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Infectious Disease and Neurocognition
health problem, while T.b. gambiense was now targeted for elimination of trans-
mission. e main impediment to achieving the latter goal would be the cryptic
reservoirs, which are those with latent infection, and other factors such as further integration of HAT surveillance and control into national health systems,
the availability of skilled health workers, the development of more ecient systems and the right tools, and the funding and coordination of elimination eorts
(Franco et al., 2022).
Currently, no vaccine or prophylactic drug exists to ght against HAT (Table
15.2), and the preventive measures basically aim to avoid or reduce contact with infected tsetse ies (Table 15.3).
In Central Africa, HAT control is carried out routinely in Cameroon, the Central
African Republic, Chad, Congo, Equatorial Guinea, and Gabon. e number of
reported cases in Cameroon is not stable and uctuates over the years, and this is
the result of variations in the intensity of control and surveillance activities. For example, there was a reduction in these activities in 2020 compared to 2019 due to the
Covid- 19 pandemic (Franco et al., 2022).
In 2019 and 2020, targeted vector control activities against T.b. gambiense HAT
were implemented by the National Sleeping Sickness Control Program (NSSCP) and
research institutes in selected endemic areas of Cameroon, Chad, Côte d’Ivoire, the
Democratic Republic of Congo, Guinea, and Uganda. Vector control activities are
also carried out by the NSSCP in Angola. Vector control reduced tsetse y density in
targeted areas and helped curb HAT transmission.
Although enormous progress has been made to better understand HAT, gaps remain in our limited knowledge, and large- scale experiments are carried out in order
to ll them, the main area of uncertainty being the unpredictable pattern of disease
presentation from one individual to another.
e clinical manifestations of HAT have been documented in the research literature, but there remain scanty data on the long- term complications of this condition.
It is important to study the neuropsychological and other somatic complications of
this pathology.
Table 15.3 Preventive measures against HAT
Author Measure
WHO and CDC • Early detection of infected individuals, with clinical evaluation and
screening tests for at- risk populations, with attention to asymptomatic cases
• Health education, covering all inhabitants of at- risk areas and travelers
Alam et al. (2011) Vector control through traps, individual protection, and mass reduction of the
vector community of symbiotic bacteria of the genera Wolbachia, Sodalis, or
Wigglesworthia, essential to y survival.
Abbreviations: CDC, Centers for Disease Control and Prevention; WHO, World Health Organization.
Human African Trypanosomiasis 239
Findings from biological models
Biological models are experimental procedures that imitate aspects of human tissue
function or disease. Biological models are used in research to study specic biological processes. eir genetic characteristics are similar to those of human beings and
are commonly used in research elds such as genetics, developmental biology, and
neuroscience. Model organisms tell us a lot about biological systems at the organ and
system, tissue, and cellular level.
Mouse models are widely used in biomedical research to study disease progression and in the development of new drugs. ese have been challenging issues for
Trypanosoma and especially for T.b. gambiense as the form isolated from infected
patients does not cause infections in rodents (Giroud et al., 2009). As T.b. gambiense
can only propagate in certain rodents such as immunocompromised mice or specic rodent species, experimental models are therefore limited to only subacute or
chronic infections, thus limiting in vivo studies of this pathology. It is in this spirit
that the researchers therefore isolated dierent strains of T.b. gambiense from HAT
patients and adapted them to in vivo culture conditions (Giroud et al., 2009). is
allowed researchers to describe dierent pathological processes similar to those seen
in humans. Since trypanosomiasis is a pathology that still conceals many mysteries,
particularly regarding its neuropathology, being able to observe its evolution more
closely will undoubtedly lead to gigantic advances in the diagnosis and management
of this disease.
Ever since the articial growth of T. brucei was made possible, exploring the path-
ogenesis of HAT has become less problematic for scientists. e sleep disturbance
characteristic of the disease were found to be due to the crossover of the BBB by
Ferreira et al., 2020). Since in human beings the neurological symptoms do not appear until later in the course of the disease, it was common knowledge that parasite
crossover of the BBB occurred much later too.
