The large amount of circulating antibodies are fixed on the red blood cells facilitating the erythrophagocytosis, resulting in anemia. It also activates the complement system and cytokines, provoking increased vascular permeability. One of the classical anatomopathological lesions is a vasculitis with perivascular infiltrate of mononuclear cells and fibrinoid deposits on the walls of the blood vessels producing obstructions and extravasations with petechial necrosis. Vasculitis alters the blood–brain barrier and contributes to the crossing of the parasites into the central nervous system. Macroscopically, the brain shows an edema with focal hemorrhages. Microscopically, a demyelinating meningoencephalitis can be observed.
Clinical Symptoms And Signs
Following the inoculation of the parasite through the bite of an infected fly, the parasite can be found in the lymph and blood. This is the hemolymphatic or first stage. Subsequently, the parasite invades the central nervous system; this is the meningoencephalitic or second stage. To determine the stage, cerebrospinal fluid must be examined.
Classically, gambiense sleeping sickness is chronic. Infected people can coexist with the parasite for months, even years, without any major signs or symptoms and are able to proceed with their usual activities. They are, however, carriers and therefore become a source of infection for tsetse flies. The natural fatal evolution of the disease can take more than 5 years. The rhodesiense form, on the other hand is acute, less adapted to its human host, rapidly produces signs and symptoms, and ends in death in a few months.
A local inflammatory reaction with a chancre, a furunclelike lesion, can appear at the site of the fly bite; these are most frequently observed in rhodesiense infections. After the chancre has resolved, the site remains hyperpigmented. Subsequently, the trypanosomes spread through the lymphatic system and into the bloodstream. The course is usually 2–3 weeks. The invasive period takes another 2–3 weeks before the appearance of the first signs and symptoms of the hemolymphatic stage. Initially, signs and symptoms are highly unspecific, resembling those of other prevalent diseases in areas endemic for sleeping sickness. This period is generally recognized as ‘normal’ by those infected and usually goes untreated or is treated as a common cold or malaria.
The usually observed signs and symptoms are irregular fevers, headaches, polyarthralgia, myalgia, asthenia, nonpruriginous cutaneous eruptions (circular maculas located on the trunk; trypanids), peripheral edema (‘moon face,’ when facial), anemia, hepatosplenomeglia, pruritus, cardiovascular disorders, palpitations, and precordial pain. The electrocardiogram presents unspecific abnormal conduction and repolarization. Colapsus occurs mainly in the rhodesiense form of the disease.
The apparition of mobile, painless, and nonsuppurative enlarged lymph nodes, classically located in the lower posterior cervical area, is the most characteristic sign (Winterbottom sign). In endemic areas, their presence should lead to a suspicion of sleeping sickness.
After a variable period ranging between a few months to more than a year, the meningoencephalitic phase starts when the trypanosomes invade the central nervous system following an alteration of the blood–brain barrier. Disorders of consciousness and sleeping patterns, including disappearance of the normal circadian rhythm of the sleep–wake cycle, subsequently occurring in short cycles, showing indiscriminately paradoxical sleep episodes during the day and the night. Disorders of tone and mobility, endocrine disorders (amenorrhea is a frequent complaint), sensory disturbances, and psychiatric disorders are also observed. Signs and symptoms characteristic of the hemolymphatic stage coexist with the neurological ones and, some of them, like loss of weight, anemia, asthenia, and headaches, are accentuated.
Diagnosis
The most frequent serological test used for screening is the card agglutination test for trypanosomiasis (CATT). Since serological methods are not specific enough, serologically positive cases should be confirmed parasitologically by microscopic examination of lymph, blood, and cerebrospinal fluid (CSF). Lymphatic juice is obtained by aspiration of enlarged cervical lymph glands and directly observed under the microscope. In the gambiense form of the disease, since blood parasitemia level is low and fluctuating, simple methods such as wet blood films or thin and thick stained smears using not more then 10 ml of blood have little chance of success in detecting the trypanosome. Thus concentration methods (using 50–300 ml) such as the microhematocrit centrifugation technique, the quantitative buffy coat, or the mini anion exchange centrifugation technique must be used to detect trypanosomes. In CSF, the double centrifugation or double modified centrifugation techniques are commonly used.
In the rhodensiense form, high parasitemia is more common, and simple parasitological methods are often sufficient to detect parasites.
