Expert Review of Anti-infective Therapy

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Inflammation in neurocysticercosis: clinical

relevance and impact on treatment decisions

Pedro T Hamamoto Filho, Gladis Fragoso, Edda Sciutto & Agnès Fleury

To cite this article: Pedro T Hamamoto Filho, Gladis Fragoso, Edda Sciutto & Agnès Fleury
(2021): Inflammation in neurocysticercosis: clinical relevance and impact on treatment decisions,
Expert Review of Anti-infective Therapy, DOI: 10.1080/14787210.2021.1912592

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EXPERT REVIEW OF ANTI-INFECTIVE THERAPY
https://doi.org/10.1080/14787210.2021.1912592

REVIEW

Inflammation in neurocysticercosis: clinical relevance and impact on treatment

decisions
a
Pedro T Hamamoto Filho , Gladis Fragosob, Edda Sciuttob and Agnès Fleuryc,d,e
a
Department of Neurology, Psychology and Psychiatry, UNESP-Univ Estadual Paulista, Botucatu Medical School, Botucatu, Brazil; bDepartment of
Immunology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México, Mexico; cDepartment of
Genomic Medicine and Environmental Toxicology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de
México, Mexico; dNeurocysticercosis Clinic, Instituto Nacional de Neurología Y Neurocirugía, Ciudad de México, Mexico, mexico;
e
Neuroinflammation Unit, Instituto de Investigaciones Biomédicas-Universidad Nacional Autónoma de México/INNN/Facultad de Medicina-UNAM,
Ciudad de México, Mexico

ABSTRACT ARTICLE HISTORY

Introduction: Neurocysticercosis is caused by the localization of Taenia solium larvae in the central Received 16 February 2021
nervous system. The disease remains endemic in most countries of Latin America, Asia and Africa. While Accepted 31 March 2021
major improvements have been made in its diagnosis and treatment, uncertainties persist regarding KEYWORDS
the clinical implications and treatment of the inflammatory reaction associated with the disease. Anti-inflammatory drugs;
Areas covered: In this review, based on PubMed searches, the authors describe the characteristics of corticosteroids;
the immune-inflammatory response in patients with neurocysticercosis, its clinical implications and the inflammation;
treatment currently administered. The dual role of inflammation (participating in both, the death of the neurocysticercosis;
parasite, and the precipitation of serious complications) is discussed. New therapeutic strategies of neuroinflammation; parasite;
potential interest are presented. taenia solium
Expert opinion: Inflammatory reaction is the main pathogenic mechanism associated to neurocysti­
cercosis. Its management is mainly based on corticosteroids administration. This strategy had improved
prognostic of patients as it allows for the control of most of the inflammatory complications. On the
other side, it might be involved in the persistence of parasites in some patients, despite cysticidal
treatment, due to its immunosuppressive properties. New strategies are needed to improve therapeu­
tical management, particularly in the severest presentations.

1. Introduction 282,937–478,123) individuals had NC in 2010, resulting in the

death of 28,114 (95% CI: 21,059–36,915) individuals [6]. The
Neurocysticercosis (NC) is caused by the localization of Taenia
estimated prevalence in Latin America, Asia and Sub–Saharan
solium larvae in the central nervous system (CNS). It is
Africa ranges from 13% to 54% [7].
a zoonotic disease that affects humans and pigs, with the
The advent of computed tomography (CT) and nuclear mag­
latter being the intermediate host in the life cycle of the
netic resonance (MRI) techniques in the 1970s and 1980s allowed
parasite. Humans become infected with the adult form of
major advances in the diagnosis and treatment of the disease.
the parasite by eating undercooked infected pork containing
Later, clinical, radiological, and immunological studies helped to
the larval form of T. solium. Both pigs and humans also acquire
establish the crucial importance of neuroinflammation in the con­
cysticercosis by ingesting eggs, that is, ingesting contami­
text of symptomatology and response to treatment [8].
nated food in the cases of humans [1].
In this review, we will focus on describing the state of the
NC is one of the main parasitic diseases of the CNS and art of this disease with regards to the relevance of inflamma­
remains endemic in Latin America, sub-Saharan Africa, and tion in clinical status and therapeutic implications.
South and South-East Asia. In addition, migratory flows have
reintroduced cases in the United States and Europe. Despite
a decreasing tendency of incidence in countries with improv­ 2. Characteristics of inflammatory reaction
ing sanitary conditions, such as Mexico and Brazil [2,3], the Main characteristics of the inflammatory reaction in patients
disease persists, especially in rural areas with animal husban­ with NC have been described in different experimental and
dry. In these areas, the contact of pigs with human feces may clinical studies.
occur, favoring the disease persistency [1], which continues to
have significant health and economic impacts, impairing the
quality of life of patients [4,5]. 2.1. Experimental studies
A systematic review of epilepsy-based data from endemic Several experimental models have been used to study differ­
countries estimated that 370,710 (95% confidence interval [CI]: ent aspects of cysticercosis, particularly in the context of

CONTACT Agnès Fleury [email protected] Department of Genomic Medicine and Environmental Toxicology, Instituto De Investigaciones
Biomédicas, Universidad Nacional Autónoma De México, Ciudad Universitaria, Apartado Postal 70228, Ciudad De México 04510, mexico.
© 2021 Informa UK Limited, trading as Taylor & Francis Group
2 P. T. HAMAMOTO FILHO ET AL.

macrophages and plasmocytes, followed by lymphocytes and

Article highlights neutrophils [26].
● Neuroinflammation is the main pathogenic mechanism in patients
Swine have also been used for natural [27] or surgical [28]
with parenchymal and extraparenchymal neurocysticercosis. infection. In both cases, an exacerbated local inflammatory
● Neuroinflammation is involved in the main symptoms of NC, namely response is detected [21]. Interestingly, in the surgical infec­
seizures, epilepsy, intracranial hypertension, and symptoms related to
vasculitis and arachnoiditis.
tion model, despite the intense local inflammation and few
● Corticosteroids are able to control the inflammatory reaction in most Th2 cells, a high expression of the regulatory cytokine IL-10
patients, significantly improving their prognosis. was found, which is in accordance with the other studies in
● Corticosteroids could be involved in the non-response to cysticidal
treatment mainly observed in patients with extraparenchymal dis­
humans [29].
ease, due to their immunosuppressive effects. The use of rhesus monkeys has also been reported, with
● The development of new strategies to control the inflammatory the advantaged of phylogenetic proximity with humans, even
response is necessary.
though its use is restricted due to strictly ethical regulations
and the need of huge infrastructure. The histopathologic find­
ings closely resemble those of humans, including inflamma­
tion, granuloma formation, and disturbances of cerebrospinal
immune response and inflammatory reactions. Taenia crassi­ fluid (CSF) flow [30].
ceps, Mesocestoides corti, and T. solium are the main parasites Altogether, despite the obvious limitations of the differ­
employed, inoculated mainly in rats, mice, swines and mon­ ences with the human infection, these models can provide
keys. Chinchillas and hamsters have also been used for models insightful roadmaps for understanding the role of inflamma­
of taeniasis with the advantage of providing viable eggs of tion in NC as well as for evaluating treatment options.
T. solium after proglottid infection [9–11].
The first model used, the intraperitoneal inoculation of
T. crassiceps in mice [12,13], led to an understanding of the
2.2. Immune-inflammatory reaction in human NC
inflammatory mechanisms involved in the host response
against the parasite. Initially, there is an early protective To describe the characteristics of the immune-inflammatory
response characterized by a Th1 profile (interleukin [IL]-2 and response accurately, the location of parasites in the CNS must
interferon-γ). Four weeks after infection, IgG1 antibodies can be taken into account. Indeed, patients affected by parenchy­
be detected, and there is a shift into a Th2 permissive profile mal and extra-parenchymal NC have different clinical features,
(IL-4, IL-6 and IL-10) [14]. This change is related to the para­ severity degree, and prognosis, linked in part to different
site’s production of specific proteins with specific defensive immune-inflammatory responses [31] (Table 1). Although the
roles in evading the host immune responses [15]. This model location of parasites is clearly the main factor involved in the
has also allowed to document the relevance of substance-P in heterogeneity of immune-inflammatory response, it is relevant
the development of granulomas and in the risk of seizure to note that there is also a great heterogeneity between
recurrence [16,17]. The proinflammatory role of substance patients with cysts located in the same compartment, with
P is particularly done by stimulation of mast cell degranula­ some patients presenting a high immune–inflammatory
tion, release of inflammatory mediators, and increase of vas­ response, while others, a much more discrete one [32,33].
cular permeability [18]. Mice with intracranial T. crassiceps Such differences may be related to the host genetic makeup
infection showed similar pattern of initial Th1 and late Th2 (including polymorphisms in genes involved with
responses, and a systemic immune response that parallels the
in-situ response [19,20]. T. crassiceps can also be used as
a model for extraparenchymal NC (EP-NC), allowing for Table 1. Main differences between parenchymal and extraparenchymal
a better understanding of the factors involved in the genesis neurocysticercosis.
of hydrocephalus [21]. Parenchymal
NC Extraparenchymal NC
M. corti is another cestode that has been used for parench­
Incidence Higher Lower
ymal intracranial infection. Using this model, it was demon­ Mostly reported from All endemic Latin America
strated that the parasite releases different tegument countries (seems to be much less
glycoconjugates throughout the course of infection as an frequent in Asia and Africa)
Age of patients Younger Older
immune evasion strategy [22]. It has also been shown that Main symptoms Seizure/ Intracranial hypertension
the Th1 response is dependent upon gamma-delta T cells [23] epilepsy
and that the disruption of the barriers of the CNS for leukocyte Location of Mainly around Diffusion in all the
neuroinflammatory parasites extraparenchymal
infiltration is different between different sites, with more junc­ reaction compartment
tional proteins degradation and more intense matrix metallo­ CSF inflammation No Yes
proteinase activation near the blood-brain barrier within pial Severe complications due + +++
to inflammation
vessels and in the ependyma [24,25]. Prognosis Generally More complicated
The use of T. solium for intracranial infection in rodents is good
more recent. This model requires the collection of parasite Use of anti-inflammatory ++ ++++
drugs
eggs before with subsequent incubation and oncosphere Response to cysticidal High Low
hatching and activation. Inflammatory cells were observed treatment
mainly in the perivascular space, with a predominance of
 EXPERT REVIEW OF ANTI-INFECTIVE THERAPY 3