However, this information has been challenged and contradicted recently in
Uganda, where in some cases of T.b. rhodesiense, it was noted that the neurological
signs expected in the second phase of the disease appeared much earlier at the same
time as the symptoms and signs of the rst phase, thus demonstrating that there may
not be a direct link between the stage of evolution, neurological signs of infection,
and neuroinammatory responses in T.b. rhodesiense HAT (Maclean et al., 2010).
During experiments in mouse models, parasites were detected only a few hours
aer infection in the brain parenchyma using intravital brain imaging, with minimal
to no inammation. Additionally, increased parasitaemia was associated with greater
microvascular inammation but not with neurological manifestations (Frevert et al.,
2012). Nevertheless, this study was limited as there was no histological evidence that
the parasites were actually present in the brain parenchyma as they could have been
present in the choroid plexus as previously proven but not in the neuropil (Laperchia
Infectious Disease and Neurocognition
et al., 2016). In the same vein, evidence of the presence of trypanosomes in the neuropil was found later but aer the appearance of neurological signs, the main one
here being the appearance of SOREM episodes thus indicating that SOREM periods
cannot provide a biomarker per se of the second stage of sleeping sickness, but a
high frequency of these sleep changes may be an indicator of this stage (Laperchia
et al., 2016).
e WHO has developed a staging system based on CSF analysis: rst stage—
absence of trypanosomes and ve or fewer white blood cells/ mm3 in the CSF; second
stage— presence of trypanosomes and/ or more than ve white blood cells/ mm3 in
the CSF (Njamnshi et al., 2017). However, as shown above, the parasites invade the
choroid plexus early on during the infection and thus invade the CSF.
erefore, new techniques need to be explored and new diagnostic criteria dened that will be more specic in the staging of HAT as management depends on
accurate staging. In this optic, several hypotheses have been listed to explain the
mechanism by which parasites cross the BBB, including transcellular (Masocha
& Kristensson, 2012; Mulenga et al., 2001) and paracellular (Grab & Kennedy,
2008; Grab et al., 2004; Nikolskaia et al., 2006) approaches. Biological models of
the human BBB constructed from human cerebral microvascular endothelial cells
cultured on Costar Transwell inserts were developed and used in vitro to further investigate the mechanisms by which T.b. gambiense crosses the BBB (Grab
et al., 2004). us, it was nally proven that the entry of the parasite into the BBB
is modulated by both transcellular and paracellular mechanisms occurring consecutively combining the actions of signaling pathways and parasite- associated
proteases and hydrolases (Nikolskaia et al., 2006). However, the molecular actors
involved in parasite- induced signaling and BBB crossover are still currently unknown (Nikolskaia et al., 2006).
Following the same vein, biomarkers found either in blood or CSF have been the
target of several experiments in order to nd more reliable diagnosis and staging
methods. Not long ago, immunoglobulins, cytokines such as interleukin- 10, and
chemokines such as CXCL10 and CXCL1312 were found to be useful biomarkers
(Amin et al., 2010). In a recent literature review (Ngay et al., 2019), it has been
stated that:
• CSF white blood cell count with a dened cut- o value most accurately assesses
treatment outcome.
• Intrathecal immunoglobulin M synthesis is a specic and sensitive param-
eter for the detection of CNS involvement in HAT cases caused by T. brucei
gambiense.
• Decreasing trypanosome- specic antibody concentrations in CSF could be a
good parameter for denitive cure.
• Elevated levels of interleukin- 10 in the CSF during treatment follow- up indicate
recurrent CNS inammation and treatment failure.
Human African Trypanosomiasis 241
• An increase in neopterin in the CSF and the presence of trypanosome- spliced
leader RNA in the blood have high potential as predictors of treatment failure
but require further validation.
