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Neurocysticercosis Infection and Disease–A Review.Acta Tropica
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Neurocysticercosis Infection and Disease – A Review
1
Division of Infection and Pathway Medicine, Edinburgh Infectious Diseases,
Abstract
Neurocysticercosis (NCC) is the most common parasitic disease of the human central
nervous system (CNS), a pleomorphic disease with a diverse array of clinical manifestations.
including number and size of the cysticerci, their stage of development and localisation
within the brain with resulting difficulties in accurate diagnosis and staging of the disease.
This review examines the factors that contribute to the accurate assessment of NCC
distribution and transmission that are critical to achieving robust disease burden calculations.
Control and prevention of T. solium transmission should be a key priority in global health as
intervention can reduce the substantial healthcare and economic burdens inflicted by both
global burden, NCC will remain - along with other endemic zoonoses, of low priority in the
1
Key Words
Tropical Diseases; taeniasis; cestode; Taenia solium; lateral flow assay; epilepsy
Index
1. Introduction
1.1.Parasite Lifecycle
2. Epidemiology
3. Clinical Presentation
3.1.Parenchymal NCC
3.2.Extra-parenchymal NCC
4. Diagnosis
4.1 Neuroimaging
5. Treatment
5.2 Anti-Epileptics
5.3. Steroids
5.4 Surgery
7. Acknowledgements
8. References
2
1. Introduction
Neurocysticercosis (NCC) is the most common parasitic disease of the human central
nervous system (CNS) (Del Brutto, 2012). Caused by the larval form of the cestode, Taenia
solium, commonly referred to as the ‘pork tapeworm’ (Fogang et al, 2015), NCC is not to be
confused with ‘taeniasis’, the condition resulting from adult tapeworm infection. Human or
porcine NCC originates from the ingestion of food or water that is contaminated with T.
solium eggs; these hatch within and then penetrate the intestine, following which, a period of
widespread tissue dissemination occurs. Multiple body tissues may be invaded, including the
eyes, skin and muscles (WHO, 2015), however the larvae display a strong affinity for the
CNS (Sinha and Sharma, 2009). NCC has a diverse array of clinical manifestations,
depending on a complex range of interconnecting factors, including the number and size of
the cysticerci present, their stage of development and localisation within the brain with
resulting difficulties in accurate diagnosis and staging of the disease (Takayanagui and
Odashima, 2006).
Aristotle was aware of NCC in 424 BC, describing the presence of muscle cysts, compared to
hailstones in appearance, evident in certain porcine diseases (Del Brutto et al, 1998). Until
the development of CT and MRI scans in the 20th century, knowledge of NCC was very
limited, as the majority of diagnoses were based on clinical manifestations visible externally
made at autopsy (Garcia et al, 2002). This advance in diagnostic capabilities was a watershed
in our understanding of NCC, redefining prognoses. Previously only the severest cases had
been apparent to clinicians, giving a distorted view of disease severity; advances in scanning
allowed for the diagnosis of previously undetected milder cases and further consideration was
3
1.1 Parasite Lifecycle
T. solium belongs to the class Cestoda, one of the largest and most successful groups of
divided into three genera: Taenia (sub-divided into Taenia and Versteria; Nakao et al, 2013)
The lifecycle of T. solium is complex and may result in a range of pathologies, affecting both
pigs and humans. Humans are the only definitive hosts, within which the tapeworm can
complete its lifecycle and exist in adult form, however both humans and pigs have been
documented as intermediate hosts, in which the tapeworm eggs can develop up to the
metacestode larval stage (Coral-Almeida et al, 2015). Dogs have also been implicated as
Human NCC, porcine NCC and dog NCC are mainly due to direct contact with human
faeces. Humans become infected most commonly through the ingestion of food or water
contaminated with T. solium eggs; pigs and dogs through scavenging human faeces. Eggs
come from an adult tapeworm that has reached maturity in the small intestine of a human
host entering the environment within human faeces; one adult tapeworm can expel a
minimum of 100,000 eggs per day. Serological studies in endemic areas have shown that
eggs can be distributed in the environment at large distances from the infected individual
(Lescano et al, 2009). It has also been suggested that humans may be able to autoinfect
In the host intestinal tract, eggs become uncoated liberating the enclosed larvae, known as
oncospheres. These penetrate the intestinal wall and are transported in the bloodstream to
4
various tissues of the body, including the brain, eyes, skin and muscles, where they are