inflammation [34–36]), and differences in the endocrinological, with this possibility, parasite-derived antigen levels detected in
oxidant, and proinflammatory status that achieve the brain serum positively correlate with CSF levels in EP-NC patients [52].
[37,38]. This implies that in the extraparenchymal presentation, a peripheral
In parenchymal NC (P-NC), the inflammation is mainly immune response is also established and is capable of modulating
restricted to the parenchyma itself. Cysticerci can be destroyed the central response [53]. In this sense, an expansion of the Treg cells
without or with cysticidal treatment, probably mediated by the response is observed in the periphery, which probably reflects an
release of damage-associated molecular patterns (DAMPS) and attempt to control the central inflammatory response [46].
pathogen-associated molecular patterns (PAMPs) derived from Regardless of their functional activity, these observations point to
cysticerci, that are recognized by the pattern recognition recep­ the possibility of controlling the central response by controlling the
tors (PRRs) of the host, resulting in exacerbated perilesional peripheral response.
inflammation [39,40]. No DAMPs or PAMPS have been identified Heterogeneity in the humoral immunoinflammatory response in
in vivo in cysticerci, however, some PAMPS-like molecules, such NC has also been documented. Indeed, increased levels of IgG, IgM,
as annexin, have been found in the secretome of Taenia solium and IgE were found in symptomatic patients harboring cysts in the
[41]. On the other side, the local inflammatory features involved subarachnoid space compared to asymptomatic individuals [45,54].
are only histologically described. Degenerative or calcified cysts IgG and IgM can activate the complement, promoting the inflam­
are surrounded by a mature granuloma composed of multinu­ matory immune response through the anaphylatoxins C3a and C5a.
cleated giant cells surrounded by a dense fibrous layer rich in IgE mediates the inflammatory response through the release of pro-
collagen [29]. The most abundant cell types are macrophages, inflammatory factors of mast cells and eosinophils. In asymptomatic
CD3/CD8 + T cells, plasmatic cells, and, in less proportion, CD3/ NC subjects, increased levels of IgG4 were observed [45]. This
CD4 T and B (CD20+) lymphocytes [29]. The presence of neutro­ immunoglobulin does not activate the complement nor mediates
phils, eosinophils and mast cells have also been reported [42]. the antibody-dependent cell-mediated cytotoxicity (ADCC),
The immune-inflammatory response is also characterized by accounting, therefore, to a less inflammatory profile.
edema and reactive gliosis at different stages, according to the
degree of the parasite stage [43]. Otherwise, a strong immune-
inflammatory peripheral response with a mixed Th1/Th2 cyto­
kine (IL-12, IFN-γ/IL-4, IL-13) and proinflammatory cytokine (IL-8,
2.3. Radiological characteristics of the inflammatory
TNFα) profile was described in the supernatant of peripheral
reaction
blood mononuclear cells stimulated in vitro with parasite anti­ CT and MRI are important tools for the diagnosis and treat­
gens [44]. Interestingly, in parenchymal calcified NC, a typical ment follow-up of NC. Specific radiological signs are diagnos­
peripheral Th2 profile was observed, with increased levels of tic criteria for the disease as described elsewhere [55,56].
IgG4 and IL-4, IL-5, and IL-13 produced by specifically stimulated Moreover, inflammatory reactions can be identified through
mononuclear cells [45]. the evolutionary phases of the cysts, and edema and contrast
When parasites are located in the subarachnoid compartment, enhancement are key radiological elements for the identifica­
lower levels of Th1/Th2 cytokines in periphery are found com­ tion of inflammatory reactions [55].
pared to the parenchymal presentation. These levels are as low In the initial phases of NC (the vesicular stage), cysts con­
that resemble to those from non-infected subjects. However, tain clear fluid and may present with invaginated marginal
a stronger regulatory immune response is achieved when cells nodule (the scolex). The parasite is able to evade the host’s
are stimulated with parasite antigens in vitro [44], a result that is in immune response and, therefore, there are few or no inflam­
accordance with the increased levels of regulatory cytokines matory findings surrounding the cysts [55].
found in the CSF. Also, an increased number of CD4+/CD25 Treg When the cysts start to degenerate (the colloidal stage), the
cells without previous specific stimulation has also been observed scolex is destroyed, and the protein content of the fluid
in the periphery, closely correlating with the increased number of increases. It is in this phase that the inflammatory reaction is
these cells in the CSF [46]. In contrast to P-NC, in EP-NC it is most evident (Figure 1). A ring-enhancement is observed
apparently rare for cysticerci to be damaged as part of the natural around the parasite due to the breakdown of the blood–
course of the disease, and the destruction generally requires brain barrier. The surrounding pericystic vasogenic edema
cysticidal treatment [47]. In the CSF, increased levels of different can be observed as a hyperintense rim within the white matter
pro-inflammatory cytokines, such as IL-6 and IL-1 [45,48] and Th1/ in T2 and fluid attenuated inversion recovery images (FLAIR)
Th2 cytokines and chemokines, such as IFNγ, IL-12p70, CXCL-10/IL- [57,58]. These features are similar to those observed in other
10, and IL-13 [49], have been reported. The increased levels of IL- infectious and neoplastic diseases, such as tuberculomas, brain
10 and TGFβ may counteract the effect of inflammatory cytokines abscesses, and metastasis [59].
[50]. Moreover, this inflammatory profile is associated with an The progression of cyst degeneration leads to a reduction in their
increase in the central number of Treg cells and a decrease in size, accompanied by the change into a small enhanced nodular
the number of CD4 and CD8 activated T cells [51]. This apparently lesion (the granular nodular stage) that may be surrounded by
tightly regulated response is accompanied by different degrees of edema of variable degree. The intensity of the inflammatory reaction
disease severity, directly related to the degree of CSF inflammatory decreases with time, and peripheral gliosis can be observed as
response. a result of previous inflammation [60]. Finally, the lesion calcifies as
It seems that the increased inflammation in the CSF of these the result of the organization of the granuloma. Episodic surround­
patients affects the permeability of the blood-CSF barrier. According ing edema is not commonly found in this phase, although it has
4 P. T. HAMAMOTO FILHO ET AL.

Figure 1. Degenerating (colloidal) cyst. A: contrast enhanced 3D FSPGR MRI showing the ring enhancement around the cyst. B: MRI FLAIR showing perilesional
edema.

been reported to occur in 50% of NC patients who suffer from relevant to mention that the prevalence of parenchymal and
seizures (see below) [61–63] (Figure 2). extraparenchymal NC seems to vary between endemic coun­
For EP-NC, the identification of the cysts within the CSF compart­ tries. In particular, extraparenchymal NC is much less fre­
ments may be improved using 3D MRI volumetric acquisitions [64]. quently diagnosed in Asia than in Latin America [66]. The
In these compartments, the classical radiological signs of inflamma­ causes of this observation have not been studied in depth,
tion (ring-contrast enhancement and edema) are rarely observed as but it is surely an aspect that deserves attention.
the parasites lie in the CSF [60]. However, in case of arachnoiditis,
a leptomeningeal enhancement is frequently observed (Figure 3).
Also, radiological tools provide evidence of other complications of 3.1. Parenchymal NC (P-NC)
the inflammatory reaction, particularly hydrocephalus, vasculitis, The main symptom of P-NC is seizure, and inflammation is
and stroke [65] (Figures 4 and 5). probably the main cause. Seizures occur in 77% of patients
with this type of the disease [33] and can be of two types:
acute symptomatic or recurrent unprovoked [67]. The former
3. Clinical aspects
is defined by a clinical event occurring at the time of
The clinical implications of inflammatory reactions in patients a systemic attack or in close temporal association with
with NC differ depending on the parasite location. It is a cerebral attack [68]. They are not always followed by the

Figure 2. Calcified cysticercus with episodic surrounding edema. A: CT scan appearance. B: MRI FLAIR where the edema is much better observed.
 EXPERT REVIEW OF ANTI-INFECTIVE THERAPY 5

3.1.1. Inflammatory reaction around degenerating

(colloidal) cysts (Figure 1)
This is the most well-known link between inflammation and
symptomatology. Indeed, the association between parasite
degeneration and seizures is clear. In a study including NC
patients who had presented with a first attack, the most
frequent finding of NC was the presence of colloidal cysts
[70]. Pathological studies have shown that an intense inflam­
matory reaction occurs in the brain parenchyma around para­
sites at this stage, with astrogliosis, microglial proliferation,
edema, neuronal degeneration, and perivascular cuffing of
lymphocytes [43]. This reaction is a clear irritating factor that
has the ability to trigger seizures, and residual gliosis has been
found to be associated with seizure recurrence [71,72].
However, it is interesting to note that not all inflammatory
cysts are associated with seizures. Although we still do not
know the respective relevance of the number, locations, and
size of parasites, the quality of immune response and genetic
factors are surely also involved [73,74].
It is also relevant to mention a particular NC presentation
clearly linked to inflammation: cysticercotic encephalitis. It
results from the acute inflammatory response that occurs
when multiple degenerating parasites are localized in the
brain parenchyma. This inflammatory reaction generates
Figure 3. Severe arachnoiditis of the basal cisterns associated with diffuse severe cerebral edema, which manifests as intracranial hyper­
subarachnoid neurocysticercosis (contrast enhanced 3D FSPGR MRI). tension (headache, vomiting, and papillary edema), convul­
sions, and alterations in visual acuity and in consciousness
[60,75]. This very severe presentation, which is highly fatal
and mainly affects young women and children, requires
urgent therapeutic management, mainly focused on control­
ling the inflammatory reaction.

