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The experimental production of esophageal achalasia by electrolytic lesions in the medulla
The experimental production of esophageal achalasia by electrolytic lesions in the medulla Brian Higgs, M.B. (by invitation), Frederick W. L. Kerr, M.D. (by invitation), and F. Henry Ellis, Jr., M.D., Rochester, Minn.
xxchalasia of the esophagus is considered to be a neuromuscular disorder of the eso phageal wall associated with degenerative changes in Auerbach's plexus. Although the cause and pathogenesis of the condition re main obscure, there is evidence to suggest that the extrinsic vagal nerve supply of the esophagus may be primarily involved. Kimura1 first raised the possibility that the primary lesion might be in the central ner vous system. He demonstrated degenerated cells in the dorsal motor nucleus of the vagus nerve in postmortem specimens from 3 patients with esophageal achalasia. In a more detailed study, Cassella and his asso ciates2 examined serial sections of the brain stem from 2 patients with a clinical diag nosis of esophageal achalasia and counted the cells of the vagal dorsal motor nucleus. They found a marked loss of cells bilaterally as compared with a normal control. The present study was undertaken to From the Mayo Clinic and Mayo Foundation: Section oi Neurologic Surgery (Dr. Kerr) and oi Surgery (Dr. Ellis), and the Mayo Graduate School of Medi cine (University of Minnesota), Rochester, Minn.: Research Assistant (Dr. Higgs). This investigation was supported in part by Research Grants AM-05457 and NB-4905 from the National Institutes of Health, U. S. Public Health Service. Read at the Forty-fifth Annual Meeting of The American Association for Thoracic Surgery, New Orleans, La., March 29-31, 1965.
determine the relationship of these findings to the possible cause of esophageal achalasia by studying the effect of focal lesions in the medullary vagal motor nuclei on esophageal function in experimental animals. Material and methods Thirty-eight animals were used (22 dogs and 16 cats). On the basis of previous studies to localize the efferent visceral vagal nuclei,3 chronic electrolytic lesions were placed in the appropriate regions. Thirty-two of these 38 animals survived sufficiently long to permit adequate study, and they form the basis of this report. Dogs were used because their normal eso phageal function has been well documented and can be easily studied.4-5 Cats, however, are more suitable animals for study, as their esophageal musculature contains a higher proportion of smooth muscle than that of the dog and, in this respect, more closely resembles the human. Neurosurgical proce dures are more easily performed in the cat than in the dog, but the esophageal motility of the cat is less easily studied in the unanesthetized state. 6 - 7 Manometric techniques. Esophageal func tion was studied by the use of manometric methods that were designed by Code and associates 4 - 5 - 8 and which have now become 61 3
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standardized. Preoperative and postopera tive motility tests were performed on dogs that had been trained to lie quietly and on cats that had been lightly anesthetized with ether and then restrained. Time was allowed for the cats to recover fully from anesthesia before the studies were begun. Intraluminal pressures were detected by means of three water-filled polyethylene tubes connected proximally to strain-gauge pressure transducers. A 0.5 cm. latex bal loon covered the open end of the most distal tube. The other tubes each had a lateral opening, one at 5 cm. and the other at 10 cm. proximal to the balloon. The phases of respiration were recorded with a tubular pneumograph belt attached to a strain gauge. The outputs of the strain gauges were re corded photokymographically. The detection units were passed down into the stomach and withdrawn in 0.5 cm. steps while the resting esophageal pressures were recorded. The tubes were then reintroduced into the stomach, and deglutitive responses were ob tained at intervals of 0.5 cm. in the gastroesophageal sphincter and of 1 cm. in the rest of the esophagus. Esophageal pressures were recorded also during electric stimulation of the medulla in order to identify the appropriate vagal motor nuclei at operation. For this purpose, two 0.5 cm. balloons were mounted 10 cm. apart on the open ends of two water-filled polyethylene tubes that were connected prox imally to strain gauges and an optical re corder. Preoperative and postoperative motility records were analyzed; and resting pres sures at end-expiration and end-inspiration were measured at the gastroesophageal junc tion. In the deglutition study, the incidence and character of responses were noted, and the maximal pressures were measured in the four quarters of the esophagus. Calcula tions were made of the resting and de glutitive pressures to determine the mean, standard deviation, and standard error of the mean. Statistical comparisons, which employed the "t" test for the significance of differences,
were made between preoperative and post operative values.9 Operative procedures. All operative pro cedures were performed with the animal under sodium pentobarbital anesthesia (25 mg./Kg. of body weight). The animal was placed in a stereotaxic apparatus (Baltimore Instrument Co.) and a posterior fossa craniectomy was performed to expose the dorsal aspect of the medulla and the floor of the fourth ventricle (Fig. 1). The pressure-de tection unit described previously was then introduced into the esophagus and secured with the distal balloon at the gastroesopha geal junction. Coordinates taken from histo logie sections were used as a guide to the localization of the target nuclei. An insu lated, steel microelectrode was introduced into the medulla by a microdrive at an angle of approximately 15 degrees from the per pendicular. When the estimated position of the nucleus was reached, the electrode tip was advanced in 250 μ steps. At each step, stimulation of 6 volts/msec, pulse dura tion and 60 per second was delivered. When a maximal esophageal response was ob tained, an electrolytic lesion was made using a DC source of 50 to 100 μΆ applied for 5 to 10 seconds. In this manner, a linear series of 16 electrolytic lesions at intervals of 0.25 mm. was placed bilaterally in the appropriate vagal motor nuclei. Postoperative management. In the post operative period all animals were given daily parenteral fluids and antibiotics for 5 days. Animals that vomited or regurgitated were maintained by additional parenteral fluids or by esophageal tube feeding. In addition, all animals received daily vitamin supple ments. Esophageal function was studied by the use of manometric techniques as described previously,4· s<8 by roentgenoscopy, and by cineradiography at intervals from 48 hours to 8 weeks after operation. After the com pletion of each study, the animals were anesthetized with sodium pentobarbital; the aorta was cannulated through the left ven tricle, and they were perfused with normal saline followed by 10 per cent neutral for-
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Strain gauges
-Obex Recorder 4th ventricle Fig. 1. Diagram of experimental technique. The animal is placed in the stereotaxic apparatus. The esophageal balloons (dark areas in esophagus) are in position and connected to the recording system. The stimulator and DC source are connected to the microelectrode. Inset, Craniectomy with microelectrode entering medulla. A.N. = Ambiguous nucleus. D.N. = Dorsal motor nucleus of the vagus.
