Sleeping sickness …

Sleep Disorders

Updated 07.14.2025
Released 07.19.1993
Expires For CME 07.14.2028

Sleeping sickness

Authors: Ali Karaki MD, Hrayr P Attarian MD

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Editor: Christina M Marra MD

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Sleeping sickness

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Introduction

Overview

Sleeping sickness is a prevalent and serious, yet often ignored and understudied, infectious illness. In this article, the authors summarize the key features of this illness and provide information about promising treatment and prevention methods.

Key points

	• African sleeping sickness is a devastating but unfortunately forgotten epidemic that affects tens of thousands of sub-Saharan Africans.
	• Underdiagnosis remains a major barrier to effective control and diagnosis is usually established by parasite identification, although PCR and other gene tests are being developed.
	• The causative agent usually belongs to one of three species of the Trypanosoma genus and is transmitted to humans through a vector, the tsetse fly.
	• Effective vaccination does not exist, and most available chemotherapeutic agents have some degree of toxicity although research is ongoing to find an effective, nontoxic alternative.
	• Vector control remains an effective yet not often utilized method of prevention.

Historical note and terminology

African sleeping sickness or human African trypanosomiasis (HAT), in French la maladie du sommeil, was described in the last half of the 19th century by European explorers of West Africa who observed patients with enlarged glands and dramatic neurologic symptomatology, often in epidemic settings. Sleeping sickness was an established part of the tribal lore of West Africa, especially in the Congo and Niger basins and the Upper Voltas. Beginning in 1885, the commercial development of the Congo Free State, with soldiers, settlers, and laborers plying the Congo River basin, led to the extensive spread of the disease from "primordial" riverside foci, aided by the clearing of the forests and their replacement with low thicket that favors the tsetse fly (Glossina genus) vector. During the early 1900s, several legendary pioneers of tropical medical science, including D Bruce, A Castellani, JE Dutton, H Koch, A Laveran, P Manson, FW Mott, and E Rouband, elucidated the disease cycle and causative protozoal trypanosomes now known collectively as the Trypanosoma brucei subspecies.

Clinical manifestations

Presentation and course

HAT is caused by two Trypanosoma brucei variants based on their geography: Trypanosoma brucei rhodesiense, the cause of rHAT, and Trypanosoma brucei gambiense, the cause of gHAT. HAT evolves in two distinct stages. In the first stage (stage 1), the illness principally affects the hemolymphatic system with the parasite confined to the blood and lymphatic system. The second or late stage (stage 2) affects the nervous system, causing meningoencephalitis. Neurologic symptoms and CSF inflammatory markers can appear in the first stage of rHAT. rHAT has an acute course that is fatal in a few months from damage to the heart or viscera; gHAT has a chronic course of several years, leading to the extensive nervous system involvement of classic HAT. Progression from the first to second stage occurs after an average of 300 to 500 days. Rarely, even the initial symptoms manifest after a long incubation period lasting up to 7 years (35; 67; 54). Depending on the parasite strain, the clinical picture varies, as do virulence and degree and rate of progression. Concurrent infections are common.

Non-neurologic manifestations. In the rHAT variant, a chancre develops at the site of the infective bite of the tsetse fly (Glossina). In both variants, local lymph node enlargement occurs near the bite. Fever develops when the parasite invades the blood several hours or weeks after the bite. In gHAT, there may be enlarged cervical lymph nodes (Winterbottom sign). In rHAT, the adenopathy principally involves the axillary and epitrochlear nodes. In both forms, irregular febrile episodes are accompanied by endocrine disorders (sterility, impotence or amenorrhea) and moderate splenomegaly and hepatomegaly. Cardiac abnormalities progress from early tachycardia to other arrythmias to pericarditis and, in more advanced disease, peri-myocarditis. Anemia is also a consistent symptom, probably caused by changes on the red blood cell membranes that lead to erythrophagocytosis during acute stages of the disease (60).

