Introduction of Human African Trypanosomiasis (HAT):
Human African trypanosomiasis (HAT) is also known as African sleeping sickness. It is an infectious disease caused by an extracellular protozoan parasite belonging to the genus Trypanosoma, species brucei. Two subspecies of Trypanosoma brucei are pathogenic for humans are T. b. gambiense and T. b. rhodesiense.
It is a zoonotic disease, affecting mainly animals such as livestock and wildlife, with humans being only accidentally infected. Transmission occurs through the bites of the tsetse fly vector, which belongs to the genus Glossina.
Pathogenesis, Causative Agent, and Transmission:
Antigenic variation is a mechanism that allows trypanosomes to evade immune clearance. The entire surface of trypanosomes is covered in variant surface glycoproteins (VSG). Periodically, the entire VSG surface coat is altered, and current antibodies are no longer able to identify it.
Immunoglobulin levels rise sharply as a result of this recurring interaction between the host antibody response and parasite antigenic diversity. Polyclonal B-cell activation results in the induction of non-trypanosome-specific antibodies, including a broad range of autoantibodies. The cerebrospinal fluid (CSF) and blood of HAT patients, as well as the brains of T. brucei-infected rodents, have been shown to contain elevated levels of prostaglandin D₂ reactive oxygen species and free radicals, such as nitric oxide; inflammatory cytokines, specifically interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and interleukin-1β; and anti-inflammatory cytokines, such as interleukin-10.
Blood-Brain Barrier (BBB) Invasion and CNS Pathogenesis:
The parasite’s penetration through the blood–brain barrier (BBB) and subsequent invasion of the central nervous system (CNS) parenchyma is the primary pathogenetic event that occurs during African trypanosomiasis. Although neuroinflammatory signals can be highly noticeable even in the early stages of the illness, this event signifies the second stage of the infection. Early after infection, before entering the central nervous system, T. brucei has been shown in animal models to localize to the dorsal root ganglia, which may explain early sensory symptoms, as well as to brain regions outside the blood-brain barrier, specifically the circumventricular organs (CVOs).
Even before parasite neuroinvasion, early parasite localization to the meninges and CVOs may result in the production of chemicals that impact neuronal subsets. Early host-parasite interaction may also entail glial activation in areas of the brain parenchyma close to the CVOs. Patients with HAT have been shown to have diffuse inflammatory alterations with inflammatory cell infiltrates in the leptomeninges and surrounding blood arteries in the parenchyma. Lymphocytes and plasma cells are the primary constituents of perivascular cuffs. Mott’s cells are morular, mulberry-like cells that can be detected in the brain parenchyma alone or in clusters with inflammatory cells.
Mott’s cells, which are characteristic of HAT but can also be found in other long-term inflammatory brain disorders, contain immunoglobulins of the IgM type. There hasn’t been much research done on the pathophysiology of neuropsychiatric changes during HAT. It’s interesting to note that CVOs reside in close proximity to the suprachiasmatic nucleus in the anterior hypothalamus, the master circadian pacemaker, and hypothalamic cell groups that are crucial for controlling sleep and wakefulness.
Clinical Features:
Trypanosomes proliferate at the site of infection and spread throughout the entire body, triggering the host immunological response that results in hepatosplenomegaly, fever, and adenopathies. Other organs that may be impacted include the skin, heart, and eyes. The first acute skin inflammatory reaction at the site of the infectious tsetse bite is known as the trypanosomal chancre, and it is common in infections caused by T. b. rhodesiense. Two to ten days after inoculation, this three to four centimeter lesion appears. It starts off as a painful nodule, but after a few days it changes into a furunculous-like lesion. Eventually, it becomes an erythematous chancre, which is tender and non-suppurative, sometimes accompanied by regional lymphadenopathy. It leaves a discolored scar after healing in two to three weeks.
Early Clinical Signs and Systemic Symptoms:
The pattern of fever during HAT is not constant. With fluctuating cycles of fever lasting several days and non-febrile periods accompanied by a relative clinical recovery, the temperature graph is erratic and may stay abnormal for months. Papuloerythematous eruptions (trypanides) of varying size, pattern (ring-like regions), and duration can manifest as skin rash. The erythema is more noticeable in those with light skin and primarily affects the trunk, shoulders, and thighs. According to Thomas M. Winterbottom, adenopathies affect all lymph nodes (axillary, inguinal, epitrochlear, etc.), but the laterocervical localization is common and is referred to as Winterbottom’s sign.
Edema primarily affects the face, causing swelling of the lower eyelids and a “puffy face.” It is more common in T. b. gambiense infections, while in T. b. rhodesiense infections, it is more commonly described as arm and leg swelling. Endocrine dysfunction, interruption of lymphatic outflow, and increased capillary fragility and permeability are all associated with edema. Fatigue, general malaise, and asthenia are additional common symptoms. Patients frequently characterize these symptoms as “weakness,” along with anorexia, weight loss, and joint and muscle pain (myalgias, arthralgias, and lumbalgia).
Conjunctivitis, keratitis, iritis, iridocyclitis, and choroidal atrophy are examples of ocular pathology brought on by parasite invasion of the eye. Even though neurological involvement is thought to be typical of second-stage HAT, early symptoms could be caused by both CNS changes and peripheral nervous system involvement. Pruritus and deep hyperesthesia are common symptoms at an advanced stage. Scratch marks often accompany pruritus, which can be localized or widespread. Behavioral changes, mood swings, anger, difficulty focusing, clumsiness, temporospatial disorientation, apathy, poor hygiene, decreased activity, and manic or depressed episodes are examples of early mental and neurological abnormalities.
Neurological Manifestations and Sleep-Wake Cycle Disturbances:
The disease can progress to neuropsychiatric features like sleep problems and psychological disturbances. At first, psychiatric symptoms are mild, characterized by a slowing down of mental processes, attention deficit, apathy, and indifference, along with behavioral changes that are typically noticed by family members and neighbors. Emotional instability, stereotypical behavior, impulsive conduct, antisocial behavior, melancholy, manic episodes, hallucinations, and ultimately delirium and/or dementia can all accompany anxiety, irritation, and agitation. The most distinctive symptoms of the illness are sleep problems. The symptoms of HAT include nocturnal insomnia, daytime somnolence, and an increasing disruption of the sleep-wake cycle throughout 24-hour.