3.1.2. Inflammatory reaction around calcified NC (Figure

2)
Another situation in which inflammation is apparently involved in
NC patients that develop seizures is the presence of intermittent
edema around calcified parasites, a more recently described phe­
nomenon that is opposed to the classic first pathologic and
radiological descriptions [43]. In the first descriptions, calcifica­
tions were considered to represent the ‘inactive’ stage of the
disease and although their association with seizures was well
described, the main reason given was the presence of gliosis,
considered a scar of previous inflammatory processes [76,77].
Over time, the widespread use of MRI has helped to describe
this phenomenon. This finding was observed in 50% of patients
with calcified NC and seizure recurrence [62]. A previous study by
the same team did not find a statistically significant relationship
between the presence of perilesional edema and seizure recur­
rence [78], while a more recent study showed that the presence
of perilesional edema was associated with a significant 12-fold
increase in the risk of seizure recurrence within a year after the
Figure 4. Typical hydrocephalus complicating extraparenchymal NC (MRI FLAIR).
edema [63]. These results were confirmed by another recent
longitudinal study, in which the presence of perilesional edema
around calcified cysticerci on initial and follow-up MRIs was sig­
development of epilepsy and are probably the most common nificantly associated with persistent seizures [79].
types of seizures in patients with NC [69]. The factors underlying the development of this edema are
Inflammation is linked to the development of seizures in still unclear. It is feasible that although the parasite looks
patients with P-NC by different mechanisms. calcified, parasite antigens or genetic material are still present
6 P. T. HAMAMOTO FILHO ET AL.

Figure 5. Contrast enhanced 3D FSPGR MRI. left putaminal stroke (A) in relation with basal arachnoiditis, mainly located in left carotid and sylvian cisterns (B).

and elicit some degree of local inflammation by the host [61]. comparing patients with calcified NC with HS to patients with
In this context, the histopathologic characteristics of calcifica­ calcified NC alone, NC was found to be significantly more
tion with perilesional edema surgically excised in a patient frequently localized in the temporal lobes in the first group
with refractory epilepsy are interesting [80]. A marked mono­ than in the second [87]. All these observations could be argu­
nuclear infiltrate in the capsule around the calcified cysticerci ments in favor of a causal association between the two dis­
and extending to the adjacent brain was found, in clear con­ eases in some patients, although in others the association may
trast with the classic description of cysticercal calcification, in be coincidental.
which the capsule is fibrous without noticeable inflammation Two probable mechanisms have been proposed in the
[43]. It is also relevant to note that the presence of scolex event of a causal association. The first is associated with the
remnants within the calcified lesion was significantly more known increased susceptibility of the hippocampus to
frequently observed in calcifications associated with edema damage in the event of repetitive seizures or status epilepti­
than in calcified lesions without edema [81]. The presence of cus [88]. As NC is one of the most frequent causes of seizures
scolex remnants in certain parasites could probably be inter­ in endemic countries, this situation could favor the develop­
preted as incomplete degradation of the parasite with preser­ ment of HS even if NC is not located close to the hippocam­
vation of certain antigenic components [81] and would be in pus [89]. Another mechanism could be mediated by the
accordance with the inflammatory hypothesis. inflammatory phenomenon, independently of the presence
of seizures [89]. Indeed, the hippocampus is known to have
3.1.3. Association between NC and hippocampal sclerosis a particular sensitivity to inflammation [88,90]. Although ima­
Another mechanism by which the inflammatory reaction asso­ ging tools show an inflammatory reaction around degenerat­
ciated with NC could influence the onset of seizures is its ing parenchymal cysticerci only in close contact with the
possible role in the development of hippocampal sclerosis parasite, we cannot exclude the possibility of it having
(HS), and therefore of mesial temporal lobe epilepsy (MTLE). a much more extensive spread that eventually can damage
NC and MTLE-HS are two common forms of focal epilepsy the hippocampus even if the cysticercus is not close to it. In
worldwide, and in regions where NC is endemic, both diseases this context, it is interesting to note that HS has been
can be observed in the same patient [82]. Several studies were detected in the murine model of peritoneal infection with
conducted to evaluate whether this association was coinciden­ T. crassiceps [91], and similar results were also observed after
tal or if a causal relationship might exist. subcutaneous inoculation of a T. crassiceps metacestode fac­
The first large-scale studies evaluating their association tor [92]. Using the same murine model, other researchers also
concluded that it was probably a coincidence [83,84]; how­ found alterations in neurotransmitters and cytokines in the
ever, more recent studies support the hypothesis that the hippocampus of infected mice [93]. Another interesting find­
association between NC and HS is causal. The main reasons ing in a NC rat model (T.solium) was that authors evaluating
are: 1) in patients with refractory epilepsy due to any cause, the presence of axonal swelling evidenced by the formation
there is an increased frequency of calcified NC associated with of spheroids demonstrated that these alterations were not
MTLE-HS compared to that in patients without MTLE-HS confined to the area of gliosis around parasites, but extended
[85]; 2) a lower frequency of classical initial precipitating lesion into otherwise normal tissue [94]. Based on this information,
(IPI) in patients with MTLE-NC than patients with MTLE with­ and also because women are more frequently affected by
out NC, possibly implying that NC might act as an IPI itself both NC-HS and more inflammatory NC [95], the hypothesis
[86]; 3) in patients with MTLE-HS and calcified NC, NC occurred that inflammatory mechanisms participate in the HS in NC
significantly more often on the same side as HS [86]; and 4) by patients is very probable.
 EXPERT REVIEW OF ANTI-INFECTIVE THERAPY 7

