Sleeping sickness is the name used to describe the human form of African trypanosomiasis (
Trypanosoma spp.), a protozoan parasitic disease affecting humans, livestock, and a large number of sylvatic species in much of sub-Saharan Africa (Figure ). Transmitted by the tsetse fly vector (
Glossina spp.), trypanosomiasis represents an important public health and economic burden in sub-Saharan Africa [
6-
8]. Sleeping sickness is characterized by highly variable and non-specific symptoms in its early stages [
9], which are often mis-diagnosed as malaria [
10]. Late stage sleeping sickness includes body weakness, progressive emaciation, slurred speech, mental confusion, and coma leading to death in all untreated cases [
9]. There are two sub-species of human-infectious trypanosomes, including
T. b. gambiense, which causes a more chronic disease, and is dominant in Western Africa, and
T. b. rhodesiense, which causes more acute disease, and is generally found in East and Southern Africa, east of the Rift Valley [
11]. The two forms of disease have different ecology, pathology, and epidemiology.
T. b. rhodesiense progresses from early non-specific symptoms to infection of the central nervous system and death within months, while
T. b gambiense typically follows a chronic clinical course progressing over several years.
Sleeping sickness treatment is expensive, complicated, and can be dangerous for the patient [
12]. Current drugs are in scarce or uncertain supply, and there is limited optimism with respect to forthcoming drugs entering the market, particularly for the treatment of late-stage
T. b. rhodesiense [
12-
17]. The dominant treatment for late-stage sleeping sickness that involves the central nervous system is melarsoprol, an organoarsenic compound with high toxicity and varying rates of treatment failure [
12,
18]. Active surveillance and case treatment have been found to be extremely effective in reducing disease transmission, particularly for
T. b. gambiense [
12,
18], which is generally confined to a human-fly-human cycle [
19].
T. b. rhodesiense transmission to humans is influenced by prevalence of the parasite in the animal reservoir; in east Africa, livestock represent an important reservoir for disease, and control of livestock infection and tsetse populations are important for reducing transmission to humans [
12,
19].
Sleeping sickness was first identified and characterized in Africa in the last few years of the 19
th century, a period that coincided with widespread and severe epidemics of the disease in Kenya, Tanzania, Uganda, Nigeria, and the Democratic Republic of the Congo (DRC). These epidemics have been associated with social and environmental disruptions during colonial administration [
11,
20], as well as livestock restocking following an 1889–1892 rinderpest epidemic [
21]. The disease was generally brought under control by the 1960s in much of Africa but has re-emerged in many countries since the 1970s [
8]. The re-emergence has been attributed to post-independence political turbulence, unstable governments, limited public health resources, and re-allocation of domestic and international funding towards malaria, HIV/AIDs, and tuberculosis.
In Uganda, a large epidemic of
T. b. rhodesiense began in 1976 in the south-east of the country (Figure ). Between 1976 and the decline of the epidemic in the mid-1990s, over 40,000 cases were reported in this region. Given estimates of significant under-reporting due to passive surveillance and diagnostic difficulties, the actual number of cases may have been ten times higher, with all unreported and untreated cases assumed to be fatal [
3,
22,
23]. Though incidence declined in the 1990s, the disease continues to spread into new regions. Recent research suggests that central Ugandan districts may be at particularly high risk of infection and increased incidence [
24]. These reports are particularly pertinent given that Uganda represents the boundary between the ranges of the two sub-species of sleeping sickness. While
T. b. rhodesiense continues to spread from its traditional focus in the south and east, cases of
T. b. gambiense continue to be recorded in north-western Uganda in the West Nile Region. These foci are currently separated by fewer than 200 kilometers, much of which is inhabited by tsetse flies. The two diseases differ widely in their treatment and control: it is very difficult to distinguish the two sub-species clinically [
25]; a seriological card agglutination test (CATT) is commonly used for
T. b. gambiense diagnosis, but is inappropriate for
T. b. rhodesience – the test would not be effective in the presence of both diseases [
26]; drug treatment regimes, which are expensive and can be dangerous, differ depending on the sub-species of infection [
26]; approaches to control, such as focus on vector eradication, livestock treatment, or active livestock or human surveillance, will be more or less appropriate based on sub-species [
25,
26]; there may be potential for exchange of genetic material and increased drug resistance where the sub-species overlap [
26,
27]; cost-effective and successful control of sleeping sickness would become extremely difficult to achieve where both species were present. The potential for overlap of the two disease foci is therefore a considerable economic and public health concern [
2].
Similar re-emergent outbreaks and incidence have been recorded in other countries (Figure ). Angola experienced outbreaks in the late 1800s and early 1900s. By 1974, the year before Angola's independence, however, only three new cases of sleeping sickness were recorded [
5]. Sleeping sickness re-emerged in Angola during a prolonged civil war following the country's independence in 1975 [
19]. Although a peace agreement was signed in 2002, Angola's infrastructure and political situation remain highly unstable; the country is classified as 'epidemic' for sleeping sickness by the World Health Organization (WHO), along with the Democratic Republic of the Congo (DRC) and southern Sudan [
28]. In Sudan, disease resurgence in the late 1970s was largely controlled by a Belgian-Sudanese trypanosomiasis treatment and control initiative [
18]. Civil war in the 1980s and 1990s, however, lead to collapse of the control programme, and by 1997, sleeping sickness had re-emerged in Sudan with prevalence rates as high as 19% in south-western communities bordering the Democratic Republic of the Congo [
18]. Re-emergence of disease and new epidemics were reported in the DRC in the 1970s and 1980s [
29]. The DRC continues to experience Africa's highest burden of disease from sleeping sickness; in 1994, 72% prevalence was reported in one village, Kimbanzi [
19]. The DRC represents an important source of infection for neighbouring countries. According to the WHO [
28], Angola and southern Sudan have also reported high prevalences: between 20% and 50% in some communities. In several areas, sleeping sickness is the first or second greatest cause of mortality, ahead of HIV/AIDS [
19]. Currently, the DRC, Angola, and Sudan remain the countries most affected by sleeping sickness.
Countries considered to be 'highly endemic', with sleeping sickness re-emergence and expected incidence increase include Cameroon, Uganda, Central African Republic, Chad, Congo, Côte d'Ivoire, Guinea, Mozambique, and Tanzania [
28]. Incidence and prevalence are highly focal. In the Central African Republic, for example, villages bordering Sudan have reported epidemic levels of disease [
18]. Sporadic or low endemic levels of sleeping sickness have been reported in Benin, Burkina Faso, Equatorial Guinea, Gabon, Kenya, Mali, Togo and Zambia. Unreported foci are likely to exist in additional countries, including Africa's most populated nation, Nigeria [
30]. While few sleeping sickness cases have been reported in Kenya since the late 1960s and early 1970s, cattle infection remains an economic burden and there is ongoing incidence of disease across the border in south-eastern Uganda.
1,2
This article has been 
geographical distribution,
