African trypanosomiasis
African trypanosomiasis is an insect-borne parasitic infection of humans and other animals.
Human African trypanosomiasis, also known as African sleeping sickness or simply sleeping sickness, is caused by the species Trypanosoma brucei. Humans are infected by two types, Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense. Trypanosoma brucei gambiense causes over 92% of reported cases.
Both are usually transmitted by the bite of an infected tsetse fly and are most common in rural areas.
Initially, the first stage of the disease is characterized by fevers, headaches, itchiness, and joint pains, beginning one to three weeks after the bite. Weeks to months later, the second stage begins with confusion, poor coordination, numbness, and trouble sleeping. Diagnosis involves detecting the parasite in a blood smear or lymph node fluid. A lumbar puncture is often needed to tell the difference between first- and second-stage disease.
Prevention of severe disease involves screening the at-risk population with blood tests for Trypanosoma brucei gambiense. Treatment is easier when the disease is detected early and before neurological symptoms occur. The use of pentamidine or suramin treats the hemolymphatic stage of T. Brucei infection but if the disease progresses to the neurological stage dosages of eflornithine or a combination of nifurtimox and eflornithine can serve as a treatment for late-stage African Sleeping Disease. Fexinidazole is a more recent treatment that can be taken by mouth, for either stage of Trypanosoma brucei gambiense. While melarsoprol works for both types, it is typically used only for Trypanosoma brucei rhodesiense, due to its serious side effects. Without treatment, sleeping sickness typically results in death.
The disease occurs regularly in some regions of sub-Saharan Africa with the population at risk being about 70 million in 36 countries. An estimated 11,000 people are currently infected with 2,800 new infections in 2015. In 2018 there were 977 new cases. In 2015 it caused around 3,500 deaths, down from 34,000 in 1990. More than 80% of these cases are in the Democratic Republic of the Congo. Three major outbreaks have occurred in recent history: one from 1896 to 1906 primarily in Uganda and the Congo Basin, and two in 1920 and 1970, in several African countries. It is classified as a neglected tropical disease. Other animals, such as cows, may carry the disease and become infected in which case it is known as nagana or animal trypanosomiasis.
Signs and symptoms
African trypanosomiasis symptoms occur in two stages: 1) the hemolymphatic stage and 2) the neurological stage. The hemolymphatic stage refers to the period when parasites are present in the blood and lymphatic system, prior to central nervous system involvement. The neurological stage, also called the meningoencephalitic phase, begins when Trypanosoma parasites cross the blood–brain barrier and invade the central nervous system. In addition to the hemolymphatic stage neurological symptoms can still present themselves, resulting in a difficulty in distinguishing the two stages based on clinical features alone.The disease has been reported to present with atypical symptoms in infected individuals who originate from non-endemic areas. The reasons for this are unclear and may be genetic. Delayed or missed diagnosis in infected individuals who originate from non-endemic areas has been reported symptoms including higher susceptibility and quicker progression of advanced stages of the disease. The reasons for this are unclear, but certain symptoms, such as high fever, could be due to genetic factors or a lack of previous exposure to non-human-pathogenic forms of trypanosomes. The low number of such cases may also have skewed findings. In such persons, the infection is said to present mainly as fever with gastrointestinal symptoms and with lymphadenopathy rarely developing.
Trypanosomal ulcer
Systemic disease is sometimes presaged by a trypanosomal ulcer developing at the site of the infectious fly bite within 2 days of infection. The ulcer is most commonly observed in T. b. rhodesiense infection and rarely in T. b. gambiense infection, where ulcers are more common in persons from non-endemic areas.Hemolymphatic phase
The incubation period is 1–3 weeks for T. b. rhodesiense, and longer in T. b. gambiense infection. The first/initial stage, known as the hemolymphatic phase, is characterized by non-specific, generalised symptoms like: fever, headaches, joint pains, itching, weakness, malaise, fatigue, weight loss, lymphadenopathy, and hepatosplenomegaly.Diagnosis may be delayed due to the vagueness of initial symptoms. The disease may also be mistaken for malaria.