Neurologic manifestations. Neurologic symptoms, including headache and mood changes, may occur during the initial febrile period before trypanosomes can be detected in the cerebrospinal fluid, and are they associated with meningeal inflammation. In the Rhodesian variety, the neurologic changes do not always become marked, with only drowsiness, tremors, and unsteadiness, preceding the terminal coma. In the Gambian form, meningitis progresses to encephalitis with serious motor impairment (dyskinesia and choreoathetosis); dysregulation of the circadian clock including reversal of sleep patterns with daytime somnolence interspersed with bouts of delirium, mania, and schizoid and aggressive behavior; and finally permanent sleep, coma, and death. A peculiar deep hyperesthesia (Kerandel sign, described in 1907 by Dr. Jean-François Kerandel) can occur in a small number of patients. HAT can also be considered in cases with anterior uveitis in patients coming from endemic areas (52).

The HAT-related meningitis and encephalitis are characterized by extensive cerebral and meningeal infiltrations of monocytes, lymphocytes, and plasma cells. With rHAT, the interval between the start of the infection and the encephalitic stage is usually a few months. With gHAT, the interval is about 2 years, but an interval of as long as 8 years may elapse. The prominence of one symptom over the other, the rate of progression, and prognosis vary with geographic location as well (32; 54). Symptoms may also be different among natives of endemic areas and those spending short periods of time in those areas primarily because of a difference in the pathogen. gHAT is extremely rare among tourists and visitors from nonendemic areas who tend mostly to develop rHAT. They, therefore, present with the more acute symptomatology (09).

Fever among Caucasian visitors is common with both species (rHAT 97.8% and gHAT 93.3%), as is headache (50% each). Chancres are more common with rHAT (84.4%) than with gHAT (46.7%). Surprisingly, although sleep symptoms are prevalent in endemic HAT, they are rarely reported in travelers. Insomnia is more common (rHAT 7.1%, gHAT 21.4%) than daytime sleepiness (rHAT 4.8%, gHAT none). Jaundice, a symptom never described in endemic HAT, is reported in 28% of travelers with rHAT (09). Neurologic and psychiatric symptoms predominate in the presentation of HAT among Africans from nonendemic areas because the early symptoms are often missed. The common symptoms are daytime sleepiness (46.2%), weakness (64.3%), hyperreflexia (14.3%), hallucinations (21.4%), and depression (21.4%) (63).

A 2022 study tried to investigate the long-term effects of gHAT that may have been overlooked (44). A significant burden of depression and anxiety was identified in patients who were treated for stage 2 gHAT more than 15 years before. Furthermore, there was reduced physical and mental quality of life in former gHAT patients. Hence, there is a need for further research to investigate the long-term burden of this disease.

Prognosis and complications

With the advent of PCR, the presence of asymptomatic human carriers of T brucei is well documented. Treating infected asymptomatic individuals may significantly cut down the risk of transmission, especially in areas of low disease prevalence. Early detection reduces mortality significantly, even in the second stage. Without chemotherapy, the outcome is inevitably fatal once there is neurologic involvement. A study estimated that survival in stage 1 and stage 2 Trypanosoma brucei gambiense infections was 3 years in the absence of treatment. In both forms of the disease, prognosis is excellent, provided chemotherapy is given early. After the parasite is established in the central nervous system, chemotherapy with toxic drugs is required, and cure rates of around 90% may be obtained. Single or multiple relapses may occur, but the melarsoprol used in the second stage may itself induce a fatal reactive encephalopathy in up to 10% of treated individuals (56; 03). Surveillance should continue for up to 4 years after treatment of gHAT. Sequelae of successful treatment of advanced meningoencephalitis include insomnia or sometimes attacks of violent behavior.

Biological markers were developed to assess treatment outcome in late stage gHAT. Six months after treatment, CSF WBC counts of less than 5 cells/mL were a marker of low risk of relapse. Twelve to 24 months after treatment, the combination of high CSF white blood cell counts and high anti-Trypanosoma brucei gambiense IgM levels were accurate markers of subsequent treatment failure (47).

CSF neopterin is the most accurate marker to date of response to treatment as well as a predictor of treatment failure. High levels of neopterin in the CSF of those with gHAT were associated with a higher rate of treatment failure. In addition, 6 months after treatment, neopterin discriminated between cured and relapsed stage 2 patients with 87% specificity and 92% sensitivity, showing a higher accuracy than white blood cell numbers (61; 07). CXCL13 is currently being studied as a prognostic marker. Using a combination of neopterin and CXCL13 could be a stronger predictor of disease staging than each alone. In addition, those markers can be detected in blood, thus, avoiding lumbar punctures (07).

