enteromegaly and cardiomegaly in chagas disease · enteromegalyandcardiomegaly in chagasdisease...

Gut, 1963, 4, 399

Enteromegaly and cardiomegaly in Chagas diseaseFRITZ KOBERLE

From the Medical School of Ribeirdo Preto, Sdo Paulo, Brazil

EDITORIAL SYNOPSIS Chagas disease due to a trypanosome infection may lead to extensive destruc-tion of ganglion cells in the peripheral autonomic system and may result in gross enlargement of theoesophagus, colon, and heart. From studies on nerve cell counts it is concluded that the number ofganglion cells in the oesophagus must be reduced to less than half to produce functional distur-bances in the oesophagus and to one tenth to produce a megaoesophagus.

Problems of terminology are discussed.

Megaoesophagus, megacolon, and dilatations ofother muscular hollow organs are extraordinarilyfrequent in Brazil, so frequent that several authorshave used the term endemic. In two towns of fewerthan 50,000 inhabitants in the southern part of thestate of Minas Gerais, Mineiro (1958) and Freitas(1950) found and published 1,514 and 2,000 casesrespectively of megaoesophagus. This number ismany times greater than the total number of casesin various European countries, and these figuresalone are sufficient to suggest that in Brazil, or atleast in parts of it, there must be a disease responsiblefor the extraordinarily high incidence of 'megas'.This suspicion has been expressed more than once,but could not gain acceptance in the face of thetheory that these conditions were due to vitamin B1deficiency (Etzel, 1935). Chagas (1916a and b) indeedexpressed the view that the dysphagia observed byhim after the acute phase of the disease might be theinitial stage of megaoesophagus.The 'megas' so often seen in Brazil are typical late

manifestations of Chagas disease (Koberle, 1956a),and Trypanosoma cruzi infection gives rise to twofundamentally distinct disease processes (Koberle,1959c): 1 Chagas disease in the strict sense, that is,infections with trypanosomes with an acute septic-aemic phase, passing after the development ofspecific resistance into a chronic phase with fewparasites; 2 sequelae of Chagas disease, or latemanifestations, which develop as a result of theextensive destruction of ganglion cells in the peri-pheral autonomic system and/or the central nervoussystem during the acute phase (Fig. 1). The destruc-tion of ganglion cells is due to the liberation of aneurotoxin from the Leishmania forms dying in theneighbourhood of ruptured pseudocysts during theacute phase (Koberle, 1956d). In rats, Alcantara

FIG. 1. Diagram of the course of Chagas disease.

(1959) found up to 80% of the ganglion cells in theheart irreversibly damaged during this phase.These considerations have lead to a change of

opinion regarding the nature and treatment ofChagas disease, in particular the part played bynerve lesions in its pathogenesis. Since Trypanosomacruzi is chiefly a parasite of muscle, destruction ofthe ganglion cells is to be expected wherever nervecells are to be found within or close to musculartissue. This is especially true of the parasympatheticganglion cells associated with the muscular holloworgans and heart. The ganglion cells of the sym-pathetic paravertebral chain, on the other hand,show only slight lesions, if any (Brandao, 1961).Since in Chagas disease there is more or less exten-sive destruction of the parasympathetic ganglioncells of the muscular hollow organs, it is possible toestimate the degree of denervation by counting theganglion cells, and to investigate the possible con-sequences of this denervation. In the digestive tract,the parasympathetic system determines motility,secretion, and absorption. There are disturbances of

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all three functions in Chagas disease, and Rezende(1959), on the grounds of our new concept of Chagasdisease, has used the term 'forma digestiva' to sumup all these functional disturbances of the digestivetract. This study deals with the disturbances ofmotility and their consequences, because they arefairly easy to recognize morphologically, and can bedetected even in the absence of correspondingclinical findings.

