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Infectious Disease and Neurocognition
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15
Neurocognitive and Neuropsychiatric
Manifestations of Human
African Trypanosomiasis
Leonard Ngarka and Alfred K. Njamnshi
Introduction
Human African trypanosomiasis (HAT), commonly known as sleeping sickness, is
a parasitic infection caused by the protozoan Trypanosoma brucei (World Health
Organization (WHO), 2022). It is a vector- borne disease and is transmitted via infective bites of the tsetse y (Glossina species), which is only found in sub- Saharan
Africa. Sleeping sickness evolution follows two distinct patterns attributable to the
two morphologically indistinguishable subspecies of the trypanosomes (Centers for
Disease Control and Prevention, 2020):
• T.b. gambiense, also known as west African or Gambian African trypanosomi-
asis, can be found in 24 countries of west and central Africa, and is the cause
of 97 percent of cases diagnosed. Its main reservoir is humans, and it causes a
chronic disease pattern.
• T.b. rhodesiense, or east African or Rhodesian African trypanosomiasis, is found
in the eastern and southern parts of Africa and only causes about 3 percent of all
the diagnosed cases of HAT. T.b. rhodesiense is a zoonotic infection, and its main
reservoir is domestic cattle. It causes an acute illness pattern.
It should be noted that HAT and American trypanosomiasis, or Chagas disease
caused by Trypanosoma cruzi, are completely dierent in terms of clinical manifest-
ations, vectors, and treatment (Hnaide, 2019).
More than 40,000 new cases of HAT were reported in 1998, but due to inadequate infrastructures, it is estimated that about 300,000 cases were undiagnosed
(WHO, 1998). However, thanks to the systematic global data collection that started
80 years ago with continued control eorts, these numbers have been decreasing
steadily, and in 2019, the number of cases dropped below 10,000 for the rst time
in 50 years. In 2020, 663 new cases of HAT were reported, and without treatment,
Leonard Ngarka and Alfred K. Njamnshi,
Diseases in Neurocognitive and Neuropsychiatric Medicine
Oxford University Press. © Oxford University Press 2024. DOI: 10.1093/ oso/
Infectious Disease and Neurocognition
HAT has a mortality rate as high as 100 percent. It is endemic in 36 countries, but
70 percent of all the reported cases in the past 5 years have been in the Democratic
Republic of Congo (Simarro et al., 2011). It predominantly aects people living in
rural areas, and this disease’s lethality lies in the delay of its diagnosis (Franco et al.,
2014; WHO, 1998).
Although the rst reports of sleeping sickness date back to 1734 by English naval
surgeon John Aktins, it was not until 1901 that the rst observation of trypanosomes in human blood was made. Later on, Africa was shaken by three severe epidemics: one between 1896 and 1906, mainly in Uganda and the Congo Basin, one in
1920, and the most recent outbreak began in 1970, which lasted until the late 1990s
(Steverding, 2008).
e clinical manifestations of trypanosomiasis are numerous and can be broken
down into two stages: the early or hemolytic stage and the late or neurologic stage.
However, we will be focusing more on its neurocognitive and neuropsychiatric
manifestations.
Life cycle and pathogenesis
Out of the 9000 genes of trypanosomes, 10 percent code for variant surface glycoproteins, which are distributed on the surface of the trypanosome and play a crucial role in its immunity. Antigenic variation, which is a gene conversion process
switching the variant surface glycoprotein genes in and out of the expression site,
constantly occurs at the conversion site, with only one variant surface glycoprotein
expressed at a time, thus helping the parasite to evade the host’s immunity (Kennedy
& Rodgers, 2019). As a consequence, to this day, no vaccine has been shown to be effective against Trypanosoma.
In the human serum, some proteins called trypanosome lytic factors (TLFs) are
able to cause the lysis of trypanosomes. ey are contained within two serum protein complexes, TLF- 1 and TLF- 2, and are called apolipoprotein L1, apolipoprotein
A1, and haptoglobin- related protein. However, with time, T.b. rhodesiense and T.b.
gambiense have developed dierent mechanisms to resist this lysis.
For T.b. rhodesiense, the serum resistance- associated (SRA) protein encoded by
the SRA gene binds to the TLF- 1, thus making it resistant to lysis. In T.b. gambiense,
however, the SRA gene being nonexistent, another mechanism that reduces
haptoglobin- hemoglobin receptor expression is used. is eectively blocks the
binding and uptake of TLF- 1, and consequently stops the lysis process.
