transit time was assessed to examine whether injected BTX-A affected other pharyngeal muscles. The amount of piriform sinus residue after swallowing was classified into 4 grades (grade 0, no residue; grade 1, 10% of the width of piriform sinus in the VFSS; grade 2, 10% 50% of the width; grade 3, 50% of the width). 18 Pharyngeal transit time was defined as the time for the liquid to pass from the onset of hyoid bone elevation to cessation of its motion. 19 To determine the precise timing, a video counter timer was superimposed on a video screen at a rate of 30 frames per second. Patient No. Table 2: Change at Each Evaluation After BTX-A Injection Clinical Symptom Score Disability Rating Scale Score Weight (kg) Residue (grade) UES Pressure (mmhg) T0 T1 T2 T3 T0 T1 T2 T3 T0 T1 T2 T3 T0 T1 T3 T0 T1 T * 7 5 ND ND 2 2 ND ND ND ND 3 1 ND ND Abbreviations: ND, no data; T0, before injection; T1, 2nd week after injection; T2, 4th week after injection; T3, 12th week after injection. *Patient 5 was withdrawn because of a newly developed cerebral infarction at 3 weeks after BTX-A injection.

3 1348 BOTULINUM TOXIN FOR CRICOPHARYNGEAL MUSCLE DYSFUNCTION, Kim We then measured the average pharyngeal transit time from the 8 trials. UES manometry with 6 channels b was performed to obtain the resting pressure of the cricopharyngeal muscle. We used the station pull-through technique. This procedure was performed by an internal medicine physician who specialized in UES manometry. A manometric catheter was advanced into the stomach and then was advanced cephalad while the pressure was recorded. The maximal pressure at the first high-pressure zone was defined as the pressure of the lower esophageal sphincter. After further advancement of catheter, the second maximal pressure was defined as the pressure of the UES. BTX-A (Botox) was obtained as a freeze-dried lyophilized preparation, and 100U of BTX-A were dissolved into 2.0mL of 0.9% sterile saline. This diluted solution, equivalent to 100U of BTX-A, was injected with a small butterfly cannula under the guidance of a flexible endoscope. We selected 3 injection sites: the posterior part and both lateral sides of the cricopharyngeal muscle; these sites were chosen for easy identification and avoidance of laryngeal side effects. The amount of injected BTX-A at each portion was 50U for the posterior site and 25U each at the lateral sites. We used the nonparametric Wilcoxon test of SPSS c for each parameter. We compared the postinjection clinical symptom score, disability rating scale for swallowing impairment, body weight, residue in the piriform sinus, pharyngeal transit time, and UES pressure with the same measures used at baseline. RESULTS Clinical Score The clinical symptom score and disability rating scale for swallowing impairment at 2 weeks after BTX-A injection improved significantly compared with the baseline measures (figs 1, 2). The clinical symptom score improved from to , and the disability rating scale score for swallowing impairment improved from to After 4 and 12 weeks of follow-up, the clinical symptom score and disability rating scale score for swallowing impairment showed significant improvement compared with baseline Fig 2. Change in disability rating scale score for swallowing impairment after BTX-A injection. *Significant at P<.05. measures. The clinical symptom scores at 4 and 12 weeks were and , and the disability rating scale scores for swallowing impairment at 4 and 12 weeks were and , respectively. The body weights recorded at baseline and at 2, 4, and 12 weeks after injection were kg, kg, kg, and kg, respectively (fig 3). The body weight at 4 and 12 weeks after injection improved significantly compared with baseline measures. VFSS Findings The grade of residue at 2 weeks after the BTX-A injection decreased significantly compared with the baseline (fig 4). The grade of residue changed from to The grade Fig 1. Change in clinical symptom score after BTX-A injection. Abbreviation: T, time. *Significant at P<.05. Fig 3. Change in body weight after BTX-A injection. *Significant at P<.05.