3.2. Extra-parenchymal NC (EP-NC) associated adhesions can eventually obstruct the cavity [43].
Moreover, the increase in the inflammatory characteristics of
In patients with EP-NC, the parasites are more frequently
the CSF, in addition to being associated with a higher viscosity
localized in the basal subarachnoid cisterns, followed by the
of CSF reducing its circulation capacity, could promote hydro­
ventricular system, the Sylvian fissure, and the medullary sub­
cephalus by different mechanisms. First, the increase in CSF
arachnoid space [33].
protein levels might be associated with a decrease in CSF
Variations in the time-period between infection and the
reabsorption due to partial obstruction in the absorption
development of inflammation can cause symptoms to differ
zone. This has been described in other diseases, such as
in these patients compared patients with P-NC. It is considered
small intracranial and intraspinal tumors and Guillain-Barré
that, on average, P-NC patients will be diagnosed 5 years after
syndrome [99,100]. An immunological hypothesis has also
infection, while EP-NC patients will be diagnosed 15 to
been proposed, based on the presence of pro-inflammatory
20 years after infection [96]. This difference is mainly because
cytokines, in particular IL-17 in EP-NC, in the CSF of patients
of the characteristics of the milieu in which the parasites lie,
with idiopathic intracranial hypertension and Guillain–Barré
surrounded by cells with potential immunologic function in
syndrome [49,101–103]. Although the precise mechanism is
P-NC vs. in an acellular fluid (CSF) in which immunological
not known, there may be a reduction in CSF uptake due to
phenomena are not normally active in EP-NC. This situation
inflammation or fibrosis of arachnoid villi [101]. In addition,
explains why the characteristics of the inflammatory reaction
the increase in the osmotic gradient due to the accumulation
in the two situations are different: relatively acute in P-NC, and
of proteins in the CSF could also participate in the genesis of
much more chronic in patients with EP-NC.
hydrocephalus [104,105]. Finally, studies on a model of hydro­
Clinical consequences of inflammation are more frequent
cephalus caused by T. crassiceps suggested that differential
when the parasites are localized in the subarachnoid space
modulation of aquaporin-4 expression could also participate
(basal or medullary cisterns) than when they are localized in
in the genesis of hydrocephalus, as well as in its compensa­
the ventricular system or Sylvian fissure. The larger space of
tion [21].
the subarachnoid cisterns allows the parasites to grow silently
and slowly for years. When the immune system recognizes
them, the efficiency of the immune response is probably less 3.2.2. Vascular events (Figure 5)
than that triggered in the parenchyma [97]; indeed, it is fre­ Vascular events constitute an important source of motor and
quent, in this compartment, to observe vesicular parasites sensory sequelae associated permanent disabilities. The fre­
which apparently have not started their degenerative process quency of vascular complications in patients with distinct
while the CSF has inflammatory characteristics [33]. An equally forms of symptomatic NC varies between 3 and 12% [106].
important point to mention is the diffusion of the inflamma­ Inflammation is the primary pathological mechanism involved
tory reaction in the case of subarachnoid localization. The in these events. As shown in one of the first clinical studies
basal cisterns communicate with each other, allowing the evaluating vascular events in patients with NC, two situations
inflammatory reaction to spread and damage neurological can arise.
structures distant to the parasite itself (Figure 3). The first is when the vasculitis is clearly due to the spread
of the inflammatory process around a cyst to the vascular wall,
3.2.1. Intracranial hypertension (ICH) caused by made possible by the proximity of both structures. Both small
hydrocephalus (Figure 4) and large vessels may be affected, and in these cases, the
Two main mechanisms are involved in ICH: mass effect and number of cysts may be small [107]. A typical example of
inflammation [98]. Usually, ICH due to mass effect will appear such cases is vasculitis of the middle cerebral artery due to
earlier in the disease course than ICH due to inflammation. ICH a colloid cyst in the Sylvian fissure [108]. Vascular event is in
is the result of mechanical obstruction of CSF flow and occurs these cases are frequently the presenting symptom of NC, and
primarily when viable parasites are localized in smaller sites of CSF inflammation is generally mild. Although severe, the out­
the ventricular system, especially the fourth (most common) come is generally better than for patients in the second group.
and third ventricles, and the cerebral aqueduct [33]. This These cases were the most frequent in 1996 in Mexico [107],
mechanism can also be in play when parasites are localized but it seems that their incidence has decreased. Indeed, in
in the subarachnoid cisterns (e.g. in case of enlarged ponto­ a recent series of 238 Mexican patients affected by EP-NC,
cerebellar cysts compressing the fourth ventricle), although none of them had any initial symptomatic vascular events [33].
these circumstances are less common. The second is associated with a more diffuse form of NC
The second mechanism, probably the most frequent, affecting mainly the basal subarachnoid cisterns. In such cases,
although precise studies evaluating its prevalence are lacking, the diagnosis of NC has usually been made several years ago,
is the inflammatory reaction, which involves two factors: first, significant CSF inflammation exists, viable cysts may or may
the development of ependymitis when inflammatory cysts are not be present, and arachnoiditis is the main finding. In these
in contact with the ependyma, and second, the inflammatory patients, the intensity of CSF inflammation is associated with
features of CSF per se (increase in proteins, cells, and proin­ increased cerebral blood flow [109]. Since vascular events are
flammatory immunological factors) [98]. Ventricular cysts often generally associated with other symptoms related to NC (espe­
adhere partially to the ependyma, and the resulting inflamma­ cially ICH), the prognosis is poor. Several types of strokes, such
tion can cause ependymal cells proliferation and subependy­ as symptomatic and silent lacunar can occur, and different
mal gliosis. This overgrowth (granular ependymitis) and arteries can be affected [107]. In these cases, the vascular
8 P. T. HAMAMOTO FILHO ET AL.

events are mainly caused by the development of the inflam­ release of antigens of central cells that are not in contact
matory reaction, rather than by the presence of inflammatory with the immune system under normal conditions and can
cysts, as in the first situation. break tolerance, leading to an autoimmune reaction [133].
In both cases, infiltration of the arterial walls by lympho­ Further studies will be needed to decipher the role of inflam­
cytes, plasma cells, and eosinophils causes occlusive endarter­ mation, genetic and epigenetic factors in the genesis of auto­
itis, and consequently, a reduction in the diameter of the immunity in patients with NC [134].
arteries. In addition, atheroma–like deposition resulting from In some viral infections, this phenomenon is the origin of
disruption of the endothelium may occur, which in turn can manifestation, with severe clinical conditions occurring weeks
participate in the blockage of the lumen of the arteries [110]. or months after the initial event [135]. Close monitoring of
Regarding the type of infarcts generated by this vasculitis, patients who present with such antibodies is necessary to
the most frequent are lacunar infarctions, but large infarcts better understand their clinical implications and to determine
involving deep and superficial sites of major intracranial whether specific therapeutic management is necessary.
arteries can also occur [111–113]. Progressive midbrain syn­
drome, associated with multiple ischemic areas in the mid­
4. Therapeutic aspects of inflammation in NC
brain and thalamus, and transient ischemic attacks have also
patients
been reported [107,114].
Hemorrhages are less frequent. They are usually due to As we have seen in this review, inflammation is the main
a weakening of the arterial wall by the adherence of cysticerci factor involved in the morbidity associated with NC.
to the subarachnoid blood vessels, resulting in the formation Based on the evidence available, anti-inflammatory drugs
of an inflammatory aneurysm [106]. The intense inflammatory have been empirically used since the beginning of the modern
infiltrates surrounding the parasite adjacent to the aneurysm management of patients, and have shown relevant beneficial
suggest, in most cases, that inflammation might play an effects, particularly in patients with EP-NC who required the
important role in its genesis [115–119]. implantation of a ventriculoperitoneal shunt. Before the use of
corticosteroids, the mortality rate of these patients was almost
3.2.3. Other symptoms related to arachnoiditis 50%, with most patients dying within the first 2 years of CSF
Arachnoiditis is a chronic process that may persist even in the shunting [136]. Treatment with corticosteroids significantly
absence of viable cysts. The scar tissue on the cranial base or improved the functionality of patients by reducing the need
within the spinal canal distorts the normal anatomy of the for subsequent surgery due to shunt dysfunction [137].
subarachnoid space and may lead to cranial nerve–related or Early reports also showed that the administration of corti­
spinal radicular symptoms due to nerve entrapment followed costeroids concomitantly with cysticidal drugs decreased the
by demyelination and dysfunction [106,120]. When these exacerbation of neurological symptoms in patients with P-NC.
symptoms are related to direct compression due to the pre­ Indeed, in the first studies evaluating the administration of
sence of the cysts, clinical improvement can be achieved by albendazole and praziquantel without anti–inflammatory
successful cyst destruction with either clinical treatment or drugs, 80-92% of the patients presented with exacerbation
surgical removal [121–124]. However, symptoms related to of neurological symptoms, usually 2 to 4 days after the treat­
longstanding compression and entrapment may not be rever­ ment initiation [138,139]. It was clear that these symptoms
sible [125], especially in cases of optic nerve injury with vision were not due to drug toxicity, but to the inflammatory reac­
loss. Any cranial nerve could be potentially affected by NC- tion associated with the degeneration of the parasite. As it was
related arachnoiditis; however, the most commonly affected determined that the simultaneous administration of corticos­
are the second, third, fifth, and seventh nerves, even though teroids with praziquantel decreased the plasma levels of pra­
sixth and eighth nerves lesions have also been reported [126]. ziquantel by 50%, the administration of steroids was initially
Regarding spinal EP-NC, cysts can be found in any level recommended only for cases with adverse reactions [139].
(cervical, thoracic, and lumbosacral regions) [127,128]. Direct Nevertheless, later evidence showed that the positive
compression of the spinal cord by the cysts is the most effects of corticosteroids administration with cysticidal drugs
common cause of symptoms, but arachnoiditis can also be were superior to their eventual negative effects [140].
found and poses considerable difficulties in surgical removal.
Clinical improvement is quite variable and highly dependent
4.1. Drugs used to control inflammatory reaction
upon the presence of arachnoid adhesions [129,130].
4.1.1. Corticosteroids
3.2.4. Presence of autoantibodies Corticosteroids are the most potent anti-inflammatory drugs
It was recently observed that the CSF of EP-NC can have widely used since 1948. This family of drugs has strong anti-
significant levels of anti-myelin oligodendrocyte glycoprotein inflammatory and immunosuppressive effects impacting both
(MOG) and anti-tubulin autoantibodies [131,132]. These auto­ innate and acquired immune responses. They affect neutro­
antibodies were absent in the CSF of patients with P-NC and phils, eosinophils, and macrophages by repressing their pro­
had a significant positive correlation with CSF cellularity. Their duction of cytokines, lipid inflammatory mediators, and nitric
clinical significance and the precise mechanisms involved in oxide, as well as by preventing the recruitment of cells to sites
this increase are not yet clear, but it is possible that the of inflammation [141]. They also regulate the adaptive
intensity of the neuroinflammatory reaction could be relevant immune response from the initial phase of antigen recogni­
in this regard. Indeed, neuroinflammation can cause the tion and presentation by dendritic cells to the effector phase
 EXPERT REVIEW OF ANTI-INFECTIVE THERAPY 9

