NEUROLOGICAL PROGRESS The Continuing Problem of Human African Trypanosomiasis (Sleeping Sickness) Peter G. E. Kennedy, MD, PhD, DSc Human African trypanosomiasis, also known as sleeping sickness, is a neglected disease, and it continues to pose a major threat to 60 million people in 36 countries in sub-Saharan Africa. Transmitted by the bite of the tsetse fly, the disease is caused by protozoan parasites of the genus Trypanosoma and comes in two types: East African human African trypanosomiasis caused by Trypanosoma brucei rhodesiense and the West African form caused by Trypanosoma brucei gambiense. There is an early or hemo- lymphatic stage and a late or encephalitic stage, when the parasites cross the blood–brain barrier to invade the central nervous system. Two critical current issues are disease staging and drug therapy, especially for late-stage disease. Lumbar puncture to analyze cerebrospinal fluid will remain the only method of disease staging until reliable noninvasive methods are developed, but there is no widespread consensus as to what exactly defines biologically central nervous system disease or what specific cerebro- spinal fluid findings should justify drug therapy for late-stage involvement. All four main drugs used for human African trypano- somiasis are toxic, and melarsoprol, the only drug that is effective for both types of central nervous system disease, is so toxic that it kills 5% of patients who receive it. Eflornithine, alone or combined with nifurtimox, is being used increasingly as first-line therapy for gambiense disease. There is a pressing need for an effective, safe oral drug for both stages of the disease, but this will require a significant increase in investment for new drug discovery from Western governments and the pharmaceutical industry. Ann Neurol 2008;64:116–127 Human African trypanosomiasis (HAT), which is also tracellular form in the host. There are two forms of the known as sleeping sickness, is one of the “neglected human disease, the East African variant caused by diseases,” a group that includes visceral leishmaniasis, Trypanosoma brucei rhodesiense and the West African schistosomiasis, and Chagas’ disease.1 Although these form caused by Trypanosoma brucei gambiense3 (Fig 1). diseases kill or disable hundreds of thousands of people If untreated, the disease is always fatal. Transmission of in underdeveloped tropical regions, current treatment the disease in both humans and cattle is by the bite of for them is often antiquated, highly toxic, and fre- the blood-sucking tsetse fly of the Glossina species.4 In- quently ineffective. The pharmaceutical industry and festation by the tsetse fly covers 10 million square ki- Western governments have until recently shown little lometers, one third of Africa’s landmass, which is an interest in developing new drugs for these diseases be- area slightly larger than the United States.1 African an- cause this is associated with little or no prospect of imal trypanosomiasis, important in domestic livestock generating significant short- or long-term financial such as cattle that suffer from a wasting disease called gain. Although there has been an entirely understand- nagana, as well as wild animals, was first shown to be able emphasis in recent times on combating such caused by Trypanosoma brucei by David Bruce in 1899 global killers as malaria, acquired immune deficiency while investigating a major outbreak of nagana in Zu- syndrome, and tuberculosis, it should be appreciated luland.5,6 Subsequent work by Aldo Castellani enabled that HAT is a major threat to the health of 60 million the identification of trypanosomes in the blood and ce- people in 36 countries in sub-Saharan Africa.2 More- rebrospinal fluid (CSF) in human patients with HAT over, HAT is the world’s third most important para- in 1903,6,7 and parasites causing the two human dis- sitic disease affecting human health after malaria and ease variants were identified during the period 1902 to schistosomiasis, as defined by the global burden of par- 1910.6 Both animals and humans can act as reservoirs asitic disease, calculated as the disability adjusted life of parasites capable of causing the human disease, but years lost.1 the detailed mechanisms by which this occurs are not HAT is caused by protozoan parasites of the genus fully understood. Animal trypanosomiasis has a major Trypanosoma, single-celled organisms that remain in ex- human and economic impact because it adversely af- From the Department of Neurology, Division of Clinical Neuro- Published online in Wiley InterScience (www.interscience.wiley.com). sciences, Faculty of Medicine, University of Glasgow Institute of DOI: 10.1002/ana.21429 Neurological Sciences, Southern General Hospital, Glasgow, GS1, 4TF, Scotland, UK. Address correspondence to Dr Kennedy, Southern General Hospi- tal, Glasgow G51 4TF, United Kingdom. Received Mar 11, 2008, and in revised form Apr 23. Accepted for publication