malin. Serial sections of 20 μ thickness were made from the medulla and stained by Nissl's thionine method and Luxol fast blue stain. Results To facilitate the interpretation of results, the animals have been grouped according to species and the groups subdivided accord ing to the site of the medullary lesions. Dogs. Lesions in dorsal motor nucleus. Of the 6 surviving dogs with bilateral lesions in the vagal dorsal motor nucleus, none showed evidence of dysphagia and all thrived without difficulty. Esophageal func tion was normal except for a slight diminu tion in the resting pressure of the gastroesophageal sphincter (Fig. 2,A and B). Per istalsis and sphincteric relaxation proceeded in an orderly fashion in response to degluti tion (Fig. 3, upper and middle). Roentgen-
oscopic examination failed to reveal any evidence of esophageal dilatation or ob struction to the passage of contrast medium. The animals were killed from 4 to 15 weeks after operation. The destruction of a large proportion of the cells in the dorsal motor nuclei of the vagus was confirmed histologically. Lesions in nucleus ambiguus. Ten dogs with bilateral lesions in the rostral part of the nucleus ambiguus were available for study. Five of these regurgitated and vomited after all feeds. Solid material was regurgi tated in the form of casts. Survival ranged between 72 hours and 23 days; inhalation pneumonitis was the cause of death in each instance. Esophageal motility studies showed complete aperistalsis with simultaneous lowamplitude contractions in the body of the esophagus, together with a reduced incidence of relaxation in the gastroesophageal sphinc-
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ter (Fig. 3, lower, and Table I ) . The sphincteric resting pressure showed a slight reduc tion similar to that seen after lesions of the dorsal motor nucleus (Fig. 2, C ) . During roentgenoscopy, the esophagus filled passively and was considerably dilated
(Fig. A,A and B). Some motor activity was visible. Occasionally, low-amplitude tertiary contractions were seen in the lower portion of the esophagus. There was complete ob struction to the passage of medium into the stomach. Both the manometric and roent-
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of esophageal dysfunction and the site of the lesions. The 5 achalasic dogs showed greater regions of destruction in the ambiguus nu clei than did the nonachalasic dogs (Fig. 5,A). In the nonachalasic animals, the lesions were located dorsal to the nucleus ambiguus and had only destroyed some of the intra-axial fibers of the vagus. Cats. Lesions in dorsal motor nucleus. There were 13 cats with bilateral lesions in the dorsal motor nucleus of the vagus that survived from 4 days to 9 weeks. Eight ani mals in this group had preoperative manometric studies, the details of which will be published separately.7 All had postoperative studies.
genoscopic observations resembled the pat tern seen in human patients with esophageal achalasia. The remaining 5 nonachalasic dogs were able to feed and survive without difficulty. Esophageal pressure studies showed evidence of low-amplitude peristaltic waves and a reduction in the resting pressure at the gastroesophageal sphincter. Roentgenoscopy disclosed normal transit through the esoph agus, but gastroesophageal reflux occurred frequently. Four dogs were killed at 4 weeks and 1 dog at 20 weeks after operation. Histologie examination of sections from the brain stem provided a correlation between the pattern
Table I. Incidence of sphincteric relaxation in response to esophageal contractions during deglutition No. of animals studied
Condition
A nimal
No. of esophageal contractions
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relaxations Per cent
Dogs
Control Lesions in vagal dorsal motor nucleus Lesions in nucleus ambiguus
6 6 5
110 75 113
83 48 45
75.5 64.0 39.8
Cats
Control Lesions in vagal dorsal motor nucleus Lesions in nucleus ambiguus
8 9 3
177 154 53
135 51 37
76.3 33.1 69.8
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Nine of these animals regurgitated and vomited during feeds. Manometric studies revealed a slight elevation of the resting pressure in the lower portion of the esoph agus. The mean resting pressure at the gastroesophageal junction was reduced by 39
per cent (Fig. 6 ) . However, in 4 cats in this group, there was no significant change in the resting sphincteric pressure. Esophageal responses to deglutition were infrequent, simultaneous, and of low amplitude (Fig. 7, upper and middle). There was a reduced
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Fig. 3. Resting and deglutitive pressures in canine esophagus. Upper, Normal resting pressures at esophageal junction. Normal deglutitive responses at the sphincter and in the esophagus. (In this and subsequent figures, upward-pointing arrows indicate 0.5 cm. withdrawals; down ward-pointing arrows indicate swallows. Middle, After bilateral lesions in the vagal dorsal motor nucleus. Lower, After bilateral lesions in the nucleus ambiguus. Note normal pattern after bilateral destruction of the vagal dorsal motor nucleus. After lesions in the nucleus ambiguus, simultaneous low-amplitude contractions appear in the body of the esophagus, and there is no sphincteric relaxation after deglutition.
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incidence of relaxation in the gastroesophageal sphincter (Table I ) . During roentgenoscopy, the body of the esophagus appeared to be slightly dilated
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and completely aperistaltic. There was com plete arrest of the column of barium at the gastroesophageal junction demonstrated (Fig. 4, C and D ) . Single stationary seg-
Fig. 4. Esophageal roentgenograms. A and B, Two dogs with bilateral lesions in the nucleus ambiguus showing dilatation of the esophagus and achalasia. C and D, Two cats with bilateral lesions in the vagal dorsal motor nucleus. Dilatation of the esophagus and achalasia are seen in C and low-amplitude segmental contractions is seen in D.
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Fig. 5. A, Transverse section of canine medulla shows bilateral lesions in the nucleus ambiguus (arrows). (Nissl's thionine; x5.) B, Transverse section of cat's medulla with bilateral lesions in the dorsal motor nucleus (arrows). (Nissl's thionine; xl6.)
mental contractions of sufficient magni tude to occlude the lumen were a prominent feature in the lower part of the esophagus. Smaller multiple simul taneous contractions of a nonpropulsive nature gave an intermittent saw-tooth outline to the barium shadow (Fig. 4,D). Of the remaining 4 animals, 1 showed a completely patulous lower sphincter with frequent gastroesophageal reflux, although peristalsis was preserved. Esophageal func tion was essentially normal in the other 3 animals, except for the occasional appear ance of a chain of small waves traveling in close succession down the esophagus and through the lower sphincter. In two in stances, gastric retention and complete pa
ralysis of the small bowel were seen up to 72 hours after operation. Histologie examination of the medulla in the achalasic cats revealed considerable re gions of destruction in the vagal dorsal motor nuclei (Fig. 5,B). Lesions in nucleus ambiguus. Three cats with bilateral lesions in the nucleus ambiguus were studied. Survival in this group ranged from 2 to 5 days. Postoperative pressure studies revealed a slight reduction in the resting pressure at the gastroesophageal junc tion, and the gastroesophageal sphincter re laxed normally in response to deglutition (Fig. 7, lower). Peristalsis was absent in the upper third of the esophagus in 1 animal and was of diminished amplitude in the other
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Esophageal achalasia 6 2 1
"End inspiration • End expiration.
