Trends in

Parasitology
Review

Onchocerciasis-associated epilepsy: an
update and future perspectives
Amber Hadermann , 1 Luis-Jorge Amaral , 1 Gilles Van Cutsem , 1 Joseph N. Siewe Fodjo , 1 and
Robert Colebunders 1,*

Onchocerciasis-associated epilepsy (OAE) is an important neglected public Highlights

health problem in areas with high ongoing onchocerciasis transmission. The There is strong epidemiological evidence
risk that children in such areas develop epilepsy is related to their Onchocerca that onchocerciasis directly or indirectly
volvulus microfilarial (mf) load. Before the implementation of mass treatment induces epilepsy.

with ivermectin, microfilariae were detected in cerebrospinal fluid (CSF). More re- The risk for children to develop epilepsy
cently, neither O. volvulus microfilariae nor DNA were detected in CSF or brain in onchocerciasis-endemic regions in-
tissue; however, these samples were obtained years after seizure onset. It is pos- creases with their Onchocerca volvulus
microfilarial (mf) load.
sible that during fever-induced increased blood–brain barrier permeability,
microfilariae enter the brain and, upon dying, cause an inflammatory reaction in- During the pre-ivermectin era, O. volvulus
ducing seizures. Including OAE in the onchocerciasis disease burden estimation mf were observed in cerebrospinal fluid
may mobilise extra resources for onchocerciasis disease elimination and treat- (CSF) and their levels increased following
the administration of diethylcarbamazine
ment/care of OAE-affected persons/families. (DEC).

Fever-induced increased blood–brain

Onchocerciasis epidemiology and clinical spectrum barrier permeability could allow the pas-
sage of mf through the choroid plexus
Onchocerciasis, commonly called ‘river blindness’, is a neglected tropical disease (NTD) into the brain.
caused by the filarial nematode O. volvulus transmitted through bites of blackflies (Simulium)
[1]. Worldwide, 20–25 million people are infected with onchocerciasis, and over 200 million Strengthening onchocerciasis elimina-
people are still at risk [2]. More than 99% of infected people live in 31 countries in sub- tion programmes via optimal ivermectin
coverage and vector control in areas
Saharan Africa (SSA) [3]. Onchocerciasis is known to be a skin and eye disease. In 2017, the with high ongoing transmission reduces
Global Burden of Disease Study estimated that at least 220 million people required preventive the incidence of epilepsy, including nod-
chemotherapy against onchocerciasis, 14.6 million of the infected people already had skin disease, ding syndrome.
and 1.15 million had vision loss [3].

Recent epidemiological studies strongly suggest that onchocerciasis may also directly or indi-
rectly induce seizures, that is, OAEi [4]. OAE is a type of epilepsy that appears in
onchocerciasis-endemic regions with high ongoing transmission in previously healthy children
between the ages of 3 and 18 years without an obvious cause [4]. A broad spectrum of seizures
has been observed in persons with OAE [5,6]. OAE is often associated with cognitive decline, be-
havioural and psychiatric problems, and high premature mortality [7,8]. Nodding syndrome (see
Glossary) and Nakalanga syndrome are considered clinical presentations of OAE which have
been identified only in places with high onchocerciasis transmission [9]. Children with nodding
syndrome often initially present head nodding seizures but later may develop other types of sei-
1
zures [8,10]. Nakalanga syndrome is characterised by stunting, physical deformities, endocrine Global Health Institute, University of
Antwerp, Antwerp, Belgium
dysfunction without external signs of sexual development, mental impairment, and epilepsy
[11]. The highest prevalence of OAE is found in villages and households close to blackfly breeding
sites along fast-flowing rivers. For this reason, OAE is also referred to as ‘river epilepsy’ [9]. A re-
cent study in Cameroon further suggested that onchocerciasis may cause cognitive impairment
*Correspondence:
in children without epilepsy [12], but larger comprehensive and longitudinal studies are needed to robert.colebunders@uantwerpen.be
ascertain these preliminary observations. (R. Colebunders).