Clinical vignette

A 58-year-old man presented to an emergency room with lethargy and fever in Düsseldorf, Germany. He had just returned home from a 15-day vacation at a Lusaka game reserve in Zambia. Three days earlier he had noticed painful swelling on his right leg. During the examination he was drowsy, had slurred speech, and was febrile. He was mildly tachypneic and tachycardic with a Glasgow coma scale of 12. He was also noted to have facial swelling, a macular rash, two indurated chancres on his leg, and hepatosplenomegaly. Blood smears detected Trypanosoma brucei rhodesiense. Treatment was initiated first with pentamidine, but the patient failed to respond, and his condition deteriorated until he ended up in the intensive care unit, intubated. He then received intravenous suramin with six weekly doses of 20 mg/kg. After the second dose, the patient improved clinically, and both CSF and blood analyses showed no evidence of Trypanosoma. The patient recovered completely and was discharged after the last treatment. He was followed for 18 months after discharge and had no residual sequelae.

Biological basis

Etiology and pathogenesis

Sleeping sickness is caused by two subspecies (rhodesiense and gambiense) of the flagellated protozoa Trypanosoma brucei (order Kinetoplastida) transmitted to humans by the bite of the tsetse fly, Glossina. The acute infection with Trypanosoma brucei rhodesiense (the cause of rHAT) is transmitted by flies of the G mortisans group, and the chronic infection with Trypanosoma brucei gambiense (the cause of gHAT) is transmitted by the G palpalis group, but all 23 species of Glossina appear capable of acting as vectors. Although the terminology Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense are adhered to, application of isoenzyme electrophoresis and DNA analysis is leading to more accurate understanding of the strains, which correlate with clinical features and geographical distribution. Human blood, unlike the blood of other mammals, has efficient trypanolytic activity due to apolipoprotein L1, an ionic-pore-forming apolipoprotein. However, the two subspecies rhodesiense and gambiense have developed resistance to this lipoprotein, which allows them to infect humans (55).

Tsetse flies acquire parasites by feeding on infected animal reservoirs, including domestic animals and cattle, game, and sometimes, humans. For instance, according to a study from Chad, 12% of domestic animals (pigs, dogs, sheep, and goats) in endemic areas harbored Trypanosoma brucei gambiense (66). A complex developmental cycle in the fly leads to infective metacyclic trypanosomes that are extruded during the probing and feeding process. The parasites spread to the human hemolymphatic system, and they also occupy perivascular and connective tissue spaces. There is a general increase in inflammatory perivascular cellularity (lymphocytes and plasma cells). Waves of parasitemia are controlled by specific host antibodies to surface proteins, but some parasites escape immune lysis by the mechanism of antigenic variation, a genetic switching process that enables the parasite to produce antigenically different surface proteins (02).

Immunology. Another mechanism by which the trypanosomes evade the immune response and, in addition, divert the host reactions to their benefit is the release of a specific substance termed trypanosome lymphocyte-triggering factor (TLTF). This substance binds to CD8+ T-cells and activates them to produce interferon-gamma, which in turn triggers proliferation of the parasite. Progression from stage 1 to stage 2 in human African trypanosomiasis is associated with high CSF levels of IL-6, IL-10, and INF-gamma (59). Rather than clearing the parasites, tumor necrosis factor-alpha may act as an agent of host pathology. TNF-alpha-mediated inflammatory pathology is associated with rapid disease progression. The different severities observed in different populations may result from either differing trypanosome virulence phenotypes or from host immune response polymorphisms. CSF levels of CD19+ B cells increase with disease severity, whereas in the blood, CD19+ B cells are consistently high. Activated CD8+ T cells, on the other hand, are not elevated, and memory CD8 T-cell levels are suppressed in both the blood and CSF fluids (04; 36; 54).

Studies on animal models and humans indicate that rHAT is associated with low-grade parasite-independent endotoxemia. Plasma endotoxin concentration is correlated to the occurrence of splenomegaly and lymphadenopathy. The source of endotoxin in this disease comes from increased intestinal leakage initiated by the parasite; elevated endotoxins in turn correlate with the increase in nitric oxide and other proinflammatory cytokines such as IFN-γ and TGF-β (40).

