African trypanosomiasis (sleeping sickness)’ is a disease of the central nervous system caused by the protozoan Trypanosoma brucei (Plimmer and Bradford, 1899). The disease occurs in several clinico-epidemiologic patterns. The two principal patterns are Rhodesian sleeping sickness, which is relatively acute, and Gambian sleeping sickness, which is chronic. Another form, Zambezi sleeping sickness, although chronic, is more like the acute (Rhodesian) form in its epidemiologic behavior. The terms “Rhodesian” and “Gambian” are used without geographic implication.
It was formerly believed that each type of the disease was caused by a sharply characterized species of trypanosome (T. rhodesiense and T. gambiense). Zoologists are tending to abandon this concept, because the strains involved are largely indistinguishable except for their behavior in man. As it is now realized that even in man there is no clear-cut distinction, there is little justification for retaining the terms T. rhodesiense and T. gambiense in the medical literature. The name of the “type species” Trypanosoma (Trypanozoon) brucei (previously restricted in its use to strains of animal trypanosomes that do not infect man) is now used for the various strains that cause disease either in man or in other animals.
T. brucei is variable in size; the first forms to appear are long and thin (approximately 20 x 3 fj.), but by the time infection is established, short stumpy forms (approximately 10 x 5 /a) are present together with a full range of intermediate sizes. It was discovered in the 1890’s by Sir David Bruce to be the cause of nagana in cattle in Zululand. The Gambian disease of man was first found in 1902 by Todd and the Rhodesian disease in 1910. T. congo-lense and T. vivax are important causes of trypanosomiasis in cattle, but, as they do not infect man, they are of no direct medical interest. Trypanosomiasis can cause serious losses in domestic cattle and where good husbandry is practiced can reduce the food supply, but in Africa where husbandry is usually bad, and the yields’ are- negligible, the existence of cattle trypanosomiasis acts as an important restraint on overgrazing and consequent soil erosion.
The term “Zambezi sleeping sickness” describes the disease as it occurs today in the Zambezi-Okavango basin. It was previously ascribed to T. rhodesiense; indeed, the original strain of T. rho-disease, was-described in this area, but there are now known to be significant differences between these strains and those in Tanzania, Uganda, and Kenya that are now said to cause “Rhodesian” sleeping sickness.
Prevalence of African Trypanosomiasis.
Although animal strains of T. brucei occur throughout the tsetse belt of Africa, that is to say, south of the Sahara and north of the Limpopo River and the Kalahari, human strains are not so widespread. The chronic (Gambian) form is to be found in West Africa from the Gambia to the Congo, penetrating inland to Lakes Tchad, Victoria, and Tanganyika. The chronic (Zambezi) form with similar pathology is also to be found in Botswana, Rhodesia, Zambia, and Portuguese East Africa but, as mentioned above, in its epidemiology it resembles the more acute (Rhodesian) form now found in Tanzania, Uganda, Kenya, and (most recently) Ethiopia. Distinction among these forms is not always useful to the clinician because today the treatment of all forms is the same. Nevertheless, there is some difference in the prognosis of the different forms, and to the epidemiologist the differences are of great importance.
Transmission of African Trypanosomiasis.
T. brucei is transmitted by several species of the tsetse fly Glossina. When the fly bites an infected host, if its feeding is interrupted it can pass the infection to a second host by regurgitating part of the first feed. This mode of infection may occur at the height of an epidemic when other biting flies such as Stomoxys or tabanid (horse) flies may also be involved. Usually, however, the trypanosomes develop in the tsetse into noninfective forms, and this process continues for about 20 days until infective trypanosomes are formed; these remain in the salivary gland of the fly until it dies from other causes. The duration of the developmental cycle in the fly varies with temperature and does not continue below 18° C. Thus, temperature and altitude form a limit on the cyclical transmission of trypanosomiasis.