ENTEROMEGALY

The term 'enteromegaly' is suggested for all thosedilatations of the muscular hollow organs which arenot due to any obstruction, either mechanical orfunctional. Enteromegaly therefore includes all so-called idiopathic hypertrophies and dilatations, forwhich there are more than 50 different names, thebest known being 'megaoesophagus' and 'mega-colon'. Terminology is important, for an unsuitablename may lead to completely erroneous conceptionsof pathogenesis, which can even have adverse effectson the patient. The best example of misleadingterminology is 'congenital megacolon', becatuse itresulted, for over half a century, in the removal of aperfectly healthy colon, affected by purely secondarydilatation and hypertrophy. However, as early as1898, Treves of London had obtained a completecure in a case of Hirschsprung's disease by excisionof the entire rectum, sigmoid flexure, and descendingcolon. After Dalla Valle, in 1920, had demonstratedthe absence of ganglion cells in the distal colon, theexistence of an 'aganglionic segment' was repeatedlyconfirmed, and was carefully investigated by Bodianand his collaborators (1949, 1951). Bodian thereforerightly maintained that the misleading term 'con-genital megacolon' should be finally abandoned andHlirschsprung's disease used instead.The names 'enteromegaly' and 'mega' should be

reserved for all those conditions in which the dilatedsegment itself is diseased, and in this sense one mightspeak of 'idiopathic' dilatation. It will be objectedthat dilatation of a muscular hollow viscus andfunctional hypertrophy of the muscle can only occurabove an obstacle to free passage. Lee and Bebb(1951) do not accept an idiopathic type of megacolonin this sense, and write: 'If such an interpretationwere correct, it would represent the only instanceknown to medical science of a hollow viscus becom-ing chronically dilated and hypertrophied in theabsence of obstruction'. And yet there exists a formof dilatation and hypertrophy in which the cause liesin the diseased viscus itself and may be called 'neuro-genic dilatation and hypertrophy' (Koberle, 1957c).Examination of the function of the muscular hollowviscera shows it quite convincingly. The automatic

activity of the smooth muscle of the digestive tract isconverted by the ganglion cells of Auerbach's plexusinto coordinated peristalsis and adapted to theimmediate local and systemic conditions. In this waythe same contents entering the organ are passed outagain after a certain time, brief for the oesophagusand longer for the stomach and large intestine. It willbe understood without further explanation that anydisturbance in peristalsis, especially if it leads to inco-ordination of the wave-like forward motion, willdelay the passage of the contents, causing stagnationand retention, and necessarily also dilatation of theviscus. Since distension of the muscle fibres is thechief cause of hypertrophy, continuous dilatation andhypertrophy lead to the well-known mega forma-tions based on a disturbance of the intrinsic innerva-tion of the organ. This pathogenetic mechanism doesnot apply to the digestive tract only, but to all themuscular hollow viscera. Figure 2 shows thefrequency of the various mega formations in 250necropsies of cases of Chagas disease. It must, how-ever, be stated that this clinical material shows thatmegaoesophagus is more frequent than megacolon.In the post-mortem material megacolon, however,is the more frequent, because of spontaneous orpost-operative fatal complications.The necropsy statistics show clearly that mega-

oesophagus and megacolon are far more frequentthan mega formations in other hollow viscera, andthe same applies to all clinical statistics. SinceChagas disease spreads by way of the bloodstream,it might be expected that the extent of denervationwould be approximately the same in all the hollowviscera, or at least in those of a particular system oforgans. A case in point was published in 1932 by

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FIG. 2. Enteromegaly in 250 cases of Chagas disease.

Fritz Koberle400


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Enteromegaly and cardiomegaly in Chagas disease

Amorim and Correa Netto, who, in a patient withmegaoesophagus and megacolon, found lesions ofAuerbach's plexus in the whole digestive tract, andnot only in the oesophagus and colon. There musttherefore be other factors than denervation inChagas disease which favour mega formation ormake it possible.

Several factors play a decisive part in the patho-genesis of enteromegaly. A functional disturbancecannot be detected or cause recognizable conse-quences unless some demand is made on the dis-ordered function. Megacolon will not develop even ina severely denervated large intestine if the organ isexcluded by a colostomy. Conversely, markedregression may occur in a megacolon in the sectionof the intestine which has been excluded for a fewweeks before operation by a colostomy in the trans-verse colon. The contrast between the radiographmade before colostomy and the specimen obtainedon resection a few weeks later is striking. In the ruralpopulation of Brazil, dysphagia occurs chiefly wheneating cold rice, and since the transport of solids is aharder task for the peristalsis of a hollow viscus thanthe transport of fluids, it follows that dilatation ismore frequent in the oesophagus and colon, whichhave to deal with solid material, than in the rest ofthe digestive tract.A sphincter is by no means essential in mega

formation, as is shown by the occurrence of mega-duodenum and megajejunum, but some contributoryimportance must be attributed to a sphincter. Thesuccess of Heller's cardiomyotomy in certain casesconfirms this hypothesis.

