Estudo clínico e experimental da neuroparacoccidioidomicose

Abstract

Paracoccidioidomycosis (PCM) is the most important systemic mycosisin Latin America and has great relevance in Brazil, especially in the states of Sao Paulo and Minas Gerais. It is related to social and economic costs derived from the active disease and from the frequent sequelae. PCM can affect several organs and central nervous system (CNS) involvement occurs in approximately 9.9 to 27% of the cases. It is a severe and potentially disabling complication of PCM, which, frequently, leads to death. For these reasons, Neuroparacoccidioidomycosis (NPCM) must be considered in the differential diagnosis of the meningeal and the tumoral/expansive processes of the CNS, in order to establish early treatment and to avoid the development of disabling sequelae. This work is a comprehensive study of NPCM. This is the first NPCM systematic review of the literature. 257 cases were found in 81 published worksfrom 1919 to 2008, mainly after the 1970-1980 decades. Approximately 93% of the patients were men, especially rural workers, with mean age of 43 years. The commonest symptoms were those of motor deficits or intracranial hypertension. The chronic pseudotumoral form predominated. The mean period of evolution was 4.9 months. Lesions were mainly supratentorial, localizing in the frontal and parietal lobes. Diagnosis was determined by biopsy in 57.2% of the cases and neuroimaging methods were used by 64.6% of them. Most cases were associated with the pulmonary form of disease (59.1%). The mean mortality rate was 44.1%, and 50.1% of the survivors developed sequels, especially motor impairment. Epidemiological, clinical and therapeutic characteristics of eight NPCM patients which belonged to a cohort of 213 PCM cases assisted at the Infectious Clinic of the University Hospital, Federal University of Minas Gerais, Belo Horizonte, Brazil, from October 1976 to August 2008, were compared to PCM cases without neurological involvement in order to define singular features that could differentiate NPCM from PCM. The observed NPCM prevalence was 4.0%. One patient presented the sub acute form of PCM and the other seven presented the chronic form of the disease. The pseudotumoral form of NPCM occurred in all patients. 60.0% of the patients who proceeded from the north/northeast region of Minas Gerais state developed NPCM. Theneurological involvement of a mother and her son was observed. NPCMpatients exhibited demographical and clinical profiles similar to what isdescribed in the literature. When NPCM cases were compared to PCM patients, there were differences in relation to origins, higher educational level, presence of neurological symptoms, and positive PCM family history. The differences in relation to patients origins and family history point to the need of further studies to determine the susceptibility factors involved in the neurological compromise. An experimental study was conducted to permit the observation of the physiopathological mechanisms of NPCM. However, there is no registers in theliterature concerning to experimental models of NPCM. Thus, a murine model of NPCM was developed. The model was defined by the intracranial inoculation of 106 Paracoccidioides brasiliensis yeast cells (strain Pb18)/animal. Morbidity was evaluated by the SHIRPA protocol, which revealed behavioral changes in the clinical domains reflex and sensory function, neuropsychiatric state, motor behavior, autonomous function, muscle tone and strength. Intravitalmicroscopy revealed an increased leukocyte rolling and adhesion in the brain microvasculature of infected mice at 4 weeks post infection, but not after 8 weeks. Fragments of the brain were removed to evaluate cerebral levels of NAG and MPO enzymes, cytokines, chemokines and histopathological alterations. NAG and MPO enzymes were elevated in the brain of infected mice at 4 and 8 weeks post infection. There was an increase in the levels of the chemokine MIG/CXCL9 at 4 weeks post infection and of the chemokines MIG/CXCL9, MIP-1/CCL3, MCP-1/CCL2 e RANTES/CCL5 at 8 weeks post infection. Histological analysis showed granulomatous and pseudotumoral lesions similar to the histopathological alterations classically attributed to NPCM, including dissemination to other parts of the CNS. Thus, the establishment of a NPCM experimental model can provide the conditions to study further aspects of the disease which could help to diminish its severe consequences.