Epidemiology of Sleeping Sickness
Rhodesian Sleeping Sickness. The P.nodesian strains of T. brucei are transmitted mainly by G morsitans. This fly is associated with the edge of Brachystegia woodland (the miombo of Tanzania) and with the woodland that fringes watercourses in which, during the dry season, its habitat resembles that of G. pallidipes, also a transmitting agent. Although these flies feed on the blood of a wide range of specie; of game animals, there is evidence that the only important wild animal reservoir of Rhodesian sleeping sickness is the bushbuck Trce Lapkus scriptus.
This small antelope differs from other game in that it can live in close proximity to man, runs only a short distance when disturbed, and returns to its original “stand- in a thicket where it shares the same population of Glossina with man if he happens to be present. Zambezi and sporadic Rhodesian disease are spread by this means, but epidemic Rhodesian strains are spread by G. morsitans, ranging widely in or between scattered thickets at the edge of the miombo, and under these conditions direct “man-flv-man” transmission occurs. Recent evidence suggests that domestic cattle may also act as a reservoir ‘ Onyango et al.).
Epidemic Rhodesian sleeping sickness occurred in Tanzania an the 1930’s, and large areas remain depopulated, because the disease has become “enzootic” and is still liable to break out again and cause acute disease in man. To the north of Lake Victoria, where epidemics have occurred more recently, the disease is spread mainly by G. pallidipes, which ranges widely in the lakeside thickets. In Kenya a recent epidemic has been attributed to G. fuscipes, a fly related to G. palpalis, which has otherwise always been associated with Gambian sleeping sickness. This serves to emphasize the unstable and fluctuating epidemiology of the disease in this area.
Gambian Sleeping Sickness. Ganlbian sleeping “sickness is transmitted mainly by G. palpalis. This fly obtains its blood meal from reptiles, birds, and man; it is 4 shade- and moisture-loving fly, and consequently transmission occurs most readily when a population of flies becomes isolated by unfavorable cli-
Pathology of sleeping sicknesss.
The extent of pathologic lesions depends on the duration of the disease. The most acute cases, those in which death occurs within two months, show little effect other than that associated with infectious disease generally. There are general wasting, hemorrhages into lung and bone marrow, and cellular proliferation in lymph nodes and in the malpighian bodies of the spleen. Acute myocarditis rarely occurs but is said to be the cause of death in some cases. Most cases of acute disease show some small round-cell infiltration of the meninges, but the brain appears normal. After about six months, the lymph nodes and malpighian bodies lose much of their cellularity, and fibrosis occurs in lymph nodes and vessels.
At this stage the red bone marrow decreases, and a normocytic anemia and a leukopenia with a relative increase in lymphocytes occur. There is slight infiltration of the brain substance with small round cells, but heavy infiltration of the leptomeninges. Where the leptomeninges extend into the AschofF-Robin space that surrounds meningeal vessels as they penetrate into the brain substance, the lesion known as perivascular cuffing is produced; this may vary from a single layer of infiltrating cells surrounding the vessel in cases lasting for about six months, to a depth of about 20 cells when the disease has continued for two or more years. The nature of the cellular reaction has not been studied in detail, but there is one type of cell, the large morular cell (Mott’s cells) with loculated eosinophilic cytoplasm, that is present in the leptomeninges or the cuffing (rarely in the brain substance). The presence of this cell is considered pathognomonic of advanced sleeping sickness. Thrombosis is liable to occur in the cuffed vessels and gives rise to the cerebral degeneration that causes the progressive mental deterioration and coma from which the disease is named.
Pathogenesis of African Trypanosomiasis .
The tsetse fly feeds by rupturing small vessels and sucking from the subcutaneous pool that is formed. It may inject trypanosomes either into the bloodstream or into the pool where they lodge and grow to form a chancre, a hard painful nodule that contains trypanosomes. Initial growth of the trypanosomes is in the blood and seldom reaches a level greater than one organism per cubic millimeter, probably because of the action of antibodies that are produced in response to an exoantigen secreted by the trypanosome.
The antigenic nature of this exoantigen can change with remissions in the infection, thereby favoring the prolonged survival of the organism. The host responds by production of globulins in amounts sufficient to produce very high erythrocyte sedimentation rates; these globulins are in the IgM 19S) rather than in the IgG (7S) range, which is normally associated with infectious disease. In the advanced disease, when lesions are maximal, the smallest numbers of trypanosomes are to be found in the blood. An occult stage of T. brucei, consisting of amastigotes (Leishman-Donovan bodies) has been found in the capillaries of the choroid plexus (Ormerod and Veteran), but its full significance remains to be assessed.