126 Trends in Parasitology, February 2023, Vol. 39, No. 2 https://doi.org/10.1016/j.pt.2022.11.010

© 2022 Elsevier Ltd. All rights reserved.
Trends in Parasitology

OAE is an important neglected public health problem Glossary

A high prevalence of epilepsy is observed in onchocerciasis-endemic areas where onchocercia- BALB/c mouse model: an albino,
sis elimination programmes were suboptimal, interrupted, or never started, mainly due to an inse- laboratory-bred strain of the house
cure environment [9]. Population-based studies in certain onchocerciasis meso- and mouse, widely used in animal
experimentation.
hyperendemic villages in the Democratic Republic of the Congo (DRC) [13–15], Cameroon [16], Blood–brain barrier (BBB): highly
Uganda [17], Tanzania [18], and South Sudan [19–21] documented an epilepsy prevalence of selective semipermeable border of
2–8% [4], which is significantly higher than the median prevalence of 1.4% in SSA [22]. Cases endothelial cells that prevents solutes
of nodding and Nakalanga syndrome were also reported in villages with a high prevalence of and pathogens in the circulating blood
from crossing into the CSF and the
epilepsy [4]. Recently, an area of high epilepsy prevalence with nodding syndrome cases and brain.
high ongoing onchocerciasis transmission was detected in the Central African Republic Choroid plexus: secretory tissue
[23,24]. It is estimated that 200 000−400 000 persons may suffer from OAE [25]. The negative present in each of the brain ventricles, its
main function being the production of
psychosocioeconomic consequences of OAE on affected individuals, families, and communities
CSF. It consists of simple cuboidal
are enormous [26,27]. epithelial cells surrounding a core of
fenestrated capillaries and connective
OAE can be prevented tissue and forming the blood–CSF barrier.
Diethylcarbamazine (DEC): a
Recent evidence suggests that mass drug administration of ivermectin prevents OAE [5]. In
compound used for treating filarial
northern Uganda, the incidence of nodding syndrome decreased once ivermectin distribution infections; it is known to cause severe
was initiated, and ceased after implementing biannual community-directed treatment with iver- side effects in heavily infected patients.
mectin (CDTI) and ground larviciding of blackfly-infested rivers [17]. Similarly, OAE stopped ap- Ground larviciding: the use of
insecticides to kill blackfly larvae in
pearing in western Uganda when onchocerciasis was eliminated [28]. In Cameroon, a drastic
rapid-flowing rivers at blackfly breeding
decrease in epilepsy incidence (from 773.5 to 98.0 per 100 000 persons per year, P <0.001) sites.
was noted after 13 years of onchocerciasis control using CDTI in onchocerciasis-endemic villages Ivermectin: a compound used for
in the Mbam and Sanaga river valleys [29]. treating onchocerciasis; it kills only
microfilariae and temporarily reduces the
fertility of the adult female worm.
Arguments for and against a causal association between onchocerciasis and Metagenomics: the study of
epilepsy nucleotide sequences from
Many epidemiological studies have confirmed the association between onchocerciasis and epi- environmental samples, often used to
describe the microbiome of a certain
lepsy [4,28,30–33] (Box 1). However, the association between both conditions is not yet unani- environment, for example, the worm
mously accepted by the scientific community, based mainly on the following arguments. intestinal tract.
Moxidectin: a microfilaricidal drug
more potent than ivermectin; however, it
Argument 1
is not yet approved for children under
Before the implementation of onchocerciasis-control programmes, onchocerciasis was known to 12 years of age nor for mass drug
cause skin and eye disease, but reports about increased epilepsy prevalence in onchocerciasis- administration.
endemic regions were scarce. A high prevalence of epilepsy in onchocerciasis-endemic areas Nakalanga syndrome: a type of OAE
characterised by growth delay, physical
was reported in 1938 by Casis Sacre (Mexico) [34], in 1965 by Aall-Jilek (Tanzania) [35], and in
deformities, endocrine dysfunction,
1991 by Boussinesq et al. (Cameroon) [36]; however, in many other onchocerciasis meso- and mental impairment, and epilepsy.
hyperendemic areas, such as the DRC, a high prevalence of epilepsy had never been reported. Nodding syndrome: a severe type of
OAE characterised by head nodding
seizures (head bobbing to the chest).
Explanation 1
Ov16: a worm protein to which
Prior to the implementation of onchocerciasis control programmes, the prevalence of antibodies are produced; it is often used
onchocerciasis-related blindness in onchocerciasis hyperendemic regions was very high. For for diagnosis of O. volvulus infections.
example, in 1989–1990, more than 10% of the population was blind and 16.1% had vision im- Parasite tolerance: a general
decreased immune response towards
pairment in certain villages in the Taraba River Valley, Nigeria [37]. In the presence of such an the parasite.
important public health problem caused by onchocerciasis-related blindness and in the ab- Pathogenesis: the process by which a
sence of clinicians to diagnose seizure disorders in these remote areas, an epilepsy problem disease or disorder begins and
among children and adolescents may have gone unnoticed. Moreover, epilepsy, certainly in develops.
Proteomics: the study of the
the past, was considered to be the consequence of evil spirits and a very stigmatising condition proteome, that is, proteins within the
by local communities [38]. Therefore, the link with onchocerciasis was often not suspected. In context of a system – for example, within
such rural communities, persons with epilepsy were often confined to their homes, consulted an organism.
traditional healers, and were not seen by medical doctors in hospitals – resulting in gross

