The scientific journey taken by Neiva and Penna: a blueprint for studies of diseases from the Brazilian hinterland

Abstracts

Analisa o relatório de Arthur Neiva e Belisario Penna , focalizando a contribuição dos autores ao estudo de uma das doenças endêmicas por eles encontrada ao longo de todo o trajeto percorrido, de longa data conhecida popularmente por 'mal de engasgo'. Observaram e descreveram com minúcia os sintomas apresentados pelos doentes e a associação frequente do mal de engasgo com outro mal endêmico conhecido por 'vexame' ou 'vexame do coração', que consistia em crises de palpitações. Os estudos epidemiológicos e clínicos de Neiva e Penna sobre o mal de engasgo muito contribuíram para o conhecimento dessa afecção e representaram um incentivo para todos os pesquisadores que se dedicaram ao seu estudo, especialmente quanto a sua relação com a doença de Chagas.

doença de Chagas; tripanossomíase; mal de engasgo; acalásia

DOSSIER SANITARISM AND INTERPRETATIONS OF BRAZIL

ANALYSIS

The scientific journey taken by Neiva and Penna: a blueprint for studies of diseases from the Brazilian hinterland

Joffre M. de Rezende

Emeritus professor at Universidade Federal de Goiás. Honoris Causa professor at Universidade de Brasília. Rua João de Abreu, 744/02. 74120-110 - Goiânia - GO - Brazil. [e-mail]

ABSTRACT

Analyze the report by Neiva and Penna, focusing on the contribution these authors made to the study of one of the endemic diseases encountered throughout their journey, which had been long known under the popular name of mal de engasgo (choking disease). They recorded their observations and detailed descriptions of the patients' symptoms and the association frequently encountered between mal de engasgo and another endemic disease, known as vexame or vexame do coração, characterized by bouts of palpitations. Neiva and Penna's epidemiological and clinical observations of mal de engasgo were crucial for all the researchers interested in the disease, especially its relationship with Chagas disease.

Keywords: Chagas desease; choking disease; trypanosomiasis; acalásia.

The report submitted by Arthur Neiva and Belisario Penna to the Inspetoria de Obras Contra a Seca [Inspectorate of Works to Combat Drought] and published under the title "Viagem cientifica pelo norte da Bahia, sudoeste de Pernambuco, sul do Piauhi e de norte a sul de Goiaz" [Scientific journey to the north of Bahia, south-east of Pernambuco, south of Piauhi and north to south of Goiaz] (Neiva, Penna, 1916) is a milestone in the history of Brazilian science for the wealth of information with which it portrays the conditions in the country's inland regions at the time, of which the Republic's ruling classes and the inhabitants of its coastal towns and cities were entirely ignorant. It gives precise scientific data on the geography, climate, animal and plant life and sanitation conditions, as well as the diseases that afflicted man and beast throughout the great length of their journey.¹ Our interest here is in mal de engasgo, an endemic condition that was common in rural inland areas of Brazil, which we now know to be caused by Chagas disease, and which was observed and described by the researchers under the name of spasmodic dysphagia.

Our interest in mal de engasgo derived from the great number of patients of this condition we attended in Goiânia state. Reviewing the literature on the topic, we were inspired by Neiva and Penna's study to undertake our own research and observations of the much-debated question concerning the relationship between the trypanosomiasis and endemic megaesophagus.

The literature and medical discussions at the time about mal de engasgo

At the beginning of the chapter about spasmodic dysphagia, the authors highlight the dearth of publications in the Brazilian medical literature "about a widespread condition in the country." They go on: "Apart from the study by U. Paranhos, none other exists about the ailment in Brazil. ... The only references we found are on page 1,799 of the 18th edition of Formulário - Chernoviz - Paris, 1908, and pp.298-299 of the well-known novella, Inocência, by Taunay" (Neiva, Penna, 1916, p.132, 133). They add that the "most precise reference about it ... [is] contained in pp. 204-205 of A geografia física do Brasil refundida [A revised physical geography of Brazil] by J.E. Wappoeus (condensed edition), submitted for publication by J. Capistrano de Abreu and A. do Valle Cabral-Rio de Janeiro-1884" (p.133).²

In their literature review, the authors fail to include an importance reference work at the time, which was Dicionário de medicina doméstica e popular [Dictionary of domestic and popular medicine] by Theodoro J.H. Langgaard, a Danish physician who had emigrated to Brazil in 1842. He had his medical degree accredited at Faculdade de Medicina do Rio de Janeiro [Faculty of Medicine of Rio de Janeiro] in 1848 then moved to Campinas, São Paulo state, where he worked as a general practitioner until 1870, when he moved to Rio de Janeiro. The first edition of his dictionary is dated 1865, which means it predates the novel by Taunay, which came out in 1872.

The entry for mal de engasgo in Langgaard's dictionary reads: "Dysphagia or difficulty with deglutition. This condition may have different causes ... . However, we mention here a kind of dysphagia which in many respects seems to us worthy of being studied by my Brazilian colleagues, especially because it is so widespread and hard to cure" (Langgaard, 1865, p.2-5). He goes on to describe the main symptoms of the ailment, how it develops, its diagnosis, prognosis and treatment, the latter based on empirical practices no efficacy whatsoever.

In the second edition of the same dictionary, which was published in 1873, the entry is somewhat larger. It states that "this ailment has long been endemic in the province of Goiás, but has recently spread to a certain part of Minas Gerais and entered the province of S. Paulo". It discusses its etiology and allows that it could be caused by a toxin or parasite, the latter of which (entozoa) could be the cause of "that spasmodic constriction of the cardiac orifice, by the constant and permanent irritation it produces". He believes mal de engasgo is a different condition "than the cases described by previous authors" (Langgaard, 1873, p.3-5), in a reference to the classic descriptions of idiopathic achalasia, which in Europe went under the name of cardiospasm.

Esophageal achalasia, or just achalasia, is the name most commonly used nowadays to refer to the affection described by Hoffman in 1733 under the name of spasmodic dysphagia. It is characterized by the difficulty of getting food from the esophagus to the stomach, as it gets stuck in the esophagus and causes the organ to dilate. As the etiopathogenesis of the condition was unknown, several authors proposed different names for it, inspired by its anatomical and functional aspects or by theories about its pathogenesis. In a literature review focusing on this topic, Vaz (1991) found no fewer than 71 different names. The ones that were most widely accepted, aside from spasmodic dysphagia, were cardiospasm, given by Mikulicz in 1882, megaesophagus, adopted by Von Hacker in 1907 (Correia Neto, 1935), and esophageal achalasia, proposed by Hertz in 1914. It should be noted that Hertz changed his name to Hurst, which is why the name of achalasia is cited as having been given by Hurst, rather than Hertz (Hertz, 1914-1915; Hurst, 1927).³

In Brazil, a condition that was endemic and whose symptoms identified it with achalasia had long been known by its common names, entalação or entalo [literally 'squeezing'] and mal de engasgo [choking disease]. Though the latter name was what the local people called it, it was this name that was adopted in medical circles and cited in the first studies into the condition.⁴