Once parasitological diagnosis has been established, procedures for stage determination must be implemented to determine the adequate drug for treatment. Stage determination is done using white blood cell count and parasite presence in the CSF. The cutoff number for the first stage is 5 cells/ml. If over 5 cells/ml or in the presence of trypanosomes in the CSF, the patient is considered in the second stage.
Increased immunoglobulin M (IgM) concentration in CSF, using simplified test procedures, has been proposed as a marker for the second stage. Studies to evaluate IgM test sensitivity and feasibility are now ongoing.
Treatment
Appropriate sleeping sickness treatment relates to the stage of the disease. Only two drugs can cross the blood–brain barrier, and they must be used for the second stage. Melarsoprol is effective in both forms of infection, and eflornithine is only effective in gambiense infections.
Nifurtimox, which is only registered for Trypanosoma cruzi infection (American trypanosomiasis), has occasionally been used with uncertain results in African trypanosomiasis. It is now being evaluated in combination with eflornithine in the treatment of the second stage of the disease in consideration of the observed synergism between the two molecules.
For the first stage, pentamidine is used for gambiense and suramine for rhodesiense disease. These drugs are easy to administer, have mild undesirable effects, and provide a good prognosis. This is why the disease should be diagnosed and treated as early as possible.
Pentamidine isethionate is administered by intramuscular injections of 4 mg per kg of body weight (mg/kg bw) once daily for 7 consecutive days. It is generally well tolerated; adverse reactions include local pain and sterile abscess at injection site, hypotension associated with nausea, vomiting, dizziness occasionally occurs, and collapse has been seen although rarely. To avoid such undesirable effects, it is recommended to give sugar prior to administration of the drug and keep patients supine for at least 1 h after each injection. These measures should be sufficient to resolve side effects. Administration of glucose fluids, corticoids, or epinephrine can be useful but is rarely needed. Pentamidine has been reported to alter liver function and provoke transitory diabetes.
Suramin is administrated intravenously. Due to an occasionally observed hypersensitivity to the drug (1/20 000), it is recommended to start treatment with a test dose of 5 mg/kg bw of suramin on the first day. In absence of reaction, treatment will consist of injection of 20 mg/kg bw (up to a maximum of 1 g per injection) each spaced by a week’s rest. Adverse effects such as fever, urticaria, arthralgia, exfoliative dermatitis, and conjunctivitis have been described. These adverse effects are more frequent with a concomitant onchocerciasis infection. Suramin has a long half-life, and some adverse effects are related to its cumulative toxicity. Bone marrow toxicity has occasionally been observed, with agranulocytosis and thrombocytopenia. Suramin also accumulates in the renal tubes and is therefore not recommended in patients with altered renal function, which should be evaluated before and monitored during treatment. Nephrotoxicity is common but reversible on interruption of treatment.
Melarsoprol is a trivalent organic arsenical drug combined with heavy metal chelator, dimercaptopropanol, and propylene glycol as a solvent. It is therefore an extremely toxic drug. Melarsoprol is the last arsenical derivate used in humans. It is administered intravenously. Treatment consists of 1 daily dose of 2.2 mg/kg bw for 10 days Before starting treatment, it is recommended to correct anemia, hypoproteinemia, and cardiovascular disorders, and other parasitological infections should be treated. The protective role of corticoids in the appearance of side effects during melarsoprol administration is controversial, but widely used.
There are two types of side effects. Fever, nausea, vomiting, and abdominal pain are immediate and should disappear spontaneously or with the administration of analgesics or spasmolitics. The appearance of such side effects does not call for the interruption of treatment. The so-called ‘reactive encephalopathy,’ which occurs in 5–10% of treated patients, usually takes place 5–7 days after the first dose. The causes underlying this severe side effect are a matter of discussion, and no consensus has been reached. There are two forms of encephalopathy. The first is acute and severe, starting with a rapid deterioration of consciousness, fever, convulsions, coma, and death in less than 48 h. It is almost always fatal. The other type of encephalopathy starts with abnormal behavior and psychotic reactions and is considered to have a more favorable outcome.
A sudden peak of fever, the appearance of proteinuria, hematuria, hiccups, and diarrhea could be warning signs. The management of reactive arsenical encephalopathy is uncertain and complicated. Melarsoprol administration is first interrupted and followed by a high dose of parenteral corticoids and anticonvulsants, which contribute to the reduction of cerebral edema and convulsions. Any other concomitant treatments are done according to other observed symptoms.
