NEUROLOGICAL PROGRESS
The Continuing Problem of Human African
Trypanosomiasis (Sleeping Sickness)
Peter G. E. Kennedy, MD, PhD, DSc
Human African trypanosomiasis, also known as sleeping sickness, is a neglected disease, and it continues to pose a major threat
to 60 million people in 36 countries in sub-Saharan Africa. Transmitted by the bite of the tsetse fly, the disease is caused by
protozoan parasites of the genus Trypanosoma and comes in two types: East African human African trypanosomiasis caused by
Trypanosoma brucei rhodesiense and the West African form caused by Trypanosoma brucei gambiense. There is an early or hemolymphatic stage and a late or encephalitic stage, when the parasites cross the blood–brain barrier to invade the central nervous
system. Two critical current issues are disease staging and drug therapy, especially for late-stage disease. Lumbar puncture to
analyze cerebrospinal fluid will remain the only method of disease staging until reliable noninvasive methods are developed, but
there is no widespread consensus as to what exactly defines biologically central nervous system disease or what specific cerebrospinal fluid findings should justify drug therapy for late-stage involvement. All four main drugs used for human African trypanosomiasis are toxic, and melarsoprol, the only drug that is effective for both types of central nervous system disease, is so toxic that
it kills 5% of patients who receive it. Eflornithine, alone or combined with nifurtimox, is being used increasingly as first-line
therapy for gambiense disease. There is a pressing need for an effective, safe oral drug for both stages of the disease, but this will
require a significant increase in investment for new drug discovery from Western governments and the pharmaceutical industry.
Ann Neurol 2008;64:116 –127
Human African trypanosomiasis (HAT), which is also
known as sleeping sickness, is one of the “neglected
diseases,” a group that includes visceral leishmaniasis,
schistosomiasis, and Chagas’ disease.1 Although these
diseases kill or disable hundreds of thousands of people
in underdeveloped tropical regions, current treatment
for them is often antiquated, highly toxic, and frequently ineffective. The pharmaceutical industry and
Western governments have until recently shown little
interest in developing new drugs for these diseases because this is associated with little or no prospect of
generating significant short- or long-term financial
gain. Although there has been an entirely understandable emphasis in recent times on combating such
global killers as malaria, acquired immune deficiency
syndrome, and tuberculosis, it should be appreciated
that HAT is a major threat to the health of 60 million
people in 36 countries in sub-Saharan Africa.2 Moreover, HAT is the world’s third most important parasitic disease affecting human health after malaria and
schistosomiasis, as defined by the global burden of parasitic disease, calculated as the disability adjusted life
years lost.1
HAT is caused by protozoan parasites of the genus
Trypanosoma, single-celled organisms that remain in ex-
tracellular form in the host. There are two forms of the
human disease, the East African variant caused by
Trypanosoma brucei rhodesiense and the West African
form caused by Trypanosoma brucei gambiense3 (Fig 1).
If untreated, the disease is always fatal. Transmission of
the disease in both humans and cattle is by the bite of
the blood-sucking tsetse fly of the Glossina species.4 Infestation by the tsetse fly covers 10 million square kilometers, one third of Africa’s landmass, which is an
area slightly larger than the United States.1 African animal trypanosomiasis, important in domestic livestock
such as cattle that suffer from a wasting disease called
nagana, as well as wild animals, was first shown to be
caused by Trypanosoma brucei by David Bruce in 1899
while investigating a major outbreak of nagana in Zululand.5,6 Subsequent work by Aldo Castellani enabled
the identification of trypanosomes in the blood and cerebrospinal fluid (CSF) in human patients with HAT
in 1903,6,7 and parasites causing the two human disease variants were identified during the period 1902 to
1910.6 Both animals and humans can act as reservoirs
of parasites capable of causing the human disease, but
the detailed mechanisms by which this occurs are not
fully understood. Animal trypanosomiasis has a major
human and economic impact because it adversely af-
From the Department of Neurology, Division of Clinical Neurosciences, Faculty of Medicine, University of Glasgow Institute of
Neurological Sciences, Southern General Hospital, Glasgow, GS1,
4TF, Scotland, UK.
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI: 10.1002/ana.21429
Received Mar 11, 2008, and in revised form Apr 23. Accepted for
publication May 1, 2008.
116
Address correspondence to Dr Kennedy, Southern General Hospital, Glasgow G51 4TF, United Kingdom.