CNS involvement. Many studies have focused on the mechanisms underlying the changes in the CNS, especially those associated with alterations in sleep that accompany the late disease stage. Most information is obtained from animal models. The neuropathology has many components; these include a meningeal and generalized parenchymal perivascular inflammation, with the infiltrations consisting chiefly of lymphocytes and plasma cells. There is breakdown of the choroid plexus and compromise of the blood-brain barrier. Throughout the brain, there is activation of astrocytes and microglia, with alterations in cytokine and inflammatory mediator expression and production, such as IFN-γ, CXCL10, and nitric oxide. Studies in mouse models suggest that parasites gain entry to the brain parenchyma by capitalizing on the translocation of T cells across the blood-brain barrier. Release of TNF-alpha is necessary for their penetration of the endothelial tight junctions, and IFN-gamma activation of the chemokine CXCL10 is required for crossing the astrocyte basement membrane (41). Elevated levels of glial fibrillary acidic protein (GFAP) and light subunit neurofilament protein; autoantibodies against cerebrosides, gangliosides, and myelin basic proteins; as well as immune complexes can be detected in the CSF.

Pathophysiology. The oscillatory activities and circadian timing capacities of the suprachiasmatic nuclei of the hypothalamus become dysregulated. CSF hypocretin-1 levels were significantly higher in patients with HAT (423.2 +/- 119.7 pg/mL) than in narcoleptic patients (40.16 +/- 60.18 pg/mL) but lower than in neurologic controls (517.32 +/- 194.5 pg/mL). No differences were found in CSF hypocretin levels between patients with stage 1 or stage 2 HAT; however, the presence of major sleep-wake cycle disruptions was significantly associated with lower CSF hypocretin-1 levels (18). CSF tryptophan and kynurenine concentrations were elevated in first and second stages of the disease. Kynurenine pathway activation was associated with increased neuroinflammatory markers; however, a relationship with neurologic symptoms was not established (59). Studies suggest that trypanosomes shorten the period of the circadian clock in infected mice, most likely secondary to a secreted substance, as the effect precedes the detection of parasites in the brain (57). This period shortening accumulates over time and leads to significant disruption of the mouse activity cycle. Such a disruption would be consistent with the observation that patients with HAT sleep the same amount during a 24-hour period as controls, but that sleep occurs at irregular intervals.

Epidemiology

Human African trypanosomiasis (HAT) is only endemic in areas where Glossina species are found. This is in turn determined by climate through its effect on vegetation. The ecological range of Glossina is bound approximately by a line commencing 14 degrees north from Senegal in the West to 10 degrees north in Somalia in the East, and 20 degrees south corresponding to the northern fringes of the Kalahari and Namibian deserts. The area is about 11 million square km or one third of the African continent. HAT of either strain is endemic in 36 countries, an area of approximately 10 million square kilometers. The annual incidence used to be approximately 300,000 cases; however, thanks to new chemotherapeutic agents, awareness campaigns, and the World Health Organization’s efforts of controlling transmission, the number of

HAT cases have significantly declined. In 2021 and 2022, there were a total of 940 reported cases from the Democratic Republic of Congo (under 1000), which makes up 61% of all gHAT cases, and there were a total of 73 reported cases in Malawi, which makes up 78% of all rHAT cases (22).

With increased awareness of the illness and increased travel to endemic areas, there is an increase in the number of HAT reported among European and other nonendemic expatriates. A comprehensive study reported 244 cases of HAT in people from nonendemic countries over a period of 110 years. The two peaks of incidence were from 1902 to 1920 (110 cases) and 2000 to 2012 (125 cases). Of the former group, 74.3% were missionaries and soldiers, and gHAT accounted for 78% of cases. Of the latter group, 73% were short-term tourists to game reserves, and rHAT was the more prevalent infection, accounting for 76.4% of all HAT cases in this cohort (50). An additional 11 cases were reported from 2013 to 2018 in nonendemic areas, including the United States, China, and Europe; 90% were among those who had traveled to endemic regions (23).

On June 20, 2024, Chad was validated by the WHO as the seventh country to eliminate gHAT as a public health problem. The previous six are Togo, Benin, Côte d’Ivoire, Uganda, Equatorial Guinea, and Ghana. This milestone reflects decades of progress through early diagnosis, vector control, improved treatment options, and community engagement. Although gambiense HAT has significantly declined across Africa, it remains a concern in countries like the Democratic Republic of Congo, where elimination will require sustained regional collaboration and support (06).