Cm. proximal
Fig. 6. Mean resting pressures in the gastroesophageal sphincter of cats before {A) and after (B) bilateral electrolysis of the dorsal motor nucleus.
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Fig. 7. Resting and deglutitive pressures in the cat's esophagus. Upper, Normal. Middle, After bilateral lesions in the vagal dorsal motor nucleus. Lower, After bilateral lesions in the nucleus ambiguus. Note that, after bilateral destruction of the dorsal motor nucleus, simultaneous responses appear in the body of the esophagus, and the gastroesophageal sphincter does not relax. However, after lesions in the nucleus ambiguus, a relatively normal deglutition response is seen.
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2. It was difficult to induce deglutition in these animals. During roentgenoscopy, the barium flowed passively through the upper part of the esophagus and accumulated temporarily be hind the cardiac shadow. As the volume of barium was increased, peristalsis developed in the lower portion of the esophagus, and the wave passed normally across the gastroesophageal junction. Comment The evidence suggesting that a process of denervation has a leading part in the pathogenesis of esophageal achalasia is derived chiefly from histologie10· " and pharma cologie studies 12 ' 13 of the esophageal wall. Although the precise nature and site of the primary neural lesion have remained sub jects for speculation, significant pathologic changes have been described at all levels of the vagal efferent pathway, in the medullary nuclei, 1 ' 2 in the peripheral vagi,2' " · 1 5 and in the ganglion cells and intramural fibers of the myenteric plexus. 2 · 10 · 16 Although there have been many attempts to produce achalasia in experimental ani mals, 1720 relatively few have been successful. None, as far as we know, have involved lesions in the central nervous system. In contrast to the techniques of peripheral vagotomy19'23·2" which interrupt both motor and sensory fibers, we have achieved a se lective interruption of the motor vagal path ways at their origin within the medulla. We were able to demonstrate that a condition resembling human achalasia of the esoph agus could be produced by electrolytic lesions in the dorsal motor nucleus of cats and the nucleus ambiguus of dogs. Comparison of the esophageal motor activity in our preparations and that reported in patients with esophageal achalasia28 re vealed some similarities and some differ ences. The responses that were seen in the body of the esophagus after deglutition were similar in that they were infrequent, simul taneous, repetitive, and of low amplitude. In addition to a significant reduction in the in cidence of relaxation in the gastroesophageal
sphincter in our achalasic animals, contrac tions in the sphincter were feeble and infre quent. This contrasted with the pattern seen in patients with esophageal achalasia in whom premature sphincteric contractions have been observed. In human cases of achalasia the resting pressure in the gastro esophageal sphincter was usually within nor mal limits or was slightly elevated, in con trast to our animals in which the resting pressure was diminished. Segmental esophageal contractions similar to those seen in our preparations have been observed in patients with achalasia. In ad vanced cases the amplitude of simultaneous motor activity became reduced until the esophagus was completely inert. A correla tion has been described2 between the dura tion of the disease and the degree of de generation observed in the intramural nerve plexuses. Perhaps the simultaneous contrac tions seen in our animals and in patients with achalasia of short duration may reflect the persistence of reflex activity within the esophagus, despite the absence of extrinsic vagal control. The esophageal motility pattern after medullary lesions was similar to that seen after bilateral cervical vagotomy, 27 · 29 except that the resting pressure of the gastroeso phageal sphincter after bilateral cervical vagotomy showed a more marked reduction. This may have been a reflection of the in completeness of the medullary lesions in our animals, which resulted in only a partial withdrawal of vagal tone. Although sufficient nerve cells were de stroyed to produce marked disturbances in esophageal function, subsequent histologie examination showed that some of the cells in the target nuclei survived. A consistent correlation was found between the site and extent of the electrolytic lesions and the pattern of esophageal function. Thus, the achalasic dogs had considerable cellular de struction in the rostral parts of the ambiguus nuclei, and the achalasic cats showed com parable changes in the vagal dorsal motor nucleus. In animals in which lesions were less accurately placed, esophageal function
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was usually normal; however, if the lesions involved the intra-axial vagal fibers, some mild and temporary changes were observed in which both the amplitude of peristalsis and the resting pressure in the gastroesophageal sphincter were reduced. Roentgenoscopic evidence of spontaneous gastroesophageal reflux was observed frequently in these circumstances. It is noteworthy that destructive lesions in the dorsal motor nucleus of the vagus nerve produced no significant esophageal motility disturbance in the dog, whereas achalasia resulted from similarly placed lesions in the cat. An achalasic picture was produced in the dog only by bilateral de structive lesions in the nucleus ambiguus. This difference is probably related to the proportions of striated and smooth muscle in the esophageal wall of the two species. In the dog, all but a portion of the gastroesophageal sphincter is provided with striated muscle,30 while only the upper third of the cat's esophagus is similarly supplied.31 Since the nucleus ambiguus is regarded as the central origin of efferent fibers supply ing the striated muscle of the esophagus, whereas esophageal smooth muscle is be lieved to receive its innervation from the dorsal motor nucleus of the vagus, it is not surprising that esophageal motility distur bances result from differently placed lesions in the two species. Summary In this study, linear series of electrolytic lesions were placed in the medullary vagal motor nuclei of dogs and cats by a stereotaxic technique. Postoperative esophageal function was investigated by manometric, roentgenoscopic, and cineradiographic meth ods. It has been possible to demonstrate that a condition closely resembling human esophageal achalasia can be produced by focal destruction of the nucleus ambiguus in dogs and of the dorsal motor nucleus in cats. The results provide further support for the concept that esophageal achalasia occurs as the result of an extraesophageal vagal lesion.