E-mail: [email protected]
Published 2008 by Wiley-Liss, Inc., through Wiley Subscription Services
Fig 1. Distribution of East and West African sleeping sickness
in sub-Saharan Africa. Green areas represent Trypanosoma
brucei gambiense infection; brown areas represent Trypanosoma brucei rhodesiense infection. (Modified from Atouguia
and Kennedy.)
fects livestock production and farming. During the first
half of the twentieth century, HAT caused by T.b.
gambiense decimated entire communities in central Africa,8 but then the disease was almost brought under
control during the 1960s primarily as a result of highly
effective surveillance programs. But HAT then quickly
reemerged with a progressive increase in the numbers
of new cases and deaths. The World Health Organization (WHO) provided estimates during the period
1986 to 2004 about the disease that have been widely
quoted, with an annual prevalence of 300,000 to
500,000 cases.2,9,10 Factors causing this increase were
primarily war and famine, which resulted in severe disruption of disease surveillance and treatment, especially
in Uganda, Angola, Sudan, and the Congos where the
disease occurred in epidemics.11 Although it is still difficult to provide accurate estimates of disease incidence
and prevalence, more recent WHO estimates have suggested that as a result of more efficient surveillance, a
significant improvement has occurred with currently as
low as 70,000 existing cases, mainly infected with T.b.gambiense.10 However, HAT has already demonstrated
its ability to recur even after it had been virtually
brought under control. About 50 cases of HAT occur
annually outside of Africa,12 usually as a result of
Western travelers returning to North America or Europe from the East African game reserves; therefore, all
physicians need to be aware of the key features of the
disease and its most appropriate drug therapy.
Outline of Parasite-Host Biology
Details of parasite-host biology have been given elsewhere.3,4 Although animals are the main reservoir for
T.b. rhodesiense parasites, humans are the main reservoir for T.b. gambiense parasites.1,4 In brief, the tsetse
fly vector feeds on an infected animal or human, after
which the ingested trypanosomes undergo a number of
biochemical and structural alterations in the fly’s midgut. Infective forms of the trypanosome then reach the
fly’s salivary glands from which they are transmitted to
the human host through biting. A fly remains infective
for life, and the whole infective cycle is probably completed successfully in only 1 in 10 flies.4 Approximately
5 to 15 days after infection, a painful skin lesion called
a trypanosomal chancre may develop at the site of the
bite.4 The parasites spread in the host bloodstream 1 to
3 weeks after the initial bite, and invade the lymph
nodes and systemic organs including the liver, spleen,
heart, endocrine system, and eyes in what is termed the
early, stage 1, or hemolymphatic stage.3,4 If untreated,
within a few weeks in the case of rhodesiense infection,
or many months in the case of gambiense infection, the
parasites will cross the blood–brain barrier (BBB) and
enter the central nervous system (CNS), which marks
the late, stage 2, or encephalitic stage of the disease.4,13
The entire tempo of the disease is faster in the more
aggressive rhodesiense infection compared with the
chronic gambiense infection, probably as a result of the
greater adaptation of the latter parasite to the host.1,3
Much is known about the molecular biology of the
trypanosome, and the entire T. brucei genome was sequenced in 2005.14 It has about 9,000 genes, about
10% of which are variable surface glycoprotein (VSG)
genes encoding the VSG that are distributed on the
entire surface of the trypanosome.3 During infection,
the trypanosome is able to rapidly switch the expression of the VSG genes in and out of the expression
site, the result of which is antigenic variation in which
the surface VSG genes change so fast that the parasite
is able to constantly evade the host’s immune response.15 For this reason, it has not been possible, so
far, to develop a vaccine for HAT.
Clinical Features of the Disease
There is seldom a clear clinical distinction between the
early and late stages of HAT that may appear to run
into each other. Patients in the early, or hemolymphatic, stage may report nonspecific symptoms such as
malaise, headache, weight loss, arthralgia, and fatigue,
and also have episodes of fever accompanied by rigors
and vomiting, which may be misdiagnosed as malaria.13,16 There may also be generalized lymphadenopathy, and enlargement of posterior cervical lymph nodes
is typical of gambiense disease (“Winterbottom’s sign”).