Mammalian stage
e life cycle of T. brucei starts with a blood meal of the tsetse y from an infected
host, that is from either a human or an animal reservoir (Buscher et al., 2017; Centers
Human African Trypanosomiasis 231
for Disease Control and Prevention, 2020; Simarro et al., 2011). Two to 3 weeks aer
ingestion of the metacyclic trypanosomes, which are highly infective, the parasites
aer multiplication migrate to the salivary glands from where they will be injected
into the skin of their mammalian host, thus causing the appearance of a painful
chancre at the site of the bite 5– 15 days later. Further multiplication by binary ssion
occurs, and the parasites, which are now blood trypomastigotes, move throughout
the body and invade the various bodily uids (lymph, blood, cerebrospinal uid
(CSF), etc.), thus infecting almost every organ in the body including the liver, spleen,
heart, endocrine organs, and visual system. is is called the early or hemolymphatic
stage. ey eventually reach the central nervous system (CNS), causing neurological disorders and behavioral changes. is is known as the late, CNS or encephalitic stage.
Arthropod stage
Blood trypomastigotes are ingested by the tsetse y during a blood meal and reach
the midgut of the vector where they are transformed into procyclic trypomastigotes
and multiply further by binary ssion. Procyclic trypomastigotes then leave the
midgut, become epimastigotes, and travel to the vector’s salivary glands, where they
multiply further and evolve into metacyclic trypomastigotes.
Although the tsetse y bite is the main mode of transmission, there are other ways
sleeping sickness can be contracted, namely:
• Mother- to- child transmission— the parasite can cross the placenta and infect
the fetus
• Mechanical transmission— through other blood- sucking insects
• Accidental transmission— in laboratories through needle pricks
• Blood transfusion
• Sexual intercourse.
Clinical manifestations
e patterns of progression of HAT vary according to (WHO, 1998):
• Parasite subspecies: T.b. rhodesiense has a more acute progression than T.b.
gambiense, and healthy carriers and self- cure have been identied in the latter
(Jamonneau et al., 2012); see Table 15.1.
• e level of host susceptibility: travelers from non- endemic countries do not always present the same clinical characteristics as those residing in endemic areas.
Furthermore, even within the same African country, disease patterns can vary
widely.
Infectious Disease and Neurocognition
Table 15.1 Comparison between the two types of trypanosomes
Factor of comparison T.b. rhodesiense T.b. gambiense
Percent of HAT cases 3 97
Reservoir Cattle Human
Disease pattern Acute Chronic
Chancre Common Rare
Winterbottom sign Absent Present
Onset of late- stage
symptoms
Abbreviations: HAT, human African trypanosomiasis.
21– 60 days 300– 500 days
Though two stages have been defined, the signs and symptoms of both stages
usually overlap, and differentiating the two based on clinical features alone is
almost impossible. Recent studies show that, in some cases, neurological symptoms may occur during the early phase of the disease. In Uganda, for example,
cranial nerve palsies, urinary incontinence, somnolence, tremor, and abnormal
gait were detected in some patients with early- stage T.b. rhodesiense disease in
two distinct regions.
Early stage
e hemolymphatic stage is characterized by vague nonspecic symptoms such as
malaise, arthralgia, and intermittent fever lasting from 1 to 7 days. Five to 15 days
aer the infected tsetse y bite, a painful chancre appears at the inoculation site. is
occurs mostly when the host is infected with T.b. rhodesiense and is rare with T.b.
gambiense infection, except in cases where the host is a traveler from a non- endemic
region.
With the spread of the trypanosomes throughout the body, there is the appearance
of lymphadenopathies especially in the posterior cervical region (Winterbottom
sign characteristic of T.b . gambiense) but also possible in the inguinal, epitrochlear,
and axillar regions. Hepatosplenomegaly, hemolytic anemia, and endocrine and
visual involvement may also occur.
Intermittent fever with rigors 1– 3 weeks following infection is common.
Accompanied with myalgia, arthralgia, and headaches, it usually renders the diagnosis
challenging as this leads to a misdiagnosis of malaria, which may occur concurrently.
In travelers from non- endemic areas, however, the presentation is atypical with
mainly an acute febrile disease and gastrointestinal symptoms such as diarrhea and
jaundice and rarely lymphadenopathy.
Human African Trypanosomiasis 233
In addition, dermatological reactions such as transient urticarial, erythematous,
or macular rashes 6– 8 weeks aer onset and trypanids, which are ill- dened, centrally pale, evanescent, annular, or blotchy edematous erythematous macules on the
trunk, may occur as a result of a hypersensitivity reaction.