Thoracic and Cardiovascular Surgery
Dr. C. F. Code assisted in the interpretation of the motility studies, and technical assistance was given by Mr. Patrick Bowron and Mr. Jerry Schlegel. REFERENCES 1 Kimura, K.: The Nature of Idiopathic Eso phageal Dilatation, Jap, J. Gastroenterol. 1: 199, 1929. 2 Cassella, R. R., Brown, A. L., Jr., Sayre, G. P., and Ellis, F. H., Jr.: Achalasia of the Esophagus: Pathologic and Etiologic Consider ations, Ann. Surg. 160: 474, 1964. 3 Kerr, F. W. L., and Higgs, B.: Unpublished data. 4 Schlegel, J. F., and Code, C. F.: Pressure Characteristics of the Esophagus and Its Sphincter in Dogs, Am. J. Physiol. 193: 9, 1958. 5 Greenwood, R. K., Schlegel, J. F., Code, C. F., and Ellis, F. H., Jr.: The Effect of Sympathectomy, Vagotomy, and Oesophageal Interruption on the Canine Gastro-oesophageal Sphincter, Thorax 17: 310, 1962. 6 Clark, C. G., and Vane, J. R.: The Cardiac Sphincter in the Cat, Gut 2: 252, 1961. 7 Higgs, B„ Ellis, F. H., Jr., and Kerr, F. W. L.: Esophageal Motility in the Normal and Decerebrate Cat: A Manometric Study. (Un published data.) 8 Fyke, F. E., Jr., Code, C. F., and Schlegel, J. F.: The Gastroesophageal Sphincter in Healthy Human Beings, Gastroenterologia 86: 135, 1956. 9 Fisher, R. A.: Statistical Methods for Research Workers, ed. 2, Edinburgh, 1930, Oliver & Boyd, 283 pp. 10 Rake, G. W.: A Case of Annular Muscular Hypertrophy of the Oesophagus (Achalasia of the Cardia With Esophageal Dilatation), Guy's Hosp. Rep. 76: 145, 1926. 11 Harman, J. W., O'Hegarty, M. T., and Byrnes, C. K.: The Ultrastructure of Human Smooth Muscle. I. Studies of Cell Surface and Connec tions in Normal and Achalasia Esophageal Smooth Muscle, Exper. & Molec. Path. 1: 204, 1962. 12 Kramer, P., and Ingelfinger, F. J.: II. Cardiospasm, A Generalized Disorder of Esophageal Motility, Am. J. Med. 7: 174, 1949. 13 Ellis, F. G., Kauntze, R., and Trounce, J. R.: The Innervation of the Cardia and Lower Oesophagus in Man, Brit. J. Surg. 47: 466, 1960. 14 Heyrovsky, H.: Casuistik und Therapie der idiopathischen Dilatation der Speiseröhre. Oesophagogastroanastomose, Arch. klin. Chir. 100: 703, 1912-1913. 15 Loeper, M., and Forestier, J.: Les lésions
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19
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nerveuses du pneumogastrique et le cardiospasme récurrent dans le cancer de l'estomac, Arch. mal. appl. digest. 11: 307, 1921. Adams, C. W. M., Brain, R. H. F., Ellis, F . G., Kauntze, R., and Trounce, J. R.: Achalasia of the Cardia, Guy's Hosp. Rep. 110: 191, 1961. Agrifoglio, M.: Richerche sperimentali sulla dilatazione diffusa dell' esofago, Arch. ital. chir. 28: 337, 1931. DeFrancesco, F.: Richerche sperimental sull blocco chirico e chirurgico del tratto esophago sopra cardiale e sotto diaphragmatico, Clin. chir. 6: 558, 1934. Grondahl, J. W., and Haney, H. F.: Attempt to Produce Experimental Cardiospasm in Dogs, Proc. Soc. Exper. Biol. & Med. 44: 126, 1940. Deloyers, L., Cordier, R., and Duprez, A.: A New Approach to the Physiology of SoCalled "Cardiospasm": Experimental Produc tion of "Cardiospasm" in Cats After Destruc tion of Auerbach's Plexus, Ann. Surg. 146: 167, 1957. Corelli, D., Canciullo, D., and Panebianco, G.: Cardiospasmo sperimentale con alterazione die plessi nervosi intramurali dell'esofago epicardio-cardiale, Ann. ital. chir. 34: 144, 1957. Alnor, P.: On the Pathogenesis of Cardio spasm: An Experimental Study, J. THORACIC SURG. 36:
141,
25
26
27
28
29
30
1958.
23 Long, D . M., Nice, C. M., Jr., Thai, A. P., and Truex, R. C : The Experimental Produc tion of Cardiospasm in Dogs, S. Forum 9: 408, 1958. 24 Harris, L. D., Ashworth, W. D., and Ingel-
31
finger, F . J.: Ësophageal Aperistalsis and Achalasia Produced in Dogs by Prolonged Cholinesterase Inhibition, J. Clin. Invest. 39: 1744, 1960. Okumura, M., and Corrêa, A.: Produçâo ex perimental de "megas" em animals inoculados com Trypanosoma cruzi, Rev. Hosp. clin. 16: 338, 1961. Ackermann, E., Mann, C. V., and Shorter, R. G.: Exposure of the Gastrointestinal Tract of the Dog to 750 K C Ultrasound. In Scientific Proceedings of the Seventh Annual Meeting of the American Institute of Ultrasonics in Medicine, New York, 1963, American Institute of Ultrasonics in Medicine, pp. 61-73. Carveth, S. W., Schlegel, J. F., Code, C. F., and Ellis, F. H., Jr.: Ësophageal Motility After Vagotomy, Phrenicotomy, Myotomy and Myomectomy in Dogs, Surg., Gynec. & Obst. 114: 31, 1962. Butin, J. W., Olsen, A. M., Moersch, H. J., and Code, C. F.: A Study of Ësophageal Pressures in Normal Persons and Patients With Cardiospasm, Gastroenterology 23: 278, 1953. Higgs, B., and Ellis, F . H., Jr.: The Effect of Bilateral Supranodosal Vagotomy Canine Esophagel Function. Surgery. In press. Mann, C. V., and Shorter, R. G.: Structure of the Canine Esophagus and Its Sphincters, J. S. Research 4: 160, 1964. Botha, G. S. M.: The Gastro-oesophageal Junction: Clinical Applications to Oesophageal and Gastric Surgery, Boston, 1962, Little, Brown & Company, pp. 65-81. (For Discussion,
see page
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xxchalasia of the esophagus is considered to be a neuromuscular disorder of the eso phageal wall associated with degenerative changes in Auerbach's plexus. Although the cause and pathogenesis of the condition re main obscure, there is evidence to suggest that the extrinsic vagal nerve supply of the esophagus may be primarily involved. Kimura1 first raised the possibility that the primary lesion might be in the central ner vous system. He demonstrated degenerated cells in the dorsal motor nucleus of the vagus nerve in postmortem specimens from 3 patients with esophageal achalasia. In a more detailed study, Cassella and his asso ciates2 examined serial sections of the brain stem from 2 patients with a clinical diag nosis of esophageal achalasia and counted the cells of the vagal dorsal motor nucleus. They found a marked loss of cells bilaterally as compared with a normal control. The present study was undertaken to From the Mayo Clinic and Mayo Foundation: Section oi Neurologic Surgery (Dr. Kerr) and oi Surgery (Dr. Ellis), and the Mayo Graduate School of Medi cine (University of Minnesota), Rochester, Minn.: Research Assistant (Dr. Higgs). This investigation was supported in part by Research Grants AM-05457 and NB-4905 from the National Institutes of Health, U. S. Public Health Service. Read at the Forty-fifth Annual Meeting of The American Association for Thoracic Surgery, New Orleans, La., March 29-31, 1965.