Other symptoms and signs may correspond to particular organ involvement. Thus, there may be several dif-
Kennedy: Human African Trypanosomiasis
117
ferent kinds of skin rash, as well as pruritus, especially
in European patients in whom a macular, irregular, evanescent rash has been described as occurring in the
shoulders, trunk, and upper legs.17 Derangement of
liver function, hepatomegaly, a mainly hemolytic anemia, splenomegaly and cardiac dysfunction such as
tachycardia, myocarditis, pericarditis, and congestive
cardiac failure have been described.16,17 Many types of
endocrine dysfunction may occur such as loss of libido
and impotence, problems with menstrual function and
fertility (abortion, premature births or stillbirths, sterility), hair loss, gynecomastia, orchitis, and testicular atrophy.4,16 Parasite invasion of the eye may result in
iritis, conjunctivitis, iridocyclitis, keratitis, and choroidal atrophy.4,16 Patients are also prone to facial edema.
The neurological features of late- or encephaliticstage HAT are also protean and are summarized in Table 1. The various psychiatric and mental symptoms
such as anxiety, lassitude and indifference, agitation, irritability, mania, sexual hyperactivity, suicidal tendencies, and hallucinations could all be misdiagnosed either as only early-stage disease or as manifestations of a
primary psychiatric illness, but they are unlikely to occur in isolation. The neurological symptoms and signs,
which may develop insidiously, have been described
previously4,13,16,17 and are summarized here. A large
number of motor features may occur in late-stage HAT
with virtually every motor system at risk. Tremors in
the hands and tongue are common, choreiform movements of the head, limbs, and trunk may occur, as may
pyramidal weakness of the limbs.4 Lower limb paralysis
may also occur as a result of spinal cord involvement
(myelopathy or myelitis) or peripheral motor neuropathy. Patients may also show cerebellar ataxia with walking difficulties and slurred speech. Muscle fasciculation
may also be a feature.4 The most characteristic sensory
feature of late-stage HAT is a painful limb hyperesthesia that, when it has a deep quality, is called Kerandel’s
sign and is common in European patients, a quarter of
whom experience it, but is unusual in African sufferers.17 Abnormal reflexes indicating frontal lobe involvement such as pout reflex and palmomental reflexes may
also be present. The visual system may also be affected
by late-stage disease producing diplopia, optic neuritis,
papilledema, and subsequent optic atrophy.13,16
The characteristic sleep disturbances that occur in
the encephalitic stage give the disease its common
name. There is a disruption of the normal sleep/wake
cycle so the patient sleeps during the day but has nocturnal insomnia.18 Uncontrollable urges to sleep occur
without warning, and this becomes continuous in the
final stages. Recently, it has been shown using polysomnography that there is an alteration of sleep structure in these patients with the frequent onset of sleep
onset of rapid eye movements.18 Normally, REM sleep
occurs at the end of stage 4 sleep; these abnormalities
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Table 1. Neurological Features of Human African
Trypanosomiasis
Psychiatric and mental features
Lassitude and mental disturbances
Anxiety and irritability
Behavior disturbances (eg, violence, suicidal
tendencies)
Uncontrolled sexual impulses
Hallucinations, delirium
Sleep disturbances
Reversal of normal sleep/wake cycle
Daytime somnolence
Nocturnal insomnia
Uncontrollable urges to sleep
Alteration of sleep structure with sleep onset of
REM sleep
Motor disturbances
Pyramidal weakness
Extrapyramidal features (tremors and abnormal
movements)
Myelopathy and myelitis
Muscle fasciculation
Slurred speech
Cerebellar ataxia
Peripheral motor neuropathy
Pout reflex
Palmarmental reflexes
Sensory disturbances
Pruritus
Deep hyperesthesia
Also anesthesia, paraesthesia
Visual involvement
Diplopia
Optic neuritis
Papilledema
Optic atrophy
Drug induced
Peripheral neuropathy
Posttreatment reactive encephalopathy
Multifocal inflammatory syndrome
Seizures
Modified from Atouguia JLM, Kennedy PGE. Neurological
aspects of human African trypanosomiasis. In: Davis LE,
Kennedy PGE, eds. Infectious diseases of the nervous system.