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under-reporting of epilepsy despite a high prevalence of onchocerciasis. In recent population Psammoma bodies: small focal
calcifications with unknown aetiology,
surveys in the DRC, a high prevalence of epilepsy has been documented in many often found in tumours and in ageing
onchocerciasis-endemic areas [15,39]. brains.
Slash and clear: a vector-control
In a meta-analysis of epilepsy data in onchocerciasis-endemic areas in West Africa, a high prev- method based on removing the
vegetation that acts as the substrate for
alence of epilepsy was reported in certain areas with reports of clinical phenotypes similar to nod- the immature stages of the blackflies (the
ding syndrome [30]. For example, in 1983, an epilepsy prevalence of 4.9% was reported in rural vector of onchocerciasis) in their riverine
Grand Bassa County among the Whroghbarh clan in Liberia [40]. Moreover, in West Africa, higher breeding sites.
precontrol onchocerciasis endemicity and a shorter duration of onchocerciasis control were as- Tauopathy: a degenerative
neurological disease characterised by
sociated with increased epilepsy prevalence [30]. the deposits of tau (tubulin-associated
units) in the brain.
Argument 2 Vertigo: a sensation of spinning, or that
the world around you is spinning, often
It was unclear why epidemics of epilepsy and nodding syndrome appeared suddenly in the late
caused by an inner ear problem but also
1990s in the onchocerciasis-endemic areas of the Western Equatoria State in South Sudan by a brain problem (brain stem and
and northern Uganda, while those areas had been endemic for onchocerciasis long before cerebellum).
1990 without reports of high epilepsy prevalence. Wolbachia: intracellular bacterial
symbiont present in all life cycle stages of
O. volvulus and essential for the
Explanation 2 development of larvae, embryos, and
Before the implementation of CDTI, due to the high prevalence of blindness in certain areas close the long-term survival of adult worms.
to the river, it was known that it was ‘unhealthy’ to live there. However, since the implementation
of CDTI, the incidence of blindness has decreased [41]. Due to increased population and poverty,
new communities started to establish themselves close to blackfly breeding sites, increasing the
risk of developing OAE.

For instance, in Mvolo, South Sudan, Lewis et al. documented very high blackfly biting rates, with
up to 10% of infectious flies in 1949 [42]. At that time, Mvolo was merely a police post, and very
few people lived there. In contrast, nowadays, Mvolo is a rural city where many people have set-
tled because of the fertile grounds close to the Naam river and fishing opportunities [43]. The fact
that new communities started to establish themselves close to blackfly breeding sites most likely
increased the risk for the children to develop OAE.

Similarly, in Maridi, South Sudan, the spillway of an electric dam repaired by the Chinese in early
2000 was the only blackfly breeding site in the area [44]. An epilepsy prevalence of 11.9% was
documented in a nearby village [21]. This village was a relatively recent settlement because the
area surrounding the dam had previously been an enclosed forest. In addition, the epilepsy prev-
alence in Maridi increased with increasing duration of stay [21]. When taken together, these ob-
servations may explain the sudden appearance of epilepsy in the newly established
communities very close to blackfly breeding sites.

Similar factors to those in South Sudan may have played a role in causing an epilepsy epidemic in
northern Uganda, and an additional reason could have been the theft of about 300 000 cattle
from the Acholi people in 1996 [17]. The sudden disappearance of cattle from an area can poten-
tially increase the blackfly biting rate in humans and decrease the immune protection against on-
chocerciasis conferred by O. ochengi antibodies [45,46].

Argument 3
Some case–control studies did not confirm the association between onchocerciasis and epi-
lepsy. For example, Druet-Cabanac et al., in their meta-analysis of nine papers searched until
2002, reported no statistical association between O. volvulus infection and epilepsy [odds ratio
(OR): 1.21; 95% confidence interval (CI): 0.99–1.47; P = 0.06] [39,47].