determine the relationship of these findings to the possible cause of esophageal achalasia by studying the effect of focal lesions in the medullary vagal motor nuclei on esophageal function in experimental animals. Material and methods Thirty-eight animals were used (22 dogs and 16 cats). On the basis of previous studies to localize the efferent visceral vagal nuclei,3 chronic electrolytic lesions were placed in the appropriate regions. Thirty-two of these 38 animals survived sufficiently long to permit adequate study, and they form the basis of this report. Dogs were used because their normal eso phageal function has been well documented and can be easily studied.4-5 Cats, however, are more suitable animals for study, as their esophageal musculature contains a higher proportion of smooth muscle than that of the dog and, in this respect, more closely resembles the human. Neurosurgical proce dures are more easily performed in the cat than in the dog, but the esophageal motility of the cat is less easily studied in the unanesthetized state. 6 - 7 Manometric techniques. Esophageal func tion was studied by the use of manometric methods that were designed by Code and associates 4 - 5 - 8 and which have now become 61 3
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standardized. Preoperative and postopera tive motility tests were performed on dogs that had been trained to lie quietly and on cats that had been lightly anesthetized with ether and then restrained. Time was allowed for the cats to recover fully from anesthesia before the studies were begun. Intraluminal pressures were detected by means of three water-filled polyethylene tubes connected proximally to strain-gauge pressure transducers. A 0.5 cm. latex bal loon covered the open end of the most distal tube. The other tubes each had a lateral opening, one at 5 cm. and the other at 10 cm. proximal to the balloon. The phases of respiration were recorded with a tubular pneumograph belt attached to a strain gauge. The outputs of the strain gauges were re corded photokymographically. The detection units were passed down into the stomach and withdrawn in 0.5 cm. steps while the resting esophageal pressures were recorded. The tubes were then reintroduced into the stomach, and deglutitive responses were ob tained at intervals of 0.5 cm. in the gastroesophageal sphincter and of 1 cm. in the rest of the esophagus. Esophageal pressures were recorded also during electric stimulation of the medulla in order to identify the appropriate vagal motor nuclei at operation. For this purpose, two 0.5 cm. balloons were mounted 10 cm. apart on the open ends of two water-filled polyethylene tubes that were connected prox imally to strain gauges and an optical re corder. Preoperative and postoperative motility records were analyzed; and resting pres sures at end-expiration and end-inspiration were measured at the gastroesophageal junc tion. In the deglutition study, the incidence and character of responses were noted, and the maximal pressures were measured in the four quarters of the esophagus. Calcula tions were made of the resting and de glutitive pressures to determine the mean, standard deviation, and standard error of the mean. Statistical comparisons, which employed the "t" test for the significance of differences,
were made between preoperative and post operative values.9 Operative procedures. All operative pro cedures were performed with the animal under sodium pentobarbital anesthesia (25 mg./Kg. of body weight). The animal was placed in a stereotaxic apparatus (Baltimore Instrument Co.) and a posterior fossa craniectomy was performed to expose the dorsal aspect of the medulla and the floor of the fourth ventricle (Fig. 1). The pressure-de tection unit described previously was then introduced into the esophagus and secured with the distal balloon at the gastroesopha geal junction. Coordinates taken from histo logie sections were used as a guide to the localization of the target nuclei. An insu lated, steel microelectrode was introduced into the medulla by a microdrive at an angle of approximately 15 degrees from the per pendicular. When the estimated position of the nucleus was reached, the electrode tip was advanced in 250 μ steps. At each step, stimulation of 6 volts/msec, pulse dura tion and 60 per second was delivered. When a maximal esophageal response was ob tained, an electrolytic lesion was made using a DC source of 50 to 100 μΆ applied for 5 to 10 seconds. In this manner, a linear series of 16 electrolytic lesions at intervals of 0.25 mm. was placed bilaterally in the appropriate vagal motor nuclei. Postoperative management. In the post operative period all animals were given daily parenteral fluids and antibiotics for 5 days. Animals that vomited or regurgitated were maintained by additional parenteral fluids or by esophageal tube feeding. In addition, all animals received daily vitamin supple ments. Esophageal function was studied by the use of manometric techniques as described previously,4· s<8 by roentgenoscopy, and by cineradiography at intervals from 48 hours to 8 weeks after operation. After the com pletion of each study, the animals were anesthetized with sodium pentobarbital; the aorta was cannulated through the left ven tricle, and they were perfused with normal saline followed by 10 per cent neutral for-
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Strain gauges
-Obex Recorder 4th ventricle Fig. 1. Diagram of experimental technique. The animal is placed in the stereotaxic apparatus. The esophageal balloons (dark areas in esophagus) are in position and connected to the recording system. The stimulator and DC source are connected to the microelectrode. Inset, Craniectomy with microelectrode entering medulla. A.N. = Ambiguous nucleus. D.N. = Dorsal motor nucleus of the vagus.