Oxford: Butterworth-Heinemann, 2000:321-372, by
permission.
resolve with effective treatment. If untreated, or unsuccessfully treated, the natural course of HAT is for the
patient to progressively deteriorate with increasing
sleep disturbances, cerebral edema, incontinence, mental deterioration, seizures, and finally, death. The entire
course of the disease to death takes several weeks in
rhodesiense and several months or even years in gambiense disease. Because of the relative paucity of detailed
systematic studies of the neurological features of HAT,
it is difficult to say precisely how frequently the various
symptoms and signs occur individually or in combination. However, an early insight into this issue was provided by the classic study of Duggan and Hutchington17 of 109 cases of HAT in Europeans. They found
that in patients with both early- and late-stage disease,
the percentage of patients showing somnolence was
37.8%, headache was 24.5%, hyperesthesia was 26.6%,
tremor and abnormal movements was 25.7%, psychiatric symptoms was 20.1%, ataxia was 16.6%, and
slurred speech was 10.6%. Blum and colleagues19 recently provided considerable clarification of neurological feature frequency in HAT. In what is the most extensive analysis performed to date, these authors
defined the frequency of specific neurological involvement in a total of 2,541 patients with late-stage HAT
over a period of 3 years. They reported that the percentage of patients showing a sleep disorder was, as
would be expected, high at 74.4%, motor weakness
was 35.4%, gait disturbance was 22%, tremor was
21.2%, headache was 78.7%, behavior disturbance was
25%, speech impairment was 14.2%, and abnormal
movements was 10.7%.19 As the authors pointed out,
the reasons for the high variability of neurological
symptoms and signs in different geographic areas and
in the previous publications of HAT have yet to be
clarified.
Diagnostic Considerations
The correct diagnosis of HAT can be suspected in the
appropriate context that occurs when an individual develops a fever and suggestive symptoms in a HATendemic or epidemic region. The most important
differential diagnosis is malaria, especially when inappropriate antimalarial treatment is given to a patient
who actually has HAT and who then shows a temporary reduction of an intermittent fever.4,13 This dangerous situation may be complicated by the fact that
HAT and malaria may occur together in the same patient. Other infectious diseases that may enter into the
differential include human immunodeficiency virus infection, tuberculosis, toxoplasmosis, viral encephalitis,
brucellosis, lymphoma, typhoid fever, and hookworm.4
The physician confronted with a patient with HAT
would expect to find a number of nonspecific peripheral blood abnormalities such as a mainly hemolytic
anemia, increased erythrocyte sedimentation rate,
thrombocytopenia, abnormal liver function tests, increased IgM antibodies, and possibly a range of autoantibodies resulting from autoimmune responses.4 The
definitive method of establishing a diagnosis of HAT is
by demonstrating the presence of trypanosomes in the
peripheral blood or lymph-node aspirates (Fig 2). This
is easier in rhodesiense infection because of the persistently high parasitemia that generally occurs than in
gambiense disease, where the parasitemia tends to be
low. In the latter case, parasitological confirmation using concentration techniques is usually preceded by serological suspicion established using the card agglutination trypanosomiasis test, which is simple, quick, and
easy to perform.20 Problems in management may arise,
however, when the card agglutination trypanosomiasis
test is equivocally positive. Recently, new molecular diagnostic techniques for diagnosing HAT have been
tested. Thus, DNA amplification techniques such as
polymerase chain reaction21 and loop-mediated amplification22 have been used to detect trypanosomes in
patients’ peripheral blood, CSF, or both. Polymerase
chain reaction may have a high sensitivity rate, but it is
also associated with problems with test reproducibility,
an issue that appears to be less of a problem with loopmediated amplification.22
One of the most important issues in HAT is the
correct staging of the disease so that the early and late
stages can be distinguished reliably. This is absolutely
critical because the current treatment of late-stage disease, when the parasites have invaded the CNS, is so
toxic23 (see later). Because there are no reliable markers
of early-stage disease, all patients who are suspected of
having CNS involvement, including all those with a
positive card agglutination trypanosomiasis test, must
undergo a lumbar puncture to examine the CSF. The
physician dealing with such a case might expect a typical late-stage HAT CSF to show a pleocytosis, mainly
lymphocytes, with a white blood cell (WBC) count between 0 and 300/␮l, and at times even as high as
1,000/␮l or more, a moderate increase in protein concentration between 40 and 200mg/100ml, and an increase in the immunoglobulin concentration, especially
IgM caused by the strong IgM intrathecal synthesis.4,24
To give some idea of the most frequently encountered
CSF findings, in a major study of 181 patients with
Fig 2. Giemsa-stained light photomicrograph showing the presence of Trypanosoma brucei parasites (original magnification
⫻1,000), which were found in a thin film blood smear.