In 1895 Sociedade de Medicina e Cirurgia de São Paulo [São Paulo Society of Medicine and Surgery] was founded.⁵ At its first session held on April 1st of that year, Bettencourt Rodrigues proposed that it should concern itself primarily with the "affections specific to or most common in São Paulo, among which was 'mal de engasgo'; for this reason he proposed that it be discussed at the next session" (Minutes..., 1895, p.8). From then on, mal de engasgo was the topic of discussion at many of the society's meetings, as can be see from the minutes published in its publication (Boletim). The discussions mainly focused on finding out whether mal de engasgo was the same disorder known in European countries as spasmodic dysphagia and cardiopasm, or if it was an endemic disease from the Brazilian hinterland of as yet unknown etiology. At the root of this controversy was a conceptual difference between disease and syndrome concerning mal de engasgo. For diseases, there is a single, albeit unknown, etiology, while syndromes have more than one cause, even if the pathogensis and clinical manifestations are identical.⁶

Some members of Sociedade de Medicina e Cirurgia de São Paulo, including Carlos Botelho⁷ and Pereira Barreto⁸, supported the idea that mal de engasgo had a unique etiology. In correspondence to Sergio Meira Filho, which was transcribed, undated, by Enjolras Vampré (1919), Botelho states: "the etiology cannot but be parasitic or pseudomalarial, and located in the vicinity of the cardiac orifice".

In a later letter, also to Sergio Meira Filho and transcribed by Vampré (1919), Botelho refers to Neiva and Pena's report:

Thanks to your kindness, I have become acquainted with the work of the distinguished Dr. Neiva, which makes some references to 'mal de engasgo'. I had assumed that this work was a communiqué to our scientific societies; but I discovered that it was written for a journal and, thus finished, is already being prepared for printing ... . Even so, as proof of the esteem with which I hold Dr. Neiva's scientific contribution, I would say that mal de engasgo, the only name by which it is known among us, is still widespread in the hinterland of São Paulo, between the great malarial rivers, as such, more than the others, the Mogy and the Rio Grande ...

Later, he refers to mal de engasgo as "tropical dysphagia, a name I propose for the disorder, for the latter word always brings to mind a parasitic association" (Vampré, 1919).⁹

Pereira Barreto supported the idea that malaria was the cause of mal de engasgo, as he explains in a letter to Enjolras Vampré of July 27th, 1918, which is transcribed in Raphael Parisi's doctoral thesis (1925): "From my observations over forty years, I have found that all the patients with mal de engasgo, without exception, previously had malaria. There is an irrefutable link between mal de engasgo and malaria".

When Neiva and Penna embarked on their scientific journey, there was a widespread belief amongst Brazil's medical practitioners that mal de engasgo was caused by some parasite, as can be deduced from an article published by Ulysses Paranhos¹⁰ in 1913, where the author states: "the hypothesis that it is a parasitic disease has many supporters"; and later: "Recently, in a private conversation, we heard that some physicians would make mal de engasgo a clinical variety of Chagas's trypanosomiasis. It would appear, however, that no experiments have ratified this viewpoint, for it has so far not been possible to demonstrate the presence of the trypanosome in the blood of the patients" (Paranhos, 1913b).¹¹ Paranhos does not name these physicians, nor does he endorse the parasite theory. Rather, in the same paper, he hypothesizes that it could be caused by a toxin from manioc flour, one of the staples of the dwellers of Brazil's rural areas which, when incorrectly prepared, would retain certain toxins from the wild manioc (Manihot esculenta).

Paranhos's use of tropical dysphagia as a synonym for mal de engasgo was sharply criticized by Neiva and Penna: "The name of tropical dysphagia given by Paranhos is inappropriate, confining the disorder as it does to one geographical area, which may not be the only area where it occurs, and which would only increase the denigration of the tropics ... . It is high time one stood up against such inappropriate names which simply heighten the discredit in which tropical zones are held" (Neiva, Penna, 1916, p.133).

The Report and observations about mal de engasgo and american trypanosomiasis

The Report does not contain any comment on Paranhos's assertion that there were those who already considered it feasible that mal de engasgo could be caused by Chagas disease. Neiva and Penna certainly contemplated the possibility that mal de engasgo was the consequence of an infectious or parasitic disease, otherwise they would not have injected the blood of a mal de engasgo patient who accompanied them on their field trip into guinea pigs. At no point, however, did they mention that the purported disease could be the trypanosomiasis.

The first written document that refers to the possibility that mal de engasgo could be caused by Chagas disease is by Carlos Chagas (1916a) himself in his study of the severe form of the trypanosomiasis published in Memórias do Instituto Oswaldo Cruz in the same volume in which the report by Neiva and Penna was published. Giving voice to his suspicion that both endemics could be etiologically related, Chagas writes: "could mal de engasgo be another element of Brazilian Trypanosomiasis and this dysphagia in severe forms represent the initial phase of the syndrome?". Later, he concludes: "new research is needed to incontrovertibly sanction the inclusion of mal de engasgo among the multiple symptoms caused by infection by Trypanosoma cruzi". The fact that Chagas referred to the syndrome and not the disease implies that he accepted there could be more than one etiology for the condition.

One of the barriers against the acceptance of Chagas disease as the cause of mal de engasgo was the latter's identification with idiopathic achalasia, which was encountered in regions where Chagas disease was not. It is possible that Chagas's attention was drawn to this possibility by the observations made by Neiva and Penna on their scientific journey, whose report he was familiar with, as he states in "Processos patogênicos da tripanossomíase americana" [Pathogenic processes of American trypanosomiasis] (Chagas, 1916b).

One of the aims of Neiva and Penna's expedition was to search for evidence of the presence of American Trypanosomiasis. Wherever they went, they tried to capture, identify and examine the triatomines they encountered in houses and wild habitats, looking for specimens infected with Trypanosoma cruzi. The species they managed to capture were Triatoma maculata, Triatoma brasiliensis, Triatoma sordida and Triatoma megista (Panstrongylus megistus), the last two of which were the most prevalent. They did not find any Triatoma infestans, a strictly domestic species, which can be explained by the fact that it is not indigenous to Brazil, unlike the others.¹²

At the time, investigations into the pathology of Chagas disease focused on the thyroid and the central nervous system, followed by cardiac alterations. The main indicators used to diagnose it were the presence of triatomines in the region and the existence of patients with goiter or serious neurological alterations. They noted that "the nervous forms of Chagas disease were encountered throughout the journey, especially in Goiás," (Neiva, Penna, 1916, p.125; italics added). They believed Goiás to be the state that was worst affected by Chagas disease as it had the highest rate of infestation by triatomines and the largest number of people with goiter and cases of idiocy, cretinism, infantilism and deafness.

In the second part of the report, entitled "Itinerário (parte descriptiva)" [Itinerary -(descriptive part)], and in "Diário e itinerário da excursão científica pelo interior do Brasil" [Journal and itinerary of the scientific excursion to inland Brazil] by Arthur Neiva, they told of cases not just of goiter and the "nervous forms of the trypanosomiasis", but also cases of cardiac alterations, vexame and entalação or mal de engasgo, which were found in the different places they visited during their journey through Bahia, Pernambuco, Piauí and Goiás states.

They attempted to correlate the existence of goiter with the occurrence of the infected triatomines they captured, and concluded that there may be some association between the two variables, without going so far as to state that this of itself proved that the trypanosomiasis was the cause of the goiter.