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Explanation 3
One of the studies included in the meta-analysis was performed in a village that was already
hypoendemic following more than 14 years of the Onchocerciasis Control Programme in West
Africa (OCP) activities [40]. In such communities with recently achieved hypoendemicity, persons
with epilepsy could either be OAE survivors from the era of high onchocerciasis transmission or,
more frequently, have epilepsy unrelated to onchocerciasis, making it difficult to find an associa-
tion. In another study [48], epilepsy cases were compared with non-epileptic controls with re-
tarded growth, also most likely related to onchocerciasis [11]. If these two studies were
excluded from the meta-analysis, a relative risk of 1.30 (95% CI: 1.04–1.62; P = 0.02) would be
obtained [49].

Even in onchocerciasis hyperendemic areas not yet exposed to ivermectin, it may be difficult to
demonstrate an association between skin snip positivity and epilepsy because almost everyone
is infected. Only the intensity of O. volvulus infection, assessed by the mf load or the number of
onchocerciasis nodules, will be significantly higher among persons with epilepsy than among
controls [36]. Also, no difference in O. volvulus antibody prevalence may be found because nearly
everybody would have been exposed to O. volvulus and because of the low sensitivity of the
Ov16 ELISA antibody test [50].

In areas where CDTI has been implemented for several years, because of low community mf load,
large sample sizes will be needed to document a difference in O. volvulus infection between cases
and controls. This is particularly true if household members or neighbours are used as controls
because they are often equally exposed to infected blackflies.

In case–control studies, the previous intake of ivermectin needs to be considered [51]. Indeed, it
is possible that cases used more ivermectin than controls because they presented with
onchocerciasis-related itching more frequently or because they believed ivermectin would de-
crease the seizure frequency [52]. In addition, children with epilepsy may be, because of their dis-
abilities, more likely to be at home at the moment of ivermectin distribution.

Certain case–control studies identified risk factors other than O. volvulus infection, such as expo-
sure to ammunition, consumption of crushed roots [53], and exposure to poultry [54]. Some risk
factors may be related to confounders, such as socioeconomic status. Moreover, random asso-
ciations are to be expected when a vast number of risk factors are investigated.

A major problem with case–control studies is that findings about the cases at the moment of
the study can be very different from the condition of these cases before the onset of the first
epileptic seizures. As the incidence of OAE has considerably declined since CDTI initiation,
most OAE cases in case–control studies were enrolled several years after the onset of their
first seizures. This makes interpreting the results difficult because children's lives change dra-
matically after developing epilepsy. For example, children with epilepsy may be bitten less by
blackflies than healthy controls because they are less likely to bath or swim in a river for fear
of drowning. Because of the belief that epilepsy may be transmitted by direct contact
[55,56], children with epilepsy may not be allowed to sleep under a bed net together with
other children by their parents [54] and may therefore be more at risk for developing malaria.
Some children with OAE may become malnourished because of poverty and because eating
may induce seizures [57].

Argument 4
No biological mechanism for OAE has been established.

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Explanation 4
So far, no mechanism has been established to explain the pathogenesis by which O. volvulus
directly or indirectly causes epilepsy. The fact that O. volvulus infections occur only in humans
has hampered the progress towards developing an optimal animal model to demonstrate
whether this parasite can induce seizures.

Box 1. Main epidemiological findings in favour of an association between onchocerciasis and epilepsy
1. The higher the onchocerciasis endemicity, the higher the incidence and prevalence of epilepsy [33].
2. In onchocerciasis-endemic areas, the epilepsy prevalence increases with decreasing distance of the village to the river
and with increasing community microfilarial (mf) load [36]. The highest epilepsy prevalence is observed in households
living close to blackfly breeding sites, and in such families several children may have OAE [21, 44].
3. Most persons with epilepsy in meso- and hyperendemic onchocerciasis areas present different clinical characteristics
(OAE characteristics) than in non-onchocerciasis areas [4, 6].
4. In two cohort studies in Cameroon, a temporal and mf dose-dependent association was discovered between the mf
load in early childhood and the development of epilepsy later in life [31,32].
5. An epidemic of epilepsy, including nodding syndrome, emerged in onchocerciasis-endemic areas where there was no
ivermectin distribution or where the onchocerciasis elimination programme had been interrupted [16].
6. When onchocerciasis transmission is reduced, the incidence of epilepsy decreases [17], and OAE stops appearing
once onchocerciasis is eliminated [28].

Hypothesis about the pathogenesis of OAE

Already in 2002 in Cameroon, Boussinesq et al. showed that villages with a greater mean com-
munity mf load had a higher frequency of epilepsy [36]. Later, two retrospective cohort studies
in Cameroon showed that the risk of children developing epilepsy was related to their mf load
[31,32].