However, in resource- limited countries, such as the ones which are the most
aected by HAT, the use of these biomarkers as a diagnosis or even a staging tool
would be a huge challenge. us, Njamnshi and colleagues have shown in a study
that actigraphy— a non- invasive method of monitoring human rest/ activity cycles—
could be used to evaluate clinical evaluation and monitoring in HAT (Njamnshi
et al., 2012). Moving forward, they demonstrated the ecacy of this method in HAT
staging during a pilot study. In this study, actigraphy sleep scores ranged from 67 to
250. Healthy individuals had scores ranging from 0 to 25, those in the early stage of
HAT from 67 to 103, those in the intermediate stage ranged from 111 to 126, and
late- stage patients ranged from 133 to −250 (Njamnshi et al., 2020). Nevertheless,
further investigations with bigger sample sizes are needed in order to project these
results to the general population.
Conclusion
e main neuropsychiatric manifestations of HAT include sleep disturbances,
mental/ neuropsychiatric disturbances, and sensory and motor disturbances. Even
though the second stage of HAT owes its name to the appearance of neurological
signs, the pathogenesis of the neurological involvement associated with HAT remains incompletely understood, which is all the more important since the treatment
is based precisely on the staging of the disease. anks to the eorts of the WHO, we
can now see the end of the tunnel when it comes to the total eradication of this disease. On the other hand, we must not rest on our laurels because with this progress;
new discoveries are also made, such as the possibility of the skin being a reservoir of
the parasite (Capewell et al., 2016) and thus slowing down its eradication. More effort would therefore be needed to explore cheaper methods such as the Actigraphy
Sleep Score (Njamnshi et al., 2020) in disease stratication but also new, less toxic
molecules for treatment and why not a vaccine?
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16
Associations Between T oxocara and
Neurocognitive Function
Celia V. Holland
Introduction
Human toxocariasis remains a neglected disease despite its global distribution. It is
a classic zoonotic infection enhanced by a worldwide association between humans
and their domestic pets, especially dogs and cats. Given increasing urbanization,
which is likely to increase human– animal contact, and climate change that will enhance egg survival in the environment, human beings will continue to be exposed to
this ubiquitous helminth infection. One might ask the question— why so neglected?
One explanation relates to how infection is manifested in the human body. Because
only larval toxocariasis infection occurs in humans, it is not easy to detect the parasite; by contrast, in other soil- transmitted helminths eggs or larvae are present in the
feces. Central to diagnosis is serology, a method by which only exposure to To x oc a ra
can be identied. Furthermore, the relationship between exposure and disease remains very poorly understood. ese challenges are at their most manifest when it
comes to cerebral toxocariasis, where To xo c ar a larvae are able to enter and survive in
the human brain (Fan et al., 2015).
Recently, several authors have highlighted the neglected status of toxocariasis
(Holland, 2017; Hotez & Wilkins, 2009), and the United States Centers for Disease
Control and Prevention has included toxocariasis among ve parasitic diseases that
aict the population in the United States and are deemed to be neglected. Peter
Hotez (2014) has explicitly stated that such infections may, at least in part, account
for the achievement gap found among socioeconomically disadvantaged students.
Evidence for the link between poverty and toxocariasis is now quite clear (Congdon
& Lloyd, 2011; Erickson et al., 2015; Sharghi et al., 2001). However, we must also
consider the signicant granularity in To x oc a ra exposure. Even aer allowing for
the elevated risk associated with poverty, ethnicity can still play an important role
in explaining increased risk of exposure (Congdon & Lloyd, 2011). Hotez (2008)
speculated that this elevation might reect dierential contextual exposures linked
inter alia to ethnic residential clustering and segregation, as distinct from the impact
of family poverty per se.
