oesophageal sensitivity to mecholyl in symptomatic diffuse ... · described (kramer and...

Gut, 1967, 8, 120

Oesophageal sensitivity to Mecholyl in symptomaticdiffuse spasm'

PHILIP KRAMER, BERTRAM FLESHLER, EDMUND McNALLY, AND LAURAND. HARRIS

From the Evans Memorial Department of Clinical Research, University Hospital, and Department ofMedicine, Boston University School of Medicine, Boston University Medical Center, U.S.A.

EDITORIAL COMMENT Hypersensitivity to Mecholyl has been demonstrated in a number of patientswith diffuse oesophageal spasm and this suggests that it is related to achalasia.

During radiographic examinations of theoesophagus, particularly in elderly individuals, avariety of bizarre contractions sometimes may beobserved. These motor abnormalities are frequentlyincidental findings during routine gastrointestinalradiographs of patients for symptoms which are notoesophageal in origin. Occasionally the samecontractions are seen in patients with odynophagia,dysphagia, and substernal pain and have beenidentified as responsible for such symptomsMoersch and Camp (1934). Because of their radio-graphic appearance, these motor disturbances havebeen variously called 'curling', 'tertiary contractions','segmental spasm', 'ladder spasm', 'non-sphinctericspasm', 'rosary-bead oesophagus', 'spastic pseudo-diverticulosis', 'corkscrew oesophagus', 'diffusespasm'. Some authors have implied that differentdiseases are represented while others have statedthat the changes are simply different radiographicmanifestations of the same disorder. The latter viewis the one that presently prevails (Templeton, 1964;Sheinmel, Priviteri, and Poppel, 1949; Van Exterand Keet, 1954; Creamer- Donoghue and Code,1958).

Diffuse spasm (the term most commonly used),whether symptomatic or asymptomatic, is consideredto be a neuromuscular disorder involving the bodyof the oesophagus whereas the sphincteric areausually functions normally (Creamer et al., 1958).Cardiospasm also is a neuromuscular disorder butis said to differ pathologically and clinically inseveral important respects. Degeneration of Auer-bach's plexus has been demonstrated in cardiospasmwhereas no such lesion has been found in diffusespasm (Templeton, 1964; Paden, 1954; Roth and

"This investigation was supported in part by Public Health ServiceTraining grant no. Ti AM 5025 and research grant no. AM 03560from the National Institute of Arthritis and Metabolic Diseases.

Fleshler, 1964). The cardiospastic oesophagusresponds in a hypersensitive fashion to para-sympathomimetic agents (Kramer and Ingelfinger,1949; Kramer and Ingelfinger, 1951; Hightower,Olsen, and Moersch, 1954); in diffuse spasm no suchresponse is said to occur (Creamer et al., 1958;Johnstone, 1960). Patients with symptomatic diffusespasm typically complain of pain, regurgitation israre, and on radiological examination there aresegmental spasms, relatively prompt oesophagealemptying, and little delay at the lower sphincter.In cardiospasm, pain is less common, regurgitationis frequent, the oesophagus seen in radiographs isoften markedly dilated, emptying is greatly impaired,and the sphincteric area has a narrowed, taperedappearance.

In a preliminary communication we reported thatthe oesophagus in patients with symptomatic diffusespasm manifested hypersensitivity to Mecholyl(Kramer, Fleshler and McNally, 1963). It wasalso suggested that diffuse spasm and cardiospasmare related disorders. The present paper is anextension of our previous study and a more detaileddiscussion of the findings in a larger number ofpatients with symptomatic diffuse spasm.Two other groups of patients were investigated.

One consisted of nine subjects (ages 56 to 72) witha similarly abnormal oesophagus radiologically butwithout oesophageal symptoms (asymptomaticdiffuse spasm). The final group was composed ofindividuals over 50 years of age (the age of mostdiffuse spasm patients) with normal gullets radio-logically and also without oesophageal symptoms.

Since this investigation is concerned primarilywith the oesophageal response to Mecholyl, thephenomenon of oesophageal hypersensitivity tocholinergic agents needs to be defined. In cardio-spasm this phenomenon had been characterized by

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Oesophageal sensitivity to Mec

a lumen-obliterating oesophageal contraction inresponse to a dose of Mecholyl which has littleeffect upon the normal oesophagus (Kramer andIngelfinger, 1951). Theoretically the dose whichseparates the oesophagus which is hypersensitivefrom that which is not should be an amount just lessthan that which causes a lumen-obliterating con-traction of the normal oesophagus. This dose hasnever been determined. In the previous study, thecardiospastic oesophagus was found to react witha tetanic contraction to 6 mg. or less of Mecholylintramuscularly while 10 mg. had little effect innormal control subjects or in patients with a varietyof oesophageal disorders. We have thereforeconsidered 10 mg. or less of Mecholyl as the amountwhich determines oesophageal hypersensitivity. Theaverage dose used is 6 mg.