Clinical Manifestations of African Trypanosomiasis
The clinical diagnosis of sleeping sickness is usually difficult, for there are few reliable physical signs of the disease. A history of exposure to tsetse bite is essential. A chancre may develop at the site of the bite of the infected tsetse fly, although more frequently this passes unobserved or may be confused with the reaction to a normal tsetse bite, which is often very severe. The occurrence, site, and appearance of the chancre vary greatly between different areas and individual patients.
With typical Rhodesian disease the bite will have occurred about two weeks before the first symptoms. With the Gambian and Zambezi disease, however, the symptoms may be delayed for several years; the history of, or the scar from, a chancre may be useful in diagnosing the disease in a European.
Irrespective of the demonstration of a previous bite, the most important early symptom of sleeping sickness is the severe headache. This is associated with loss of nocturnal sleep and a feeling of oppression that African patients will often recognize, causing them to trek many miles to a sleeping sickness clinic. Wasting, mental disturbance, and drowsiness occur only when the disease is established in the central nervous system.
Physical signs in the early stages include fever, which may be high and fluctuating, especially in the Rhodesian disease. A fleeting circinate erythematous rash occurs on the chest and shoulders of some European patients, but is not seen in Africans. Enlarged lymph nodes are associated with Gambian disease and are found characteristically in the posterior triangle of the neck. Periostial tenderness is described as a diagnostic sign but is neither frequent nor specific; similarly, swelling of the dorsum of the foot is easily confused with famine edema, which may coexist in the type of population at greatest risk of acquiring trypanosomiasis.
Diagnosis of African Trypanosomiasis.
Because there is nothing conclusive about the clinical manifestations of trypanosomiasis, the diagnosis depends entirely on the demonstration of the presence of the organism. In the Rhodesian disease it is usually made by microscopic examination of a thick (unfixed) blood film stained with Giemsa, a tedious but fairly reliable procedure in the hands of a well trained micro-scopist. Injection of blood into rats or mice is of value in doubtful cases. Zambezi strains are more difficult to diagnose by microscopy but are very easily isolated in rats and mice.
Gambian disease cannot with certainty be diagnosed by microscopic examination of the blood or by injection of laboratory animals. Microscopic examination of the fluid obtained by puncture o swollen lymph nodes is the best method in early cases. In later cases microscopy of cerebrospinal fluid is preferable, although concentration of the trypanosomes by centrifugation is often necessary. Culture of the organism as a method of diagnosis is difficult as compared with culture of T. cruzi. Immunologic methods are not usually successful in the diagnosis of sleeping sickness, except for the fluorescent antibody test which shows some promise as a specific diagnostic method. A simple and promising method of selecting cases for further study is based on the formation of precipitin bands by the patient’s serum or cerebrospinal fluid in a gel containing antiserum against lgM, macroglobulins, which are a feature of trypanosomal infections (Mattern et al.).
It is impossible at the present time to distinguish sleeping sickness from other febrile and wasting diseases without demonstrating trypanosomes. These organisms must be sought with care in any patient who has been exposed to tsetse bites in an area in which sleeping sickness has ever been known to occur.
Treatment of African Trypanosomiasis.
The two essential drugs for treatment of sleeping sickness are suramin (Bayer 205) and melarsoprol (Mel B). Suramin can be used in the early febrile stage of the disease but, because it is a large molecule unable to pass the blood-brain barrier, it becomes ineffective once the central nervous system has been invaded; consequently examination of the cerebrospinal fluid is of importance in deciding which drug to use. If the cerebrospinal fluid is normal, suramin alone may be used, but if trypanosomes, lymphocytes, or a raised protein is found, melarsoprol becomes the drug of choice either alone or after a preliminary course of suramin. Suramin is given intravenously in a course of five doses of 1.0 gram every second day, and this may be repeated after a week. Suramin produces some toxicity to the kidney, with the appearance of casts and albumin in the urine. It causes fetal abnormality in rats, but this has not been noted in man. In Nigeria 1 of 2000 patients has a dangerous sensitivity to suramin; this can be detected by giving a preliminary dose of 0.2 gram.