Finally, psychological influences, of which every

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layman is aware in connexion with swallowing, mustbe mentioned. The case histories of patients withChagas disease are full of statements which show theeffect of mind on their symptoms. The remark byone patient with occasional dysphagia, that when hismother-in-law was in the house he could not evenswallow coffee, is an illuminating example. It isunderstandable that the duration of the strain, aswell as its intensity, is of decisive importance.Whereas most sufferers from Chagas disease go

through the acute phase in early childhood, thesymptoms affecting the hollow viscera occurespecially frequently after the twentieth year (Fig. 3).A longer or shorter period, depending on the degreeof denervation, must pass before the functionaldisturbance leads to the development of a mega. Thefunctional disturbance can, however, be observedimmediately after the acute phase (Chagas, 1916a;Rezende, 1959). To what extent other factors favourthe development of a mega is not yet known but it iscertain that the intensity and duration of mechanicalstrains play a decisive role.The finding that the mega formations in Brazil,

and presumably also those which occur so frequentlyin the whole American continent up to the southernstates of the U.S.A., are manifestations of Chagasdisease, provides abundant material for tracing thedevelopment of these manifestations. In doing this,however, the criterion used must be functional, notmorphological. The term 'aperistalsis', suggested byBrasil (1956), therefore seems to us the most suitable,because it correctly characterizes the functionaldisturbance which is ultimately responsible. If'aperistalsis' is looked for by functional methods in

FIG. 3. Distribution of megacolon, megaoesophagus,bronchiectasis, and megastomach in 250 cases of Cliagasdisease at various ages.

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402 Fritz Koberle

various hollow viscera in apparently healthy patientswith Chagas disease, it is found in about one fifth ofthe cases. In his diagnosis. the clinician should payattention to the demonstration of aperistalsis ratherthan to the morphological final mega stage.

TABLE INUMBER OF GANGLION CELLS IN THE MYENTERIC

PLEXUS IN A RING OF OESOPHAGUS 1 MM. THICK IN 10NORMAL CASES.

Upper Third Middle Third Lower Third

QUANTITATIVE INVESTIGATIONS ONTHE DEGREE OF DENERVATION OF HOLLOW VISCERA

To determine the number of ganglion ceintramural plexus, rings 3-4 mm. thick werevarious levels of the oesophagus, colon, ancfrom normal individuals and patients witidisease. After embedding, they were cut irsections, each 7 y thick, and every sevent]was selected (to avoid counting ganglion celTwenty sections were taken from each blocka total thickness of 980 y, that is approximatBecause of the irregular distribution ofcells in the bronchi, the counts were made1 cm. thick.Tables I-III and Figs. 4, 5, and 6 show tI

of counts in the intramural nervous systeoesophagus, bronchi, and colon. Particularl:cases with severe dilatation have been selecthe denervation. especially in the oesopitherefore unusually marked. However, itfrom counts in cases of Chagas disease withooesophagus that even considerable denervalnot necessarily produce dilatation and hypcIn such cases there are disturbances ofwhich can be detected by functional exaras Godoy and Haddad (1961) showed intheir asymptomatic cases of Chagas diseaslion cell counts have been made in over 4cases and in an equal number of Chagas disour investigation, which is not yet conclugiven the impression that the number of

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TABLE II

NUMBER OF GANGLION CELLS IN CHAGAS DISEASEWITHOUT MEGAOESOPHAGUS


Average

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TABLE III

NUMBER OF GANGLION CELLS IN CHAGAS DISEASEWITH MEGAOESOPHAGUS


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FIG. 4. Number ofganglion cells in the lower third of theoesophagus.

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CHAGAS DISEASE WITHOUT CHAGAS DISEASEMEGAOESOPHAGUS WITH

MEGAOESOPHAGUS


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Enteromegaly and cardiomegaly in Chagas disease

FIG. 5. Number ofganglion cells in theright bronchus.