deposited (Del Brutto, 2012). Within these tissues oncospheres differentiate and develop into
metacestodes, which undergo multiple stages of development and establish as cysticerci. The
first stage is known as the ‘viable or vesicular stage’ in which a membrane develops around
each oncosphere, forming a vesicle that contains clear fluid surrounding the parasite head, or
scolex. Depending on the surrounding environment, and the nature of the immune response
their presence elicits, the cysts may remain at this stage for months or even years, before they
begin to degenerate. The ‘colloidal stage’ marks this transition, whereby the scolex shows
signs of deterioration and the vesicular fluid begins to appear turbid. Following this, the
vesicular fluid becomes gradually more opaque and the cyst begins to calcify, eventually
The lifecycle is completed when humans ingest undercooked pork containing viable
cysticerci. Digestive enzymes in the small intestine cause the scolices to evaginate from the
cyst vesicle and attach to the wall of the intestine using powerful suckers and hooks. Here,
the tapeworm matures to adulthood, at which point egg-containing sections of the tapeworm
body, called ‘gravid proglottids’, are released in the host’s faeces (Del Brutto, 2012). This
part of the tapeworm lifecycle accounts for the disease taeniasis only; it is a common
2. Epidemiology
Despite being one of the most prevalent parasitic disease of the human CNS (Fabiani and
Bruschi, 2013), NCC remains a neglected tropical disease, recognised in 2010 by the World
Health Organisation (WHO, 2015). Despite its substantial global impact, in terms of both
disease and economic burden, there are limited data for accurate assessment of distribution
5
increasing (Ito and Budke , 2014) and bodies such as WHO have put forward improved
strategies for the control of both taeniasis and cysticercosis (WHO, 2015).
NCC particularly affects countries burdened by poverty, as lack of adequate sanitation and
inaccessibility of clean water supplies increase contamination of both food and water with
human faeces containing T. solium eggs. Countries where NCC is endemic may also have
high numbers of free-roaming pigs that are exposed to human faeces, leading to increased
incidence of porcine NCC (Coyle et al, 2012). Once established within a population, the
factors, including the durability of the eggs and the potential for a single tapeworm to infect
multiple individuals including the tapeworm carrier (Kobayashi et al, 2013); this has
2013).
Areas endemic for NCC include Latin America, Africa, South East Asia, India, China and
Nepal (Fabiani and Bruschi, 2013). Differences are observed the clinical and radiological
presentations of NCC between countries in different continents. Patients in India show higher
compared to patients in Latin America, who more frequently exhibit multiple cysticerci in the
ventricles or subarachnoid space (Bobes et al, 2014). This may reflect genetic dispositions
associated with varying presentations between geographical areas and differing lifestyles
among human populations (Yanagida et al, 2014), where the infection was acquired
(Yanagida et al, 2010), as well as genetic differences between parasite populations (Ito et al,
2016).
Despite a lack of accurate prevalence data, various studies have applied statistical methods to
6
approximate disease burden (Coyle et al, 2012). These burden estimates indicate the relative
impact of the disease in certain areas of the world, but would be much improved if based on
surveillance and reporting systems - few of which currently exist (Martins-Melo et al, 2016).
Multiple obstacles lead to high variability between individual studies, preventing the
acquisition of accurate epidemiological data for NCC; these include inadequacy of current
between studies as to whether or not to include cases involving calcified cysts in prevalence
There have been observations of increasing incidence of NCC in high income countries,
particularly in the USA, where over 5000 infected patients have been reported in recent years
(Sorvillo et al, 2011), as well as in Canada and Europe (Coyle et al, 2012) attributed to
significant risk of sustained propagation within these newly-established populations; this risk
3. Clinical Presentation
The pleomorphic nature of clinical presentations associated with NCC can be attributed to
many factors. The parasite load, dependent on both the size and number of cysticerci, is an
important determinant of symptomatology; high loads are associated with increased risk of
significant inflammatory responses (Singhi and Suthar, 2015). In very severe cases, involving
numerous cysts with associated inflammation, an encephalitic state can occur with diffuse
cerebral oedema; such cases have a very poor prognosis (Kimura-Hayama et al, 2010).
