The ability to stage human infection accurately has become a focus of attention in recent years. The current WHO guidelines suggest that the presence of more than five white blood cells/µL of CSF or the presence of trypanosomes indicates that the infection has entered stage-2 . Nevertheless, WHO recognise that many of the patients presenting with between six and 20 white blood cells/µL are likely to be in an intermediate stage, prior to the onset of stage-2 disease . Precise disease staging is pivotal in determining the correct chemotherapeutic approach for optimal therapy. Treatment of stage-2 infections with suramin or pentamidine will fail to cure the infection resulting in relapse or exacerbation of the neuroinflammatory reaction while unnecessary use of toxic stage-2 drugs, such as melarsoprol, should be avoided due to the high incidence of extremely severe adverse reactions , . The results reported here show that BBB dysfunction and neuroinflammation manifest before the onset of stage-2 infections. In addition, parasite DNA can be detected in the brain tissue early after infection. These findings challenge the prevailing notion that parasites simply cross the BBB to enter the CNS and initiate inflammation during the transition from acute to CNS-stage disease, and also highlight the need for further research into the neuropathogenesis of trypanosomiasis. In addition the results reported here question the value of the criteria currently employed to defining stage-1 and stage-2 HAT and highlight a requirement to elucidate accurate markers of stage-2 infection to facilitate the development of improved, accurate diseases staging tools.