Late stage
e second or late or encephalitic stage of HAT is marked by the appearance of
neurological symptoms. In T.b. gambiense, it takes about 300– 500 days for the
parasites to cross the blood– brain barrier (BBB), while it takes only 21– 60 days for
T.b. rhodesiense. In the encephalitic stage of HAT, widespread leukoencephalitis
was shown in the white matter during neuropathological studies as well as in
basal ganglia, thalamus, and hypothalamus and around the third ventricle. In
chronic cases, numerous morular- shaped plasma cells loaded with immunoglobulins (Mott’s cells) are scattered in the brain. us, in addition to the symptoms of
the rst stage, patients in the second stage experience disturbances in their sleep
cycles and psychological, motor, and sensory disturbances. e characteristic daytime sleepiness, nocturnal insomnia, and sudden urges to sleep occur here in stage
2 in both T.b. gambiense and T.b. rhodesiense, and so the name sleeping sickness
takes on its full meaning. Other less specic symptoms might also occur including
headaches, which are refractory to analgesics, loss of appetite leading to weight
loss, and sensory disturbances.
Neuropsychiatric and neurocognitive manifestations
Sleep– wake cycle disturbances
During one night, a human being may go through four to ve sleep cycles. Each cycle
is made up of three main stages: wake, non- rapid eye movement (NREM), and rapid
eye movement (REM), in this order (Patel et al., 2022). In sleeping sickness, however,
the patients exhibit episodes of sleep onset rapid eye movements (SOREM), during
which the patients go directly from wakefulness to REM sleep without passing
through non- REM sleep stage (Kennedy, 2013).
One complete cycle may last for about 90– 110 minutes. Sleep regulation is done
through hormonal control by the circadian rhythm, which is driven by the suprachiasmatic nucleus of the hypothalamus (Patel et al., 2022). Before crossing
the BBB, a high number of trypanosomes accumulate in the choroid plexus and
circumventricular organs for a long time. Here, they are in close contact with the
neural centers responsible for the regulation of sleep cycles. us, the inammatory reactions elicited by these parasites release chemicals that may selectively target
Infectious Disease and Neurocognition
these structures and lead to the disruption of the circadian rhythm (Bentivoglio,
2008; Kristensson et al., 2010).
Current knowledge based on mice experiments shows that when infected with
T. brucei, the level of extracellular adenosine during wakefulness increases along
with the production of somnogens, thus increasing the sleep drive. e end results
of this cascade include daytime somnolence with sudden urges to sleep followed by
night- time insomnia (Rijo- Ferreira et al., 2020).
Psychiatric disturbances
During the invasion of the CNS by trypanosomes, dierent areas of the brain are
aected, leading to the appearance of an array of manifestations corresponding to
each aected area. Patients with stage 2 HAT usually suer from mental changes as a
result of damage to the brain tissue. ese include aggressive behavior, violent mood
swings, attention decit, emotional lability, indierence, apathy, stereotyped behavior, dissociative fugue, manic episodes, melancholy, confusion, hallucinations, dementia, and delirium. ese worsen as the disease progresses. Also, excessive sexual
impulses may be noted, as the circadian rhythm system also plays a role in arousal
(Kennedy, 2004).
Sensory disturbances
Sensory manifestations are common in HAT and usually include paresthesia, anesthesia, deep hyperesthesia, and pruritus. Abnormal reexes like the pout and palmomental reexes can also be noted in some cases.
Motor disturbances
Another consequence of cerebral damage from HAT is denoted by motor abnormalities. Patients exhibit both pyramidal and extrapyramidal syndromes,
with abnormal choreiform movements, muscle fasciculations, and tremors
of the tongue, hands, and fingers, as well as hypertonicity and hypotonicity.
Also, slurred speech and gait disorders such as cerebellar ataxia might occur
(Figure 15.1).
In the nal stage of the disease, seizures may occur (rarely in adults but more
commonly in infants) followed by progressive impairment of consciousness, incontinence, and eventually death in most cases without treatment (Kennedy &
Rodgers, 2019).
Sleep
Psychiatric/menta
disturbances
disturbances
Sensory
disturbances
Motor
disturbances
Human African Trypanosomiasis 235
• Sleep Onset Rapid Eye Movement (SOREM)
• Sudden sleep urges
• Daytime somnolence
• Nightime insomnia
• Agressive behavior
• Violent mood swings
• Attention deficits
l
• Manic episodes
• Melancholy
• Confusion
• Hallucinations
• Dementia
• Delirium
• Paresthesia
• Anesthesia
• Deep hyperesthesia
• Pruritus
• Choreiform movements
• Muscle fasciculations
• Tremors of the tongue
• Hands and fingers
• Hyper/hypotonicity
• Slurred speech
• Cerebellar ataxia
• Seizures
Figure 15.1 Neuropsychiatric manifestations of trypanosomiasis.
Management
Diagnosis
Over the years, many techniques have been developed for the diagnosis of HAT.
However, in endemic areas, most of these diagnostic tools are not used due to their
unavailability, and a positive evolution following empiric treatment is usually considered a conrmatory test (Hnaide, 2019). Some of the above- mentioned tests include the following:
• General blood studies and serology: the most commonly found anomalies in HAT include anemia, hypergammaglobulinemia, low complement
levels, elevated erythrocyte sedimentation rate, thrombocytopenia, and
hypoalbuminemia. West African trypanosomiasis can be diagnosed using the
card agglutination test for trypanosomiasis, a highly sensitive serologic test that
can be performed in 10 minutes and that does not necessitate electricity. It is the
standard serologic essay.