METHODS

Oesophageal motility was investigated in every subjectby fluoroscopy and x-ray film following barium swallows,and by balloon-kymography. In eight subjects withsymptomatic and in two with asymptomatic diffusespasm, intraluminal pressures were measured via water-filled polyvinyl catheters, Sanborn transducers, and aSanborn recorder. Balloon-kymography and manometricmeasurements were performed by methods previouslydescribed (Kramer and Ingelfinger, 1949; Fleshler,Hendrix, Kramer, and Ingelfinger, 1958).During balloon-kymography the balloon was placed

holyl in symptomatic diffuse spasm 121

under fluoroscopy in the lower one-third of theoesophagus. After a suitable control tracing, an initialdose of 2 to 3 mg. of Mecholyl was injected intra-muscularly. If a lumen-obliterating contraction was notobtained then increasing doses of Mecholyl were injectedat 25-minute intervals, a larger dose consisting of anincrement of 2 to 3 mg. of Mecholyl to the previousinjection. This procedure was continued until at least6 mg. was given or the typical hypersensitive responseoccurred. Tone was defined as the mean volume of airin the balloon in millilitres. The regularity of the wavepattern was determined by inspection. The number ofwaves per minute was counted from a representativeportion of the control tracing. If the wave pattern wasirregular, then the contractions per minute were notcounted.

RESULTS

The results are set out in Table I.

SYMPTOMATIC DIFFUSE SPASM (14 PATIENTS) Allthe varieties of bizarre contractions implied bythe synonyms commonly used were visualizedradiologically (Fig. 1). Three types of motilitypattern were observed by balloon-kymography(Fig. 2): 1 In six patients (Fig. 2a and b) the tonewas normal (average 15 ml., range 11 to 23 ml.) andthe waves occurred in regular sequence. However,the number of waves per minute (average 14 perminute, range 10 to 22 per minute) exceeded that

TABLE ISUMMARY OF CLINICAL, BALLOON-KYMOGRAPHIC, AND MANOMETRIC DATA IN PATIENTS WITH DIFFUSE SPASM

Sex Age Balloon-kymography

Tone Wave Pattern Mecholyl Effect

Response Dose (mg.)

Manometry

Motility SphincterOpening

Symptomatic Diffuse Spasm1 R.B.2 F.C.3 J.S.4 M.C.5 J.F.6 A.G.7 C.P.8 Ja.S.9 C.M.

10 J.N.11 R.G.12 S.M.13 J.C.14 C.C.

Asymptomatic Diffuse Spasm1 J.C.2 B.M.3 M.C.4 L.L.5 E.J.6 F.O.7 M.V.8 M.F.9 T.D.

FMFFMMMMFMFMMF

MFMFFFMF

5861634858736863486848726338

686770636872685672

33266126610543106

D.S.

D.S.D.S.D.S.

D.S.

D.S.

NormalNormalNormalNormalNormalNormalHighHighHighNormalNormalNormalNormalNormal

NormalNormalNormalNormalNormalNormalNormalNormalNormal

Yes

YesNot testedYes

Not tested

Yes

RegularRegularRegularRegularRegularRegularIrregularIrregularIrregularIrregularIrregularIrregularIrregularIrregular

RegularRegularIrregularIrregularIrregularIrregularIrregularIrregularIrregular

Pos.Pos.Pos.Pos.Pos.Neg.Pos.Pos.Neg.Pos.Pos.Pos.Neg.Pos.

Neg.Neg.Neg.Neg.Neg.Neg.Neg.Neg.Neg.

D.S. YesD.S. Yes

D.S. Yes1066106661010 D.S. Yes

Subject



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Philip Kramer, Bertram Fleshler, Edmund McNally, and Lauran D. Harris

a. b. C. d.FIG. 1. Demonstrations of the gamut of oesophageal radiographic appearances in symptomatic diffuse spasm.FIG. I a (R.B.) Tertiary contractions or curlingFIG. lb (F. C.) Segmental spasm

usually seen in normals (average 8 per minute,range 6 to 12 per minute). 2 In three patients(Fig. 2d) the tone was unusually high (average4-7 ml., range 3 to 8 ml.) and the wave pattern wasdifficult to discern. 3 In the five remaining patientsthe tone was normal (average 16 ml., range 10 to25 ml.) but the wave pattern was irregular andcould not be counted with any degree of accuracy(Fig. 2c).The oesophageal response to Mecholyl by balloon-

kymography was the significant finding. Eleven of14 subjects responded to 2-6 mg. of Mecholyl witha forceful contraction expelling all air from theballoon (Fig. 2), an effect similar to that seen incardiospasm (Fig. 3). Because of the high initialtone the response to Mecholyl did not look asdramatic as that usually seen in cardiospasm; the