To avoid the conclusion that goiter is linked to Chagas disease, one would have to admit the existence of other morbid conditions which were also transmitted by barbeiros [a haematophagous bug] or else an efficient cause that existed under the same nosological conditions as were favorable to the development of those hemiptera; something that supports these facts, which we recall only as a hypothesis, is the absence or small proportion of infected triatomines in some places where goiter is very widespread, such as Duro, Porto Nacional and Descoberto" (Neiva, Penna, 1916, p.124-125).

While they were in Peri-peri, Formosa municipality, Neiva wrote in his journal on July 8th, 1912: "Wherever we go there is endemic goiter, while we are forced to state that in these parts Chagas disease is benign" (Neiva, Penna, 1916, p.66 of the Itinerário).

As for mal de engasgo, they had direct contact with many patients and heard of the existence of many others among the local population. The report contains the best clinical and epidemiological study of the disease thus far published in Brazilian medical literature.

After reviewing the classic literature by European authors on cardiospasm and comparing the symptoms they described with those they observed in the mal de engasgo patients, they reached the conclusion that it was most likely the same disease. They adopted the name proposed by Hoffmann in 1733, spasmodic dysphagia, for reasons of terminological priority. Nonetheless, they noted and were struck by the high incidence of the condition in the regions they visited: "In Central Brazil, the phenomenon appears with uncommon frequency, which would initially suggest it is a local ailment; after we studied the subject we became convinced that it exists everywhere, though in Central Brazil it encounters especially favorable conditions for its development" (Neiva, Penna, 1916, p.133-134). Amongst these conditions they included poor nutrition, which they accepted could be a potential cause. To back up this hypothesis, they mention the fact that they did not observe "a single case of entalação among the inhabitants who are wealthier and, for this reason, have better nutrition" (p.135).

Despite all the arguments in favor of identifying mal de engasgo with Hoffmann's spasmodic dysphagia, they appeared unconvinced by their own conclusions: "One doubt nonetheless continues to assail our spirits; it has to do with the occurrence, which could, without overstatement, be called epidemic, so high is the number of cases observed or heard of". And later: "The dysphagia we have observed in a few hundred individuals may constitute an as yet undetermined affection" (Neiva, Penna, 1916, p.135).

Clinically speaking, the notes made in the report are invaluable. At the end of the chapter on spasmodic dysphagia, the authors include nine clinical histories of patients with the disorder, giving detailed descriptions of how it began, any antecedents, its symptoms and its development, which demonstrates the care with which the medical histories were taken and physical exams performed. Their observations include some very interesting data that give a precise picture of the clinical condition caused by chagasic megaesophagus, as it is known today. We quote some examples: "Entalação affects any age group ... [it] usually begins between 20 and 30 years of age... . It is not unusual to have several members of one family afflicted by the same condition" (Neiva, Penna, 1916, p.134-137).

One of the patients they examined in Caracol, Piauí (M.R.S., 53 years of age), came from a family which had seven cases: him, his father, one brother, three nephews and one uncle, and they also knew of five other people with the same disorder (Neiva, Penna, 1916, p.134).

Neiva and Penna (1916, p.134) note: "there are more cases amongst men ..." (p.134). A similar predominance of male patients is noted by other authors in later publications (Etzel, 1939; Freitas Júnior, 1950; Rezende, 1956; Mineiro, 1958).¹³

The existence of symptomless or oligosymptomatic cases did not go unnoticed by Neiva and Penna, as can be seen from the following comment: "Overall, the patients do not complain, except for those who have the more serious forms and who seek out medical help of their own accord in the hope for some relief; the majority, however, either because the disorder is at an early stage or because it has not developed to a point that it is a major discomfort, are only identified by asking questions" (Neiva, Penna, 1916, p.134).

They mention the sudden or insidious beginnings of the disorder, the interspersed periods of improvement and worsened symptoms, the need to take meals with repeated mouthfuls of water, the greater ease of eating hot food, the burping, the forced regurgitation, the techniques patients use to help the food go down, such as eating standing up or walking around, leaning backwards, raising the arms, hitting the wall of the thorax with the hand, stamping on the ground (Neiva, Penna, 1916, p.134). They say that the dysphagia is worse when solids are ingested, but that in some cases the dysphagia is more marked with liquids (paradoxical dysphagia). In one of the clinical histories, they record the occurrence of episodes of retrosternal pain, which immediately stopped when water was ingested (p.136).¹⁴

One of the things the patients often complained of was persistent constipation, known by the popular name of caseira. Out of the nine clinical histories included in the report, six contained complaints of constipation, while the three that did not were the histories of children aged six, seven and nine.

The chapter that follows the one on spasmodic dysphagia is devoted to another endemic disorder, known as vexame or vexame do coração [vexame of the heart]. The order of these two chapters is not insignificant, given the mutual occurrence of the endemics in the households of certain regions. Neiva and Penna note:

few are the families in which, if one of these manifestations does not exist, neither does the other; however, we did not find any family where, if there was one or more entalados [people with mal de engasgo], there were not also women and sometimes men complaining of vexame and vice-versa ... . The regions where there are most entalados are also the regions with vexame patients; where there are few cases of one condition there are few of the other ... . Seldom does a given individual have both manifestations (Neiva, Penna, 1916, p.140; italics in the original).

Vexame characteristically involves bouts of palpitations, during which patients may lose consciousness. "There are occasionally fatalities during these bouts". It was more common amongst women. One of the most frequent complaints of vexame patients was consti-pation: "There are very few people with this disorder who do not complain of con-stipation" (Neiva, Penna, 1916, p.139).

Their initial hypothesis about the cause of vexame was that it was tobacco poisoning, given there was a "widespread [habit] amongst women in the North-East to smoke and chew tobacco" (Neiva, Penna, 1916, p.139). However, they themselves rejected this hypothesis when they found no cases of vexame in other regions where this same habit was commonplace. So, just as they proceeded with mal de engasgo, they injected blood from people with the condition into guinea pigs, "always with negative results" (p.140).

The mutual occurrence of mal de engasgo and vexame amongst households raised the possibility of their having a single etiology. Even so, Neiva and Penna preferred to consider them two autonomous entities: "Despite their common occurrence, we nonetheless believe that each of these manifestations is a separate affection" (Neiva, Penna, 1916, p.141). Their justification for this opinion was the fact that in certain regions there were cases of mal de engasgo without any family members having vexame: "We ourselves encountered dozens of cases of mal de engasgo on our long journey through Goiás state, but encountered not one case of vexame" (p.141). Without drawing any conclusions, they nonetheless admitted that this could be a "nervous affection of unknown etiology" (p.140). For illustrative purposes, they recount six clinical observations of patients with vexame, five of whom were women and one a man. Two of the patients said that they had a brother and a father with "entalação" and a third said that their father was also "entalado" (p.141-142).

Impacts of the Report and discussion of the causes of mal de engasgo

The Report had significant repercussions beyond raising the nation's awareness of the conditions in the country's hinterland regions. As far as mal de engasgo was concerned, which is the focus of this paper, it served to encourage physicians in Central Brazil to undertake research and observations into the infirmity, especially the unresolved question of its relationship with Chagas disease.

The possibility that mal de engasgo was associated with Chagas disease was never entirely ruled out after Carlos Chagas initially raised the subject in 1916, but it went through a hibernation period while other putative causes were discussed, including malaria, viruses, toxins, congenital malformation, malnutrition and, finally, chronic vitamin B1 deficiency (beriberi). This last theory, put forward by Etzel in 1935 (Etzel, 1935), was very well received by scholars and continued to have many followers until the 1950s.