Infectious Disease and Neurocognition
• Blood smear: a Giemsa- stained thick smear that is highly sensitive can be examined to detect mobile trypanosomes. However, this must be done within 15–
20 minutes aer the sample collection as the parasites will no longer be mobile
aerwards.
• Lymph node or bone marrow aspiration: lymph node aspiration. which is more
useful in the case of T. b. gambiense, is a rapid test that can be done at high dry
magnication. Bone marrow aspirates sometimes show positive results.
• Lumbar puncture and CSF assay: in all patients in whom sleeping sickness is
suspected or who have positive serological tests, a lumbar puncture should be
performed to monitor the levels of white blood cells, proteins, and immunoglobulin M, as well as to identify trypanosomes in the CSF. us, if the patient is
indeed infected, these should increase.
Treatment
In the early stage of HAT, treatment focuses on managing acute symptoms such as
fever, malaise, and other nonspecic symptoms. e patient’s neurological status
should be closely monitored as the disease progresses. Patients might need airway
management to prevent aspiration if they develop severe neurological signs, and intensive care unit admission is mandatory for better monitoring of medication side
eects.
e treatment of HAT is dependent on the disease subtype and stage. e earlier
the treatment is started, the better the prognosis (Kennedy, 2013; Singh et al.,
2021). ere are six main drugs that are recognized and distributed in the endemic
areas by the WHO free of charge: pentamidine, suramin, melarsoprol, nifurtimox,
eornithine, and fexinidazole (Table 15.2). If treatment fails, the patient will continue to deteriorate, fall into a comatose state, and eventually die.
A recent phase II/ III clinical trial has shown the ecacy and safety of a single dose
of new drug, acoziborole. in the treatment of all stages of HAT. In this study, three
tablets of 320 mg of acoziborole were administered. Patients were followed up regularly for 18 months. A clinical success rate of 95 percent was recorded with very mild
complications such as asthenia and pyrexia (Betu Kumeso et al., 2022).
Current knowledge on the topic and knowledge gaps
In 2014, the WHO launched a program to eradicate HAT worldwide, including
national sleeping sickness programs, groups developing new tools to ght the
disease, international and nongovernmental organizations, and donors. e
roadmap for WHO’s neglected tropical disease program aimed to eradicate HAT
as a public health problem by 2020 and interrupt transmission by 2030. Since
2014, huge eorts have been made. In 2017 a breakthrough was attained with the
Human African Trypanosomiasis 237
Table 15.2 HAT treatment according to disease stages
Stage Subtype Drugs Route of
administration
First WA T Pentamidine IV/ IM Hypotension
EAT Suramin IV Nephrotoxicity
Second WAT Melarsoprol IV PTRE
WAT Nifurtimox IV Alcohol consumption during the
WAT Eornithine IV Very limited supply
EAT Melarsoprol IV Contraindicated in G6PD deciency
Both WAT Fexinidazole Oral Hepatotoxicity
Abbreviations: EAT, East African Trypanosomiasis; IM, intramuscular; IV, intravenous; PTRE, post- treatment reactive encephalopathy; WAT, West African trypanosomiasis.
Warnings
Nephrotoxicity
Bone marrow toxicity
Contraindicated in G6PD deciency
treatment is contraindicated
Genotoxicity
Teratogenicity
Carcinogenicity
Weight loss
Hypersensitivity reactions
Best used in combination with nifurtimox
Neutropenia
Avoid concomitant alcohol consumption
target of less than 2000 reported cases per year worldwide being achieved (Franco
et al., 2022).
Furthermore, the population at risk of developing sleeping sickness was estimated
at around 55 million people between 2016 and 2020. However, areas at high and
moderate risk for HAT have decreased signicantly since then, with only 6 percent considered as moderate or higher compared to 11 percent from 2014 to 2018.
Further, the WHO target is expected to have been reached in 2022 (Simarro et al.,
2012a, 2015).
From 2000 to 2010, 94 HAT cases were reported in non- disease endemic countries; of these, 72 percent were assigned to the T.b. rhodesiense form while only
28 corresponded to the T.b. gambiense form. e patients concerned were all
expatriates residing in the disease endemic countries for extended periods, and
refugees or economic migrants from the disease endemic countries (Simarro
et al., 2012b).
e World Health Assembly joined the WHO and validated at the end of
2020 a new roadmap for the years 2021– 2030, which sets new objectives for neglected tropical diseases including HAT (Franco et al., 2022). In this new plan,
T.b. rhodesiense remained among the diseases targeted for elimination as a public