7
The stage of cysticercus development is a crucial factor in the control of immune interactions.
It is thought that viable cysts initiate a complex immune evasion response, allowing them to
exist undetected in the body; this may persist for a prolonged period of time, with immune-
mediated symptoms sometimes being delayed for several, or as many as 10 years (Kimura-
Development of symptoms is generally associated with the immune system overcoming such
evasion mechanisms and initiating subsequent immune responses against the degenerating
cyst, leading to systemic effects and a corresponding clinical profile (Garcia et al, 2010). This
process may be accelerated by anti-helminthic drug treatment, and clinicians are cautious
when prescribing such medication to patients with high parasite loads (Tuero et al, 2015).
Finally, cyst location is a key determinant of clinical presentation, with clusters of symptoms
showing patterns of association with affected areas of the CNS. In general, cyst location is
broadly classified as either parenchymal, within the functional tissues of the brain, or extra-
parenchymal, which encompasses the remaining locations within the CNS (Garcia et al,
2002).
The brain parenchyma is most commonly infected with NCC (Bansal et al, 2014) with high
rates of cyst deposition occurring at junctions separating grey matter from white matter; this
is thought to be due to accumulation of metacestodes in the small terminal blood vessels that
converge here. Parenchymal disease generally has a more favourable prognosis than extra-
parenchymal, with seizures and headaches, tending to resolve independently with time, being
the most consistently reported manifestations (Singhi and Suthar, 2015). Psychiatric
symptoms have been reported on occasion, however the majority of studies have found this to
8
Importantly, it should be noted that the burden of NCC-associated disease is commonly
neurology clinics; as many as 50% of NCC cases had no history of symptoms (Carabin et al,
2011).
The link between NCC and epilepsy is implied to be a causal relationship by the majority of
studies, but to assume causality - not simply high rates of co-occurrence - is unwise without
further analysis of the discrepancies that are evident in existing studies. Definitions as to what
‘epilepsy’ is the occurrence of recurrent and unprovoked seizures, therefore seizures related
to active cysticerci would be classified as ‘acute symptomatic seizures’, which are not
synonymous with epilepsy (Carpio and Romo, 2014). Terminology aside, there still exist
further issues with some of the conclusions drawn from certain aspects of the literature on
this topic. Several reports use seropositivity inferred from enzyme-linked immuno-
electrotransfer blot (EITB) assay as a definitive indicator of active NCC infection, despite
both the accepted inaccuracies of this method and the fact that presence of T. solium
antibodies does not conclusively specify active disease, nor CNS involvement; such work
may therefore misrepresent the epidemiology of the epilepsy-NCC relationship (Carpio and
Romo, 2014). There also exists an evident selection bias in certain studies, where sample
populations have high rates of both epilepsy and NCC; an incidental relationship must first be
considered, as well as the potential for genetic predisposition in certain geographical areas
showing high rates of familial aggregation of NCC (Carpio and Romo, 2014). Whilst the high
relationship, these factors highlight flaws in a hypothesis that seems to have been widely
accepted.
9
Clinical manifestations of extra-parenchymal NCC show greater heterogeneity than those
associated with parenchymal disease, as a wide range of locations throughout the CNS are
included within this broad definition. In general, extra-parenchymal disease has a poorer
prognosis than parenchymal, as parasite loads tend to be higher, and growth of individual
cysticerci is less restricted and tends to be more irregular; this is associated with higher rates
The most common location of extra-parenchymal NCC is in the subarachnoid spaces and
associated meninges (Kimura-Hayama et al, 2010). In severe cases, subarachnoid NCC can
trigger mass inflammation in this area, leading to arachnoiditis; this can have multiple effects
of significant severity, one example being the development of a hydrocephalic state, in which
severe oedema leads to a sharp increase in ICP (Callacondo et al, 2012). Thickening of the
inflamed meninges, along with oedema, may also impact surrounding nerves leading to
entrapment of components of the CNS such as the optic chiasm and cranial nerves with an
assortment of nerve palsies and visual impairments (Kimura-Hayama et al, 2010). Another
fluid (CSF) flow, either due to high parasite burden in the subarachnoid space, or through
cyst deposition in the ventricular system. Prognosis for subarachnoid disease is further
impacted by the occasional development of a proliferating cyst cluster, which forms through
the aggregation of abnormal vesicles, known as a ‘racemose cyst’ (Bansal et al, 2014).