In 1935, Jairo Ramos undertook a study of the cardiological aspects of 31 megaesophagus patients, finding electrocardiographic alterations in 24 (77%) of them, which he believed could have been caused by damage to the intracardiac nerve plexus, much like the lesions of Auerbach's and Meissner's plexus described in megaesophagus and megacolon by Amorim, Correia Neto and Etzel (Amorim, Correia Neto, 1932; Etzel, 1934; Correia Neto, Etzel, 1934). Ramos alludes to Etzel's work on vitamin B1 deficiency, while it would appear that Chagas disease was not even considered as a potential cause of the electrocardiographic alterations he described, given that he does not mention this possibility, nor did he do the Machado-Guerreiro test on the patients he examined (Ramos, 1935).

In 1940, Ramos and Oria carried out an anatomopathological study which showed the existence of damage to the intrinsic innervation of the heart in five out of the seven cases of megaesophagus examined. After discussing their findings, they conclude that the damage to the intracardiac nerve plexus, which was behind the altered electrocardiographs, was primary and arose from an as yet unknown cause, which affected the nerve plexus between the walls of the esophagus, stomach and colon (Ramos, Oria, 1940).

Professor Paulo de Almeida Toledo (1975) tells us: "around this time, 1939, the first works on Chagas disease in São Paulo were being produced, based on observations made in the inland parts of the state ... . Until then, the clinical aspects of the Trypanosomosis were almost entirely unknown by our medical circle and many cases of myocarditis of unknown origin observed in hospital wards were referred to as beriberi in the absence of any better explanation."

From the 1950s onwards, the theory of vitamin B1 deficiency was gradually discredited and finally abandoned as clinical observations of patients with the disorder failed to back it up. The contributions from physicians working in rural parts of the country were particularly important in this process, especially those in Triângulo Mineiro [in Minas Gerais state] and Central Brazil. Not only did they not encounter any typical symptoms of beriberi in patients with megaesophagus and megacolon, but their clinical, epidemiological and serological data left no doubt as to the link between endemic megaesophagus and megacolon and Chagas disease.

The Medical Congresses of Triângulo Mineiro and Central Brazil held from 1947 onwards provided a forum for discussion between local clinicians, who held that the root cause of the 'megas' was Chagas disease, and guest professors from the big cities, who held opposing views or at least considered the whole question open for discussion. The importance of this topic at these conferences can be appreciated from an article by Porto and Porto (1970) entitled "História do megaesôfago nos congressos médicos do Brasil Central" [History of megaesophagus at the medical conferences in Central Brazil]. In it, the authors go through the most significant contributions chronologically, ending with the following passage: "At these thirteen medical conferences of Triângulo Mineiro and Central Brazil held between 1947 and 1965, megaesophagus was a constant presence. This constant presence had the appearance of defiance. It seemed like a protest against the professors ... who were silent for a long time about a widespread condition in Brazil known popularly even by folk and faith healers".

The gradual rejection of the vitamin B1 deficiency theory reignited interest in clinical studies into and observations of the relationship between mal de engasgo and Chagas disease. Several authors held that Chagas disease was at least a factor upon which the affection's appearance depended, if not as its single cause (Almeida Prado, 1945; Maciel, 1948; Pellegrino, Borrotchin, 1948; Bulcão, 1950; Pitão, 1951; Faggin, 1952; Borba et al., 1954). Others argued that the etiological agents were the joint appearance of the trypanosomiasis and vitamin B1 deficiency (Martins, Versiani, Tupinambá, 1945; José, 1959; Martins, 1953).

As Prata (1960) notes, in the research into this relationship, apart from reports on isolated cases, two major lines of investigation prevailed: the use of radiological exams to diagnose megaesophagus in patients with Chagas disease, and the use of the complement fixation test described by Guerreiro and Machado (1913) to diagnose Chagas disease in patients with megaesophagus. The earliest example of the former investigation model dates back to 1922, in which Chagas and Vilela (Chagas, Villela, 1922) found four cases of megaesophagus in 63 patients with Chagas disease. This was followed by several publications by other authors who sought to assess the incidence of megaesophagus in chronic Chagas patients with or without heart disease. The data supplied by these publications until 1960 summed 234 Chagas patients, of whom thirty (12.8%) had megaesophagus (Prata, 1960).

The second approach was found to be more helpful, as it sought to diagnose Chagas disease in patients with megaesophagus or megacolon by making a parasitological exam, using xenodiagnosis, or an immunological exam, using Guerreiro and Machado's complement fixation test.

As it is not very sensitive, xenodiagnosis is not suitable for use in the chronic phase of Chagas disease. The only work we know of that used xenodiagnosis for this purpose was by Martins, Versiani and Tupinambá in Belo Horizonte in 1945. The authors compared the results obtained from four groups of patients: 63 cases of myocarditis, 48 of megaesophagus, 28 of goiter and 17 with other conditions. They obtained 56 positive xenodiagnoses: 23 (36.5%) from the myocarditis group, 22 (45.89%) from the megaesophagus group, five (17.85%) from the goiter group, and one (5.88%) from the other conditions group.¹⁵

The first researcher to use the Guerreiro-Machado test was Vilela in Belo Horizonte in 1930. Of the 186 people he examined, 53 (28.5%) had a positive reaction, while eight out of the 13 patients with megaesophagus were positive (61.5%). Vilela (1930) wondered whether these results were mere coincidence, concluding that: "there must be a dysphagia syndrome that is caused by Trypanosomiasis." Also in Belo Horizonte, Alvarenga (1934) used the Guerreiro-Machado reaction on 16 cases of megaesophagus, obtaining positive results in eight of them (50%). The low percentages encountered by these authors were because of the low sensitivity of the reaction, which was done with an antigen prepared using the organs of animals infected with T. cruzi (heart, spleen).

In the 1940s, an antigen made from cultures of T. cruzi started to be used that made the reaction more sensitive and specific. In 1943, Davis described a new antigen extraction technique based on T. cruzi cultures, which was modified by Muniz and Freitas in 1944 (Davis, 1943; Muniz, Freitas, 1944). The antigen obtained by this technique, which became known as the Davis antigen, led to more reliable results from the complement fixation test by increasing its sensitivity and specificity, eliminating to a large extent the false-negative and false-positive results. From then on, several authors obtained highly significant rates of positive results from Guerreiro and Machado's complement fixation test on patients with megaesophagus and megacolon (Prata, 1960). The most compelling data were provided by Laranja, Dias and Nóbrega (1948) at the 1^st Medical Congress held in Rio de Janeiro in 1946 and published as part of a longer study into Chagas disease, and by Pedreira de Freitas (1947). The former authors obtained 97% positive results from 18 cases of megaesophagus and megacolon, while Pedreira de Freitas obtained positive results in 92.5% of eighty cases.

No statistical test would allow that these results were mere coincidence. Even so, the physicians from the big cities were reluctant to accept the possibility that Chagas disease was the cause of endemic megaesophagus and megacolon. It was argued that there was an overlap of both endemics in the same geographical region, much as had been the case with Chagas disease and goiter, and that the antigen was not specific enough, this in disregard of the improvements made to the reaction by Davis. Another group rejected the idea that megaesophagus was a syndrome, taking it for a disease, the same as occurred in regions where there was no Chagas disease, which was known as cardiospasm, esophageal achalasia or just achalasia.