4 BOTULINUM TOXIN FOR CRICOPHARYNGEAL MUSCLE DYSFUNCTION, Kim 1349 Fig 4. Change of residue in piriform sinus after BTX-A injection. *Significant at P<.05. Fig 6. Change of UES pressure after BTX-A injection. *Significant at P<.05. of the residue at 12 weeks after injection was ; this was reduced compared with the baseline measures and was not significant (P.109). However, the pharyngeal transit time did not change after injection (fig 5). Resting UES Pressures The UES pressure at 2 weeks after BTX-A injection decreased significantly compared with the baseline. The UES pressure changed from to mmHg (fig 6). The UES pressure at 12 weeks postinjection was mmHg; this was reduced compared with baseline measures and was not significant (P.310). Complications There were no side effects observed such as pharyngeal tears, vocal cord palsy, or other systemic effects. Fig 5. Change of pharyngeal transit time (PTT) after BTX-A injection. DISCUSSION In this study, we used BTX-A in a group of stroke patients with cricopharyngeal muscle dysfunction and evaluated the effects not only subjectively but also objectively. For the subjective evaluation, the clinical symptom score and disability rating scale score for swallowing impairment were used. For these 2 evaluations, dysphagia symptoms were significantly improved and continued to be improved for 12 weeks postinjection. In addition, VFSS and UES manometry were used as objective diagnostic tools for cricopharyngeal muscle dysfunction measures. The real-time demonstration of swallowing with VFSS is the most sensitive method for visualizing cricopharyngeal muscle dysfunction. 20 We could observe the total swallowing process and examine the residue of piriform sinus. To obtain quantitative information on cricopharyngeal muscle dysfunction, we used UES manometry. UES manometry is the only method that can quantify the muscle tone of the cricopharyngeal muscle. Previous studies have used manometry for objective measurement of cricopharyngeal muscle tone. 16,21 However, because of the lack of normative data and technical difficulties, the use of manometry alone for the assessment of UES function has been limited. 22 In previous research, the UES pressures did not correlate with the severity of cricopharyngeal muscle dysfunction in patients. 14 Therefore, for a precise evaluation of cricopharyngeal muscle dysfunction, a combined study of VFSS and UES manometry is essential. In our study, the results of VFSS and manometry differed somewhat from the clinical symptom score and disability rating scale for swallowing impairment. The residue from the piriform sinus and the UES pressure were improved at 2 weeks after injection. These improved findings continued 12 weeks after injection; however, the values were not statistically significant. In addition, patients body weights increased after BTX-A injection. This finding is likely due to an increase of oral intake as the swallowing problem was settled. In this study, the 2 patients with little improvement after the injection had lateral medullary infarction. Patient 7 was a 65-year-old man whose dysphagia symptom improved at the evaluation 2 weeks after BTX-A injection but then worsened after that time (see table 2). Patient 4 was a 53-year-old man whose dysphagia symptom did not change during the follow-up period. Another report also showed that cricopharyngeal mus-

5 1350 BOTULINUM TOXIN FOR CRICOPHARYNGEAL MUSCLE DYSFUNCTION, Kim cle dysfunction was worse in a patient with stroke lesion in the brainstem. Alberty et al 15 examined 10 patients for the effects of BTX-A on cricopharyngeal muscle dysfunction. The causes of cricopharyngeal muscle dysfunction were brainstem infarction in 1 patient, polymyositis in 1 patient, and idiopathic in the remaining 8 patients. After the BTX-A injection, the patient with the brainstem infarction and 1 with idiopathic cricopharyngeal muscle dysfunction were found to have the amount of barium retention by VFSS unchanged. The ineffectiveness of the BTX-A injection may be explained by the following. The first possible cause of ineffectiveness might be the involvement of the bulbar swallowing center; that made the swallowing problem a lower motoneuron lesion. The lateral medullary infarction inflicted direct trauma on the swallowing center and the nuclei of cranial nerves XI and X. If the medullary lesion involves the postnucleus neural tract, the relaxation problem of the cricopharyngeal muscle appears as a lower motoneuron lesion. Therefore, BTX-A injection might not be suitable to resolve cricopharyngeal muscle dysfunction in such a case. Another possible explanation might be that the pharyngeal phase