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The clinical course of human African trypanosomiasis has two stages. In the first stage, the parasite is found in the peripheral circulation, but it has not yet invaded the central nervous system. Once the parasite crosses the blood-brain barrier and infects the central nervous system, the disease enters the second stage. The subspecies that cause African trypanosomiasis have different rates of disease progression, and the clinical features depend on which form of the parasite (T. b. rhodesiense or T. b. gambiense) is causing the infection. However, infection with either form will eventually lead to coma and death if not treated.

T. b. rhodesiense infection (East African sleeping sickness) progresses rapidly. In some patients, a large sore (a chancre) will develop at the site of the tsetse bite. Most patients develop fever, headache, muscle and joint aches, and enlarged lymph nodes within 1-2 weeks of the infective bite. Some people develop a rash. After a few weeks of infection, the parasite invades the central nervous system and eventually causes mental deterioration and other neurologic problems. Death ensues usually within months.

T. b. gambiense infection (West African sleeping sickness) progresses more slowly. At first, there may be only mild symptoms. Infected persons may have intermittent fevers, headaches, muscle and joint aches, and malaise. Itching of the skin, swollen lymph nodes, and weight loss can occur. Usually, after 1-2 years, there is evidence of central nervous system involvement, with personality changes, daytime sleepiness with nighttime sleep disturbance, and progressive confusion. Other neurologic signs, such as partial paralysis or problems with balance or walking may occur, as well as hormonal imbalances. The course of untreated infection rarely lasts longer than 6-7 years and more often kills in about 3 years.