when T lymphocytes of both the Th1 and Th2 type act to clear inflammatory EP- or P-NC was recently published [154] and
invading pathogens. At physiological concentrations, corticos­ despite the considerable heterogeneity of cases included, the
teroids bias the immune system toward Th2 responses and authors stated that administration of TNF– α antagonist
may even contribute to tolerance [141]. They are strong med­ seemed to be able to stabilize the disease. Etanercept was
iators of thymocyte apoptosis, and, of relevance in CNS infec­ the drug used, at the doses of 25 to 50 mg/week (subcuta­
tions, repair blood–brain barrier disruption, thereby reducing neous injection) and with an extreme variability in the dura­
leukocyte infiltration into the CNS [141,142]. Their benefits in tion of treatment (31–854 days). As said by the authors, these
controlling inflammation associated with NC have become results are still anecdotal, and controlled studies to evaluate its
progressively more evident and currently corticosteroids are efficacity must be performed [154].
widely recommended in patients with different forms of
NC [143]. 4.1.4. Other drugs
Different corticosteroids have been used in NC patients, Some reports have mentioned the utilization of the antihista­
particularly prednisolone, prednisone, methylprednisolone, minic drug dextrochloropheniramine with good results, but
and dexamethasone. They are administered via oral, intrave­ these data need to be further verified [155]. The use of
nous, or intramuscular routes. The therapeutic protocols are azathioprine has also been reported by some authors in
not standardized as studies evaluating precise drugs, doses, cases with severe inflammation [156].
and durations are lacking [143,144]. Despite this situation, it is
accepted that high intravenous doses (for example dexa­
4.2. Indications of anti-inflammatory treatment
methasone 0.2-0.4 mg/kg/day) are necessary when inflamma­
tory reaction is important (cerebral edema, encephalitis, 4.2.1. Parenchymal NC
stabilization of intracranial hypertension) or when the admin­ 4.2.1.1. Vesicular p-NC. In these cases, cysticidal drugs
istration of cysticidal treatment can induce severe inflamma­ (albendazole [ABZ] and/or praziquantel [PZQ]) are generally
tory complications (for example in cases of multiple parasites administered to destroy the parasites. It is currently recom­
located in extraparenchymal compartments) [143]. In case of mended to add corticosteroids, at least during the 4 first days
parenchymal NC, oral administration of prednisone or dexa­ of treatment, to prevent aggravation of symptoms related to
methasone is generally performed. The doses vary between 4 the increase of the inflammatory reaction [157]. However, it is
and 10 mg/day of dexamethasone, or between 25 and 60 mg/ important to note that studies evaluating precise drugs, doses,
day for prednisone, taking into account the number and the and durations are lacking, and decisions are generally taken
size of the parasites. Corticosteroids will be gradually tapered on a case-by–case basis.
off after the end of cysticidal treatment, although chronic
administration is sometimes necessary due to persistent 4.2.1.2. Solitary cysticercus granuloma. This NC presenta­
inflammation. In these cases, the high frequency of potentially tion is the most frequently described in Asian countries, parti­
severe side effects (such as arterial hypertension, bone frac­ cularly India, and has also been found to be the most frequent
ture, cataract, susceptibility to infections, type 2 diabetes, and described NC form in children from other endemic countries
gastrointestinal diseases) is still a problem without a clear and in international travelers infected after visiting endemic
solution [145], even though corticosteroid-sparing agents areas [158–160]. It is the only form in which randomized
have been proposed. controlled studies evaluating the role of corticosteroids in its
management have been performed [144]. A network meta-
4.1.2. Methotrexate (MTX) analysis established that dual therapy with ABZ and corticos­
MTX is a potent immunosuppressive drug and chemotherapy teroids was the most efficacious regimen and could prevent
agent used to treat cancers and autoimmune diseases. seizure recurrence and promote lesion resolution [140]. It is
Through different mechanisms of action, MTX regulates the also interesting to note that for seizure recurrence, dual ther­
function of nearly every cell type involved in inflammation, apy was the only therapeutic option showing significant ben­
including neutrophils, monocytes, T cells, and B cells [146]. It efit, while for lesion resolution, ABZ alone and corticosteroids
has also been used as a corticosteroid–sparing agent in var­ alone were also significantly effective, although to a lesser
ious diseases [147–149]. In patients with NC, mainly EP–NC, it degree [140].
was also proposed with this objective. Although no studies
evaluating its effectiveness in a controlled manner were per­ 4.2.1.3. Cysticercotic encephalitis. As previously men­
formed, several case reports have been published showing its tioned, this condition is clearly due to a severe inflammatory
apparent benefit [125,150–152]. MTX is given in doses of 7.5 to response that causes a diffuse brain edema associated with
20 mg/week, during several years in some cases a severe intracranial hypertension that can compromise life
[125,150–152]. [75]. In this case, the use of cysticidal drugs before intense
inflammatory reaction is controlled is contraindicated. Anti-
4.1.3. Tumor necrosis factor-α (TNF-α) antagonists inflammatory drugs are imperative and must be administered
TNF-α is a pro-inflammatory cytokine that has been found at high doses and often can be the only required treatment.
increased in the periphery and in the CSF of patients with
NC [153]. Several TNF- antagonists are used to treat different 4.2.1.4. Edema around calcified cysticerci. Although this
diseases, particularly rheumatoid arthritis, inflammatory bowel phenomenon is very likely to have an immunological basis,
disease, and psoriasis. A case series of 16 patients with the utilization of anti-inflammatory/immunosuppressive drugs
10 P. T. HAMAMOTO FILHO ET AL.

is not recommended [143]. In addition, possible positive It is well known that the effectiveness of cysticidal treat­
effects should be counterbalanced by the possible side effects ment in NC is lower when the parasites are localized in the
of these drugs in a generally benign scenario; however, no extraparenchymal compartment compared to the parenchy­
controlled studies have been conducted to evaluate such mal compartment [164]. One of the main reasons for this
management, and the recurrence or appearance of new peri­ difference is probably the characteristic environment in
lesional edema after abrupt corticosteroid withdrawal have which the parasites are found. In the parenchyma, the para­
been reported [161]. sites are in contact with the immune cells, and the host
response is easier to mount, whereas in the extraparenchymal
4.2.2. EP-NC compartment, the parasites are found in a normally cell-free
In these cases, corticosteroid administration is widely recom­ medium (CSF) without close contact with immune cells. In
mended [143]. As we have seen, inflammation is frequently addition to a lower response to the first cycle of cysticidal
widespread in the extraparenchymal compartment, resulting therapy, it is also evident that some patients do not respond
in the risk of arachnoiditis, vasculitis, and their associated to treatment, even after several cycles of cysticidal drugs
complications. treatment [28]. The mechanisms of action of the two cysticidal
Currently, their administration is imperative with cysticidal drugs currently used for the treatment of NC, ABZ and PZQ,
treatment, in case of medically treatable vesicular cysts [143]. are not yet fully understood [165]. Both affect the parasite
As in case of parenchymal localizations of parasites, cysticidal tegument, allowing the exposure of parasitic antigens on the
treatment is clearly associated with increased inflammatory surface, whereas ABZ decreases energy production in larvae
reaction and thus, with possible complications. This treatment (cysticerci), disrupting their metabolism [165]. The release of
is recommended for vesicular cysts located in all the extrapar­ parasitic antigens, that can be detected by the innate immune
enchymal compartments, although the doses, durations, and response as PAMPs, following the drug action, probably allows
most appropriate drugs to be used are still not defined [143]; the host immune response to develop, which, in coordination
therefore, a case-by–case approach is necessary. In Mexico, with the effects of cysticidal drugs, results in the death of the
two parameters are taken into account to evaluate doses parasite [166].
and duration of treatment: presence and evolution of vasculi­ The relevance of host immunity in the efficacy of specific
tis on transcranial Doppler imaging, as it is used for other treatments in patients with NC is not yet fully understood. It
types of intracranial vasculitis [162,163,174]; and the change has been proposed that the inflammatory reaction is only
in CSF parameters, mainly cellularity [109]. Depending on the a consequence of cysticidal treatment, without a clear role in
results of these exams, intravenous dexamethasone can be the destruction of the parasites [167]. Other observations
administered 2-3 days before initiating cysticidal drugs, as support the hypothesis that the immune-inflammatory
well as during the treatment and for a few more days if the response is involved, as a major factor, in the response to
inflammatory reaction persists or increases. The intravenous cysticidal treatment [166]. In naturally infected pigs, adminis­
route is followed by tapered oral administration, depending tration of dexamethasone before and during PZQ treatment
mainly on clinical, Doppler, and CSF findings. has been shown to significantly reduce damage to the cyst
They are also highly recommended for arachnoiditis with or wall [167]. In another study in naturally infected pigs, ABZ
without viable cysts, which is frequently associated with ven­ alone was found to be significantly more effective than
tricular shunt dysfunction. Unfortunately, if chronic adminis­ when combined with corticosteroids [168]. A similar result
tration is necessary, serious side effects can occur resulting in was recently described using the experimental mouse model
a poor prognostic. A corticosteroid-sparing agent may be of intraperitoneal infection with T. crassiceps [169]. In the
helpful in some of these cases. human disease, this aspect has not yet been studied in
depth. However, it is relevant to mention that the results of
a cross-sectional study show that there is an association
between the presence of pro-inflammatory mediators and
4.3. Cautions associated with the anti-inflammatory/
the response to treatment in patients with EP-NC [102]. In
immunosuppressive drug administration
addition, in a recent longitudinal study including patients
Although it is evident that the inflammatory reaction is with NC and parasites in the subarachnoid compartment, it
the primary pathologic mechanism in NC, and that the use was found that an elevated IL-12p70/IL-10 ratio in the CSF of
of anti-inflammatory drugs has significantly improved the affected patients was significantly and inversely correlated
prognosis of patients, certain considerations must be with healing time, showing the relevance of the inflammatory
made. reaction in response to treatment [49]. In this context, it is
Corticosteroids are potent anti-inflammatory drugs, and interesting to mention the results of a recent review compar­
their effects on host defenses should be carefully evaluated. ing the response to treatment in patients with NC infected or
Nevertheless, they have been and are still used to treat various not with human immunodeficiency virus (HIV). Clear differ­
infectious diseases affecting the CNS [163]. For some patholo­ ences could not be established between the two groups of
gies, their use is crucial for improving patient prognosis. patients, but the poor quality of the published data prevents
However, for others, their beneficial effects are not obvious, any definitive conclusion [170].
and their use is not recommended. The negative side effects All these data suggest that corticosteroid use can be
associated with their chronic use, particularly when high doses associated with serious drawback in these patients
are required, are the main limitation for their use. (Figure 6).
 EXPERT REVIEW OF ANTI-INFECTIVE THERAPY 11