of swallowing is reflexogenic; for the successful pharyngeal phase, all reflex pathways from afferent input to efferent output should be intact. These reflex pathways consist of glossopharyngeal and vagal afferents derived from pharyngeal mucosa and hyoid bone elevation by the mylohyoid, anterior belly of digastric, hyoglossus, and geniohyoid muscles. After hyoid bone elevation, reflexogenic glottic closure and UES opening occur in sequence. If any problem in this pathway is not improved, the pharyngeal phase will not be restored, even if BTX-A decreases the cricopharyngeal muscle tone. BTX-A may influence only the hypertonus cricopharyngeal muscle in upper motoneuron disorders and not the pharyngeal swallowing reflex. Therefore, the effectiveness of BTX-A injection at the cricopharyngeal muscle depends on the pathophysiology of the brain lesion. It may be difficult to predict the effectiveness of BTX-A injection for cricopharyngeal muscle dysfunction treatment by medical history, VFSS, UES manometry, and other measures commonly used. The BTX-A dose used and the effective duration vary depending on the injected site and muscle In the case of cricopharyngeal muscle dysfunction, the optimal dose and the effective duration continue to be evaluated. Shaw and Searl 16 suggested that higher doses may result in a longer duration of action. However, they had a good result with a small dose, 50U. In our study, 100U of BTX-A (Botox) were used. This dose was 1.6 to 2.4U/kg in our patients, and was a larger dose compared with previous studies, where use of 10 to 50U of BTX-A has been reported With 100U of BTX-A, we found that the duration of the effect continued for 12 weeks. In our study, there were no side effects or other systemic effects, even though we used a higher dose of BTX-A than in prior studies. The complications reported with BTX-A injection have been pharyngeal tear, transient vocal cord palsy, and urinary retention for 2 days. 13,16 However, previous studies 7,11,14,15 also reported that BTX-A injection in the cricopharyngeal muscle was comparatively well tolerated without serious side effects. We examined the pharyngeal transit time by VFSS to examine whether the injected BTX-A spread from the cricopharyngeal muscle. If BTX-A spreads out of the cricopharyngeal muscle, the pharyngeal transit time may have been delayed because of resulting pharyngeal muscle palsy. In our study, pharyngeal transit time did not change in any of the patients after BTX-A injection. Therefore, we could examine only the cricopharyngeal muscle function without other pharyngeal involvement. The BTX-A dose of 100U dissolved in 2.0mL of 0.9% sterile saline was safe and did not have other pharyngeal effects. There are several limitations to this study. First, this was not a case-control study. Participants in this study were patients whose cricopharyngeal muscle dysfunction symptoms had not been definitely improved despite intensive interventions for more than 2 weeks. The participants were all treated by BTX-A injection. Therefore, we could not compare the BTX-A injection group with a group without BTX-A injection. Second, 5 participants in this study were subacute patients who developed stroke within 6 months. Although the patients cricopharyngeal muscle dysfunction symptom had not improved despite other interventions, the possible effect of spontaneous recovery cannot be excluded completely. Finally, the number of subjects was small. These limitations suggest the need for additional study to confirm our findings. Our study followed up patients with both subjective and objective evaluations for a longer time than has been reported in previous studies. Despite continuously improved dysphagia symptoms by the clinical symptom score and the disability rating scale score for swallowing impairment, a longer evaluation period would give us more information about the maintenance of BTX-A for cricopharyngeal muscle dysfunction treatment in stroke patients. Our findings show the effectiveness of BTX-A injection for the treatment of cricopharyngeal muscle dysfunction in pure stroke patients. This is the first study of pure stroke patients with cricopharyngeal muscle dysfunction. BTX-A injection at the cricopharyngeal muscle is a safe and effective alternative treatment even during the acute period. However, if a lesion appears to be localized in the swallowing center of the medulla, more exact neurologic examination should be performed before BTX-A injection is considered. CONCLUSIONS This study examined the effect of BTX-A for the treatment of cricopharyngeal muscle dysfunction in stroke patients. After BTX-A injection, dysphagia symptoms