(Courtesy Centers for Disease Control and Prevention/Dr Mae
Melvin, Centers for Disease Control Public Health Image
Library)
Kennedy: Human African Trypanosomiasis
119
late second stage gambiense disease, the median CSF
WBC count was 93/␮l, with an interquartile range of
22 to 266/␮l and a maximum of 1,430/␮l.25 In the
same study, the median CSF protein was 78.7mg/
100ml, with an interquartile range of 45.4 to
106.5mg/100ml, and the greatest value was 203.8mg/
100ml.25 But there is not a universal agreement as to
what criteria define CNS involvement (apart from the
detection of trypanosomes in the CSF, which is seldom
easy). Moreover, there is also some disagreement as to
which CSF criteria actually determine whether the patient should be treated with late-stage–specific
drugs.3,24 The WHO criteria are the most commonly
used and define late-stage HAT as the presence of trypanosomes in the CSF and/or more than five
WBCs/␮l in the CSF.9 However, some clinicians in
West Africa use a higher cutoff WBC count of more
than 20,25 and others have suggested, reasonably in my
view, a midway figure of 10 WBCs/␮l.26 The CSF
IgM has also been shown to be a useful indicator of
CNS involvement.25 There is an urgent need for a
more reliable diagnostic test for late-stage HAT that is
cheap, reliable, easy to perform, field adaptable, and
with a high sensitivity and specificity.27 A particular
problem with introducing a new test is that there is
currently no “gold standard” test with which to compare it.27 Currently, there is no noninvasive test that
can reliably distinguish early- from late-stage disease.
There have been a few case reports of the use of
magnetic resonance imaging (MRI) in CNS HAT, although these have been, unsurprisingly, in patients returning or managed in Western hospitals. MRI findings are nonspecific, although consistent findings have
included diffuse hyperintensities in the basal ganglia,
internal and external capsules, asymmetric white matter
abnormalities (Fig 3), and ventricular enlargement.4,28,29 Based on understandably limited data,
MRI appears to be more sensitive than computed tomography in detecting HAT-associated abnormalities,28 although computed tomography has been reported as showing such changes as focal low densities
in the internal capsules and centrum semiovale and cerebral edema.4,28 Recent reports on two patients in the
American neurological literature have indicated that
MRI may be useful in the diagnosis of HAT in patients returning from visits to Africa, and may also help
in distinguishing different CNS syndromes seen in
CNS disease.30 –32 As expected, patients with late-stage
HAT have an abnormal electroencephalogram, with
three different types of nonspecific abnormalities that
both mirror the severity of the disease and improve
markedly with successful treatment.4 These electroencephalographic types are a sustained low- voltage background similar to that seen during light sleep, paroxysmal waves, or various types of delta wave and rapid
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Fig 3. Magnetic resonance imaging scan of a 13-year-old patient with central nervous system human African trypanosomiasis 3 years after successful completion of multiple treatments
for numerous relapses. The scan shows ventricular enlargement
(especially of the frontal horns) and diffuse white matter
changes, which are prominent in the right frontal horn (arrow) and periventricular regions. (Reprinted from Atouguia
and Kennedy.)
intermittent high-voltage delta bursts between periods
of lower-voltage delta activity.4
Current Treatment of Early- and Late-Stage
Disease
Current drug therapy for both early- and late-stage
HAT is unsatisfactory with a heavy reliance on four
main highly toxic drugs, most of which would have
probably failed current rigorous safety standards.33
Three of the drugs, suramin, pentamidine and melarsoprol, were developed during the first half of the
twentieth century, and the last drug to be registered for
HAT, namely, eflornithine (also known as DFMO),
was registered in 1981.1,3,23 Another drug named nifurtimox is registered for Chagas’ disease and is currently under close evaluation in promising trials of
combination chemotherapy. This depressing paucity of
safe and effective drugs for HAT has recently attracted
increasing attention from nongovernmental organizations and other funding bodies.
The standard treatment for early-stage rhodesiense
disease is intravenous suramin given as five injections
over 3 weeks. Important adverse effects include anaphylactic shock, renal failure, and skin lesions. Earlystage gambiense disease is treated with intramuscular
pentamidine given as daily injections over 7 to 10 days.