malin. Serial sections of 20 μ thickness were made from the medulla and stained by Nissl's thionine method and Luxol fast blue stain. Results To facilitate the interpretation of results, the animals have been grouped according to species and the groups subdivided accord ing to the site of the medullary lesions. Dogs. Lesions in dorsal motor nucleus. Of the 6 surviving dogs with bilateral lesions in the vagal dorsal motor nucleus, none showed evidence of dysphagia and all thrived without difficulty. Esophageal func tion was normal except for a slight diminu tion in the resting pressure of the gastroesophageal sphincter (Fig. 2,A and B). Per istalsis and sphincteric relaxation proceeded in an orderly fashion in response to degluti tion (Fig. 3, upper and middle). Roentgen-
oscopic examination failed to reveal any evidence of esophageal dilatation or ob struction to the passage of contrast medium. The animals were killed from 4 to 15 weeks after operation. The destruction of a large proportion of the cells in the dorsal motor nuclei of the vagus was confirmed histologically. Lesions in nucleus ambiguus. Ten dogs with bilateral lesions in the rostral part of the nucleus ambiguus were available for study. Five of these regurgitated and vomited after all feeds. Solid material was regurgi tated in the form of casts. Survival ranged between 72 hours and 23 days; inhalation pneumonitis was the cause of death in each instance. Esophageal motility studies showed complete aperistalsis with simultaneous lowamplitude contractions in the body of the esophagus, together with a reduced incidence of relaxation in the gastroesophageal sphinc-
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ter (Fig. 3, lower, and Table I ) . The sphincteric resting pressure showed a slight reduc tion similar to that seen after lesions of the dorsal motor nucleus (Fig. 2, C ) . During roentgenoscopy, the esophagus filled passively and was considerably dilated
(Fig. A,A and B). Some motor activity was visible. Occasionally, low-amplitude tertiary contractions were seen in the lower portion of the esophagus. There was complete ob struction to the passage of medium into the stomach. Both the manometric and roent-
° End inspiration • End expiration
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Fig. 2. Mean resting pressures in the gastroesophageal sphincter in a series of control dogs (A), 6 dogs with bilateral lesions in the dorsal motor nucleus of the vagus (B), and 5 dogs with bilateral lesions in the nucleus ambiguus (C).
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of esophageal dysfunction and the site of the lesions. The 5 achalasic dogs showed greater regions of destruction in the ambiguus nu clei than did the nonachalasic dogs (Fig. 5,A). In the nonachalasic animals, the lesions were located dorsal to the nucleus ambiguus and had only destroyed some of the intra-axial fibers of the vagus. Cats. Lesions in dorsal motor nucleus. There were 13 cats with bilateral lesions in the dorsal motor nucleus of the vagus that survived from 4 days to 9 weeks. Eight ani mals in this group had preoperative manometric studies, the details of which will be published separately.7 All had postoperative studies.
genoscopic observations resembled the pat tern seen in human patients with esophageal achalasia. The remaining 5 nonachalasic dogs were able to feed and survive without difficulty. Esophageal pressure studies showed evidence of low-amplitude peristaltic waves and a reduction in the resting pressure at the gastroesophageal sphincter. Roentgenoscopy disclosed normal transit through the esoph agus, but gastroesophageal reflux occurred frequently. Four dogs were killed at 4 weeks and 1 dog at 20 weeks after operation. Histologie examination of sections from the brain stem provided a correlation between the pattern
Table I. Incidence of sphincteric relaxation in response to esophageal contractions during deglutition No. of animals studied
Condition
A nimal
No. of esophageal contractions
Sphincteric No.
relaxations Per cent
Dogs
Control Lesions in vagal dorsal motor nucleus Lesions in nucleus ambiguus
6 6 5
110 75 113
83 48 45
75.5 64.0 39.8
Cats
Control Lesions in vagal dorsal motor nucleus Lesions in nucleus ambiguus
8 9 3
177 154 53
135 51 37
76.3 33.1 69.8
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1
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1
| 1 Respiratory reversal
2
3
Cm. proximal
4
i
T 0=Mean
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Nine of these animals regurgitated and vomited during feeds. Manometric studies revealed a slight elevation of the resting pressure in the lower portion of the esoph agus. The mean resting pressure at the gastroesophageal junction was reduced by 39
per cent (Fig. 6 ) . However, in 4 cats in this group, there was no significant change in the resting sphincteric pressure. Esophageal responses to deglutition were infrequent, simultaneous, and of low amplitude (Fig. 7, upper and middle). There was a reduced
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Fig. 3. Resting and deglutitive pressures in canine esophagus. Upper, Normal resting pressures at esophageal junction. Normal deglutitive responses at the sphincter and in the esophagus. (In this and subsequent figures, upward-pointing arrows indicate 0.5 cm. withdrawals; down ward-pointing arrows indicate swallows. Middle, After bilateral lesions in the vagal dorsal motor nucleus. Lower, After bilateral lesions in the nucleus ambiguus. Note normal pattern after bilateral destruction of the vagal dorsal motor nucleus. After lesions in the nucleus ambiguus, simultaneous low-amplitude contractions appear in the body of the esophagus, and there is no sphincteric relaxation after deglutition.
Volume 50 Number 5 November, 1965
incidence of relaxation in the gastroesophageal sphincter (Table I ) . During roentgenoscopy, the body of the esophagus appeared to be slightly dilated
Esophageal achalasia
6 19
and completely aperistaltic. There was com plete arrest of the column of barium at the gastroesophageal junction demonstrated (Fig. 4, C and D ) . Single stationary seg-
Fig. 4. Esophageal roentgenograms. A and B, Two dogs with bilateral lesions in the nucleus ambiguus showing dilatation of the esophagus and achalasia. C and D, Two cats with bilateral lesions in the vagal dorsal motor nucleus. Dilatation of the esophagus and achalasia are seen in C and low-amplitude segmental contractions is seen in D.
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Fig. 5. A, Transverse section of canine medulla shows bilateral lesions in the nucleus ambiguus (arrows). (Nissl's thionine; x5.) B, Transverse section of cat's medulla with bilateral lesions in the dorsal motor nucleus (arrows). (Nissl's thionine; xl6.)
mental contractions of sufficient magni tude to occlude the lumen were a prominent feature in the lower part of the esophagus. Smaller multiple simul taneous contractions of a nonpropulsive nature gave an intermittent saw-tooth outline to the barium shadow (Fig. 4,D). Of the remaining 4 animals, 1 showed a completely patulous lower sphincter with frequent gastroesophageal reflux, although peristalsis was preserved. Esophageal func tion was essentially normal in the other 3 animals, except for the occasional appear ance of a chain of small waves traveling in close succession down the esophagus and through the lower sphincter. In two in stances, gastric retention and complete pa
ralysis of the small bowel were seen up to 72 hours after operation. Histologie examination of the medulla in the achalasic cats revealed considerable re gions of destruction in the vagal dorsal motor nuclei (Fig. 5,B). Lesions in nucleus ambiguus. Three cats with bilateral lesions in the nucleus ambiguus were studied. Survival in this group ranged from 2 to 5 days. Postoperative pressure studies revealed a slight reduction in the resting pressure at the gastroesophageal junc tion, and the gastroesophageal sphincter re laxed normally in response to deglutition (Fig. 7, lower). Peristalsis was absent in the upper third of the esophagus in 1 animal and was of diminished amplitude in the other
Volume 50 Number 5 November, 1965
Esophageal achalasia 6 2 1
"End inspiration • End expiration.