Prevention

Wearing protective clothing while outdoors will decrease tsetse fly bites, but tsetse flies often bite and infect hosts while they are indoors, suggesting that “fly proofing” individual houses can also be effective (64).

Using insecticide-treated traps in the shape of humans and cattle has been somewhat successful in decreasing human infections by decreasing tsetse fly population densities. However, they allow for the emergence of insecticide-resistant flies (16). More cost-effective methods include using smaller electrified nets and small, inexpensive, insecticide-impregnated targets (62). A study deployed tiny targets that are insecticide-treated and attract and kill tsetse in Bonon, Côte d’Ivoire (26). After identifying areas where locals were bitten by tsetse, they placed the traps there in 2016. Following the deployment of the tiny targets, the number of tsetse flies declined and no cases of gHAT were detected in Bonon between 2016 and 2018. These tiny targets are used in Côte d’Ivoire’s national strategy to eliminate HAT (26).

Because cattle can serve as a reservoir for Trypanosoma brucei rhodesiense, livestock markets play a role in the transmission of the illness; transmission can be prevented if the animals are treated at the point of sale as required by the government of Uganda (31).

There is evidence that infected humans can remain asymptomatic for long periods of time, thus, becoming cryptic reservoirs of the disease. Modeling from five health zones in the Democratic Republic of Congo suggests that targeting both asymptomatic and symptomatic carriers can reduce the transmission of Trypanosoma brucei rhodesiense (15). Large-scale screening and treatment for asymptomatic infected individuals might be a useful strategy for disease prevention, but it is hampered by limited participation and cost and complexity of screening strategies. A 2022 cross-sectional survey showed that the main reasons for not accepting HAT screening are fear of lumbar puncture and stigma from the community (21). Screening is usually done with a rapid diagnostic test followed by a parasitological confirmation. A study using a stochastic model for different villages found that the most cost-effective strategy is annual screening with cessation after 3 years of zero cases in moderate to high endemic regions, which is in line with the WHO guidelines (19). An alternative approach to screening whereby dried blood samples on filters were collected in villages and then tested in a regional laboratory (25) avoids the costly and time-consuming traditional method of sending experts to the field with point-of-care confirmation of disease. Restricting screening to those with suggestive symptoms, including enlarged cervical lymph nodes, weight loss, itching, and motor disorders, is more sensitive and specific for detection of infection but is not the same as screening for asymptomatic infection (11).

Vaccination is theoretically the most viable and complete option for prevention of HAT, but so far, no effective vaccine is available.

Diagnostic workup

The traditional mainstay of diagnosis has been the identification of trypanosomes in fluids or tissue, including lymph node or, occasionally, bone marrow aspirates. Blood films may be examined directly under the microscope, but the major problem with both forms of the disease is that parasites may only be present in small numbers for periods of weeks or more. Sensitivity is increased by concentrating the parasites using either thick blood films or microhematocrit triple centrifugation followed by examination under dark-ground/phase contrast microscopy. Quantitative buffy coat technique combines centrifugation with acridine orange fluorescent detection. Parasites may also be separated by passing through a miniature anion exchange column (mAECT) and then visualized under a microscope. In a study by Camara and colleagues, the skin acted as a potential reservoir for trypanosomes, and T brucei was detected in the extravascular dermis of all unconfirmed seropositive patients and all confirmed seropositive patients (10). Hence, the skin could be a target for confirmation of the disease in unconfirmed seropositive patients in the future. The main limitation of direct visualization is the inability to differentiate between trypanosome subspecies.

The advent of real-time PCR for the detection of Trypanosoma brucei in human blood has increased the accuracy of diagnosis and may eventually replace microscopy. Moreover, PCR is helpful in differentiating between Trypanosoma subspecies. There is, however, a limitation to PCR use in the follow-up of treated patients as 20% of individuals continue to have detectable trypanosomal DNA in the blood for up to 2 years after cure. A specific marker of cure is spliced leader RNA. When compared to DNA detection in serum, its specificities were 98.4% to 100% as compared to only 77% for DNA detection (24).

Two other techniques that have been developed and require fewer resources than PCR are loop-mediated isothermal amplification (LAMP) and nucleic acid sequence-based amplification (NASBA).