Intermittent fever
Fever is intermittent, with attacks lasting from a day to a week, separated by intervals of a few days to a month or longer. Episodes of fever become less frequent throughout the disease.Lymphadenopathy
Invasion of the circulatory and lymphatic systems by the parasite is associated with severe swelling of lymph nodes, often to tremendous sizes. Posterior cervical lymph nodes are most commonly affected; however, axillary, inguinal, and epitrochlear lymph node involvement may also occur. Winterbottom's sign is a clinical finding involving swollen lymph nodes at the base of the skull or along the back of the neck, particularly characteristic of T. b. gambiense infections.Other features
Those affected may additionally present with: skin rash, haemolytic anaemia, hepatomegaly and abnormal liver function, splenomegaly, endocrine disturbance, cardiac involvement, and ophthalmic involvement.Neurological phase
The second phase of the disease, the neurological phase, begins when the parasite invades the central nervous system by passing through the blood–brain barrier. Progression to the neurological phase occurs after an estimated 21–60 days in case of T. b. rhodesiense infection, and 300–500 days in case of T. b. gambiense infection.In actuality, the two phases of African trypanosomiasis—the hemolymphatic stage and the neurological stage—often overlap, and their clinical features can be nonspecific or evolve gradually, making it difficult to distinguish them based on symptoms alone. While signs such as enlarged lymph nodes and intermittent fever are more characteristic of the early stage, and neuropsychiatric symptoms such as sleep disturbances, confusion, or motor abnormalities suggest progression to the later stage, these indicators are not definitive. Consequently, to accurately determine the stage of the disease, specifically to determine central nervous system involvement, a lumbar puncture is performed to analyze the cerebrospinal fluid. The detection of trypanosome parasites in the CSF confirms that the infection has progressed to the neurological phase. This assessment is crucial because treatment protocols differ depending on whether or not the central nervous system has been affected. In the later stage, more intensive drugs that can cross the blood-brain barrier are necessary to eliminate the parasites from the brain and spinal cord.
Sleep disorders
Sleep-wake disturbances are a leading feature of the neurological stage and give the disease its common name of "sleeping sickness". Infected individuals experience a disorganized and fragmented sleep-wake cycle. Those affected experience sleep inversion resulting in daytime sleep and somnolence, and nighttime periods of wakefulness and insomnia. Additionally, those affected also experience episodes of sudden sleepiness.This sleeping impairment is also related to disruptions of circadian rhythm, the body's internal clock, which regulates rhythmic behavior, including metabolic patterns in cells. Studies indicate T. brucei alters the oscillatory expression of clock genes in the suprachiasmatic nuclei, among other brain regions, charged with circadian regulation. This alteration of expression may be moderated by the host's immune responses, such as parasitic activity and inflammation resulting from elevated TNF-α levels.
Neurological/Neurocognitive symptoms
Neurological symptoms include: tremor, general muscle weakness, hemiparesis, paralysis of a limb, abnormal muscle tone, gait disturbance, ataxia, speech disturbances, paraesthesia, hyperaesthesia, anaesthesia, visual disturbance, abnormal reflexes, seizures, and coma. Parkinson-like movements might arise due to non-specific movement disorders and speech disorders.Psychiatric/Behavioural symptoms
Individuals may exhibit psychiatric symptoms, which can sometimes dominate the clinical presentation. These symptoms include aggressiveness, apathy, irritability, psychotic reactions and hallucinations, anxiety, emotional lability, confusion, mania, attention deficit, and delirium.Advanced/Late disease and outcomes
Without treatment, the disease is invariably fatal, with progressive mental deterioration leading to coma, systemic organ failure, and death. An untreated infection with T. b. rhodesiense will cause death within months whereas an untreated infection with T. b. gambiense will cause death after several years. Damage caused in the neurological phase is irreversible.Circadian rhythm interactions
, an intrinsic clock that mediates rhythm of biological function, is affected by African trypanosomiasis. T. brucei alters the rhythmic activity of clock genes in basal forebrain, hypothalamus, thalamus, locus coeruleus, brainstem, etc. Both parasitic activity and inflammation induced by elevated TNF-α levels impairs oscillatory expression within the host. These disruptions to regulate circadian gene expression are evidenced to contribute to key symptoms of African trypanosomiasis, such as fragmented sleep, temperature changes, and abnormal hormone release.