Important adverse effects of pentamidine include hypoglycemia, hyperglycemia, and hypotension.3,4 These
drugs are usually effective if treatment is started early.
The treatment of late-stage HAT is even more problematic because the only drug that is effective for both
types of the disease is the highly toxic arsenical melarsoprol (Mel B), which was first used for such patients
in 1949.3,4,23 Until recently, the standard regimen was
two to four courses of intravenous injections (three injections per course, with 1-week intervals between
them), but a more recent 10-day continuous melarsoprol regimen has been introduced for treatment of
gambiense disease34 and is now favored in many centers. Although melarsoprol is usually effective, it is followed by a severe posttreatment reactive encephalopathy (PTRE) in about 10% of patients, half of whom
die of it. This overall mortality rate of 5% of all patients receiving melarsoprol is one of the greatest problems in this field and highlights the extreme importance of correct staging of the disease. Although
treating patients who do not, in fact, have CNS disease
with melarsoprol will lead to an unnecessary 5% risk
for death, not treating a patient who does actually have
CNS disease will inevitably lead to death because of
the 100% fatality rate of HAT if untreated.1,3,13,35 Patients who acquire PTRE (usually after the first treatment course or near the end of the continuous treatment course) may experience development of deep
coma with seizures, convulsive status epilepticus, or
rapid progressive coma in the absence of seizures or
cerebral edema.4,13 Patients with the PTRE are treated
with intravenous corticosteroids, anticonvulsants, and
intensive general medical support, and those who survive need to continue the melarsoprol course. The possible role of corticosteroid pretreatment to prevent
and/or ameliorate the PTRE is currently unclear,3,13
although the author would probably choose this option
for himself. Recently, it has been shown that a combination regimen of melarsoprol and nifurtimox for gambiense disease is more effective than standard melarsoprol monotherapy regimens.36 Melarsoprol may also
produce cardiac arrhythmias, skin lesions, agranulocytosis, peripheral neuropathy, and as recently described,
a steroid-responsive multifocal inflammatory illness.3,30,31
There are alternative treatment options for latestage gambiense disease, although not for rhodesiense
disease for which melarsoprol remains the only effective drug. Treatment failure with melarsoprol, however, is well recognized.37 The drug eflornithine is being increasingly used for CNS gambiense disease,
either alone or in combination with other drugs. Eflornithine, which is expensive, became an orphan
drug even after it had been shown to be effective
against gambiense disease in 1981.1,3 But after an innovative partnership among Medécin Sans Frontières,
WHO, and the pharmaceutical industry, the drug was
again made available for HAT use in sub-Saharan Africa1 and is being used increasingly as first-line therapy and alternative therapy. It does, however, have to
be given by daily intravenous injection over at least
14 days, and its adverse effects include bone marrow
toxicity, seizures, and gastrointestinal symptoms.3,4,23
Recent clinical trials have tested various combinations
of drugs for late-stage gambiense disease, and the
emerging results are increasingly favoring the use of a
nifurtimox-eflornithine regimen as the most promising first-line therapy.38,39 The only new drug on the
immediate horizon for HAT is the diamidine derivative DB 289, a promising development funded by the
Bill and Melinda Gates Foundation.3,13 This drug is
given orally, can treat only early-stage disease, and has
been under recent evaluation in a Phase 3 clinical
trial. However, clinical trials with this drug (manufactured by Immtech Pharmaceuticals, New York,
NY) have recently been put on hold because of possible liver toxicity, and further development of this
drug has unfortunately been discontinued. A summary of current drug therapy for HAT is shown in
Table 2.
After successful treatment, all patients need to be
followed up with blood and CSF analyses at 6-month
intervals for 2 years, after which the patient is considered cured if these tests are normal.4,13 Treatment
failures do occur, however, and it has recently been
shown that the presence of intrathecal IgM synthesis
and increased CSF IgM IL-10 concentrations are significantly associated with the failure of treatment in
early-stage gambiense disease.40 Analysis of sleep structure with polysomnography may also prove useful in
detecting patients with relapses. Follow-up of patients
in the field is problematic, and as has recently been
pointed out, counting all patients who never turn up
for follow-up CSF examination can hardly be a good
measure of cure rates, especially when half the pa-
Table 2. Summary of Drug Therapy in Sleeping Sickness
Disease
First-Line Therapy
Alternative Therapy
Early-stage Trypanosoma brucei rhodesiense
Suramin
None
Early-stage Trypanosoma brucei gambiense
Pentamidine
Suramin
Late-stage T.b. rhodesiense
Melarsoprol
None
Late-stage T.b. gambiense
Melarsoprol
Eflornithine ⫾ nifurtimoxa
a
It is likely that eflornithine with or without nifurtimox may soon be the preferred first-line therapy for treating late-stage gambiense
disease.