A CRISPR-based HAT test using SHERLOCK (Specific High-sensitivity Enzymatic Reporter unLOCKing) can differentiate between Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. With more technical advancements, this test has the potential for HAT diagnosis and monitoring in the field (58).

A study done in Eastern Zambia confirmed that a technique combining microscopy and PCR is superior in sensitivity and specificity to the microscopy technique alone. The use of PCR, however, may be limited and impractical in rural African areas where the disease is endemic. Thus, microscopy may remain the most practical diagnostic method in the field in rural areas. The study further showed that to better diagnose using microscopy, the staff should be well trained to diagnose using the microscope, the microscopes should be well maintained, there should be a better funding model, and an enhancement in quality control is needed (46).

Several serological methods are available that are based on direct agglutination, hemagglutination, gel precipitation, immunofluorescence, and antigen or antibody capture (ELISA). Due to antigen variability in the surface glycoprotein coat, the production of antibodies is relatively limited (14). Thus, the detection of antibodies against Trypanosoma brucei may not be the most effective way to detect the disease. The card agglutination test (CATT) is the most practical test and is in widespread use. Unfortunately, it has many limitations, including poor sensitivity and specificity. The immune trypanolysis test improves the accuracy of the card agglutination test in endemic areas (17), as does the ELISA test and latex agglutination. The use of these tests, however, applies primarily for the detection of Trypanosoma brucei gambiense. CATT remains the best serological screen for rHAT.

Since 2010, rapid diagnostic tests have been used as a complement of CATT. SD BIOLINE^® HAT is a rapid diagnostic test that has higher sensitivity and slightly lower specificity than CATT, which means that the need for a test with better performance persists (38). A test using similar technology, HAT Sero-K-SeT, had excellent sensitivity and specificity (100% and 97%, respectively) in a phase III diagnostic accuracy trial, although the study was limited by its small size (05). It also remains quite expensive due to the use of native antigens. In contrast, SD BIOLINE^® HAT 2.0, which is considerably cheaper due to the use of recombinant antigens, was assayed against the CATT and the original SD BIOLINE^® HAT in a much larger trial that looked at both active (healthcare providers actively seeking HAT cases in hospital databases) and passive (cases identified when the individuals with HAT came seeking medical attention) screening (48). In this trial, SD BIOLINE^® HAT 2.0 had a sensitivity of 83% in active screening and 98.4% in passive screening. There was some evidence suggesting that a test incorporating multiple antigens may be more sensitive and specific to account for parasite variation (39).

The late, or second-stage, disease with central nervous system involvement is diagnosed by identification of cerebrospinal fluid abnormalities. For identification of trypanosomes in CSF, fresh fluid must be centrifuged and quickly analyzed because the parasites are rendered more fragile than in blood. Multiple centrifugation procedures may be employed. Parasites may be absent from the cerebrospinal fluid sample even though the blood-cerebrospinal fluid barrier has been breached and meningoencephalitis is established.

The most suitable ways to determine CNS involvement in the field are miniature anion exchange and modified single centrifugation analysis.

The widely accepted criteria for CNS involvement are either the presence of trypanosomes in CSF or CSF white blood cells greater than five cells per mm2, together with CSF protein greater than 40 mg/dL. If HAT has already been diagnosed, the lymphocyte pleocytosis and elevated protein is considered a strong indication of CNS involvement or relapse. New research has been directed toward the identification of biomarkers of disease in blood that will enable discrimination between stage 1 and 2 (both with CNS involvement), removing the need for lumbar puncture from HAT-staging algorithms (65).

Attempts to create algorithms for early detection and disease staging incorporate clinical findings, CATT, and other serological testing in both blood, and CSF. Five regional algorithms exist, with a sensitivity ranging from 85% to 90% and high specificity of over 99.9% (with the exception of one algorithm that did not rely on microscopy). The latter had higher sensitivity than the other four but resulted in frequent false positives (13).

A study using brain MRI imaging in HAT demonstrated unique high FLAIR signals in the midbrain, pons, medulla, corona radiata, caudate nuclei, hypothalamus, and cerebellar white matter (08). These changes were not reported before in humans. The uniqueness of these findings and the correlation with clinical findings may be an important area to explore in order to further enhance the ability to diagnose HAT.