CHAGAS DISEASEWITHOUT BRONCHIECTASIS

CHAGAS DISEASEWITH BRONCHIECTASIS

TRANSVERSE SIGMOID TOTALCAECUM COLON COLON RECTUM AVERAGE %

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FIG. 6. Number ofgang/ion______________________________________________________________ Ucells in Aiterbach's plexus in

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cells must be reduced to less than one half to producefunctional disturbances in the oesophagus, and toone tenth of the normal to produce a megaoeso-phagus. The 'tolerance' of the oesophagus toreduction of the/intramural ganglion cells is thereforefairly wide. The 'tolerance' of the colon seems to beless, as Figure 9 shows clearly. It is not easy to explainthis difference, because denervation is not the onlypathogenic factor in enteromegaly. The difference isperhaps partly due to the presence in the oesophagusof a fairly large proportion of striated muscle, andto the fact that gravity to some extent assists the actof swallowing, but subjective factors are certainly

concerned also. Dysphagia and retention of food inthe oesophagus are always felt to be unpleasant, andthe patient tries to reduce the disturbance in swallow-ing by every possible method. Defaecation is quiteanother matter, and patients who have no bowelmovements for two or three months are by no meansrare. There are even patients who do not defaecatefor four, five, or even six months. It is not surprisingthat in these circumstances the colon, which mayhold over 30 litres, is enormously overloaded, andeven moderate denervation must lead to a hugemegacolon.The complex problem of enteromegaly cannot,

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therefore, be simplified by considering it simply as aproblem of denervation, or by trying to correlate thedegrees of denervation and dilatation. In Chagasdisease it is, however, possible to detect and measurelesions of the autonomic nervous system without thewell-known 'erratic' impregnation techniques, andavoiding, to a very great extent, all subjectivecriteria, and also to demonstrate the pathogenicsignificance of these lesions in large series of cases.In these ganglion cell counts qualitative changes inthe cells have been disregarded because they wereconstantly seen, and suggest that the de factodenervation can only be greater than that observedby us.Chagas disease is the cause of the Brazilian

endemic megas, and this aetiology applies to themajority of American megas. It has been, and is still,objected that so-called 'acquired megas' occur inEurope and in other places where Chagas diseasedoes not exist. As a result of many years' work inEurope, especially at the Pathological Institute in theUniversity of Vienna with its vast necropsy material,it can be said that Chagas disease does not exist inEurope and for that very reason megas are very muchrarer than in Brazil. Besides, these arguments missthe point of the problem, in that they look uponmegas as a disease and not as a disorder or syndrome,that is, as a consequence of a lesion of the centralnervous system. In opposition to this view it is statedthat megas have been described in which the intra-mural nervous system appeared to be intact. In thisconnexion it may be noted that many of these arecases of Hirschsprung's disease, observed when thesecondarily dilated part of the colon was excised as amegacolon, and in this segment of intestine theintramural nervous system is not affected. Otherfindings merely refer to the presence of ganglioncells, no quantitative investigation of serial sectionshaving been made. There are also cases caused bydisturbances in intrinsic innervation, without anymorphologically recognizable changes in the intra-mural nervous system. Cases of this kind have beendescribed by Siegmund (1935) in Parkinsonismtreated for many years with atropine, that is to say,in patients whose parasympathetic intestinal inner-vation has been suppressed phdrmacologically.Finally, it is conceivable that infections or poisoning(war gases) may produce similar functional lesionsin the autonomic nervous system, with little or nomorphological change. In certain circumstances itmay therefore be extremely difficult, ifnot impossible.for the pathologist to detect morphological evidenceof the disturbance of innervation responsible for thecondition found.

There has been much discussion of the questionwhether atony or hypertonia of the mural muscula-

ture plays the decisive part in the pathogenesis ofenteromegaly. In the advanced stage, it is oftenimpossible to decide, because atony is nearly alwayspresent. Whereas in cases due to atropine there isalways primary atony, the condition in Chagasdisease is always due primarily to hypertonia. Thiscan be deduced purely theoretically from Cannon'slaw of denervation, and can easily be demonstratedin numerous patients with Chagas disease. It hasbeen clearly shown in the oesophagus by Vasconselosand Botelho (1937), Brasil (1956), Rezende (1956),and Godoy and Haddad (1961).Thus in Chagas disease a more or less marked

decrease in the number of parasympathetic ganglioncells in the hollow viscera leads in time because ofpermanent over-loading to enteromegaly, which maybe limited to a single organ or appear in all kinds ofcombinations.