A typical example of this confusion, aided by ignorance of the facts, can be found in an article by a professor of anatomical pathology, Walter Maffei (1955), entitled "Anatomia patológica e patologia dos megas" [Anatomical pathology and pathology of the megas], in which the author suggests that all the megas are congenital. After analyzing the macroscopic and microscopic alterations encountered in megaesophagus and megacolon, he concludes: "this is not an acquired process that is secondary to some external cause, but a congenital process, i.e. embryo malformation" (italics in the original). And later: "Though the localized process is most evident in the anatomoclinical condition, other parts of the organism are also affected, by which the organism does not function as a whole. Thus, for instance, it is common for there to be some disturbance of the cardiovascular apparatus, a variable in clinical manifestations".

Our studies of the topic

When we started working as gastroenterologists in Goiânia in 1954, we came across a large number of patients complaining of dysphagia who sought medical treatment in the city's hospitals and clinics, especially at Santa Casa de Misericórdia, where the poorest patients from rural areas tended to go. In almost all the cases, the x-ray of the esophagus showed that they had megaesophagus. The patients were treated by pneumatic dilation of the cardiac orifice or by surgery, depending on how far developed the condition was.

We were also surprised by the large number of cases, mostly from Minas Gerais and Goiás, which were reported by physicians from Triângulo Mineiro, such as Sabino Vieira Freitas Jr. (1950) and Virgílio Mineiro (1958), who worked in Uberaba and Uberlândia. Since the 1930s, Uberaba had become a leading medical center, which is why patients with mal de engasgo from Goiás tended to go there for treatment.

In the huge array of cases that Virgilio Mineiro (1958) presented at the 2^nd Medical Congress of Triângulo Mineiro in Uberlândia in 1948, of the 1,514 cases he treated, 939 (62%) were from Goiás. Clearly, we were facing a serious endemic in the state of Goiás and the Triângulo Mineiro area of Minas Gerais.

Goiás, which Neiva and Penna regarded to be the state with the highest prevalence of both Chagas disease and mal de engasgo, was clearly a perfect place to study the link between the two endemics. After the state capital was transferred from Vila Boa to Goiânia in 1937, there was a period of accelerated development in the 1940s, which had a direct impact on the medical profession. From 1951 onwards, medicine in the state developed at a fast pace, especially after the founding of Associação Médica de Goiás [Goiás Medical Association], which played a major role in this process.

From its inception, the association considered the possibility of establishing a medical faculty in Goiânia, which came to pass in 1960. By this time, there was already a faculty of medicine in Ribeirão Preto, part of São Paulo University (founded in 1952) and the Faculdade de Medicina do Triângulo Mineiro in Uberaba, established in 1954, signaling the start of a period of consolidation of medical knowledge in inland parts of the country, counterbalancing the concentration of academic institutions in the large coastal cities.

The association served as a focal point for the aspirations of the physicians from Goiás and became the driving force for their technical and scientific development, encouraging them to take further study and make clinical observations of the diseases and endemics that were common to the state. As such, it produced or was an official participant at the Triângulo Mineiro and Central Brazil congresses; it held medical seminars in towns around the state; and in 1955, it created a scientific medical journal, Revista Goiana de Medicina, which gained national and international readership for its editorial line, which was entirely devoted to regional pathologies, especially Chagas disease, at the time considered the main endemic in the state.

Knowing of the controversy that already abounded concerning the etiology of mal de engasgo and the evidence that suggested it derived from Chagas disease, we decided to delve deep into all the literature on the disease. Among the many publications on the topic, we were particularly struck by Neiva and Penna's work for the epidemiological data it contains and for its special reference to the state of Goiás, which they traveled through from north to south. This epidemiological data indicated that the areas infested by triatomines were the same areas where mal de engasgo and vexame do coração occurred, the latter of which was by then identified with bouts of paroxystic tachycardia, one of the symptoms of chronic Chagas heart disease. Meanwhile, the concomitance of mal de engasgo with vexame in the same households suggested they had the same etiology, as the authors themselves acknowledged, which only went to reinforce the idea that mal de engasgo was also related to Chagas disease.

Neiva and Penna had looked for correlations between endemic goiter and the presence of triatomines in the endemic areas, and we decided to take the same approach with mal de engasgo. Using the data from the entomological investigation performed by the Department of Rural Endemics in Goiás, then headed by Átila Gomes de Carvalho (Carvalho, Verano, 1956), we confirmed that there was an overlap of the area where mal de engasgo occurred most frequently with the area where there was not only a greater infestation but also a greater rate of natural infection of triatomines.

Alongside cardiologist Anis Rassi, who was also keen to study Chagas disease in Goiânia, we developed a protocol in January 1955 in which two study methods would be used to identify the relationship between chronic Chagas heart disease and megaesophagus: the esophagus and colon of patients with Chagas heart disease would be x-rayed, while patients with megaesophagus would have their hearts examined, using clinical exams, radiography of the thorax and electrocardiogram.

After 18 months' observations, we had examined 170 patients with megaesophagus and were convinced that the disorder that had so long been known as mal de engasgo was yet another of the manifestations of Chagas disease. This belief was reinforced when we learnt of the initial research by Koeberle and Nador (1955), working at Faculdade de Medicina de Ribeirão Preto, into the denervation of the enteric nervous system in Chagas disease, offering anatomopathological support for the clinical observations.

We presented the data from our observations at the 8th Medical Congress of Triângulo Mineiro and Central Brazil, held in Uberaba from September 3rd to 8th, 1956, and published them in the same year in Revista Goiana de Medicina. It was the first paper in which the title used "Megaesôfago por doença de Chagas" [Megaesophagus from Chagas disease], rather than the usual "megaesophagus and Chagas disease" adopted by authors who had previously addressed the issue (Rezende, 1956). The analysis of the electrocardiograms of fifty patients, 46 of whom had a positive serum reaction, showed that 22 had normal traits and 28 had abnormalities. Of the 22 patients with normal electrocardiograms, 15 were under thirty years of age, while all but four of the 28 patients with abnormal tests were over thirty. This seemed to indicate that the esophagus condition, when present, was manifested earlier than the heart disease, which was later confirmed by a larger case study (Rezende, Rassi, 1958).

Another piece of evidence gleaned from our observations was that many megaesophagus patients with a long history of dysphagia had no heart conditions, making it one of the clinical forms of Chagas disease, alongside the indeterminate and cardiac forms.

At the 7^th Medical Congress of Triângulo Mineiro and Central Brazil held in Uberlândia from July 5th to 10th, 1955, in our comments on a presentation given by Calil Porto (1955) about the likely existence of a Chagas gastropathy, we spoke up in favor of a separate digestive form of Chagas disease, to characterize not just the morphological or functional alteration of a given organ, but also the disturbance of the digestive tract as a whole. Both Calil Porto and Isaac Barreto Ribeiro, both researchers of Chagas disease, voiced their agreement.