Kennedy: Human African Trypanosomiasis
121
tients never show up.8 Patients who have been successfully treated for late-stage disease may still experience development of long-term neurological sequelae
such as weakness, ataxia, cognitive impairment, epilepsy, and psychiatric disorders.4
Neuropathogenesis
Pathological data in HAT have been obtained from a
relatively small number of autopsy studies. The key
findings in CNS HAT are an extensive meningoencephalitis, widespread infiltration of white matter with
inflammatory cells such as macrophages, lymphocytes
Fig 4. Brain pathology in central nervous system (CNS) human African trypanosomiasis. (A) Late-stage disease in a patient dying 3 to 5 months after first injection of melarsoprol.
Many large astrocytes are located in white matter. Stained for
glial fibrillary acidic protein by immunoperoxidase. Original
magnification ⫻400. (B) Morular (Mott) cells (arrows) observed in the brain of a patient with CNS trypanosomiasis
who had not received melarsoprol. Morular cells are plasma
cells filled with immunoglobulin. Hematoxylin and eosin (HE)
stain. Original magnification ⫻400. (C) Posttreatment reactive encephalopathy (PTRE) in a patient 9 days after receiving
melarsoprol. Ischaemic cell changes (arrows) are seen in neurons in the hippocampus. HE stain. Original magnification
⫻250. (D) PTRE with acute hemorrhagic leukoencephalopathy in a patient 9 days after receiving melarsoprol. There is
fibrinoid necrosis in an arteriole (arrow) and focal hemorrhage in the pons. Martius scarlet blue stain. Original magnification ⫻250. (Reprinted from Adams and colleagues,41 by
permission.)
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Fig 5. A schematic of the sleeping sickness mouse model of central nervous system (CNS) disease. PTRE ⫽ posttreatment reactive encephalopathy. (Reprinted from Kennedy,1 by permission.)
and plasma cells, extensive perivascular cuffing, astrocyte and macrophage activation, and a small amount of
demyelination.41– 43 A pathognomonic finding in the
white matter is the presence of morular or Mott cells,
which are plasma cells containing IgM eosinophilic inclusions41,42 (Fig 4).
The neuropathogenesis of HAT has been described
in considerable detail elsewhere,3,42– 45 and only few
key aspects are mentioned here. Not surprisingly,
only limited data have been obtained from patients in
the African field, primarily from analysis of immune
factors in blood and CSF where cause and effect can
be difficult to establish. Recently, it was shown in
two sites in Uganda that a greater plasma interferon-␥
level correlated with a greater severity of neurological
impairment in rhodesiense HAT patients, indicating a
pathological role of this cytokine.46 Patients with latestage rhodesiense disease have been shown to have significantly increased levels of the counterinflammatory
cytokine IL-10 in the plasma and CSF, declining to
normal levels after treatment.47 It is possible that it is
the balance of cytokines that is a key determinant of
the outcome of CNS disease.
Much of our mechanistic knowledge in this area
has been derived from animal models, in particular, a
highly reproducible mouse model of HAT that closely
mimics human late-stage disease and also allows the
identification of new therapeutic targets44,45,48 (Fig
5). Subcurative therapy of infected mice with the
drug berenil leads to an exacerbation of CNS disease
with neuropathological features that show strong similarities with the human PTRE.49 This approach has
allowed the identification of key players in the generation of the neuroinflammatory response such as the
roles of astrocyte activation, the neuropeptide substance P, and the balance of proinflammatory and
counterinflammatory cytokines, including tumor necrosis factor-␣ and IL-10, respectively50 –53 (summarized in Fig 6). Knock-out mice lacking specific inflammatory factors have also been used in several
laboratories.54,55 It appears likely that there is a complex array of CNS-cytokine interactions that ultimately determine the CNS damage in HAT.3,45
Moreover, several drugs and novel drug combinations
have been tested in the mouse model.56 –58 Rodent
models have also provided insights into the mechanism of BBB traversal by trypanosomes, an area of
crucial importance. For example, trypanosomes show
Fig 6. Schematic representation of possible immunopathological pathways leading to brain dysfunction in human African trypanosomiasis, based on data and concepts from both human and animal data. Cytokines shown in red probably have important roles in
neuropathogenesis. The schematic emphasizes the central importance of early astrocyte activation, cytokine responses, and macrophage
activation. There are likely to be multiple factors acting together to produce brain damage and also multiple potential sources of
different cytokines. IFN ⫽ interferon; MHC ⫽ major histocompatibility complex; NK ⫽ natural killer; NO ⫽ nitric oxide;
Tltf ⫽ trypanosome-derived lymphocyte triggering factor; TNF ⫽ tumor necrosis factor; VSG ⫽ variable surface glycoprotein. (Reprinted from Kennedy,3 by permission.).