CHAGAS CARDIOMEGALY

Heart disease is by far the most frequent manifesta-tion of Chagas disease. It was described in a masterlymanner by Chagas himself in many papers (1909-1920) and by Chagas and Villela (1922). The classicdescriptions of Chagas have been fully confirmed oncountless occasions. As regards pathogenesis, theopinion was generally held that the disease was achronic myocarditis. It would be far beyond thescope of this paper to discuss the pathogenesis ofthis remarkable heart disease in detail. Clinically, thedisease is characterized by disturbances in stimulusformation and conduction (Chagas) and sometimesenormous enlargement of the heart, which cannotbe explained by the existing 'tonogenic' and 'myo-genic' theory. The valves are quite normal in thesehearts. The blood pressure in Chagas disease may beraised but is usually considerably lowered. Foci ofparasites and inflammatory reactions are extremelyrare in the chronic phase, and cannot often be foundeven if hundreds of serial sections from all parts ofthe heart are examined. It is true that in advancedcases there are necrobiotic and necrotic lesions ofthe heart muscle but these are the expression ofcoronary insufficiency, that is, results of the cardiacenlargement and not causes of it. Besides, suchlesions are often absent, or limited to the field of theleft coronary artery whereas the dilatation is moremarked on the right. Routine examination of theheart thus often fails to disclose any reason for theoften severe dilatation and hypertrophy of the heart.The cause of the cardiomegaly in Chagas disease is

thought to be the same disturbance of intrinsicinnervation as described in enteromegaly. Thedilatation and hypertrophy of the heart are thus'neurogenic' (Koberle, 1957a). As regards pathogene-

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Enteromegaly and cardiomegaly in Chagas disease 405

sis, the same arguments apply as in enteromegaly. Theautomatic action of the heart is adapted to the needsof the moment by the autonomic nervous system.Any disturbance of this regulation must give rise, inthe long run, to dilatation, with distension of thefibres and subsequent hypertrophy, especially if thereis overloading in the form of an increased amount ofresidual blood. A vicious circle of dilatation andhypertrophy leads finally to severe cardiomegaly,with characteristic hypoxaemic lesions of the leftventricle, and, in particular, to typical aneurysms ofthe apex of the left ventricle. The importance of theduration and severity of the strain in the pathogene-sis of this form of cardiomegaly is shown by the factthat chronic cardiopathy in Chagas disease is two orthree times as common in men as in women.As in other hollow viscera, the parasympathetic

ganglion cells of the heart are seriously damaged inthe acute phase of Chagas disease. The degree ofdestruction was determined by cutting serial sectionsof the posterior wall of the right atrium between thesup-rior and inferior vena cava in the manneralready described. Here again, all identifiableganglion cells were counted, whether they showeddegeneration or not, so that the degree of degenera-tion observed is obviously less than the true degree.Because of the observed loss of parasympatheticganglion cells in Chagas disease, it may be called'cardiopathia parasympathicopriva' (Koberle, 159b).The course, clinical symptoms, frequency of suddendeath, and the very unusual morphological findingsstamp Chagas cardiopathy as a disease sui generis.Chagas therefore spoke with every justification of anew chapter in human pathology, of the greatestpathogenic curiosity', for he already suspected thatthe nervous system played a part in the pathogenesis.

REFERENCES

Alcantara, F. G. de (1959). Experimentelle Chagas-Kardiopathie. Z.Tropenmed. Parasit., 10, 296-303.

Amorim, M., and Correa Netto, A. (1932). Histopathologia e patho-genese do megaesophago e megarecto. Ann. Fac. Med. S. Paulo,8, 101-127.

Bodian, M., Stephens, F. D., and Ward, B. C. H. (1949). Hirsch-sprung's disease and idiopathic megacolon. Lancet, 1, 6-11.Carter, C. 0., and Ward, B. C. H. (1951). Hirschsprung'sdisease. Lancet, 1, 302-309.