Celia V. Holland, Associations Between Toxocara and Neurocognitive Function In:
Medicine
DOI: 10.1093/ oso/ 9780192870414.003.0017
Toxocara 245
In this chapter, I briey outline the biology and epidemiology of toxocariasis
before focusing upon cerebral toxocariasis and the evidence for the impact of toxocariasis on neurocognitive function in humans. I also demonstrate how animal
models can enhance our understanding of the possible mechanisms behind such
eects.
Biology and epidemiology of T oxocara
To xo c ar a species (family: Toxocaridae) adult worms infect a wide range of domestic and feral denitive hosts. Toxocara canis (T. c an is ) infects domestic dogs
(O’Lorcain, 1994), foxes (Roddie et al., 2008), wolves (Segovia et al., 2001), and
coyotes (Wapenaar et al., 2013). Toxocara cati (T. ca ti ) infects cats and other felids
(Maciag et al., 2022). A related species also in the Toxocaridae family, Toxascaris le-
onine, can infect both dogs and cats (Miyazaki, 1991). Highly fecund adult worms
release resistant eggs into the environment (Mizgajska- Wiktor & Uga, 2006). Under
certain conditions of temperature and moisture, eggs can undergo development,
embryonate, and become potentially infective. In a recent systematic review and
meta- analysis of the prevalence of To x oc ar a eggs in public places, Fakhri et al. (2018)
revealed a global prevalence of 21 percent, with a range of 13– 35 percent depending
upon the World Health Organization region. A relationship between a higher prevalence and high relative humidity was also observed. Furthermore, in a subsequent
analysis, Rostami et al. (2019) revealed a non- signicant but upward trend in seroprevalence values as environmental contamination with Tox o ca ra eggs increased.
Human toxocariasis
To xo c ar a eggs can infect a wide range of paratenic hosts including humans (Holland
& Hamilton, 2006). e main routes of transmission are through the ingestion of
embryonated eggs from soil or soil- contaminated hands, food, or utensils. Organs
from paratenic hosts can be consumed by humans, and undercooked bovine beef
liver has been implicated in human infection (Yoshikawa et al., 2008). To xo ca r a
larvae have also been found to survive and persist in the tissues of experimentally
infected chickens even at low temperatures (Taira et al., 2011, 2012). More recently,
another potential source of infection has been identied with the discovery of the
presence of Tox o ca ra eggs on the hair of domestic denitive hosts such as dogs and
cats. However, based upon the available evidence, there is a low risk of transmission associated with the very low numbers of embryonated eggs found on hair (e.g.,
Keegan & Holland, 2010), but the suitability of hair as a medium for oval development should not be ignored (Holland, 2017).
In paratenic hosts, eggs do not develop to adulthood but remain as third- stage
larvae that migrate within the tissues and can enter organs such as the eye and the
Infectious Disease and Neurocognition
brain (Strube et al., 2020). As a consequence, diagnosis of human toxocariasis can
prove challenging. e direct detection of Tox o ca r a larvae in a histological section is rarely performed (Smith et al., 2009). e main diagnostic tool is therefore serology— the detection of To xo ca r a- specic antibodies in the sera— utilizing
the excretory– secretory products released from in vitro- maintained second- stage
larvae— but the diagnostic sensitivity and specicity can vary (Rostami et al., 2019;
Smith et al., 2009). Furthermore, and importantly, it is still not possible to distinguish between dierent Tox o ca ra species serologically, a knowledge gap that remains
fundamentally problematic and limits our understanding of To x oc a ra epidemiology
(Holland, 2017).
Seroprevalence
A recent global analysis estimated that the worldwide seroprevalence of To xo c ar a
species was 19 percent, with seroprevalence being highest in the African region
(35 percent) and lowest in the Eastern Mediterranean region at 8.2 percent (Rostami
et al., 2019). Statistically signicantly higher Tox oc ar a seroprevalence was associated
with lower national income, lower human development index, lower latitude, higher
humidity, and higher temperature and rainfall. Potential risk factors included young
age, male sex, living in a rural area, close contact with dogs, cats, or soil, consumption of raw meat, and drinking of untreated water.
