Human African trypanosomiasis of the CNS: current issues and challenges

Abstract

Human African trypanosomiasis (HAT), also known as sleeping sickness, is a major cause of mortality and morbidity in sub-Saharan Africa. Current therapy with melarsoprol for CNS HAT has unacceptable side-effects with an overall mortality of 5%. This review discusses the issues of diagnosis and staging of CNS disease, its neuropathogenesis, and the possibility of new therapies for treating late-stage disease.

Figure 1

Diagrammatic representation of the distribution of the two types of human African trypanosomiasis in Africa. Figure modified with permission from Butterworth-Heinemann (5).

Figure 2

Diagrammatic representation of the life cycle of Trypanosoma brucei in the human and the tsetse fly. Image credit: Alexander J. da Silva and Melanie Moser, Centers for Disease Control Public Health Image Library.

Figure 3

Colored scanning electron micrograph of Trypanosoma brucei in human blood. Image credit: Science Photo Library.

Figure 4

MRI scan (proton density) of a 13-year-old patient with CNS trypanosomiasis 3 years after successful completion of multiple treatment regimens for numerous relapses of the disease. Ventricular enlargement (especially of the frontal horns) is seen as well as diffuse white matter changes, which are prominent in the right frontal (see arrow) and periventricular regions. Reproduced with permission from Butterworth-Heinemann (5).

Figure 5

Neuropathology of CNS human African trypanosomiasis. (a) Late-stage disease in a patient who died 3–5 months after first injection of melarsoprol. Many large astrocytes are located in white matter. Stained for glial fibrillary acidic protein by immunoperoxidase. Original magnification, ×400. (b) Morular cells (indicated by arrows) observed in the brain of a patient with CNS trypanosomiasis who had not received melarsoprol. Morular cells are plasma cells filled with immunoglobulin. H&E stain. Original magnification, ×400. (c) PTRE in a patient dying 9 days after receiving melarsoprol. Ischaemic cell changes (indicated by arrows) are seen in neurons in the hippocampus. H&E stain. Original magnification, ×250. (d) PTRE with acute haemorrhagic leukoencephalopathy in a patient 9 days after receiving melarsoprol. There is fibrinoid necrosis in an arteriole (indicated by arrow) and focal haemorrhage in the pons. Martius scarlet blue stain. Original magnification, ×250. Reproduced with permission from Neuropathol. Appl. Neurobiol. (34).

Figure 6

Schematic representation of possible immunopathologic pathways leading to brain dysfunction in late-stage human African trypanosomiasis. Concepts are based on a combination of human and animal model data and ideas, particularly from refs. , , , , and . Cytokines shown in red probably have important roles in neuropathogenesis. The schematic emphasizes the central importance of early astrocyte activation, cytokine responses, and macrophage activation. One should note that there are likely to be multiple factors acting together to produce brain damage and also multiple potential sources of different cytokines. Tltf, trypanosome-derived lymphocyte triggering factor.