Brandao, H. J. S. (1961). Estudo quantitativo de neur6nios simpaticose parasimpaticos na M6l6stia de Chagas experimental, emratos. Inaug. Dis. Fac. Med. Ribeirao Preto, 0, 1-64.

Brasil, A. (1956). Etiopatogenia da "aperistalsis" do es6fago. Rev.bras. Med., 13, 577-590.

Chagas, C. (1909). Nova tripanozomiaze humana. Mem. Inst. Osw.Cruz, 1, 159-218.

--(1916a). Processos patojenicos da tripanozomiase americana,Ibid., 8, (2), 5-36.

(1916b). Tripanosomiase americana. Forma aguda da molestia,Ibid., 8, (2), 37-60.

, and Villela, E. (1922). Forma cardiaca da tripanosomiaseamericana. Ibid., 14, 5-61.

Correa Netto, A. (1934). Tratamento cirurgico do megacolo pelaresec~&o dos chamados esfincteres funcionaes do intestinogrosso. Rev. Cirurg. S. Paulo, 1, 249-295.

Dalla Valle, A. (1920). Ricerche istologiche su di un caso di megacoloncongenito. Pediatria (Napoli), 28, 740-752.

Etzel, E. (1935). A avitaminose como agente etiol6gico do megaes6-fargoe do megacolon. An. Fac. Med. S. Paulo., 11, 59-85.

Freitas, S. V. Jr. (1950). Megacolo e megaes6fago no Brasil central.Resen Clin.-cient., 19, 411-423.

Godoy, R. A., and Haddad, N. (1961). Temopo de transito esofagicoem portadores de Molestia de Chagas. Ann. Congr. int. Doencade Chagas, 2, 591-602.

Koberle, F. (1956a). Die Chagaskrankheit; eine Erkrankung derneurovegetativen peripherie. Wien. klin. Wschr., 68, 333-339.

(1956b). Patogenese dos megas. Rev. goiana Med., 2, 101-1 10.--(1956c). Pathologische Befunde an den muskularen Hohlorganen

bei der experimentellen Chagaskrankheit. Zbl. allg. Path. path,Anat., 95, 321-329.

(1956d). Ober das Neurotoxin des Trypanosoma cruzi. Ibid., 95.468-475.

(1956e). Zur Frage der Entstehung sog. "idiopathischer Dilatat-ionen muskularer Hohlorgane. Virchows Arch. path. Anat.,329, 337-362.

(1957a). Patogenia de Mol6stia de Chagas. Rev. goiana Med., 3,155-180.

--(1957b). Uber Enteromegalie. Zbl. allg. Path. path. Anat., 96,244-259.

(1957c). Die chronische Chagaskardiopathie. Virchows Arch.path. Anat., 330, 267-295.

(1957d). Zur lehre von der Herzhypertrophie. Munch. med.Wschr.. 99, 247-249, and 296-298.

(1959a). Ober hypoxydotische Herz- und Aortenveranderungen.Zbl. allg. Path. path. Anat., 100, 113-123.

(1959b). Cardiopathia parasympathicopsiva. Munchn. med.Wschr., 101, 1308-1310.

(1959c). Die Chagaskrankheit - ihre Pathogenese und ihrBedeutung als Volksseuche. Z. Tropenmed. Parasit., 10, 236-268.

Lee, C. M. Jr., and Bebb, K. C. (1951). The pathogenesis and clinicalmanagement of megacolon with emphasis on the fallacy of theterm "idiopathic". Surgery, 30, 1026-1048.

Mineiro, V. (1958). Contribuisao a etiologia do megaes6fago. Rev.goiana Med., 4, 29-34.

Rezende, J. M. de (1956). Megaesofago por doenea de Chagas. Ibid.,2, 297-314.

(1959). Forma digestiva da molestia de Chagas. Ibid., 5, 193-227.Siegmund, H. (1935). Anatomisch nachgewiesene Folgen von Tonus

und motilittts-storungen des Verdauungskanals bei Enzepha-litikern, die mit Atropin behandelt wurden. Munch. med.Wschr., 82, 453-454.

Treves, F. (1898). Idiopathic dilatation of the colon. Lancet, 1, 276-279.Vasconselos, E., and Botelho, G. (1937). Cirurgia do megaes6fago,

Comp. Edit. nacional S. Paulo, -, 1-434.


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