The remarkable pioneering contribution of Gaspar Vianna to the study of the neuropathology of Chagas disease

ABSTRACT Gaspar Vianna is considered one of the great names in Medicine and Science in Brazil. Yet, little prominence has been given to his studies in Neuropathology. He was the first to describe, in 1911, the histopathology and pathogenesis of chagasic encephalitis in the acute phase of Chagas disease, as well as the intracellular life cycle of Trypanosoma cruzi. Over 100 years have elapsed and Gaspar Vianna's pioneering study remains an example of a meticulous and still up-to-date description of central nervous system involvement in the acute phase of Chagas disease.

chemotherapy 3 . Gaspar Vianna died on June 15, 1914, at the premature age of 29, as a result of an acute tuberculosis infection acquired while performing an autopsy on an infected patient.

HISTOPATHOLOGY AND PATHOGENESIS OF CHAGASIC ENCEPHALITIS
Following the clinical description, in 1909 7 , of the new human disease caused by Trypanosoma cruzi, Carlos Chagas (1879Chagas ( -1934 invited Gaspar Vianna to write a histopathologic description of this new entity. Working hard and with dedication, Gaspar Vianna studied organ specimens from 10 patients autopsied by Carlos Chagas, one of whom, a three-month-old infant, was the first fatal case in the acute phase of the disease. His findings were published in 1911 1 . Below is a summary of the description by Gaspar Vianna of the chagasic encephalitis observed in the threemonth-old infant. Irregularly distributed inflammatory foci of leukocytic infiltration of variable size were seen in all examined regions of the CNS. The parasite, round-shaped, and containing a nucleus and a kinetoplast (amastigote form), was identified in variable numbers in many of the inflammatory foci, sometimes distending the parasitized cell. Based on the position of the parasitized cell in the nerve tissue, the structure of its nucleus, and its relation to the other components of this tissue, the author concluded that the parasitized cell was a neuroglial cell.
Parasite multiplication occurs by successive binary divisions of the amastigotes, followed by transformation of these into trypomastigotes, still inside the parasitized cell. With rupture of the parasitized cell membrane, the trypomastigotes are released and become capable of invading other cells. It is upon rupture of the parasitized cell membrane that the inflammatory reaction is observed, leading to progressive disappearance of the parasite in these foci. Also found are cells containing a large number of parasites, but with no inflammatory reaction surrounding them, a finding that, according to the author, corresponds to the early phases of CNS involvement in Chagas disease (Figure 2). Over 100 years have elapsed, but very little has been added to Gaspar Vianna's observations 8 . Chagasic encephalitis is characterized by multiple foci of microglia, macrophages, and neutrophils arranged in a nodular pattern ("microglial nodes"). When examined under an electron microscope, the amastigote nests are located within the cellular bodies and astrocyte processes, indicating that these are the main target cells for T. cruzi 9 invasion and proliferation. The perivascular arrangement of the astrocyte processes could facilitate invasion by the parasite.
The pathogenesis of CNS involvement, as described by Gaspar Vianna, was confirmed by subsequent studies. It consists of an inflammatory reaction produced by rupture of the membrane of the parasitized cells. Macrophages from the blood or activated microglia, along with neutrophilic granulocytes, are the cells responsible for phagocytosis and removal of the parasites. Kinetic studies of experimental T. cruzi infection in rats show that the greater number of microglial nodes occurs one week after the finding of an increased number of amastigote nests, indicating that the microglial nodes are a reaction to the rupture of the parasitized cells 9 . The inflammatory nodes tend to disappear as the acute phase ends.
The first case of chagasic encephalitis in a chronic chagasic patient with chronic lymphocytic leukemia (reactivated acute form) 10 was described in 1969. Other cases in immunodeficient individuals were subsequently reported, particularly after the emergence of AIDS in 1981, many of whom presented with the tumoral form of the disease (brain chagoma). This form is characterized by multifocal necrotizing encephalitis, abundant amastigotes within astrocytes, apart from isolated forms dispersed through the cerebral parenchyma, microglial nodules, and exudates of macrophages, lymphocytes and plasma cells and, to a lesser degree, neutrophilic granulocytes within the nerve tissue and perivascular spaces 9 .
These pathological changes can also be explained by the pathogenic mechanism proposed by Gaspar Vianna in 1911. In immunocompetent individuals, a robust cellular and humoral immune response controls parasite replication during the acute phase 11 . However, if for any reason the immune system fails, reactivation of the acute phase may occur: the amastigotes will be able to reproduce, differentiate into bloodstream trypomastigotes that are released upon rupture of the host cell membrane, and extensively invade the neighboring cells, which may result in necrosis of the nerve tissue, producing the brain chagoma.
Gaspar Vianna deserves prominence as a rare example of a scientist who, in a single publication involving the study of a single patient, made such an important contribution to the knowledge of new aspects of a new human disease that had been discovered only two years earlier. Also remarkable is that his description of the intracellular life cycle of T. cruzi, and the histopathology and pathogenesis of CNS involvement in T. cruzi infection remains accurate and up to date.