FIG. 1c. (J.S.) Spastic pseudodiverticulosisFIG. I d (C.P.) Corkscrew oesophagus

response was unequivocal nevertheless. Four subjectsexperienced retrosternal pain at the time of thecontraction, typical of the pain they felt clinically.The three patients who did not respond to Mecholylwere in no way different by radiography, balloon-kymography, and manometry from those who did.

Intraluminal pressures were measured at rest andduring deglutition in eight of the 14 subjects (twowith a negative Mecholyl test). In the body of theoesophagus, the normal peristaltic pressure waveswere replaced on swallowing by exaggerated,repetitive and simultaneous contractions over a longsegment typical of diffuse spasm (Fig. 4) asdescribed by Creamer et al. (1958). Sphinctericopening, i.e., a decrease in pressure of the highpressure zone during swallow, was determined in sixsubjects and observed in all six (Fig. 4).

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Oesophageal sensitivity to Mecholyl in symptomatic diffuse spasm1

FIG. 2. Balloon-kymographictracings of the four patientswhose radiographs are seen inFigure 1. All show a hyper-sensitive response to Mecholyl.

ASYMPTOMATIC DIFFUSE SPASM (9 SUBJECTS) Theoesophageal radiographs in these patients weresimilar to those seen in the symptomatic subjects(Fig. 5); none, however, showed the exaggeratedappearance demonstrated in Figures lc and d. Twotypes of balloon-kymographic motility pattern were

obtained because of the character of the waves. Thetone was normal in all tracings. In two subjects a

regular wave pattern was seen with 11 and 8 contrac-tions per minute. In the other seven subjects, thewave pattern was very irregular so that the numberof waves could not be counted. Mecholyl in doses of6 to 10 mg. intramuscularly produced minoralterations in motility similar to those seen innormals (Fig. 6). Manometric tracings, on swallow-ing, in two subjects were typical of diffuse spasm.

PATIENTS 50 YEARS OR OLDER WITH NORMAL MOTILITY

BY X-RAY STUDIES (10 SUBJECTS) By balloon-

kymography, the average tone was 15 ml. The wave

pattern was regular in seven subjects with an averageof 7.8 waves per minute, and irregular in six subjects.Six to 10 mg. of Mecholyl intramuscularly producedslight minor changes in motility.

DISCUSSION

The validity of our findings depends upon whetheror not our subjects had symptomatic diffuse spasmand not cardiospasm. Patients originally were

selected because their symptoms and radiographicfindings were typical of diffuse spasm.

In eight, the diagnosis was verified by themanometric tracings which were characteristic ofdiffuse spasm as they demonstrated exaggerated,repetitive, simultaneous, non-peristaltic contractionsover a large area of the oesophagus with sphinctericopenings in the six so tested. The radiographic

AIRC.C.

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124 Philip Kramer, Bertram Fleshler, Edmund McNally, and Lauran D. Harris

AIRC.C.0 M.B. Mechol l-8mg.I.M.

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FIG. 3. Balloon-kymographicrecordings in five patientswith cardiospasmdemonstrating the oesophagealhypersensitivity to Mecholyl.(From Kramer, P., andIngelfinger, F. J. EsophagealSensitivity to Mecholyl inCardiospasm, 1951, Gastro-enterology, 19, 242.)

FIG. 4. Manometric tracingsfrom a normal oesophagusandfrom a patient, J.N., withsymptomatic diffuse spasm.The three catheter tips are6 cm. apart. The distal tip isin the sphincter. A line isdrawn through the apex of thewave obtained via theproximal tip. D.S. denotes adry swallow. In the normal,the middle wave occurs laterthan the proximal oneindicating a peristalticsequence. The tracingobtained via the distalcatheter shows a high restingpressure (closed sphincter)and an 'opening pattern' onswallowing. In the patientwith diffuse spasm theoesophageal contractions aresimultaneous and repetitivebut in the sphincteric area thehigh resting pressure and the'opening pattern' is like thatof the normal; however, thespasm often involves thesphincter as shown here.

D.S.I40m

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FIG. 5. Theoesophagealradiographs seen itnthree asymptomaticindividuals. Theseare representative ofasymptomaticdiffuse spasm.

J. L.MECHOLYL 10 MG. IM.

AIR CC.