The idea matured and in the study already mentioned, "Megaesôfago por doença de Chagas", we sought to justify the need to have the digestive form recognized as a separate clinical form of Chagas disease, which would include

all the lesions of the digestive tube and the resulting alterations to its motility: megaesophagus, Chagas gastropathy, megaduodenum, megajejunum, megaileum, megacolon, and any others to be subsequently described. We base ourselves on the fact that, clinically speaking, we have often found patients with Chagas disease with major, exclusive digestive conditions, without, however, any clinical sign or electrocardiograms to show any damage to the heart. It is these cases, regarded as potential cardiac forms and thus far classed as "indeterminate", which, in our view, should only be reserved for completely symptomless cases (Rezende, 1956).

In 1959 we published an article expanding on the concept of the digestive form to take account not just of the motor dysfunctions, but the changes to the secretion and absorption of the digestive apparatus that were already known or should come to be described in the future (Rezende, 1959). An abstract of this article was published in the Year book of medicine de 1960/1961, followed by an extended commentary by the editor on the Brazilian experience of 'achalasia', in which our work in Goiânia was mentioned: "Dr. Rezende's accomplishments deserve special mention. In a small city in what the dwellers on the Brazilian coast refer as the hinterland, he has purely through his own efforts carried out an extensive and thorough analysis of over 400 cases of the esophageal disorder he calls megaesophagus, although as he points out many of the cases do not have any esophageal dilatation" (The year book..., 1960-1961).

The large number of patients we treated at Santa Casa de Misericórdia de Goiânia and at our private clinic during the first five years (1954-1959) provided us with a set of 506 cases, which we communicated at the International Congress on Chagas Disease held in Rio de Janeiro from July 5th to 11th, 1959. At the time, there was still some doubt as to whether endemic megaesophagus was caused by Chagas disease. A look through the pages of the proceedings, which were published between 1960 and 1964, shows that eleven of the total of 102 papers were on the topic, as summarized below in alphabetical order of the authors' first names:

- Almeida Prado, from São Paulo, São Paulo state, discusses at length the history of Chagas disease and addresses different aspects of its pathology. He considers there to be sufficient proof to accept that mal de engasgo is etiologically related to Chagas disease (Almeida Prado, 1963).

- Aluizio Prata, from Salvador, Bahia, addresses the topic from several viewpoints, with a comprehensive review of publications pertaining to the subject. Even while regarding the pathogenesis of megaesophagus a moot point, he stresses that neither "the unknown factors nor the disagreements about the pathogenesis invalidate the positive data that exist, which point to Chagas disease as the cause of megaesophagus" (Prata, 1963).

- Fritz Koeberle, from Ribeirão Preto, São Paulo, sets out the results of research he carried out at the Department of Pathology, Faculdade de Medicina de Ribeirão Preto. He reports on the findings of autopsies of 250 cases of Chagas disease, among which he found 101 cases of megaesophagus, some with and some without megacolon, of which 31 had no evidence of heart disease. In a few cases, the megaesophagus was accompanied by distention of other segments of the digestive apparatus. In tests on lab animals, he showed that during the acute phase of infection by T. cruzi, there was parasitaemia of the smooth muscle fibers of the esophagus and colon walls, a specific intramural inflammatory process, and "degenerative lesions of the neurons of the myenteric plexus". He highlights the importance of Auerbach's plexus in coordinating the motility of the digestive tract, and explains the distention of the organ as a phenomenon that was secondary to the motor alterations arising from the intrinsic denervation. He accepts the possibility that the lesion of the neurons could be caused by a neurotoxin released by T. cruzi (Koeberle, 1961).

- G. Koeberle, D. Penha and F. Koeberle, from Ribeirão Preto, São Paulo, presented a quantitative study of the neurons from Auerbach's plexus in ten cases of megaesophagus, documenting denervation resulting from the inflammatory process caused by T. cruzi (Koeberle, Penha, Koeberle, 1961).

- Jairo Ramos, from São Paulo, São Paulo state, makes a retrospective analysis of his studies into the heart conditions encountered in patients with megaesophagus, then, after discussing the existing literature, presents "a series of open questions about Chagas disease and suggest[s] some guidelines for future research to resolve the question of whether megaesophagus and myocarditis are dependent on the same etiology" (Ramos, 1963).

- João Vale Maurício, from Montes Claros, Minas Gerais, recounts his experience of Chagas disease over 15 years' clinical practice in his home town. He states that he found alterations of the esophagus in 30% of the forty patients with Chagas disease associated with advanced heart disease. He concludes: "We are of the opinion that megaesophagus - aperistalsis of A. Brasil - and megacolon are manifestations of schizotrypanosis. We acknowledge that in certain regions the esophageal disorders are more frequent than the myocardial [disorders], the reason for which we do not know; they may be strains of trypanosomes with a proclivity for those organs; maybe regional conditions are favorable for them" (Maurício, 1962).

- Joffre Rezende, from Goiânia, Goiás, presents his clinical experience based on 506 cases of megaesophagus he investigated in his home town over a period of five years. The Guerreiro-Machado complement fixation test was conducted on 332 patients, with 89.1% of the results showing positive. Cardiac tests (clinical, radiology and electrocardiography) were done on 282 of the patients, of whom 153 (54.3%) showed no sign of heart disease. In the author's view, this fact justified "adding another clinical form to Chagas disease, to be called the digestive form", as he proposed in 1956 (Rezende, 1963a).

- Jorge Guimarães and Aluisio Miranda, from Rio de Janeiro, Distrito Federal, report on an autopsy of a monkey from the labs at Instituto Oswaldo Cruz, which had been inoculated with T. cruzi ten years previously and had megaesophagus. While acknowledging that the megaesophagus could have been caused by trypanosomiasis, they attribute the fact to the weakening of the muscle wall of the esophagus, rather than to the denervation of the myenteric plexus, which was a pathogenesis accepted by "certain medical circles", but which the authors considered "baseless speculation" (Guimarães, Miranda, 1961).

- Magarino Torres, from Rio de Janeiro, Distrito Federal, wrote a lengthy, detailed literature review supported by his own studies. He sets out the foundations of the anatomic pathology of Chagas disease in its different forms, paying attention to heart disease. He casts into doubt the "degenerative inflammatory lesions of the fibers and ganglion cells in Meissner's and Auerbach's plexus of the esophageal-gastrointestinal tube", and concludes: "If we accept the digestive form of Chagas disease, where, we recall, the lesions of the ganglion cells in Auerbach's plexus are not and, theoretically speaking, could not be the anatomical substratum, one could admit that inflammatory and vascular lesions, with a humoral mechanism akin to that found in the heart, may also exist in the esophageal-gastrointestinal tube" (Torres, 1964, p.1630).

- Paulo Borba, Jaime Scherb and Hoel Sette, from Recife, Pernambuco, set forth their experience of the clinical and radiological diagnosis of chagasic esophagopathy, which could be symptomless. They accept the digestive form and propose that the clinical forms of Chagas disease be classified as cardiac form, digestive form and mixed form (Borba, Scherb, Sette, 1960).

- Renato Godoy and Nagib Haddad, from Ribeirão Preto, São Paulo, present a comparative study of the esophagus, measuring the bolus transport time in 41 patients with symptomless Chagas disease and the same time for 37 healthy individuals. Seven of the Chagas disease patients had delayed bolus transport time (Godoy, Haddad, 1960).