Cm. proximal
Fig. 6. Mean resting pressures in the gastroesophageal sphincter of cats before {A) and after (B) bilateral electrolysis of the dorsal motor nucleus.
622
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Higgs, Kerr, Ellis
OPEN-TIP
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Fig. 7. Resting and deglutitive pressures in the cat's esophagus. Upper, Normal. Middle, After bilateral lesions in the vagal dorsal motor nucleus. Lower, After bilateral lesions in the nucleus ambiguus. Note that, after bilateral destruction of the dorsal motor nucleus, simultaneous responses appear in the body of the esophagus, and the gastroesophageal sphincter does not relax. However, after lesions in the nucleus ambiguus, a relatively normal deglutition response is seen.
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2. It was difficult to induce deglutition in these animals. During roentgenoscopy, the barium flowed passively through the upper part of the esophagus and accumulated temporarily be hind the cardiac shadow. As the volume of barium was increased, peristalsis developed in the lower portion of the esophagus, and the wave passed normally across the gastroesophageal junction. Comment The evidence suggesting that a process of denervation has a leading part in the pathogenesis of esophageal achalasia is derived chiefly from histologie10· " and pharma cologie studies 12 ' 13 of the esophageal wall. Although the precise nature and site of the primary neural lesion have remained sub jects for speculation, significant pathologic changes have been described at all levels of the vagal efferent pathway, in the medullary nuclei, 1 ' 2 in the peripheral vagi,2' " · 1 5 and in the ganglion cells and intramural fibers of the myenteric plexus. 2 · 10 · 16 Although there have been many attempts to produce achalasia in experimental ani mals, 1720 relatively few have been successful. None, as far as we know, have involved lesions in the central nervous system. In contrast to the techniques of peripheral vagotomy19'23·2" which interrupt both motor and sensory fibers, we have achieved a se lective interruption of the motor vagal path ways at their origin within the medulla. We were able to demonstrate that a condition resembling human achalasia of the esoph agus could be produced by electrolytic lesions in the dorsal motor nucleus of cats and the nucleus ambiguus of dogs. Comparison of the esophageal motor activity in our preparations and that reported in patients with esophageal achalasia28 re vealed some similarities and some differ ences. The responses that were seen in the body of the esophagus after deglutition were similar in that they were infrequent, simul taneous, repetitive, and of low amplitude. In addition to a significant reduction in the in cidence of relaxation in the gastroesophageal
sphincter in our achalasic animals, contrac tions in the sphincter were feeble and infre quent. This contrasted with the pattern seen in patients with esophageal achalasia in whom premature sphincteric contractions have been observed. In human cases of achalasia the resting pressure in the gastro esophageal sphincter was usually within nor mal limits or was slightly elevated, in con trast to our animals in which the resting pressure was diminished. Segmental esophageal contractions similar to those seen in our preparations have been observed in patients with achalasia. In ad vanced cases the amplitude of simultaneous motor activity became reduced until the esophagus was completely inert. A correla tion has been described2 between the dura tion of the disease and the degree of de generation observed in the intramural nerve plexuses. Perhaps the simultaneous contrac tions seen in our animals and in patients with achalasia of short duration may reflect the persistence of reflex activity within the esophagus, despite the absence of extrinsic vagal control. The esophageal motility pattern after medullary lesions was similar to that seen after bilateral cervical vagotomy, 27 · 29 except that the resting pressure of the gastroeso phageal sphincter after bilateral cervical vagotomy showed a more marked reduction. This may have been a reflection of the in completeness of the medullary lesions in our animals, which resulted in only a partial withdrawal of vagal tone. Although sufficient nerve cells were de stroyed to produce marked disturbances in esophageal function, subsequent histologie examination showed that some of the cells in the target nuclei survived. A consistent correlation was found between the site and extent of the electrolytic lesions and the pattern of esophageal function. Thus, the achalasic dogs had considerable cellular de struction in the rostral parts of the ambiguus nuclei, and the achalasic cats showed com parable changes in the vagal dorsal motor nucleus. In animals in which lesions were less accurately placed, esophageal function
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was usually normal; however, if the lesions involved the intra-axial vagal fibers, some mild and temporary changes were observed in which both the amplitude of peristalsis and the resting pressure in the gastroesophageal sphincter were reduced. Roentgenoscopic evidence of spontaneous gastroesophageal reflux was observed frequently in these circumstances. It is noteworthy that destructive lesions in the dorsal motor nucleus of the vagus nerve produced no significant esophageal motility disturbance in the dog, whereas achalasia resulted from similarly placed lesions in the cat. An achalasic picture was produced in the dog only by bilateral de structive lesions in the nucleus ambiguus. This difference is probably related to the proportions of striated and smooth muscle in the esophageal wall of the two species. In the dog, all but a portion of the gastroesophageal sphincter is provided with striated muscle,30 while only the upper third of the cat's esophagus is similarly supplied.31 Since the nucleus ambiguus is regarded as the central origin of efferent fibers supply ing the striated muscle of the esophagus, whereas esophageal smooth muscle is be lieved to receive its innervation from the dorsal motor nucleus of the vagus, it is not surprising that esophageal motility distur bances result from differently placed lesions in the two species. Summary In this study, linear series of electrolytic lesions were placed in the medullary vagal motor nuclei of dogs and cats by a stereotaxic technique. Postoperative esophageal function was investigated by manometric, roentgenoscopic, and cineradiographic meth ods. It has been possible to demonstrate that a condition closely resembling human esophageal achalasia can be produced by focal destruction of the nucleus ambiguus in dogs and of the dorsal motor nucleus in cats. The results provide further support for the concept that esophageal achalasia occurs as the result of an extraesophageal vagal lesion.