What may be the best approach to suppress the inflamma­ complications. There is evidence that its control is undoubt­
tory reaction without affecting the response to treatment in edly necessary in most scenarios of this highly heterogeneous
these patients? disease, resulting in improved patient prognosis. The main
This remains an unanswered question. The administration drugs used for this purpose are corticosteroids, which have
of long-term immunosuppressive therapy has been proposed an inhibitory effect on a wide range of immune-inflammatory
[125]. We believe that this is not the solution, not only responses. There are positive effects when they are used dur­
because of the well-known side effects that these drugs can ing a short time period; however, their chronic use, which is
have upon chronic use, but also because although the inflam­ frequently required in patients with EP-NC, is associated with
matory reaction can be controlled, the consequences in terms severe side effects and it needs to be used with caution in
of the survival of the parasites could be very deleterious. patients with other diseases, such as diabetes. In these cases, it
The use of immunosuppressive agents without such has been proposed to use corticosteroid-sparing agents, such
a broad spectrum could allow for the control of the inflam­ as methotrexate and an anti-TNF-α monoclonal antibody.
matory reaction without promoting the survival of the para­ These two drugs, whose effectiveness is still not proven by
site. TNF-α antagonist is the only drug that has been controlled studies, require strict monitoring and it is relevant
evaluated. Currently, although anecdotal results seem to to observe that almost all the case-reports on their use come
show some interest, there is a lack of data to fully assess the from a non-endemic country, the United States. In this coun­
effects of this drug in the treatment of NC. It is also important try, their administration to well monitored patients with strict
to note that high cost and the need of monitoring due to the control of side effects is possible, a strategy that will be very
risks of such treatment will likely prevent its widespread use in difficult to achieve on a large scale in most endemic countries.
most endemic countries [171]. Another important aspect to consider is that the intensity of
Other options could also be useful. For seizures control, the the immune-inflammatory response is very heterogeneous
use of substance P inhibitors or antagonist of its receptor between patients. Considering patients with parasites located in
could be an interesting alternative, although the results are the same compartment, some of them develop high inflamma­
still preliminary and investigations must be pursued [17]. On tion, others do not [33]. The latest guidelines recommend the use
the other hand, the use of novel delivery systems improving of anti-inflammatory therapy for all patients undergoing cysticidal
corticosteroids administration by allowing a much higher con­ treatment [143], and we agree that currently it is the therapeutic
centration in the CNS, with less systemic immunosuppressive regimen of choice; however, this recommendation should be
effect, could be an interesting alternative [172]. In addition, modulated in the future, taking into account the intensity and
although this option needs to be studied in depth, immu­ the composition of the inflammatory reaction in each
notherapy targeting inhibitory pathways might be considered patient [166].
to achieve a more specific immune response and reduce Regardless of this aspect, there is also some evidence that
bystander damage [133,173]. Again, although the use of the immune-inflammatory response is not only the conse­
such strategies is probably very difficult to achieve in endemic quence of parasite death but is also involved in the processes
countries for the reasons mentioned above, they would be associated with the degeneration of the parasite.
interesting options to explore. Thus, the inflammatory response in NC is a double-edged
sword: it is necessary for the death of the parasite, but it is also
at the origin of the main clinical complications. In EP-NC,
5. Expert opinion several cycles of cysticidal drugs are commonly required to
As we have seen, it is clear that the immune-inflammatory achieve the death of the parasites. The immunosuppressive
response in patients with NC is the main pathogenic mechan­ effect of corticosteroids could be involved in this observation,
ism involved in the initial symptoms and in the associated at least in some of the patients.

Figure 6. Use of corticosteroids in NC: the double-edged sword.

12 P. T. HAMAMOTO FILHO ET AL.

There are several ways to improve this situation. First, we need 4. Bhattarai R, Budke CM, Carabin H, et al. Estimating the
to decipher which patients are at higher risk of inflammatory non-monetary burden of neurocysticercosis in Mexico. PLoS Negl
Trop Dis. 2012;6(2):e1521.
complications, and therefore require strong anti-inflammatory
5. Singh BB, Khatkar MS, Gill JP, et al. Estimation of the health and
therapy; and which patients are at lower risk, in whom anti- economic burden of neurocysticercosis in India. Acta Trop.
inflammatory therapy can be reduced. Specific factors of the 2017;165:161–169.
disease (number, volume, location of the parasites) and of the 6. Torgerson PR, Devleesschauwer B, Praet N, et al. World Health
host (quality of the immune response, genetic background) are Organization estimates of the global and regional disease burden
of 11 foodborne parasitic diseases, 2010: a data synthesis. PLoS
probably involved in these differences. The identification of mar­
Med. 2015;12(12):e1001920.
kers of inflammatory risk would allow for the administration of 7. Landscape analysis: management of neurocysticercosis with an
a more personalized anti-inflammatory treatment. emphasis on low- and middle-income countries [Internet].
In addition, all the strategies to control inflammation cur­ Geneva, switzerland: world Health Organization; 2015. [cited
rently in use have their pitfalls and new immune-inflammatory 2021 Feb 3]. Available from: http://apps.who.int/iris/bitstream/
10665/152896/1/WHO_HTM_NTD_NZD_2015.05_eng.pdf
control strategies are needed. A better understanding of the
8. Nash TE, Garcia HH. Diagnosis and treatment of neurocysticercosis.
key molecules present in the immune-inflammatory reaction Nat Rev Neurol. 2011;7(10):584–594.
would make possible to focus anti-inflammatory treatment on 9. Arora N, Tripathi S, Kumar P, et al. Recent advancements and new
the elements more directly involved in the pathogenesis of NC perspectives in animal models for neurocysticercosis
without reducing the effectiveness of cysticidal drugs. immunopathogenesis. Parasite Immunol. 2017;39(7):e12439.
10. De Lange A, Mahanty S, Raimondo JV. Model systems for investi­
On the other hand, the implementation of novel delivery
gating disease processes in neurocysticercosis. Parasitology.
systems for administration of corticosteroids might allow 2019;146(5):553–562.
higher concentrations to be achieved in the CNS with fewer 11. Flisser A, Avila G, Maravilla P, et al. Taenia solium: current under­
peripheral side effects. standing of laboratory animal models of taeniosis. Parasitology.
2010;137(3):347–357.
12. Blair LS, Campbell WC. The rat (rattus norvegicus) as a laboratory
Funding host for the metacestodes of taenia crassiceps. J Parasitol. 1976
Feb;62(1):163–164.
This work was partially supported by the Consejo Nacional de Ciencia 13. Sciutto E, Fragoso G, Diaz ML, et al. Murine taenia crassiceps
y Tecnología (CONACYT, grant numbers S0008-2015-1, 261153 and cysticercosis: h-2 complex and sex influence on susceptibility.
FOSISS-272519).. Parasitol Res. 1991;77(3):243–246.
14. Terrazas LI, Bojalil R, Govezensky T, et al. Shift from an early
protective Th1-type immune response to a late permissive
Th2-type response in murine cysticercosis (Taenia crassiceps).
Declaration of interest J Parasitol. 1998;84(1):74–81.
The authors have no relevant affiliations or financial involvement with any 15. Díaz-Zaragoza M, Jiménez L, Hernández M, et al. Protein expression
organization or entity with a financial interest in or financial conflict with profile of Taenia crassiceps cysticerci related to Th1- and Th2-type
the subject matter or materials discussed in the manuscript. This includes responses in the mouse cysticercosis model. Acta Trop.
employment, consultancies, honoraria, stock ownership or options. 2020;212:105696.
16. Garza A, Tweardy DJ, Weinstock J, et al. Substance P signaling
contributes to granuloma formation in taenia crassiceps infection,
a murine model of cysticercosis. J Biomed Biotechnol.
Reviewer disclosures 2010;2:010:597086.
Peer reviewers on this manuscript have no relevant financial or other 17. Robinson P, Garza A, Weinstock J, et al. Substance P causes seizures
relationships to disclose. in neurocysticercosis. PLoS Pathog. 2012;8(2): e1002489.
18. Suvas S. Role of substance p neuropeptide in inflammation, wound
healing, and tissue homeostasis. J Immunol. 2017;199
ORCID (5):1543–1552.
19. Moura VB, Lima SB, Matos-Silva H, et al. Cellular immune response
Pedro T Hamamoto Filho http://orcid.org/0000-0001-6436-9307 in intraventricular experimental neurocysticercosis. Parasitology.
2016;143(3):334–342.
20. Milhomem AC, Souza AJS, Silva HM, et al. Histopathologic aspects
References of experimental cysticercosis and in situ cytokines profile in C57BL/
6 mice. Arq Neuropsiquiatr. 2018;76(5):339–345.
Papers of special note have been highlighted as either of interest (•) or of 21. Hamamoto Filho PT, Fogaroli MO, Oliveira MAC, et al. A rat model
considerable interest (••) to readers. of neurocysticercosis-induced hydrocephalus: chronic progressive
1. 10 facts about neurocysticercosis [Internet]. World Health hydrocephalus with mild clinical impairment. World Neurosurg.
Organization. [cited 2021 Feb 3]. Available from: https://www. 2019;132:e535–e544.
who.int/features/factfiles/neurocysticercosis/en/#:~:text= 22. Alvarez JI, Rivera J, Teale JM. Differential release and phagocytosis
Neurocysticercosis%20is%20a%20preventable%20parasitic,or% of tegument glycoconjugates in neurocysticercosis: implications for
20through%20poor%20hygiene%20practices immune evasion strategies. PLoS Negl Trop Dis. 2008;2(4):e218.
2. Flisser A, Correa D. Neurocysticercosis may no longer be a public 23. Cardona AE, Restrepo BI, Jaramillo JM, et al. Development of an
health problem in Mexico. PLoS Negl Trop Dis. 2010;4(12):e831. animal model for neurocysticercosis: immune response in the cen­
3. Martins-Melo FR, Ramos AN Jr, Cavalcanti MG, et al. tral nervous system is characterized by a predominance of gamma
Neurocysticercosis-related mortality in Brazil, 2000-2011: epide­ delta T cells. J Immunol. 1999;162(2):995–1002.
miology of a neglected neurologic cause of death. Acta Trop. 24. Alvarez JI, Teale JM. Breakdown of the blood brain barrier and
2016;153:128–136. blood-cerebrospinal fluid barrier is associated with differential leu­
 EXPERT REVIEW OF ANTI-INFECTIVE THERAPY 13