The spoken comments by many of the participants at the sessions, which were unfortunately not included in the proceedings, were generally against accepting categorically that Chagas disease was the cause of endemic megaesophagus and megacolon. There were fears that the experience of the concomitance of endemic goiter with Chagas disease would repeat itself, and the argument of the geographical overlap of the two endemics was again voiced. Those who agreed that megaesophagus could be caused by Chagas disease played down the importance of the enteric nervous system and strongly opposed the pathogenesis defended by Koeberle, drawing attention to other researchers who had failed to prove the existence of a neurotoxin in T. cruzi. It was shown later that the mechanism that destroys the neuron is of an immunological nature, and the neurotoxin theory was eventually thrown out, even by Koeberle himself (Santos, Oliveira, Koeberle, 1976; Santos, Hudson, 1981; Teixeira et al., 1980).

As we proceeded with the protocol established with Dr. Anis Rassi, we managed to accumulate 820 cases of megaesophagus by 1962. In the same year, the 2nd World Congress on Gastroenterology was held in Munich, Germany, between May 13th and 19th, at which there was also an International Symposium on Esophageal Achalasia. We were invited to take part in this symposium alongside three other Brazilians: Geraldo Siffert de Paula e Silva, Fritz Koeberle (who had gained Brazilian citizenship) and Luiz Heraldo Câmara Lopes. The participants were noticeably impressed by our presentation of our cases (Rezende, 1963b), after which Koeberle talked about the pathology of chagasic megaesophagus (Koeberle, 1963). His theory that the dilatation was a consequence of motor alterations arising from primary intrinsic denervation was very well received, and Brazil's experience dealing with chagasic megaesophagus was noted as a model for future investigations into idiopathic achalasia. The symposium's chairman, Prof. Franz Ingelfinger (1963), acknowledged as the leading authority on the physiology and physiopathology of the esophagus, made the following comment:

It thus seems to me that we should accept the Brazilian form of achalasia as a model pointing out to us a possible way in which our own cases may develop. Perhaps our cases too are the late results of an infection or infestation which damages Auerbach's plexus by a toxic or possibly autoimmune mechanism and then subsides, leaving no traces at the time when the late effects of the neurological damage finally make themselves manifest in the form of achalasia. The Brazilians have given us a major lead.

In Brazil, the recognition that Chagas disease was the etiology of endemic megaesophagus and megacolon came slowly and gradually in the big cities. The counterarguments still expressed were that; (1) mal de engasgo (megaesophagus) is the same as cardiospasm or esophageal achalasia, which are found in regions where there is no Chagas disease; (2) few patients with Chagas disease have dysphagia or megaesophagus; (3) mal de engasgo does not always occur where Chagas disease is endemic, such as in Venezuela and Central America; (4) the association of mal de engasgo with Chagas disease is due to the overlapping of two endemics in the same geographical area, which would explain the high rate of positive serum tests among mal de engasgo patients; (5) no parasites were found in the wall of the esophagus, surgical specimens or autopsies; (6) the inflammatory alterations and the neuronal degeneration of the esophagus wall could be secondary to the dilatation and not its cause.

These arguments were ruled out one by one. The fallacy of the first argument lies in considering both affections as a single disease and not as a syndrome. The second argument is baseless, as the same thing occurs with other diseases. As Prata showed, not all patients with syphilis develop aortic aneurism. The non-existence of megaesophagus in areas where Chagas disease is endemic could be attributed to the different strains of T. cruzi, as demonstrated at a later date (Andrade, Andrade, 1968). The overlapping of both endemics, as is the case of endemic goiter and Chagas disease, could never explain the difference in the indices of positive serum test results between the cases of megaesophagus and healthy people living in the endemic areas. The difficulty of finding parasites in the wall of the esophagus is due to the scarce parasitaemia during the chronic phase of Chagas disease and depends on an exhaustive search in tissue samples. The doubt as to the primary or secondary nature of the inflammatory process and of the neuronal damage of the esophagus wall remained much longer, also in relation to idiopathic achalasia. In the case of chagasic megaesophagus, as Koeberle proved, the inflammatory process starts on the muscle wall and not in the submucous layer, coming into the region of Auerbach's plexus between the longitudinal and circular layers.

One of the last times Chagas disease was refuted as the true cause of endemic megaesophagus and megacolon was at the 2nd International Congress on Proctology, held in São Paulo from September 11th to 17th, 1960. There was a round table discussion that touched on different aspects of megacolon, including its connection with Chagas disease (Rezende, 1960; Koeberle, 1960). At the end of the session, a renowned professor of surgery gave an impromptu talk, during which he set out the case for the viral etiology of the condition.

The overseas publication of papers on the topic would appear to have helped the definitive acceptance of Chagas disease as the true cause of endemic megaesophagus and megacolon. Research carried out in Brazil by other scholars of Chagas disease was therefore decisive in proving the existence of the primary denervation of the nervous plexus in the digestive tract resulting from infection by T. cruzi, thus confirming Koeberle's theory (Alvarenga,1960; Okumura, Correia Neto, 1961; Tafuri, Raso, 1962; Andrade, Andrade, 1966; Tafuri, Brener, 1966, 1967; Alencar, Kastner, Cerqueira, 1968).

In their work, Alencar, Kastner and Cerqueira (1968) make reference to Koeberle's study thus: "This author first drew attention to the disturbance of the autonomous nervous system of the digestive apparatus in the general morbid condition of this parasitic disease. His monumental study showed that there was a reduction in the number of neurons in the ganglions that make up this system in chronic cases of Chagas disease". The importance of this recognition of Koeberle's contribution lies in the fact that it came from Alexandre Alencar, then the head of the Anatomic Pathology Section of the Pathology Department at Instituto Oswaldo Cruz.

As for the name, "digestive form", the first author to use it was Geraldo Siffert de Paula e Silva (1958), who nonetheless preferred the plural: digestive forms. Other authors later also opted for the plural (Silva, 1997; Dias et al., 2002).

The many studies carried out at Faculdade de Medicina de Ribeirão Preto into the physiopathology of the digestive apparatus in Chagas disease patients greatly contributed to consolidating the digestive form as a separate clinical form of Chagas disease.

Concluding remarks

The long journey that led to the confirmation of Carlos Chagas' suspicions took fifty years. In all the investigations carried out during this period, the work by Neiva and Penna was always cited as one of the main sources of information on this hinterland endemic known by the descriptive name of mal de engasgo, or choking disease.

Reading their report ninety years after its publication, one can see that it contains observations and information that helped some physicians establish, as of the 1950s, a connection between Chagas disease, mal de engasgo (megaesophagus), vexame (heart disease) and caseira (megacolon), as well as the existence of a cardiac form and digestive form of the trypanosomiasis.

With the benefit of hindsight, it would be easy to criticize Neiva and Penna for their circumspection about the nature of mal de engasgo and vexame. Had they had access to the diagnostic resources developed and perfected as of the 1940s, especially the serum reactions for Chagas disease, the electrocardiograms and contrast radiology exams of the esophagus and the colon, they would certainly have drawn other conclusions. At the time, working without any assistance in Brazil's hinterland, all they could do was to draw conclusions from what they saw and heard. Even so, the meticulous, faithful observations they leave us cast light on the studies by scientists from Brazil's coastal cities.

We finish by repeating that their "scientific journey" was an important milestone in the history of Brazilian science.

ACKNOWLEDGEMENTS

We thank doctor Simone Petraglia Kropf, of Casa de Oswaldo Cruz/Fundação Oswaldo Cruz, for her supervision during the different stages of the development of this work, and for her encouragement to publish it.