Thoracic and Cardiovascular Surgery
Dr. C. F. Code assisted in the interpretation of the motility studies, and technical assistance was given by Mr. Patrick Bowron and Mr. Jerry Schlegel. REFERENCES 1 Kimura, K.: The Nature of Idiopathic Eso phageal Dilatation, Jap, J. Gastroenterol. 1: 199, 1929. 2 Cassella, R. R., Brown, A. L., Jr., Sayre, G. P., and Ellis, F. H., Jr.: Achalasia of the Esophagus: Pathologic and Etiologic Consider ations, Ann. Surg. 160: 474, 1964. 3 Kerr, F. W. L., and Higgs, B.: Unpublished data. 4 Schlegel, J. F., and Code, C. F.: Pressure Characteristics of the Esophagus and Its Sphincter in Dogs, Am. J. Physiol. 193: 9, 1958. 5 Greenwood, R. K., Schlegel, J. F., Code, C. F., and Ellis, F. H., Jr.: The Effect of Sympathectomy, Vagotomy, and Oesophageal Interruption on the Canine Gastro-oesophageal Sphincter, Thorax 17: 310, 1962. 6 Clark, C. G., and Vane, J. R.: The Cardiac Sphincter in the Cat, Gut 2: 252, 1961. 7 Higgs, B„ Ellis, F. H., Jr., and Kerr, F. W. L.: Esophageal Motility in the Normal and Decerebrate Cat: A Manometric Study. (Un published data.) 8 Fyke, F. E., Jr., Code, C. F., and Schlegel, J. F.: The Gastroesophageal Sphincter in Healthy Human Beings, Gastroenterologia 86: 135, 1956. 9 Fisher, R. A.: Statistical Methods for Research Workers, ed. 2, Edinburgh, 1930, Oliver & Boyd, 283 pp. 10 Rake, G. W.: A Case of Annular Muscular Hypertrophy of the Oesophagus (Achalasia of the Cardia With Esophageal Dilatation), Guy's Hosp. Rep. 76: 145, 1926. 11 Harman, J. W., O'Hegarty, M. T., and Byrnes, C. K.: The Ultrastructure of Human Smooth Muscle. I. Studies of Cell Surface and Connec tions in Normal and Achalasia Esophageal Smooth Muscle, Exper. & Molec. Path. 1: 204, 1962. 12 Kramer, P., and Ingelfinger, F. J.: II. Cardiospasm, A Generalized Disorder of Esophageal Motility, Am. J. Med. 7: 174, 1949. 13 Ellis, F. G., Kauntze, R., and Trounce, J. R.: The Innervation of the Cardia and Lower Oesophagus in Man, Brit. J. Surg. 47: 466, 1960. 14 Heyrovsky, H.: Casuistik und Therapie der idiopathischen Dilatation der Speiseröhre. Oesophagogastroanastomose, Arch. klin. Chir. 100: 703, 1912-1913. 15 Loeper, M., and Forestier, J.: Les lésions
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17
18
19
20
21
22
nerveuses du pneumogastrique et le cardiospasme récurrent dans le cancer de l'estomac, Arch. mal. appl. digest. 11: 307, 1921. Adams, C. W. M., Brain, R. H. F., Ellis, F . G., Kauntze, R., and Trounce, J. R.: Achalasia of the Cardia, Guy's Hosp. Rep. 110: 191, 1961. Agrifoglio, M.: Richerche sperimentali sulla dilatazione diffusa dell' esofago, Arch. ital. chir. 28: 337, 1931. DeFrancesco, F.: Richerche sperimental sull blocco chirico e chirurgico del tratto esophago sopra cardiale e sotto diaphragmatico, Clin. chir. 6: 558, 1934. Grondahl, J. W., and Haney, H. F.: Attempt to Produce Experimental Cardiospasm in Dogs, Proc. Soc. Exper. Biol. & Med. 44: 126, 1940. Deloyers, L., Cordier, R., and Duprez, A.: A New Approach to the Physiology of SoCalled "Cardiospasm": Experimental Produc tion of "Cardiospasm" in Cats After Destruc tion of Auerbach's Plexus, Ann. Surg. 146: 167, 1957. Corelli, D., Canciullo, D., and Panebianco, G.: Cardiospasmo sperimentale con alterazione die plessi nervosi intramurali dell'esofago epicardio-cardiale, Ann. ital. chir. 34: 144, 1957. Alnor, P.: On the Pathogenesis of Cardio spasm: An Experimental Study, J. THORACIC SURG. 36:
141,
25
26
27
28
29
30
1958.
23 Long, D . M., Nice, C. M., Jr., Thai, A. P., and Truex, R. C : The Experimental Produc tion of Cardiospasm in Dogs, S. Forum 9: 408, 1958. 24 Harris, L. D., Ashworth, W. D., and Ingel-
31
finger, F . J.: Ësophageal Aperistalsis and Achalasia Produced in Dogs by Prolonged Cholinesterase Inhibition, J. Clin. Invest. 39: 1744, 1960. Okumura, M., and Corrêa, A.: Produçâo ex perimental de "megas" em animals inoculados com Trypanosoma cruzi, Rev. Hosp. clin. 16: 338, 1961. Ackermann, E., Mann, C. V., and Shorter, R. G.: Exposure of the Gastrointestinal Tract of the Dog to 750 K C Ultrasound. In Scientific Proceedings of the Seventh Annual Meeting of the American Institute of Ultrasonics in Medicine, New York, 1963, American Institute of Ultrasonics in Medicine, pp. 61-73. Carveth, S. W., Schlegel, J. F., Code, C. F., and Ellis, F. H., Jr.: Ësophageal Motility After Vagotomy, Phrenicotomy, Myotomy and Myomectomy in Dogs, Surg., Gynec. & Obst. 114: 31, 1962. Butin, J. W., Olsen, A. M., Moersch, H. J., and Code, C. F.: A Study of Ësophageal Pressures in Normal Persons and Patients With Cardiospasm, Gastroenterology 23: 278, 1953. Higgs, B., and Ellis, F . H., Jr.: The Effect of Bilateral Supranodosal Vagotomy Canine Esophagel Function. Surgery. In press. Mann, C. V., and Shorter, R. G.: Structure of the Canine Esophagus and Its Sphincters, J. S. Research 4: 160, 1964. Botha, G. S. M.: The Gastro-oesophageal Junction: Clinical Applications to Oesophageal and Gastric Surgery, Boston, 1962, Little, Brown & Company, pp. 65-81. (For Discussion,
see page
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