Other side effects are peripheral neuritis and renal and hepatic dysfunction. Furthermore, there is a hardening of the vein walls as a consequence of the irritating effect of propylene glycol, making the administration of the last doses of melarsoprol difficult.
Eflornithine is administered by slow intravenous infusion (2 h). The dose is 400 mg/kg bw diluted in sterile water in four daily doses at 6 h intervals during 14 consecutive days. In children under 12 years or less than 35 kg, the dose is 150 mg/kg bw (same interval and number of days).
Adverse reactions are related to the cytotoxic activity of the molecule (inhibition of ornithine decarboxylase activity). Bone marrow toxicity is the most severe adverse effect, resulting in anemia, leucopenia, and thrombocytopenia. Neurological symptoms like convulsions can be observed during the first days of treatment. Other adverse effects are gastrointestinal symptoms such as nausea, vomiting, and diarrhea. Alopecia and loss of hearing acuity have also been observed. Generally, adverse effects are reversible following interruption of eflornithine administration and at the end of treatment.
Eflornithine is a trypanostatic drug involved in the polyamine cycle that blocks parasite growth and reproduction. Consequently, to be effective, it needs a contribution of the immunological system; eflornithine thus should be used carefully in the treatment of immunosuppressed patients.
Eflornithine is substantially less toxic than melarsoprol and has a similar result in the majority of patients. However, due to the cumbersome administration and the need for additional material, it is not widely used by national control programs. It is generally kept as an alternative treatment for melarsoprol-refractory cases. In the field, only nongovernmental organizations involved in sleeping sickness control programs have the logistics and staff to implement eflornithine as a first-line treatment of the second-stage gambiense disease.
Nifurtimox is only registered for the treatment of American trypanosomiasis, Chagas disease. However in gambiense infections, a synergetic effect is believed to exist when combined with eflornithine. Thus, combination therapy trials have been implemented to decrease dosage on the one hand and reduce the eflornithine lengthy treatment schedule on the other, making treatment less cumbersome, ensuring better availability under field conditions, and probably preventing future resistance to the drug. Nifurtimox is given orally at the rate of 15 mg/kg bw three times per day for 10 days concurrently to the administration of eflornithine intravenously at the rate of 400 mg/kg bw in two daily doses for 7 days.
Treatment Follow-Up
Treated patients should be monitored over 2 years with 6-month controls to evaluate effectiveness. At each control, clinical and biological status is assessed and parasites are searched in blood, lymph, and CSF. If trypanosomes are present, relapse is confirmed. However, since parasites are difficult to find, clinical signs and symptoms and the elevation of the number of white blood cells in CSF over time can be considered suitable criteria for a relapse. Patients are considered cured when after 2 years of follow-up neither the parasite is present nor does the CSF show an increase in WBC count.
In some cases, neurological or psychiatric sequelae have been observed after the patient is considered cured. In children, it has been shown that ability to learn is profoundly altered.
Control
In T.b.g. sleeping sickness where human beings are the main reservoir and the disease is chronic, control aims at early detection of cases through active case finding. The advantage is dual: first, it allows identifying and removing the reservoir, avoiding sources of infection for the vector; and second, it permits implementation of early stage treatment, thus avoiding the use of second stage, highly toxic drugs and complicated treatment procedures.
Vector control in gambiense sleeping sickness is generally not done except during epidemics to buttress active and passive surveillance by rapidly reducing transmission or during the last phases of control targeted to small pockets of transmission.
In rhodesiense sleeping sickness where wild and domestic animals are the main reservoir, disease control activities are combined with treatment of animals and vector control to reduce fly density. Properly equipped health centers and appropriately trained staff in endemic areas could be sufficient to diagnose cases, provided the symptoms are recognized by the patients and lead them to seek help spontaneously at health centers.
Bibliography:
- Barrett MP, Boykin DW, Brun R, and Tidwell RR (2007) Human African trypanosomiasis: Pharmacological re-engagement with a neglected disease. British Journal of Pharmacology 152(8): 1155–1171.
- Fe` vre EM, Picozzi K, Jannin J, Welburn SC, and Maudlin I (2006) Human African trypanosomiasis: Epidemiology and control. Advances in Parasitology 61: 167–221.