It is thus very likely that mf load plays a role in the pathophysiology of OAE. In the presence of a
high mf load, it may be that occasionally mf pass the blood–brain barrier (BBB). Microfilariae
were previously detected in the CSF by Hisette (1932, in the DRC) [58], Mazotti (1959, in
Mexico) [59], and in 1976 by Duke in Cameroon in heavily infected persons with ocular onchocer-
ciasis treated with diethylcarbamazine (DEC) but without epilepsy [60]. In five of eight patients
examined by Duke, low levels of mf were already present in CSF (2 mf/ml) before DEC. After
DEC, mf levels increased in the blood and the CSF mf levels increased up to 19 mf/ml (range:
8–31 mf/ml). All mf were alive and mobile. To avoid the contamination of the CSF with mf from
the skin during lumbar puncture, the first five or six drops of CSF had not been used to determine
the CSF mf level. Six persons with increasing numbers of mf in CSF during DEC treatment devel-
oped vertigo, one of them associated with a temporary Parkinsonian condition. A high dose of
DEC administered after the mf had been killed did not produce a recurrence of vertigo, suggesting
that the vertigo was induced by the mf and not the toxicity of the drug. Duke hypothesised that mf
entered the CSF through the capillary wall of the choroid plexus [60].

In 1976, O. volvulus mf in CSF were also detected in a person who died in a coma following DEC
treatment [61]. Microfilariae were also reported in the optic nerve [62,63], urine [64], and sputum
[65]. After DEC treatment, an increase in the concentration of mf in urine and hydrocoele fluid was
reported [66].

The reason behind the increase of mf levels in the blood and CSF after DEC treatment remains
unclear. In a BALB/c mouse model, administration of a low dose of DEC (50 mg/day) was linked
to an enhanced cytokine production and a high dose (500 mg/day) enhanced the respiratory
burst of neutrophils and monocytes [66]. It can be hypothesised that this respiratory burst in-
creases the BBB permeability, allowing mf to enter the brain. Conversely, all O. volvulus stages
secrete excretory/secretory proteins (ESPs) necessary for their migration through the host tissues

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and communication with each other and the host [67]. These ESPs might help mf to cross the
BBB. In a post-mortem study in northern Uganda, signs of earlier ventriculitis (Figure 1) were
observed in eight of nine persons who died with OAE, suggesting that the choroid plexus, as
proposed by Duke, could have been the entry point of the mf. When they die, mf that crossed
the BBB may release Wolbachia and ESPs that may cause an inflammatory reaction capable
of inducing seizures.

During a post-mortem case study on a 17-year-old girl with Nakalanga syndrome, the presence
of gliosis and psammoma bodies was observed at and around the choroid plexus [68]. The
aetiology of psammoma bodies remains unclear. However, their presence has been clearly linked
to ageing [69], making their presence in the brain of a 17-year-old woman remarkable. When
taken together, the presence of gliosis and psammoma bodies with the occurrence of signs of
earlier ventriculitis suggests a pathological mechanism involving the choroid plexus (Figure 1).
The choroid plexus is known for its weaker BBB function, creating the ideal environment for
(micro)organisms to enter the brain [69].

In more recent studies, neither O. volvulus mf nor DNA could be detected in the CSF [70–72] or in
the brain during post-mortem studies [73]. However, persons who were examined in these stud-
ies had developed their first seizures several years earlier, and the parasites might have been elim-
inated by the brain’s immune system. Box 2 provides possible research directions to investigate
possible mechanisms by which O. volvulus can penetrate the brain.

Potential cofactors in the pathogenesis of OAE

As in all infectious diseases, cofactors most likely also play a role in the pathogenesis of OAE. The
fact that OAE appears in children 3–18 years of age suggests that the disease mechanism is
linked to an age-related factor. This may be related to the sharp increase in mf load in children
of this age group [74]. Another factor could be related to brain maturation [75]. Based on clinical
and electroencephalography (EEG) findings nodding syndrome resembles the Lennox–Gastaut
syndrome (LGS) [76]. LGS is an epileptic encephalopathy associated with drug-resistant seizure
types, a specific EEG pattern, and intellectual disability [77]. LGS may have a genetic aetiology,
but in 65–75% of cases, the cause is unknown [77]. LGS is characterised by age-related diffuse
cortical hyperexcitability [75].