NOTES

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1

Neiva and Penna's report has been the subject of many and varied historiographical analyses and studies. The most important published works on it are by Lima (2003, 1999, 1998) and Thielen, Alves, Benchimol (1991).

2

A free translation is provided here of the quoted titles and others that appear in different languages.

3

The name of 'cardiospasm' was given because it was believed that there was a permanent contraction of the lower esophageal sphincter which blocked the passage of food; 'megaesophagus' was because the esophagus dilates as the disease develops and becoming quite enlarged; and 'esophageal achalasia' was because, as Hertz demonstrated, there is no spasm of the cardiac orifice; rather, the sphincter does not actually open as a reflex during deglutition to allow the food down. "Achalasia" (from the Greek:

a, absence +

chalasia, relaxation) equally applies to other sphincter dysfunctions. Aristóteles Brasil (1955), a pioneering scholar of esophageal motility, showed through manometry that aside from the relaxation of the sphincter, the body of the esophagus also loses its motor coordination, with an absence of peristalsis. As a result, he proposed a new name for the affection - esophageal aperistalsis - which was also used in Brazil, albeit for a short while. In medical terminology, therefore, the following terms are all synonymous: spasmodic dysphagia, cardiopasm, megaesophagus, esophageal achalasia, esophageal aperistalsis and

mal de engasgo. The term chagasic megaesophagus expresses not just the nature of the condition, but its etiology. As there are no known etiologies for it aside from the trypanosomiasis, it is normal to call it idiopathic achalasia.

4

As of the 1930s, following the lead of the São Paulo school headed by Correia Neto, the most widely accepted name became megaesophagus (Correia Neto, 1935).

5

The society was established on February 24, 1895, at a meeting in the office of Sergio Florentino de Paiva Meira in São Paulo. Present at this preparatory meeting were several exponents of São Paulo's medical profession, including Theodoro Reichert, Luiz Pereira Barreto, Ignácio Marcondes de Rezende, Pedro de Rezende, Amarante Cruz, Cândido Espinheira, Erasmo do Amaral, Luiz de Paula, Marcos de Oliveira Arruda and Evaristo da Veiga" (Sociedade..., undated.).

6

Interestingly, when Chagas (1916a) suggested that the etiology of

mal de engasgo could be the trypanosome, he referred to it as a syndrome rather than a disease.

7

Carlos José Arruda Botelho, one of the founders of Sociedade de Medicina e Cirurgia, graduated in medicine in Paris in 1878, accrediting his degree at Faculdade de Medicina do Rio de Janeiro in 1883. He worked as a physician at Santa Casa de Misericórdia de São Paulo, where he introduced asepsis to surgical procedures. He strove hard for better medical education in São Paulo, and was a member of the first committee, set up in 1891, to establish a faculty of medicine in the city, which actually only came to pass in 1912.

8

Luiz Pereira Barreto studied medicine in Brussels and had his degree accredited by Faculdade de Medicina do Rio de Janeiro in 1865. He was elected the first chairman of Sociedade de Medicina e Cirurgia by a show of hands. He was a very cultured man whose whole life was marked by great entrepreneurialism. Aside from medicine, he was also interested in philosophy, education, the press and sociology. He was one of the first coffee and wine producers in Brazil. His experience with

mal de engasgo was first acquired in his early years as a medical practitioner, when he worked in rural São Paulo state.

9

In this second letter to Sergio Meira Filho, which must have been written between 1915 and 1917, since the author had read the report by Neiva and Penna, Botelho proposes that

mal de engasgo be given the name of tropical dysphagia, which had already been used by Ulysses Paranhos in 1913, without taking into account Neiva and Penna's criticism of the name. This begs the question: could he have used "tropical dysphagia" previously, without having left any documental evidence of this fact, or could he have been unfamiliar with Paranhos's work? Would he not have read the whole report by Neiva and Penna, or might he simply have missed the criticism it contained?

10

Ulysses Paranhos was the author of a book published in 1922 entitled

Elementos de terapêutica clínica [Elements of clinical therapy]. He was among those who conceived and founded Instituto Pasteur de São Paulo [Pasteur Institute of São Paulo]. His interest in

mal de engasgo was awakened when he learnt of its endemic nature in Brazil's rural hinterland. In the Portuguese version of the article, he adds at the end: "As we are currently interested in etiological research into tropical dysphagia, we request that our distinguished colleagues, should they observe some fatal case of the ailment, send us all, preferrably, or part of the esophagus...". There is no record of any other publication by Paranhos on this topic.

11

The article was published in French in January 1913 (Paranhos, 1913a), and in Portuguese in November of the same year (Paranhos, 1913b).

12

In a study by Forattini (1980) which went on to become a classic, the origin of the abovementioned species is referred to thus: "The heart of endemic

Triatoma sordida,

Triatoma brasilienses and

Triatoma pseudomaculata seems to be in the open spaces of the

cerrados and

caatingas, while it would appear that

Pantrongylus megistus originates from the tropical Atlantic forests. As for

Triatoma infestans, it is endemic to Bolivia, from which it has spread out through the action of man".

Triatoma infestans gradually spread through Brazil, first to São Paulo and Minas Gerais and then to Goiás, Bahia and the rest of the North-East. In 1930, just a small area of the south-east of Goiás had been infested with

Triatoma infestans, while in 1956, according to Sherlock & Serafim, Lucena had ruled out the occurrence of these species in Bahia, stating that they only occurred as far as the 16º south parallel in Minas Gerais (Sherlock, Serafim, 1972). It is fair to conclude, then, that in 1912, the year in which the expedition took place,

Triatoma infestans had not yet reached the state of Goiás.

13

It so happens that only when the esophagus was dilated (ectasic forms), with many symptoms, was the disease diagnosed, because in these cases the patients were forced to seek out medical care. Those patients without dilation (anectasic form), normally oligosymptomatic, did not usually seek treatment and so were not included in the statistics. Today, we know that the development of chagasic esophagopathy is more serious in men than it is in women. If we include the anecstatic form, which is more common amongst women, the predominance of males is not statistically significant. In 1,117 megaesophagus patients registered at Hospital das Clínicas at the Faculty of Medicine, Federal University of Goiás, Rezende and Luquetti (1994) found 56.2% were male and 43.8% were female. When the cases were analyzed separately in the four groups of radiological classification used at the hospital (Rezende, Lauar, Oliveira, 1960), they found that there were more women (62.1%) in group I, which corresponded to the anecstatic form, while in the three other groups (ecstatic forms), there were 61.2% men.

14

We have observed several similar cases. One of our patients always brought along a bottle of water in the fear that there would not be any to hand if they were taken by pain.

15

Until then, "megaesophagus" was the name given to

mal de engasgo, which was often accompanied by megacolon, as both conditions were often found in the same patient. The prefix 'mega' is used to characterize the distention and enlargement of an organ. Both megaesophagus and megacolon are manifestations of the same pathological process, as shown by Correia Neto and Etzel (1934). As they are endemic, we usually refer to endemic megaesophagus and megacolon as a single condition. Likewise, we could say megaduodenum, megajejunum, megaileum, megagallbladder, etc.

Publication Dates

• Publication in this collection
  16 July 2009
• Date of issue
  July 2009

History

• Received
  Jan 2008
• Accepted
  Oct 2008