Management

gHAT. Fexinidazole has replaced pentamidine as the first-line treatment in patients with first-stage Trypanosoma brucei gambiense infection or gHAT (37). Fexinidazole is administered orally once a day for 10 days. If the patient is an adult weighing more than 35 kgs, the patient should receive a loading dose of three tablets (1800 mg) each day for 4 days and a maintenance dose of two tablets (1200 mg) each day for 6 days. If the patient is a child over 6 years of age and weighs more than 20 kg and less than 35 kg, or if the patient is an adult weighing 35 kg or less, they should receive two tablets (1200 mg) each day as a loading dose for 4 days and then 600 mg (one tablet) each day as a maintenance dose for 6 days (37; 49; 27; 28). The approval for the usage of fexinidazole is a milestone because it is the first oral drug approved for the treatment of HAT. This eliminates the need for injectable treatment, which has been a hurdle in the elimination of HAT, because it is more accessible. Fexinidazole has not been approved for use in children younger than 6 years of age or those who weigh less than 20 kg (37; 49).

Fexinidazole has a relatively safe side effect profile when compared to other drugs. The side effects are mainly gastrointestinal, such as nausea and vomiting; they may also include headache, insomnia, tremor, and dizziness. Fexinidazole should always be taken with a meal because of low bioavailability in the fasting state. A phase 3b prospective nonrandomized cohort study assessed the feasibility and safety of unsupervised home-based fexinidazole treatment of gHAT. The study showed consistent safety results with no new safety concerns, even among women treated during pregnancy and breastfeeding (34).

For late-stage infection with gHAT, the traditional first line of treatment is a combination of eflornithine and nifurtimox (the combination is referred to as NECT). The dosing is usually eflornithine 200 mg/kg every 12 hours intravenously for 7 days and oral nifurtimox 15 mg/kg orally per day in three divided doses for a 10 days (29). Compared to eflornithine alone at the same total daily amount divided into four doses but for 14 days, NECT was equally effective and was less toxic (29). As per the CDC 2024, another treatment option is melarsoprol. The dose is 2.2 mg/kg/day (max 180 mg/day) intravenously for 10 days. Melarsoprol has several side effects, such as a fatal encephalopathy, gastrointestinal and skin reactions, pyrexia, and peripheral neuropathy. Pretreatment with corticosteroids should be considered to minimize the risk of an encephalopathic reaction (Kuepfer et al 2012; 37).

Lately, however, the recommendation for late-stage gHAT has evolved to using fexinidazole instead of nifurtimox-eflornithine combination therapy in patients with second-stage gHAT and less than 100/μL cerebrospinal fluid white blood counts. The recommendation remains to use nifurtimox-eflornithine in patients with more than 100/μL cerebrospinal fluid white blood counts (37).

A substance that has shown in vitro trypanocidal activity is the antihelminthic drug, niclosamide. In a phase 3 clinical trial, this agent was noninferior for the treatment of stage 2 gHAT (43). Its oral delivery route is a distinct advantage over NECT.

Another drug being studied for gHAT is acoziborole, a single-dose oral treatment that demonstrated 95.2% efficacy in late-stage disease and 98.1% in the evaluable population, with a favorable safety profile and no major drug-related adverse events. Compared to NECT and fexinidazole, acoziborole is simpler to administer—requiring no hospitalization or lumbar puncture—making it a highly promising option to support the goal of HAT elimination by 2030 (33).

Acoziborole had good efficacy and a favorable safety profile with a positive benefit–risk profile after a multicenter, open-label, single-arm phase 2/3 trial with a positive benefit–risk profile (33). A double-blind safety study of acoziborole is currently ongoing in the Democratic Republic of the Congo and Guinea.

rHAT. For stage 1 rHAT, suramin is given. As per the CDC in 2024, a test dose of intravenous suramin 4 to 5 mg/kg or 100 to 200 mg IV on day 0 is followed by 20 mg/kg (max 1g/injection) intravenously over several hours on days 1, 3, 7, 14, and 21. The dose should be reduced in children with a test dose of 2 mg/kg (maximum 100 mg) and a treatment dose of 10 to 20 mg/kg (maximum 1 g) (12). Reactions may include nephrotoxicity, rash (including exfoliative dermatitis), hypersensitivity reactions that may be fatal (one in 20,000 doses), peripheral neuropathy, and myelosuppression (30). Suramin is not readily available in nonendemic countries, and distribution is permitted by the WHO after a case is diagnosed.