improved, and this was shown subjectively and objectively. The clinical symptom score, disability rating scale score for swallowing impairment, and body weight continued to be significantly improved until 12 weeks after injection. The residue in the piriform sinus and the UES pressure were significantly improved for 2 weeks after injection, and the improvements continued at 12 weeks after injection; however, these findings were not significant. None of the patients reported side effects. Therefore, BTX-A injection may be an effective and safe treatment for patients with poststroke cricopharyngeal muscle dysfunction. References 1. Horner J, Massey EW, Brazer SR. Aspiration in bilateral stroke patients: a validation study. Neurology 1993;43: Veis SL, Logemann JA. Swallowing disorders in persons with cerebrovascular accident. Arch Phys Med Rehabil 1985;66: Cruse JP, Edwards DA, Smith JF, Wyllie JH. The pathology of cricopharyngeal dysphagia. Histopathology 1972;3: Baredes S, Shah CS, Kaufman R. The frequency of cricopharyngeal dysfunction on videofluoroscopic swallowing studies in patients with dysphagia. Am J Otol 1997;18: Ellis FH Jr, Crozier RE. Cervical esophageal dysphagia: indications for and results of cricopharyngeal myotomy. Ann Surg 1981;194: Ross ER, Green R, Auslander MO, Biller HF. Cricopharyngeal myotomy: management of cervical dysphagia. Otolaryngol Head Neck Surg 1982;90:

6 BOTULINUM TOXIN FOR CRICOPHARYNGEAL MUSCLE DYSFUNCTION, Kim Van den Bergh P, Francart J, Mourin S, Kollmann P, Laterre EC. Five-year experience in the treatment of focal movement disorders with low-dose Dysport botulinum toxin. Muscle Nerve 1995;18: Borodic GE, Joseph M, Fay L, Cozzolino D, Ferrante RJ. Botulinum A toxin for the treatment of spasmodic torticollis: dysphagia and regional toxin spread. Head Neck 1990;12: Blitzer A, Brin MF, Fahn S, Lovelace RE. Localized injections of botulinum toxin for the treatment of focal laryngeal dystonia (spastic dysphonia). Laryngoscope 1988;98: Graham HK, Aoki KR, Autti-Ramo I, et al. Recommendations for the use of botulinum toxin type A in the management of cerebral palsy. Gait Posture 2000;11: Schneider I, Thumfart WF, Pototschnig C, Eckel HE. Treatment of dysfunction of the cricopharyngeal muscle with botulinum A toxin: introduction of a new, noninvasive method. Ann Otol Rhinol Laryngol 1994;103: Blitzer A, Mitchell FB. Use of botulinum toxin for diagnosis and management of cricopharyngeal achalasia. Otolaryngol Head Neck Surg 1997;116: Haapaniemi JJ, Laurikainen EA, Pulkkinen J, Marttila RJ. Botulinum toxin in the treatment of cricopharyngeal dysphagia. Dysphagia 2001;16: Ahsan SF, Meleca RJ, Dworkin JP. Botulinum toxin injection of the cricopharyngeus muscle for the treatment of dysphagia. Otolaryngol Head Neck Surg 2000;122: Alberty J, Oelerich M, Ludwig K, Hartmann S, Stoll W. Efficacy of botulinum toxin A for treatment of upper esophageal sphincter dysfunction. Laryngoscope 2000;110: Shaw GY, Searl JP. Botulinum toxin treatment for cricopharyngeal dysfunction. Dysphagia 2001;16: Murry T, Wasserman T, Carrau RL, Castillo B. Injection of botulinum toxin A for the treatment of dysfunction of the upper esophageal sphincter. Am J Otolaryngol 2005;26: Han TR, Paik NJ, Park JW. Quantifying swallowing function after stroke: a functional dysphagia scale based on videofluoroscopic studies. Arch Phys Med Rehabil 2001;82: McConnel FM, Cerenko D, Jackson RT, Guffin TN Jr. Timing of major events of pharyngeal swallowing. Arch Otolaryngol Head Neck Surg 1988;114: Sonies BC, Baum BJ. Evaluation of swallowing pathophysiology. Otolaryngol Clin North Am 1988;21: Brant CQ, Siqueira ES, Ferrari AP Jr. Botulinum toxin for oropharyngeal dysphagia: case report of flexible endoscope-guided injection. Dis Esophagus 1999;12: Kelly JH. Use of manometry in the evaluation of dysphagia. Otolaryngol Head Neck Surg 1997;116: Pasricha PJ, Ravich WJ, Hendrix TR, Sostre S, Jones B, Kalloo AN. Treatment of achalasia with intrasphincteric injection of botulinum toxin. A pilot trial. Ann Intern Med 1994;121: Pasricha PJ, Ravich WJ, Hendrix TR. Intrasphincteric botulinum toxin for the treatment of achalasia. N Engl J Med 1995;332: Pasricha PJ, Rai R, Ravich WJ, Hendrix TR, Kalloo AN. Botulinum toxin for achalasia: long term outcome and predictors of response. Gastroenterology 1996;110: Ferrari AP, Siqueira ES, Brant CQ. Treatment of achalasia in Chagas disease with botulinum toxin. N Engl J Med 1995;332: Suppliers a. Schering-Plough SA, Cantabria, 2. Edificio Amura, Alcobendas, Madrid, Spain. b. Polygraf ID; Medtronic, 710 Medtronic Pkwy, Minneapolis, MN c. Version 12.0; SPSS Inc, 233 S Wacker Dr, 11th Fl, Chicago, IL