Unrestricted growth of a racemose cyst can lead to invasion of various brain spaces, and
The vascular networks of the brain are similarly affected by obstruction from cysticerci and
inflammatory exudates; there may also be direct insult to the blood vessels themselves in the
10
form of vasculitis. Consequential disruption to blood flow can lead to transient or prolonged
Circulating CSF within the subarachnoid space communicates directly with CSF surrounding
the spinal column and, as a result, cysts originating in the basal cisterns may follow a gravity-
dependent downwards course and disseminate within the spinal meninges. Spinal NCC is
rare (Jongwietiwes et al, 2011), with a reported frequency of approximately 0.25% to 5.8%
of cases (Callacondo et al, 2012) and infrequently presents in isolation without concomitant
cranial involvement (Kimura-Hayama et al, 2010). This may present as motor and sensory
dysfunction, related to the level at which the lesion occurs (Del Brutto, 2012). Symptoms
may include paraesthesia and radicular pain, along the nerve roots into the lower extremities
4. Diagnosis
Accurate diagnosis of NCC is notoriously difficult; available methods are problematic and
the diagnosis of NCC (see Table 1). This multifaceted approach allows for a diagnosis to be
11
Table 1. The ‘Del Brutto Criteria’ for diagnosis of NCC - adapted from Del Brutto et al
(2001).
‘probable’ based on the weight attributed to the criteria that have been met. While not
systematically validated, this approach does allow for otherwise unattainable diagnoses to be
made in difficult situations, with a reasonable rate of success (Fogang et al, 2012). For these
guidelines to be improved, there is an urgent need for improved diagnostic methods, which
4.1 Neuroimaging
Neuroimaging is the preferred method for NCC diagnosis, using CT and MRI scans it is
possible to visualise infecting cysticerci and assess their number and location within the
CNS. With experience, the stage of the cyst lifecycle can be defined: viable cysts appear as
small, round areas that are easily distinguished from the brain parenchyma, with the scolex
appearing as a nodule of high density within the cyst; degenerating cysts are far less well
defined and tend to be surrounded by an area of perilesional oedema (Del Brutto, 2012). A
typical indicative pattern observed for NCC is the ‘starry sky’ appearance formed by the
12
presence of multiple cysts at different evolutionary stages (Singhi and Suthar, 2015). CT
scans are cheaper and more commonly available, and also show higher sensitivity for
detection of calcifications that occur in approximately 50% of patients (Sinha and Sharma,
2009). The higher resolution of MRI scans, permit better distinction of the degenerative stage
of cysticerci and can detect parasites located in sites that would be missed by a CT scan, e.g.
those located in the posterior fossa, basal cisterns and ventricles (Takayanagui and Odashima,
2006). There are issues with sensitivity, especially for intraventricular and subarachnoid
forms, where the cyst fluid and CSF have such similar densities that visualization is unlikely,
even when using contrast-enhanced MRI scans (Kimura-Hayama et al, 2010; Singhi and
Suthar, 2015).