(A) (B)

Trends in Parasitology

Figure 1. Post-mortem microscopy images of findings in the brain from a Nakalanga case. (A) Antecedents of
ventriculitis. Glial fibrillary acidic protein staining (GAFP). (B) Psammoma bodies, indicated by arrows. Haematoxylin and
eosin (HE) staining [68].

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Box 2. How to investigate whether O. volvulus enters the brain?

Given the progress of the onchocerciasis elimination programme and the decrease in community mf load, it may be difficult
to confirm that mf enter the brain and induce epilepsy. A prospective study of children below the age of 5 years, who are
still ivermectin-naive (not yet eligible for CDTI), in an area with high ongoing onchocerciasis transmission, may be a way to
investigate this. In such a study, a lumbar puncture should be considered for children with a high O. volvulus mf load and
neurological symptoms such as cognitive decline, epilepsy, or complicated febrile seizures without an obvious cause. In
such a prospective study, children should annually be tested for O. volvulus infection and consecutive blood samples ob-
tained for biomarker assays (e.g., for BBB dysfunction).

However, very few children may meet the study criteria, warranting a large multicentric prospective study, which may be
very costly. Such a study in areas with limited resources and infrastructure would face serious medical, operational, ethical,
and – not least – financial challenges. Lumbar punctures can be performed only by trained health personnel that are gen-
erally not available in an area where such a child may be found. Besides, the parents of the child may not accept the trans-
fer of the child to a hospital to perform the lumbar puncture in ideal conditions.

A recent case–control study in northern Uganda suggested that pre-term birth could be a risk fac-
tor for nodding syndrome [78]. A study in Ecuador suggested that an O. volvulus infection in a
pregnant mother could lead to spontaneous abortion [79]. Therefore, it is possible that the pre-
term birth of children who developed nodding syndrome in northern Uganda was caused by an
O. volvulus infection of a pregnant mother. It has been shown that the O. volvulus parasite re-
duces the cellular immune response to parasite antigens [80]. This ‘parasite tolerance’ can
be transmitted from mother to child [80]. Later, when bitten by O. volvulus-infected blackflies,
these children develop a very high mf load, a risk factor for OAE [31,32], due to a lack of an ap-
propriate immune response at an early age [81].

In two case–control studies in the DRC, significantly more febrile seizures were reported in persons
with epilepsy than in non-epileptic controls [51,82]. However, a history of febrile seizure has been
reported in about 3–19% of children with epilepsy syndromes [83], and this association between
febrile seizures and epilepsy is believed to be because of a genetic predisposition [84]. Febrile sei-
zures occur because infections induce an inflammatory response that may induce a 'leaky' BBB
[85]. It is possible that similar to the increased BBB permeability induced by DEC [65], increased
BBB permeability caused by infections and/or seizures could allow the passage of mf into the
brain. The higher the mf load, the higher the likelihood that mf will be able to penetrate the brain.

Genetic factors associated with an increased risk for onchocerciasis and epilepsy may also play a
cofactor role. In a case–control study on South Sudanese samples, certain human leukocyte an-
tigen (HLA) classes were reported to be potentially associated with protection or susceptibility to
nodding syndrome [86]. Genetic testing of three Ugandan nodding syndrome cases and five un-
affected family members examined at the National Institutes of Health (NIH) in the USA did not re-
veal exosome mutations, but two genetic factors of unknown significance linked to encephalitic
epilepsy syndromes were detected [87]. However, given the small sample size and the absence
of comparable genetic reference data from an ethnically matched reference population, it is im-
possible to make any conclusion about this finding. There are no arguments that genetics
could be the main pathogenic factor. Indeed, OAE has been observed in very different genetic
populations, for example, in Mexico, and in West, Central, and East Africa. Moreover, in families,
it is usually the siblings who present different forms of epilepsy, but rarely parents or grandpar-
ents. Therefore, the risk factor for developing epilepsy does not depend on the family genes
but on the location of the family close to a blackfly breeding site. An unrelated family living at
the same spot may also have one or more children with epilepsy.

Another cofactor to consider is the nutritional status of the child. Children with OAE often have low
body weight and may be stunted [7]. However, this is most likely the consequence of

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malnourishment and an OAE-associated endocrinological dysfunction. Figure 2 provides an over-

view of possible mechanisms for OAE pathogenesis.

Alternative pathogenic mechanisms for OAE

O. volvulus ESPs or symbiotic microorganisms may cause OAE. As the basic biology of
O. volvulus remains largely uncharted, to our knowledge, no inventory of excreted/secreted pro-
teins nor metagenomic analysis into potential symbiotic microorganisms/viruses is available.