For the late stage of rHAT, melarsoprol is given by intravenous injection at 2.2 mg/kg/day for 10 days. If melarsoprol fails, then a pretreatment with a single dose of 4 to 5 mg/kg of suramin is recommended followed by a repeat course of intravenous melarsoprol 2.2 mg/kg/day for 10 days. In fact, most experts recommend pretreatment with suramin to treat the parasitemia and avoid a Jarisch-Herxheimer reaction that is a severe inflammatory reaction associated with a sudden release of endotoxins.

Because melarsoprol is highly toxic and fexinidazole showed preclinical promise against Trypanosoma brucei rhodesiense, a clinical trial was conducted to assess its efficacy in treating rHAT. The study included both stage 1 and stage 2 patients, reporting a 0% fatality rate in stage 2, one relapse, and no treatment failures in stage 1. These results support fexinidazole as a safe and well-tolerated alternative to melarsoprol or suramin for rHAT (42).

In addition to clinical and parasitological criteria, sleep-wake patterns can serve as indicators of treatment response in HAT. Polysomnography can demonstrate normalization of sleep-wake patterns after treatment is instituted. Actigraphy, a simpler and less costly sleep diagnostic tool, shows promise in evaluating sleep-wake disturbances in patients with HAT. Although actigraphic changes do not mirror white blood cell counts in the CSF, they do correspond to polysomnographic changes and may demonstrate clear sleep-wake improvement once treatment is instituted (51).

Despite all of these efforts, underdiagnosis, underdetection, and poor compliance with treatment and clinic follow-ups remain huge problems in the fight against trypanosomiasis. WHO states that the successful elimination of HAT requires the participation of existing health systems for surveillance and control sustainability; the development of new diagnostic tools and drugs is crucial to guarantee the effective participation of existing health structures, and the maintenance of a specialized central structure at national level is necessary to ensure the coordination and overall technical assistance needed. Training of nonspecialist healthcare workers improves the rate of syndromic referrals to hospitals for HAT diagnosis and management (53). Furthermore, despite the recent decline in reported cases, the high level of underreporting and increased socioeconomic instability in endemic regions create significant obstacles to the eradication of HAT (62; 01). Barriers to early treatment include difficulty of detection, logistics of treatment, regional socio-political instability, and cultural stigma (09).

References

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Ali Karaki MD

Dr. Karaki of Lebanese American University Medical Center has no relevant financial relationships to disclose.
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Hrayr P Attarian MD

Dr. Attarian, Director of the Northwestern University Sleep Disorders Program, received honorariums from Avadel and Jazz for consulting work.
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Editor

Christina M Marra MD

Dr. Marra of the University of Washington School of Medicine has no relevant financial relationships to disclose.
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Former Authors

Victor W Pentreath PhD
Annise G Wilson MD
Oriana Sanchez MD
Kathleen G Bickel PhD
Antonio Culebras MD FAAN FAHA FAASM

Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: male=female
Heredity: none
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: fishermen

game wardens

hunters

savannah workers

ICD & OMIM codes

ICD-10: Sleeping sickness NOS: B56.9
ICD-11: Gambiense trypanosomiasis: 1F51.0

Rhodesiense trypanosomiasis: 1F51.1

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Sleeping sickness

Differential Diagnosis

infected bites of insects other than tsetse
malaria
relapsing fever
typhoid
kala azar
- Hodgkin disease
- infectious mononucleosis
- brucellosis
- tuberculosis
- pediculosis
- scabies
- other skin lesions
- meningovascular syphilis
- tuberculous meningitis
- viral meningitis
- parkinsonism
- HIV-1 disease
- hookworm infections
- systemic lupus erythematosus

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NIH: Sleeping Sickness

Sleeping sickness …

Sleeping sickness

Cite this article

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Special considerations

Pregnancy

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Sleeping sickness

Cite this article

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Special considerations

Pregnancy

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Genital herpes: neurologic complications

Cryptococcal meningitis

GM2 gangliosidoses

Tuberculosis of the CNS

Developmental delay in children: evaluation and management

Levacetylleucine

Headache associated with HIV and AIDS

Whipple disease

This is an article preview.
Start a Free Account
to access the full version.