Disease syndromes
At present, four clinical syndromes associated with human toxocariasis have been
described. ese are visceral larva migrans (Beaver et al., 1952), ocular toxocariasis
(Shields, 1984), covert toxocariasis (Taylor et al., 1988), and cerebral toxocariasis or
neurotoxocariasis (Finsterer & Auer, 2007), sometimes referred to as neural larva
migrans. ere is no doubt that challenges remain in linking these syndromes to
specic symptoms or clinical features because these are nonspecic in nature (Smith
et al., 2009). However, cerebral toxocariasis remains the most cryptic of the four syndromes (Holland, 2017).
Cerebral toxocariasis
Clinical and imaging findings associated
with cerebral toxocariasis
Cerebral toxocariasis was rst described in an autopsy study of a child in whom a
larva was found in the le thalamus (Beautyman & Woolf, 1951). Initially this larva
Toxocara 247
was identied as Ascaris, but aer the work of Nichols (1956), it was correctly iden-
tied as a larva of T. ca ni s (Beautyman et al., 1966). One key question that can be
posed is the public health signicance of the presence of what are likely to be small
numbers of larvae in a human brain. However, in some cases, the impact of cerebral
infection can be profound. For example, Vidal et al. (2003) described the symptoms
of eosinophilic meningitis in a 2- year- old boy and included mental confusion, fever,
headache, tachycardia, hyperreexia, dyspnea, lethargy, irritability, motor weakness, and nuchal rigidity. Toxocara- specic immunoglobulin G antibodies were de-
tected in both cerebrospinal uid (CSF) and serum and most symptoms declined in
response to treatment with albendazole and corticosteroids. Many infections may
go undiagnosed as a consequence of being asymptomatic or manifest as nonspecic
behavioral alterations.
In a systematic review of neurotoxocariasis conducted between 1951 and 2015,
a total of 100 cases were retrieved from the published literature (Deshayes et al.,
2016). Most of the cases were middle- aged men, with 60 percent manifesting myelitis, 47 percent encephalitis, and 29 percent meningitis. Brain imaging investigations revealed an abnormal computed tomography scan in 65.2 percent of the cases,
an abnormal magnetic resonance imaging scan in 57.4 percent of the cases, and an
abnormal medullary magnetic resonance imaging scan in 92 percent of the cases.
Furthermore, in patients with encephalitis, brain computed tomography revealed
multiple subcortical, cortical, and white matter circumscribed hypodense lesions,
and brain magnetic resonance imaging demonstrated hypointense lesions on TIweighted sequences and hyperintense lesions on T2- weighted sequences.
In a similar approach, Sanchez et al. (2018) undertook a systematic review of cerebral toxocariasis diagnosed by magnetic resonance imaging that yielded 34 cases
of cerebral toxocariasis. A wide range of clinical manifestations were described, including headache, seizures, focal decits, confusion, and cognitive impairment. An
impressive range of case denitions and diagnostic evaluations were reported, and
the authors concluded that magnetic resonance imaging ndings can only be described as suggestive and certainly not specic to cerebral toxocariasis. Of interest
was that biopsy was performed in only six cases, and, of these, two yielded detectable
To xo c ar a larvae, which underlines the challenge of diagnostic certainty.
Diagnosis of cerebral toxocariasis
Diagnosis of cerebral toxocariasis remains even more challenging than that of toxocariasis in general because of the non- specicity of symptoms and the lack of conrmatory tests. It is likely that because of the levels of seroprevalence previously
described, that neuronal involvement of toxocariasis is cryptic and signicantly
underdiagnosed. Diagnosis is based upon serology and characteristics such as eosinophilia, but also requires brain imaging ndings utilizing both computed tomography and magnetic resonance imaging (Sanchez et al., 2018). As summarized by