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Figure 2. Potential pathogenesis mechanisms in onchocerciasis-associated epilepsy (OAE). (1) Direct entry of the
microfilariae through the BBB causing either a release of ESPs into the CSF, directly trigger the immune response or trigger the
immune response by the symbiont Wolbachia. This immune response could alter the brain equilibrium and induce seizures. (2) ESPs
from the MF go through the BBB and could either directly trigger seizures or trigger the immune response. External factors can
influence the permeability of the BBB and/or the susceptibility to epilepsy. Abbreviations: BBB, blood–brain barrier; CSF,
cerebrospinal fluid; DEC, diethylcarbamazine; ESP, excretory and secretory products; MF, microfilariae. Figure created with BioRender®.

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It has been suggested that OAE could be an autoimmune disorder induced by neurotoxic Outstanding questions
leiomodin-1 antibodies cross-reacting with O. volvulus [88]. However, a study by Hotterbeekx Why are only children developing OAE?
et al. rejected this hypothesis [89]. The role of autoimmunity has also been suggested in
How to confirm the diagnosis of OAE
onchocerciasis-associated chorioretinopathy [90]. However, because treatment with
with biomarkers or a low-cost test?
microfilaricides induces characteristic onchocerciasis retinopathy, the most likely cause of this
retinopathy is inflammation directed towards dead and degenerating mf [90]. However, an auto- Is an O. volvulus infection in a pregnant
immune process may explain the extension of the chorioretinopathy lesions after onchocerciasis woman a risk factor for pre-term birth
and a risk factor for their children to de-
treatment [90]. A similar process could happen if mf cross the BBB. velop OAE?

It has also been suggested that nodding syndrome is a degenerative tauopathy [91,92] because, Are there certain O. volvulus genotypes
associated with susceptibility to develop
during post-mortem studies, tau deposits, as observed in Alzheimer's disease, were detected in cer-
specific onchocerciasis-associated neu-
tain parts of the brain of persons with nodding syndrome. However, in some persons with OAE, only a rologic morbidities?
few tau deposits were found [73], suggesting that they were most likely the consequence of repeated
seizures and not the cause of the disease [93]. In addition, no tau biomarkers were found within the What is different between the O. volvulus
parasite and other filarial infections
CSF of the three nodding syndrome patients examined at NIH by Soldados et al. [87].
that could explain the fact that
onchocerciasis may trigger epilepsy?
Onchocerciasis and epilepsy: moving from observations to concrete actions
In onchocerciasis-endemic areas, it is common to find households where several children present How to explain the growth retardation,
physical deformities, and endocrine
with epilepsy, especially in families residing and/or farming on land close to blackfly breeding sites dysfunction associated with a small
[44]. Intense exposure to O. volvulus-infected vectors puts children in these households at an in- proportion of persons with OAE?
creased risk of developing OAE. The household clustering of persons with epilepsy has led com-
Could onchocerciasis cause cognitive
munities to wrongly believe epilepsy is contagious and transmissible by direct contact,
impairment in children without causing
stigmatising and discriminating against persons with epilepsy and their families [94]. epilepsy?

Conflicting messages about nodding syndrome, considering it still a ‘mysterious condition’ en- Can coinfections facilitate the passage
of mf through the blood–brain barrier?
gender epilepsy misconceptions and stigmatisation among affected communities [94]. The mes-
sage should be that OAE is preventable with proper onchocerciasis-elimination measures Could neurotoxic (O. volvulus cross-
(notably CDTI) and treatable with anti-seizure medication. Health promotion campaigns need to reacting) autoantibodies play a role in
the pathogenesis of OAE?
be implemented in onchocerciasis-endemic regions with high onchocerciasis transmission to de-
crease stigma and increase CDTI coverage and treatment of OAE with anti-seizure medication. Could O. volvulus antigens, excretory/
secretory products, or the O. volvulus
Since the risk of developing OAE is associated with O. volvulus infection intensity [31,32], oncho- microbiome – including Wolbachia or
a still unknown endosymbiont – play a
cerciasis elimination is pivotal in the response against OAE. The current approach against oncho-
role in the pathogenesis of OAE?
cerciasis relies on annual CDTI [95]. Although annual CDTI has been successful in eliminating the
disease in a limited number of foci [96], onchocerciasis is persisting in most of the 31 African en- Could early diagnosis and treatment of
demic countries, calling for alternative strategies to meet the World Health Organization (WHO) OAE prevent it from becoming a
chronic and degenerative condition?
2030 elimination targets [95].
What is the cause of the tau deposits in
Switching from annual to biannual CDTI would undoubtedly reduce the time to onchocerciasis elim- the brains of persons who died with
OAE?
ination. In settings with high onchocerciasis morbidity, including OAE, where biannual CDTI may be
too costly to implement, annual CDTI should be complemented by an extra distribution of ivermectin In addition to mf load and palpable
to children 5–15 years of age at school and other distribution points, 6 months after the CDTI round onchocercal nodules, are there other
[97]. In onchocerciasis-endemic areas with a high onchocerciasis disease burden, CDTI could be biomarkers (serological, imaging,
urinary, etc.) that could predict OAE?
complemented with blackfly control interventions such as ‘slash and clear’ [98,99] (Figure 3).
Moxidectin, a more potent and longer-lasting drug than ivermectin [100], also shows promising Which (genetic) cofactors may favour
prospects in the fight against onchocerciasis; studies are underway in that light. the development of OAE?