MECHOLYL 10 MG. IM. J.G.0 .L c c c c c

AIR CC. 20-

MINUTES 4 8 12

MECHOLYL 6 MG. IM. F.O.1A S n - a

AIR CC. 20 K-40, . . ..

MINUTES 4 8 12FIG. 6. Balloon-kymographic tracings of the patient whose radiographs are seen in Figure 5. The wave patternsbefore the injection of Mecholyl are similar to those seen in the normal. Mecholyl produces broadening of the wavesbut not a sustained lumen-obliterating contraction. C = cough; S - swallow. The end spike in J.L. is acalibration.



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Philip Kramer, Bertram Fleshler, Edmund McNally, and Lauran D. Harris

appearance of the oesophagi of patients J.S. andC.P. (Fig. lc and d) could only be that of diffusespasm. In the four remaining patients the x-rayfindings, i.e., the absence of dilatation, the failure tofind a narrowed tapered distal area, and the readyoesophageal emptying, would argue against thediagnosis of cardiospasm.

Balloon-kymographic tracings in the three groupsof patients investigated were not sufficiently differentfrom one group to another to allow this techniqueto be particularly diagnostic. In three patients withsymptomatic diffuse spasm the tone was unusuallyhigh and in six patients the number of waves perminute were increased above normal. However,even in elderly individuals without disease, all typesof bizarre balloon-kymographic patterns can beobserved (Kramer and Ingelfinger, 1951).The crucial finding was the hypersensitive response

of the oesophagus to Mecholyl by balloon-kymo-graphy in patients with symptomatic diffuse spasm,but not in the other two groups studied. This findinghas three implications. First, it supports Templeton'sand others' (Templeton, 1964; Creamer et al., 1958)conclusion that the varied x-ray appearances inreality represent one clinical entity. Thus, the fourrepresentative patients in Figure 1, showing the gamutof abnormal contractions that can be visualizedradiographically in symptomatic diffuse spasm,responded in a similar fashion to the cholinergicagent. Secondly, in cardiospasm the Mecholyl effecthas been interpreted as pharmacological evidenceconfirming the pathological finding of antemortemdegeneration of Auerbach's plexus according toCannon's Law of Degeneration. Since the response insymptomatic diffuse spasm is similar, the possibilityhas to be considered that there is degeneration ofAuerbach's plexus in this disorder. However,pathological studies, albeit few and incomplete, todate have not confirmed this speculation (Paden,1954; Roth and Fleshler, 1964). Lastly, the similarresponse to parasympathomimetic drugs in sympto-matic diffuse spasm and cardiospasm suggest thatthese two disorders may be related. Corroborativeevidence is obtained by the findings in patient F.C.His symptoms, oesophageal radiographs, andmotility studies were first suggestive of symptomaticdiffuse spasm; later they were typical of cardiospasm.This patient is the subject of a separate report(Kramer, Harris, and Donaldson page 115).

Others (Creamer et al., 1958; Johnstone, 1960)have reported a negative Mecholyl test in sympto-matic diffuse spasm, yet we have presented evidencethat it is frequently positive. The difference in resultsis probably related to the methods used in conduct-ing the respective investigations. The pharmaco-logical studies of Creamer et al. (1958) were

conducted with manometric techniques while weemployed balloon-kymography. With the lattermethod, the large balloon separates the oesophagealwalls, stretches them and acts as a constant stimulusthereby producing a continuous motility record.Consequently, when a muscle-stimulating drug suchas Mecholyl is given, the oesophageal walls canreadily react, especially when the muscle fibres arehypersensitive to the drug. Any changes which occurare readily discernible in the balloon-kymographicrecord.On the other hand, with manometric techniques,

the tiny balloon or open-tipped catheters aresufficiently small in diameter so that they do notseparate the oesophageal walls nor induce motoractivity. For intraluminal pressure to be recordeda force must be exerted over a unit area, i.e., acavity or lumen must exist and a closed chambermust be formed around the catheter ends. In theresting normal and diffuse spasm oesophagus thewalls are in apposition. Since no lumen exists, nopressure rise can be registered when Mecholyl isgiven. However, the oesophageal muscle fibres mayshorten and squeeze. Whether present methodsused to detect pressure can record this squeeze isquestionable (Harris and Pope, 1964). We stronglysuspect that the positive Mecholyl response incardiospasm by manometry is due in part to the factthat swallowed saliva, air, or ingested water, etc.,are present within the oesophageal lumen in thisdisease because there is no peristalsis. Thesesubstances act like a balloon, stretch the oesophagealwalls and permit the oesophagus to contract downwhen a cholinergic agent to which it is hypersensitiveis injected. However, a closed chamber may notalways form around the catheter tips and the pressuremay be dissipated. In balloon-kymography, theballoon in fact is a closed chamber and a changein intra-oesophageal volume will be detectedreadily.Can symptomatic diffuse spasm always be