Melarsoprol is much more toxic than suramin, but it is effective in all stages of the disease and is active on most strains of T. brucei, including some that are tryparsamide-resistant. Doses are given intravenously as the 3.6 per cent solution; three doses of 0.5, 1.0, and 1.6 ml. are given at. daily intervals, and after a week three more doses of 1.5, 2.0, and 2.5, and so on until a total of 35 ml. has been given. It must be emphasized, however, that this very high dosage should be reached only if the patient shows no signs of toxicity, notably of arsenic encephalopathy. Sudden death with encephalopathy may occur in the early stages of melarsoprol therapy, and it is believed that this may be due to the rapid liberation of trypanosomal antigen; it is therefore wise to begin therapy of the Rhodesian form with suramin to reduce the number of parasites before continuing with the melarsoprol.
The effect of melarsoprol therapy can be assessed by following the reduction of protein levels in the cerebrospinal fluid, but it can only be a rough guide because melarsoprol will of itself raise the level of protein for periods up to six months after injection. Melanson El Potassium (Mel W) may be given intramuscularly, but less experience has been acquired concerning its curative effect. Nitrofurazone, which can be given by mouth (0.5 gram three times a day for 15 days) is even more toxic, but it may be the drug of choice in cases in which the patient is known to be sensitive —or his trypanosomes resistant — to arsenic.
It is likely to .cause polyneuritis and cardiac arrhythmia, and in patients with hereditary glucose-6-phosphate dehydrogenase deficiency it can cause severe hemolytic anemia (a property which it shares with melarsoprol). Tryparsamide is also used in combination with suramin for mass therapy of Gambian disease; it is not suitable for patients treated individually and is ineffective in the Rhodesian disease. It can produce toxic amblyopia leading to optic atrophy in some patients.
Prognosis of African Trypanosomiasis.
Relapse may follow treatment, especially after suramin, when the central nervous system had been already involved at the time when the chemotherapy was started. Relapse may also occur because of drug resistance; in such a case the success of treatment depends on the use of a different and chemically unrelated drug. Recovery after treatment is usually complete when the disease is treated at an early stage. If treatment is first given late in the disease, the survivors are often mentally sluggish and sometimes obese. A patient from whom trypanosomes have been isolated will sooner or later be killed by the disease unless it is treated.
With Rhodesian disease the patient dies fairly soon, but with both Zambezi and Gambian disease the patient may survive for several years. This is especially true in Zambezi disease, of which so-called “healthy carriers” occur. It is suggested that some patients may be able to overcome the infection by natural means. If this in fact occurs, it is so exceptional that adequate treatment of diagnosed cases should always be performed. The neglect of an outbreak of sleeping sickness may result in extermination of the human population of the locality.
Prevention of African Trypanosomiasis.
African sleeping sickness can be prevented by measures aimed at destroying the habitat of the vector, the shade trees, and the other vegetation upon which the tsetse flies rest. As individual communities become larger, and especially when water sources are provided inside the villages, the risk to the inhabitant^ is reduced. The use of insecticides may also supplement this process. Elimination of the blood meal of the fly by game destruction programs has no effect on human sleeping sickness.
Probably the most effective measures against the Rhodesian disease involve the isolation of human populations from areas known to harbor infective game and systematic search for and treatment of all infected humans. Search for and treatment of cases is even more important in Gambian disease, because ..man himself is the reservoir of infection.
Pentamidine, administered intramuscularly, is the only suitable drug for chemoprophylaxis, and is of established effectiveness only against the Gambian disease. Its use is limited to the protection of a controlled population, such as a labor force, exposed to the Gambian disease. Pentamidine should not be used for therapy of individual cases of the disease because, like suramin, it is not active within the nervous system. A single injection of 4 mg. per kilogram is believed to provide a preventive effect in the Gambijan disease for at least six month.