4.2.Immunological Assays
Neuroimaging is expensive and requires both trained personnel and technological resources
that are not available in the majority of low income countries in which NCC is endemic. This
further reliance on the use of serological testing for the detection of NCC. To date, the lentil
assay, which uses targeted antigens to detect antibodies to T. solium in patient serum, has
provided the most consistent results (Fogang et al, 2015; Ito, 2015). This diagnostic test has
a reported specificity of 100%, with an overall sensitivity of 98% (Garcia and Del Brutto,
2005); these rates significantly decline in cases where only a single cysticercus is present as
the low parasite load elicits a far weaker antibody response, and sensitivity falling as low as
50% (Fogang et al, 2015; Ito, 2015). Antibodies can persist in the serum for long periods
after the parasite has been cleared from the body and can be stimulated following exposure to
the parasite in the absence of an established infection (Gilman et al, 2012). In addition, the
presence of antibodies in the serum does not inform as to the location of a cyst; testing
positive for cysticercus infection is not synonymous with CNS involvement (Fogang et al,
13
2015; Ito, 2015). These factors mean that the assay results should be interpreted within the
clinical context, and strengthen a suspected diagnosis. There has been some debate as to
whether NCC is best detected in CSF rather than serum samples (Garcia and Del Brutto,
New assays are in development that show promising results. Gabriel et al (2012) reported an
ELISA based assay that could detect T. solium antigens using monoclonal antibodies
prepared from T. saginata, indicating the presence of an established infection (as opposed to
exposure only). A lateral flow assay (LFA) has recently been developed for the diagnosis and
monitoring of extra-parenchymal NCC (Fleury et al, 2016). This assay is based on the use of
the monoclonal antibody HP10. This assay, applied to CSF samples correctly identified 34
cases of active extra-parenchymal NCC, and gave negative results for 26 samples derived
from treated and cured NCC patients. The assay format is cheaper and is suitable for
laboratories that lack the financial resources to support complex diagnostic procedures
Traditional methods such as stool microscopy have been used to visually assess the presence
of T. solium eggs within the stool of a potential carrier. Whilst this does not necessarily
indicate an NCC infection, it does assist in the detection of tapeworm carriers and the
consequent disruption of the cycle of transmission. Whilst this method can have high
specificity depending on the expertise of the examiner, it has very low sensitivity due to a
certain threshold of eggs needed to be visible under a microscope (Gilman et al, 2012).
Molecular methods applied to stool samples, such as PCR and ELISA, may improve
detection rates but like so many other available tests, the equipment and need for trained
operators is impractical in many endemic settings (Mahanty and Garcia, 2010). More
14
recently simpler and cheaper methods have been developed for identification of T. solium
5. Treatment
The heterogeneity of clinical presentations of NCC not only complicates the diagnostic
procedure but also affects the management plan for the disease; there can be no single,
Before commencing treatment, the complete disease profile must be determined, including
evidence of CNS involvement, characterisation of the existing immune response, and the
number, location and viability of cysts present. Only once these factors have been ascertained
The use of cysticidal drugs in the treatment of NCC has attracted controversy, as the use of
such drugs may pose more risk to the patient than benefit, due mostly to the extensive
inflammatory response that can be stimulated in response to the mass death of cysts within
the CNS (Sinha and Sharma, 2009). For this reason, the use of cysticidal drugs is
sub-arachnoid NCC and encephalitic NCC; in these situations, the inflammation that would
occur following treatment may pose a substantial risk of rapidly raising ICP, and even result
in death. Therefore, in cases where a definitive diagnosis and characterisation of the infection
cysticidal therapy and patients should only be treated with regards to their symptoms (Fogang
et al, 2015). Furthermore, it has been suggested that alongside their potential dangers,
cysticidal drugs may also be unnecessary, as parenchymal cysts in particular may resolve
naturally, following a completely benign and asymptomatic pathway (Garcia et al, 2002).
15
However, several studies have shown that cysticidal drugs do have a positive effect in
reducing symptoms such as seizures and headaches, and hasten the resolution of parenchymal
lesions; this argument is strengthened by many clinicians’ apprehensions over allowing a live
parasite to continue its development in the brain without challenge (Sinha and Sharma, 2009;
The two most widely accepted cysticidal drugs are albendazole, an imidazole that impairs
glucose uptake and metabolism in the parasite, and praziquantel, an isoquinolone that causes
parasite paralysis by disrupting calcium pathways and homeostasis (Bobes et al, 2014). These
drugs are only applicable in the treatment of viable cysts in the vesicular or early colloidal
stages of development, and are ineffective against calcified cysts, as these represent parasites
that are already dead (Baird et al, 2013). Albendazole is generally considered to be the drug
of choice, with superior efficacy and antiparasitic effect compared to praziquantel, alongside
better CSF penetration, less apparent interaction with commonly co-administered drugs such
as corticosteroids and a more competitive price (Fogang et al, 2015; Bansal et al, 2014).