distinguished from cardiospasm? Typical cases ofeither disease produce no problem in diagnosis.However, atypical cases may lead to diagnosticdifficulties. The clinical history may not be helpfulsince symptoms may overlap. Radiographic appear-ances may be somewhat similar since early cases ofcardiospasm may show minimal dilatation andmarked segmental contractions. Motility tracingswith balloon-kymography lack specificity. Thepositive Mecholyl test in symptomatic diffuse spasmeliminates this procedure as a differential diagnostictool. Peristalsis and sphincteric opening by mano-metric techniques are the major distinguishingfindings in diffuse spasm; they are absent in cardio-spasm. Unfortunately, approximately 25% of

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Oesophageal sensitivity to Mecholyl in symptomatic diffuse spasm 127

patients with symptomatic diffuse spasm fail to showthis opening pattern (Creamer et al., 1958).Many aspects of diffuse spasm remain an enigma.

Why symptoms are present in some patients and notin others is unexplained; why the majority ofpatients with symptomatic diffuse spasm respond toMecholyl in a hypersensitive fashion and others donot is also unknown; why the symptomatic groupresponds to cholinergic agents and the asympto-matic does not is also unanswered.

SUMMARY

Eleven of 14 patients with symptomatic diffuse spasmdemonstrate an oesophageal hypersensitivity toMecholyl by balloon-kymography. This findingsuggests that (1) the varied radiographic appearancesrepresent one disease, and (2) diffuse spasm andspasm may be related disorders.

REFERENCES

Creamer. B., Donoghue, F. E., and Code, C. F. (1958). Pattern ofesophageal motility in diffuse spasm. Gastroenterology, 34,782-796.

Fleshier, B., Hendrix, T. R., Kramer, P., and Ingelfinger, F. J. (1958).Resistance and reflex function of the lower esophageal sphincter.J. appi. Physiol., 12, 339-342.

Harris, L. D., and Pope C. E., It. (1964). 'Squeeze' vs. resistance: anevaluation of the mechanism of sphincter competence. J. clin.Inr,est., 43, 2272-2278.

Hightower, N. C., Jr., Olsen, A. M., and Moersch, H. J. (1954). Acomparison of the effects of acetyl-beta-methylcholine chloride(mecholyl) on esophagasl intraluminal pressure in normalpersons and patients with cardiospasm. Gastroenterology, 26,592-600.

Johnstone, A. S. (1960). Diffuse spasm and diffuse muscle hypertrophyof lower oesophagus. Brit. J. Radiol., 33, 723-735.

Kramer, P., Fleshler, B., and McNally, E. (1963). The pathophysiologyof symptomatic 'curling' or so-called 'diffuse spasm'. In 2ndWorld Congress of Gastroenterology, Munich, 1962, Vol. 1, pp.57-59. Karger, Basle and New York.Harris, L. D., and Donaldson, R. M., Jr. The transition fromsymptomatic diffuse spasm to cardiospasm. To be published.and Ingelfinger, F. J. (1949). I. Motility of the human esophagusin control subjects and in patients with esophageal disorders.Amer. J. Med., 7, 168-173.

(1949). II. Cardiospasm, a generalized disorder of esopha-geal motility. Ibid., 7, 174-179.

- . (1951). Esophageal sensitivity to mecholyl in cardiospasm,Gastroenterology, 19, 242-253.

Moersch, H. J., and Camp, J. D. (1934). Diffuse spasm of the lowerpart of the esophagus. Ann. Otol. (St. Louis), 43, 1165-1173.

Paden, P. A. (1954). Corkscrew esophagus. U.S. armed Forces med. J.,5, 1371-1374.

Roth, H. P., and Fleshler, B. (1964). Diffuse esophageal spasm. Ann.intern. Med., 61, 914-923.

Sheinmel, A., Priviteri, C. A., and Poppel, M. H. (1949). A study ofthe effect of certain drugs on curling of the esophagus: apreliminary report. Amer. J. Roentgenol., 62, 807-813.

Templeton, F. E. (1964). X-ray Examination of the Stomach: ADescription of the Roentgenologic Anatomy, Physiology, andPathology of the Esophagus, Stomach and Duodenum, p. 456.University of Chicago Press, Chicago.

Van Exter, P., and Keet, A. D., Jr. (1954). Curling of the oesophagus.S. Afr. med. J., 28, 206-211.



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