kocyte migration in distinct compartments of the CNS during the 45. Chavarría A, Roger B, Fragoso G, et al. TH2 profile in asymptomatic
course of murine NCC. J Neuroimmunol. 2006;173(1–2):45–55. Taenia solium human neurocysticercosis. Microbes Infect. 2003;5
25. Alvarez JI, Teale JM. Multiple expression of matrix metalloprotei­ (12):1109–1115.
nases in murine neurocysticercosis: implications for leukocyte 46. Adalid-Peralta L, Fleury A, García-Ibarra TM, et al. Human neurocys­
migration through multiple central nervous system barriers. Brain ticercosis: in vivo expansion of peripheral regulatory T cells and
Res. 2008;1214:145–158. their recruitment in the central nervous system. J Parasitol. 2012;98
26. Verastegui MR, Mejia A, Clark T, et al. Novel rat model for neuro­ (1):142–148.
cysticercosis using Taenia solium. Am J Pathol. 2015;185 47. Murrieta I, Flores X, Osorio R, et al. A. Natural history of extrapar­
(8):2259–2268. enchymal neurocysticercosis. Trans R Soc Trop Med Hyg. 2021;
27. Sikasunge CS, Johansen MV, Phiri IK, et al. The immune response in Ahead of print. doi: 10.1093/trstmh/traa174
Taenia solium neurocysticercosis in pigs is associated with astro­ 48. Cárdenas G, Carrillo-Mezo R, Jung H, et al. Subarachnoidal neuro­
gliosis, axonal degeneration and altered blood-brain barrier cysticercosis non-responsive to cysticidal drugs: a case series. BMC
permeability. Vet Parasitol. 2009;160(3–4):242–250. Neurol. 2010;10(1):16.
28. Fleury A, Trejo A, Cisneros H, et al. Taenia solium: development of 49. Harrison S, Thumm L, Nash TE, et al. The local inflammatory profile
an experimental model of porcine neurocysticercosis. PLoS Negl and predictors of treatment success in subarachnoid
Trop Dis. 2015;9(8):e0003980. neurocysticercosis. Clin Infect Dis. 2020;ciaa1128. 10.1093/cid/
29. Restrepo BI, Alvarez JI, Castaño JA, et al. Brain granulomas in ciaa1128
neurocysticercosis patients are associated with a Th1 and Th2 50. Arce-Sillas A, Álvarez-Luquín DD, Cárdenas G, et al. Interleukin 10
profile. Infect Immun. 2001;69(7):4554–4560. and dendritic cells are the main suppression mediators of regula­
30. Chowdhury N, Saleque A, Sood NK, et al. Induced neurocysticerco­ tory T cells in human neurocysticercosis. Clin Exp Immunol.
sis in rhesus monkeys (Macaca mulatta) produces clinical signs and 2016;183(2):271–279.
lesions similar to natural disease in man. Scientific World J. 51. Bueno EC, Ramos Machado L, Livramento JA, et al. Cellular immune
2014;2014:248049. response of patients with neurocysticercosis (inflammatory and
31. Fleury A, Cardenas G, Adalid-Peralta L, et al. Immunopathology in Taenia non-inflammatory phases). Acta Trop. 2004;91(2):
solium neurocysticercosis. Parasite Immunol. 2016;38(3):147–157. 205–213.
32. Fleury A, Escobar A, Fragoso G, et al. Clinical heterogeneity of 52. Fleury A, Hernández M, Avila M, et al. Detection of HP10 antigen in
human neurocysticercosis results from complex interactions serum for diagnosis and follow-up of subarachnoidal and intraven­
among parasite, host and environmental factors. Trans R Soc Trop tricular human neurocysticercosis. J Neurol Neurosurg Psychiatry.
Med Hyg. 2010;104(4):243–250. 2007;78(9):970–974.
33. Marcin Sierra M, Arroyo M, Cadena Torres M, et al., 53. Prodjinotho UF, Lema J, Lacorcia M, et al. Host immune responses
Extraparenchymal neurocysticercosis: demographic, clinicoradiolo­ during taenia solium neurocysticercosis infection and treatment.
gical, and inflammatory features. PLoS Negl Trop Dis. 11(6): PLoS Negl Trop Dis. 2020;14(4):e0008005.
e0005646. 2017; 54. Monteiro L, Almeida-Pinto J, Stocker A, et al. Active neurocysticer­
•• A large and precise descriptive series of the different presen­ cosis, parenchymal and extraparenchymal: a study of 38 patients.
tations of NC. J Neurol. 1993;241(1):15–21.
34. Verma A, Prasad KN, Gupta RK, et al. Toll-like receptor 4 poly­ 55. García HH, Del Brutto OH. Imaging findings in neurocysticercosis.
morphism and its association with symptomatic Acta Trop. 2003;87(1):71–78.
neurocysticercosis. J Infect Dis. 2010;202(8):1219–1225. 56. Carpio A, Fleury A, Romo ML, et al. New diagnostic criteria for
35. Villegas M, Sciutto E, Rosetti M, et al. Infect Immun. 2019;87(12): neurocysticercosis: reliability and validity. Ann Neurol. 2016;80
e00347–19. (3):434–442. .
36. Arora N, Tripathi S, Sao R, et al. Molecular neuro-pathomechanism 57. Kimura-Hayama ET, Higuera JA, Corona-Cedillo R, et al.
of neurocysticercosis: how host genetic factors influence disease Neurocysticercosis: radiologic-pathologic correlation.
susceptibility. Mol Neurobiol. 2018;55(2):1019–1025. Radiographics. 2010;30(6):1705–1719.
37. Vahidinia Z, Karimian M, Joghataei MT. Neurosteroids and their 58. Lerner A, Shiroishi MS, Zee CS, et al. Imaging of neurocysticercosis.
receptors in ischemic stroke: from molecular mechanisms to ther­ Neuroimag Clin N Am. 2012;22(4):659–676.
apeutic opportunities. Pharmacol Res. 2020;160:105163. 59. Delgado-García G, Méndez-Zurita VA, Bayliss L, et al.
38. Wang W, Guo DY, Lin YJ, et al. Melanocortin regulation of Neurocysticercosis: mimics and chameleons. Pract Neurol. 2019;19
inflammation. Front Endocrinol. 2019;10:683. (2):88–95.
39. Mishra BB, Gundra UM, Teale JM. Toll-Like Receptors in CNS 60. Rdd H, Durán BB, Lujambio PS. Magnetic resonance imaging in
Parasitic Infections. In: editor, Kielian T. Toll-like receptors: roles in neurocysticercosis. Top Magn Reson Imaging. 2014;23(3):191–198.
infection and neuropathology. current topics in microbiology and 61. Nash T. Edema surrounding calcified intracranial cysticerci: clinical
Immunology. Vol. 336. Springer: Berlin, Heidelberg; 2009;83-104. manifestations, natural history, and treatment. Pathog Glob Health.
40. Zindel J, Kubes P. DAMPs, PAMPs, and LAMPs in immunity and 2012;106(5):275–279.
sterile inflammation. Annu Rev Pathol. 2020;15(1):493–518. •• A well-done review of this interesting phenomenon.
41. Yuan-Jian G, Hong-Li Y, Fei-Xiang D, et al. Annexin B1 at the host–parasite 62. Nash TE, Pretell EJ, Lescano AG, et al. Perilesional brain oedema
interface of the Taenia solium cysticercus: secreted and associated with and seizure activity in patients with calcified neurocysticercosis:
inflammatory reaction. Acta Trop. 2007;101(3):192–199. a prospective cohort and nested case-control study. Lancet
42. Dametto E. Histopathology of the human brain in Neurol. 2008;7(12):1099–1105.
neurocysticercosis. 2016;1:106. J Mol Histol Med Physiol. 63. Singh AK, Garg RK, Rizvi I, et al. Clinical and neuroimaging pre­
43. Escobar A. Pathology of the nervous system. In: Palacios E, dictors of seizure recurrence in solitary calcified neurocysticercosis:
Rodriguez-Carbajal J, Taveras JM, editors. Cysticercosis of the cen­ a prospective observational study. Epilepsy Res. 2017;137:78–83.
tral nervous system. Springfield, IL: Charles Thomas; 1983. p. 27–54. 64. Carrillo Mezo R, Lara García J, Arroyo M, et al. Relevance of 3D
• One of the first in-depth pathological descriptions of NC. magnetic resonance imaging sequences in diagnosing basal sub­
Always relevant to consult. arachnoid neurocysticercosis. Acta Trop. 2015;152:60–65.
44. Tuero I, Palma S, Cabeza F, et al. A comparative study of peripheral 65. Bazan R, Hamamoto Filho PT, Luvizutto GJ, et al. Clinical symptoms,
immune responses to Taenia solium in individuals with parenchy­ imaging features and cyst distribution in the cerebrospinal fluid
mal and subarachnoid neurocysticercosis. PLoS Negl Trop Dis. compartments in patients with extraparenchymal
2015;9(10):e0004143. neurocysticercosis. PLoS Negl Trop Dis. 2016;10(11):e0005115.
14 P. T. HAMAMOTO FILHO ET AL.