May 1, 2008. E-mail: [email protected] 116 Published 2008 by Wiley-Liss, Inc., through Wiley Subscription Services Outline of Parasite-Host Biology Details of parasite-host biology have been given else- where.3,4 Although animals are the main reservoir for T.b. rhodesiense parasites, humans are the main reser- voir for T.b. gambiense parasites.1,4 In brief, the tsetse fly vector feeds on an infected animal or human, after which the ingested trypanosomes undergo a number of biochemical and structural alterations in the fly’s mid- gut. Infective forms of the trypanosome then reach the fly’s salivary glands from which they are transmitted to the human host through biting. A fly remains infective for life, and the whole infective cycle is probably com- pleted successfully in only 1 in 10 flies.4 Approximately 5 to 15 days after infection, a painful skin lesion called a trypanosomal chancre may develop at the site of the bite.4 The parasites spread in the host bloodstream 1 to 3 weeks after the initial bite, and invade the lymph nodes and systemic organs including the liver, spleen, heart, endocrine system, and eyes in what is termed the early, stage 1, or hemolymphatic stage.3,4 If untreated, within a few weeks in the case of rhodesiense infection, Fig 1. Distribution of East and West African sleeping sickness or many months in the case of gambiense infection, the in sub-Saharan Africa. Green areas represent Trypanosoma parasites will cross the blood–brain barrier (BBB) and brucei gambiense infection; brown areas represent Trypano- enter the central nervous system (CNS), which marks 4,13 soma brucei rhodesiense infection. (Modified from Atouguia the late, stage 2, or encephalitic stage of the disease. and Kennedy.) The entire tempo of the disease is faster in the more aggressive rhodesiense infection compared with the fects livestock production and farming. During the first chronic gambiense infection, probably as a result of the half of the twentieth century, HAT caused by T.b. greater adaptation of the latter parasite to the host.1,3 gambiense decimated entire communities in central Af- Much is known about the molecular biology of the rica,8 but then the disease was almost brought under trypanosome, and the entire T. brucei genome was se- control during the 1960s primarily as a result of highly quenced in 2005.14 It has about 9,000 genes, about effective surveillance programs. But HAT then quickly 10% of which are variable surface glycoprotein (VSG) reemerged with a progressive increase in the numbers genes encoding the VSG that are distributed on the of new cases and deaths. The World Health Organiza- entire surface of the trypanosome.3 During infection, tion (WHO) provided estimates during the period the trypanosome is able to rapidly switch the expres- 1986 to 2004 about the disease that have been widely sion of the VSG genes in and out of the expression quoted, with an annual prevalence of 300,000 to site, the result of which is antigenic variation in which 500,000 cases.2,9,10 Factors causing this increase were the surface VSG genes change so fast that the parasite primarily war and famine, which resulted in severe dis- is able to constantly evade the host’s immune re- ruption of disease surveillance and treatment, especially sponse.15 For this reason, it has not been possible, so in Uganda, Angola, Sudan, and the Congos where the far, to develop a vaccine for HAT. disease occurred in epidemics.11 Although it is still dif- ficult to provide accurate estimates of disease incidence Clinical Features of the Disease and prevalence, more recent WHO estimates have sug- There is seldom a clear clinical distinction between the gested that as a result of more efficient surveillance, a early and late stages of HAT that may appear to run significant improvement has occurred with currently as into each other. Patients in the early, or hemolym- low as 70,000 existing cases, mainly infected with T.b- phatic, stage may report nonspecific symptoms such as .gambiense.10 However, HAT has already demonstrated malaise, headache, weight loss, arthralgia, and fatigue, its ability to recur even after it had been virtually and also have episodes of fever accompanied by rigors brought under control. About 50 cases of HAT occur and vomiting, which may be misdiagnosed as malar- annually outside of Africa,12 usually as a result of ia.13,16 There may also be generalized lymphadenopa- Western travelers returning to North America or Eu- thy, and enlargement of posterior cervical lymph nodes rope from the East African game reserves; therefore, all is typical of gambiense disease (“Winterbottom’s sign”). physicians need to be aware of the key features of the Other symptoms and signs may correspond to partic- disease and its most appropriate drug therapy. ular organ involvement. Thus, there may be several dif- Kennedy: Human African Trypanosomiasis 117 ferent kinds of skin rash, as well as pruritus, especially Table 1.