There remains a lack of clarity surrounding prescription guidelines for these drugs and
confusion as to the clinical contexts in which their use is considered appropriate and
beneficial.
5.2 Anti-Epileptics
involving evident symptoms and multiple viable cysts, anti-epileptic pharmacological therapy
may be indicated (Takayanagui and Odashima, 2006); drugs such as phenobarbitone and
carbamazepine are effective in controlling NCC-related seizures in many cases (Del Brutto,
2012). One study found that up to 50% of patients receiving anti-epileptic therapy for NCC
suffered relapses in seizure control following drug withdrawal, suggesting that therapy was
having an inhibitory effect on seizures stimulated by the presence of cysts (Garcia and Del
16
Brutto, 2005). Again, use of these drugs has attracted controversy, with some studies
5.3 Steroids
CNS to control the acute inflammatory process that occurs following degradation of viable
and should be administered around 3 days before the cysticidal drugs are administered, then
continued for approximately a week following the end of the course (Sinha and Sharma,
2009). In patients with a heavy parasite load and diffuse infection, the use of cysticidal
therapy is considered too great a risk and steroids may be used in isolation (Fogang et al,
severe inflammatory complications; however, there are still some concerns regarding their
use, including the potential for increased parasite survival due to immune suppression and the
need for further studies into what constitutes appropriate doses and timing of administration
5.4 Surgery
In cases involving extensive infection, such as racemose NCC and severe extra-parenchymal
NCC, anticysticidal therapy may not be an option due to risks associated with mass
inflammation, but these types of NCC are associated with substantial risk of complications if
left untreated. In these cases, a more aggressive approach may be indicated, including cyst
extirpation via surgery (Bansal et al, 2014). More commonly, surgery may be advised in
severe cases to insert shunts allowing for fluid drainage and resolution of hydrocephalus;
shunt dysfunction in these cases is unfortunately relatively common, and associated with
increased mortality; simultaneous steroid administration can reduce this risk (Garcia et al,
17
2002). Surgery was the primary intervention for NCC therapy but with the development of
advanced pharmacological therapeutics in this field, the use of surgery has significantly
Control and prevention of T. solium transmission should be a key priority in global health as
intervention can reduce the substantial healthcare and economic burdens inflicted by both
The high biotic potential and environmental stability of tapeworm eggs presents a significant
challenge for control but there are a number of simple solutions that could easily be
sanitation, increased education within communities to highlight and inform local populations
as to the disease and corralling pigs to prevent their contact with human waste are all
essential components of any intervention in low and middle income countries (Schantz et al,
1993; Pawlowski, 2016). Increased awareness of infection and transmission is also required
in non-endemic developed countries where the disease has shown signs of increasing
(Fabiani and Bruschi, 2013; Gilman et al, 2012) and where human carriers of T. solium
require to be identified and treated on public health grounds (Nkouawa et al, 2016).
One option for prevention and control of NCC is the development of vaccines for application
in pigs, of which the TSOL18 vaccine, comprised of a recombinant protein originating from a
T. solium oncosphere shows promise (Jayashi et al, 2012). The sequencing of the T. solium
genome also offers exciting prospects in the further improvement of such vaccines through
the identification and direct targeting of highly specific antigens (Bobes et al, 2014).
18
achieving robust disease burden calculations and for targeting of public health interventions.
Carpio et al (2016) provides recommendations for policymakers for a range parasitic diseases
affecting the CNS, and if adopted, would provide much needed data that can be used to direct
future initiatives. In the absence of reliable estimates of its global burden, NCC will remain -
along with other endemic zoonoses of low priority in the eyes of funding agencies (Maudlin
7. Acknowledgements
This work received financial support from the European Union seventh framework
programme from the European Union's Seventh Framework Program (FP7/2007-2013) under
grant agreement nº 221948, ICONZ (Integrated Control of Neglected Zoonoses) and THEME
[KBBE.2012.1.4-03] under grant agreement nº312030, Advocacy for the fight against
Neglected Zoonotic Diseases (ADVANZ). The contents of this publication are the
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