Kennedy: Human African Trypanosomiasis
123
early invasion in brain areas that lack a BBB, such as
the pineal gland and median eminence.59 A seminal
study showed that in interferon-␥ knock-out mice,
parasites accumulated in the perivascular compartment, confined between the endothelial and parenchymal basement membranes, thus confirming the
critical role of interferon-␥ in parasite entry into the
CNS.60 The same group has shown that, in
trypanosome-infected rats, there is immunological
and biochemical disruption of the suprachiasmatic
nuclei of the hypothalamus with resultant disorganization of normal circadian rhythms61,62 (Fig 7).
These findings strongly suggest a credible neuropathological basis for the altered sleep/wake cycles
seen in HAT.
Conclusions
HAT continues to be a major
throughout sub-Saharan Africa and
for the foreseeable future. The two
in disease management are disease
health problem
is likely to be so
key related issues
staging and drug
therapy. Regrettably, progress in both of these areas
continues to be modest. In the absence of a noninvasive method of staging, it is inevitable that distinction
between early- and late-stage HAT will continue to
rely entirely on CSF examination. But not only is
there disagreement as to what biologically constitutes
CNS disease, there is also an absence of a consensus
as to what are the correct grounds for making therapeutic choices. Current drug therapy, especially for
late-stage HAT, is unacceptably toxic, and remarkably, there are no new drugs at all on the horizon for
treating CNS disease. If there were available a nontoxic oral drug for late-stage HAT, then most of the
staging problems would be immediately obviated.
These difficult problems are a direct result of many
decades of underinvestment in this neglected disease,
a trend that is beginning to be addressed. However,
they must be seen in the context of the wider efforts
to control the disease at the level of the tsetse fly vector1,63 because disruption of the man/tsetse fly contact through various technologies probably holds the
Fig 7. (A, B) Images of the hypothalamic suprachiasmatic nucleus (which plays a role of circadian pacemaker in the mammalian
brain) in sections processed for glial fibrillary acidic protein (GFAP) immunoreactivity. (A) Control noninfected rat. (B) Rat infected with Trypanosoma brucei brucei; note the astrocytic activation (shown by hypertrophy and increased immunoreactivity of
astrocytes) in the infected animal. (C–E) Images of the cingulate cortex of a rat infected with Trypanosoma brucei brucei (processed for double immunohistochemistry to show GFAP-immunolabeled astrocytes (red: C) and the proinflammatory cytokine tumor
necrosis factor (TNF)-␣ (green: D); (E) merging of two images (yellow) and, therefore, the colocalization of the two markers. (C)
Note the activation of astrocytes, (D) the induction of TNF-␣ expression in cells of the brain parenchyma, and (E) that TNF-␣ is
expressed in astrocytes. Scale bars ⫽ 100␮m (A, B); 25␮m (C–E). oc ⫽ optic chiasm; 3v ⫽ third ventricle. (Courtesy Maria Palomba, Gigliola Grassi-Zucconi and Marina Bentivoglio, University of Verona, Verona, Italy)
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key to the potential ultimate control of sleeping sickness.
The authors research is supported by grants from the Wellcome
Trust and the Medical Research Council.
I thank Drs J. Ndung’u and V. Lejon for their helpful comments on
the manuscript, and Dr J. Atouguia for advice. I am grateful to Prof
M. Bentivoglio for generously providing the unpublished Figure 7.
This article is dedicated to the memory of my recently departed
father, Philip Kennedy, a man of great compassion, outstanding intelligence, and unquenchable humor.
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