What is the onchocerciasis disease

Concluding remarks burden if OAE is considered as a man-
Existing evidence for the epidemiological association between onchocerciasis and epilepsy is ifestation of onchocerciasis?
compelling, although the underpinning biological mechanisms remain unknown to date and

134 Trends in Parasitology, February 2023, Vol. 39, No. 2

Trends in Parasitology

multiple questions remain (see Outstanding questions). Research on the pathogenesis of OAE How to strengthen onchocerciasis-
elimination programmes in the most
needs to focus on whether mf could cross the BBB in children too young to be eligible for iver- cost-efficient way to prevent OAE?
mectin treatment in the presence of a high mf load and during periods of coinfections and/or
central nervous system (CNS) inflammation. We also need to increase our knowledge about How to scale up a community-
based ‘slash and clear’ vector-
the O. volvulus worm, its ESPs, and its microbiome. Proteomics and metagenomics studies
control method in different ecologi-
of the worm may not only reveal a potential pathogenetic mechanism of OAE but also may cal settings?
lead to new ways to treat and diagnose onchocerciasis.

Advocacy for the implementation of better onchocerciasis elimination strategies is required

as these will decrease the OAE incidence in the affected villages. However, the burden of
disease caused by OAE will persist for a long time. Therefore, similar to other NTDs, such
as lymphatic filariasis [101], we need a Morbidity Management and Disability Prevention
plan for onchocerciasis that includes OAE. To do so will require close collaboration
between onchocerciasis, mental health, and epilepsy-control programmes. The current in-
ternational focus is on onchocerciasis elimination. However, the priority should be eliminating
onchocerciasis disease rather than eliminating the parasite in areas where there is (nearly) no
disease.

Hopefully, OAE will soon be recognised internationally as a manifestation of onchocerciasis and

included in the calculation of the onchocerciasis disease burden. The latter is important to mobi-
lise the urgently needed extra resources for onchocerciasis disease elimination and support and
treatment of OAE-affected persons and families.

PROPOSED INTERVENTIONS EXPECTED OUTCOME

high persistent onchocerciasis transmission

Decreased onchocerciasis elimination time

OAE awareness
programme Increased CDTI
Onchocerciasis endemic regions

coverage

↓ Economic and Society benefit

Extra distribution of Decreased OV
Decreased onchocerciasis-
ivermectin to school age transmission
children
associated disabilies
↓ Improved quality of life
Decreased incidence
Onchocerciasis-
Community directed
associated morbidity
treatment with
moxidectin

Community based Decreased blackfly bing

slash and clear vector nuisance
control Improved quality of life

Trends in Parasitology

Figure 3. Proposed new interventions to decrease the onchocerciasis disease burden. Abbreviations: CDTI, community-directed treatment with ivermectin;
OAE, onchocerciasis-associated epilepsy; OV, Onchocerca volvulus.

Trends in Parasitology, February 2023, Vol. 39, No. 2 135


Acknowledgments
We thank An Hotterbeekx, Guido Van Ham, Inge Mertens, Sarah Weckhuysen, Marin Lammens, Henri Deckx, and Henk
Schallig for their critical review. We also thank An Hotterbeekx for providing the images of the post-mortem study. This work
was funded by the Research Foundation Flanders [Fond Wetenschappelijk Onderzoek (FWO)], grant number G0A0522N,
and by La Caixa Foundation, grant number B005782. The content of this study is the sole responsibility of the authors
and does not represent the official views of the FWO or La Caixa Foundation.
Declaration of interests
The authors declare no competing interests.
Resources
i
www.uantwerpen.be/en/research-groups/oae/
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