66. Singh G. Neurocysticercosis in South-Central America and the 87. Rathore C, Thomas B, Kesavadas C, et al. Calcified neurocysticerco­
Indian subcontinent. A comparative evaluation. Arq sis lesions and hippocampal sclerosis: potential dual pathology?
Neuropsiquiatr. 1997;55(3A):349–356. Epilepsia. 2012;53(4):e60–e62.
67. Carpio A, Romo ML. The relationship between neurocysticercosis 88. Walker MC. Hippocampal sclerosis: causes and prevention. Semin
and epilepsy: an endless debate. Arq Neuropsiquiatr. 2014;72 Neurol. 2015;35(3):193–200.
(5):383–390. 89. Bianchin MM, Velasco TR, Takayanagui OM, et al. Neurocysticercosis,
68. Beghi E, Carpio A, Forsgren L, et al. Recommendation for mesial temporal lobe epilepsy, and hippocampal sclerosis: an asso­
a definition of acute symptomatic seizure. Epilepsia. 2010;51 ciation largely ignored. Lancet Neurol. 2006;5(1):20–21.
(4):671–675. 90. Heine J, Prüß H, Scheel M, et al. Transdiagnostic hippocampal
69. Monteiro L, Nunes B, Mendonça D, et al. Spectrum of epilepsy in damage patterns in neuroimmunological disorders. Neuroimage
neurocysticercosis: a long-term follow-up of 143 patients. Acta Clin. 2020;28:102515.
Neurol Scand. 1995;92(1):33–40. 91. Zepeda N, Solano S, Copitin N, et al. Apoptosis of mouse hippo­
70. Carpio A, Hauser WA. Prognosis for seizure recurrence in patients campal cells induced by Taenia crassiceps metacestode factor.
with newly diagnosed neurocysticercosis. Neurology. 2002;59 J Helminthol. 2017;91(2):215–221.
(11):1730–1734. 92. Zepeda N, Copitin N, Chávez JL, et al. Hippocampal sclerosis
71. Singh G, Burneo JG, Sander JW. From seizures to epilepsy and its induced in mice by a Taenia crassiceps metacestode factor.
substrates: neurocysticercosis. Epilepsia. 2013;54(5):783–792. J Helminthol. 2019;93(6):690–696.
72. Pradhan S, Kathuria MK, Gupta RK. Perilesional gliosis and seizure 93. Morales-Montor J, Picazo O, Besedovsky H, et al. Helminth infection
outcome: a study based on magnetization transfer magnetic reso­ alters mood and short-term memory as well as levels of neuro­
nance imaging in patients with neurocysticercosis. Ann Neurol. transmitters and cytokines in the mouse hippocampus.
2000;48(2):181–187. Neuroimmunomodulation. 2014;21(4):195–205.
73. Nash TE, Mahanty S, Loeb JA, et al. Neurocysticercosis: a natural 94. Mejia Maza A, Carmen-Orozco RP, Carter ES, et al. Axonal swellings
human model of epileptogenesis. Epilepsia. 2015;56(2):177–183. and spheroids: a new insight into the pathology of
74. Lachuriya G, Garg RK, Jain A, et al., Toll-like receptor-4 polymorph­ neurocysticercosis. Brain Pathol. 2019;29(3):425–436.
isms and serum matrix metalloproteinase-9 in newly diagnosed 95. Fleury A, Dessein A, Preux PM, et al. Symptomatic human neuro­
patients with calcified neurocysticercosis and seizures. Medicine cysticercosis–age, sex and exposure factors relating with disease
(Baltimore). 95(17): e3288. 2016; heterogeneity. J Neurol. 2004;251(7):830–837.
•• Important study showing the relevance of host genetics in the 96. Hamamoto Filho PT, Singh G, Winkler AS, et al. Could differences in
heterogeneity of NC. infection pressure be involved in cysticercosis heterogeneity?
75. Rangel R, Torres B, Del Bruto O, et al. Cysticercotic encephalitis: Trends Parasitol. 2020;36(10):826–834.
a severe form in young females. Am J Trop Med Hyg. 1987;36 97. Cangalaya C, Zimic M, Marzal M, et al. Inflammation caused by
(2):387–392. praziquantel treatment depends on the location of the taenia
76. Sotelo J, Guerrero V, Rubio F. Neurocysticercosis: a new classifica­ solium cysticercus in porcine neurocysticercosis. PLoS Negl Trop
tion based on active and inactive forms. A study of 753 cases. Arch Dis. 2015;9(12):e0004207.
Intern Med. 1985;145(3):442–445. 98. Hamamoto Filho PT, Zanini MA, Fleury A. Hydrocephalus in neuro­
77. Medina MT, Rosas E, Rubio-Donnadieu F, et al. Neurocysticercosis cysticercosis: challenges for clinical practice and basic research
as the main cause of late-onset epilepsy in Mexico. Arch Intern perspectives. World Neurosurg. 2019;126:264–271.
Med. 1990;150(2):325–327. 99. Gardner WJ, Spitler DK, Whitten C. Increased intracranial pressure
78. Nash TE, Pretell J, Garcia HH. Calcified cysticerci provoke perile­ caused by increased protein content in the cerebrospinal fluid; an
sional edema and seizures. Clin Infect Dis. 2001;33(10):1649–1653. explanation of papilledema in certain cases of small intracranial
79. Herrick JA, Maharathi B, Kim JS, et al., Inflammation is a key risk and intraspinal tumors, and in the Guillain-Barre syndrome. N Engl
factor for persistent seizures in neurocysticercosis. Ann Clin Transl J Med. 1954;250(22):932–936.
Neurol. 5(5): 630–639. 2018;. 100. Wang T, Wang Z, Guo Z. Headache and intracranial hypertension in
•• Interesting study on the role of inflammation in persistent Guillain-Barré syndrome: a case report and literature review.
seizures in patients affected by parenchymal NC. Int J Neurosci. 2019;129(12):1179–1182.
80. Ooi WW, Wijemanne S, Thomas CB, et al. Short report: a calcified 101. Edwards LJ, Sharrack B, Ismail A, et al. Increased levels of inter­
Taenia solium granuloma associated with recurrent perilesional leukins 2 and 17 in the cerebrospinal fluid of patients with idio­
edema causing refractory seizures: histopathological features. Am pathic intracranial hypertension. Am J Clin Exp Immunol. 2013;2
J Trop Med Hyg. 2011;85(3):460–463. (3):234–244.
81. Gupta RK, Kumar R, Chawla S, et al. Demonstration of scolex within 102. Cárdenas G, Fragoso G, Rosetti M, et al., Neurocysticercosis: the
calcified cysticercus cyst: its possible role in the pathogenesis of effectiveness of the cysticidal treatment could be influenced by the
perilesional edema. Epilepsia. 2002;43(12):1502–1508. host immunity. Med Microbiol Immunol. 203(6): 373–381. 2014;
82. Bianchin MM, Velasco TR, Santos AC, et al. On the relationship •• Interesting study addressing the role of inflammation in the
between neurocysticercosis and mesial temporal lobe epilepsy response to treatment in cases of extraparenchymal NC.
associated with hippocampal sclerosis: coincidence or 103. Zhao PP, Ji QK, Sui RB, et al. Increased intracranial pressure in
a pathogenic relationship? Pathog Glob Health. 2012;106 Guillain-Barré syndrome: a case report. Medicine (Baltimore).
(5):280–285. 2018;97(30):e11584.
83. Leite JP, Terra-Bustamante VC, Fernandes RM, et al. Calcified neu­ 104. Krishnamurthy S, Li J. New concepts in the pathogenesis of
rocysticercotic lesions and postsurgery seizure control in temporal hydrocephalus. Transl Pediatr. 2014;3(3):185–194.
lobe epilepsy. Neurology. 2000;55(10):1485–1491. 105. Krishnamurthy S, Li J, Shen Y, et al. Normal macromolecular clear­
84. Da Gama CN, Kobayashi E, Li LM, et al. Hippocampal atrophy and ance out of the ventricles is delayed in hydrocephalus. Brain Res.
neurocysticercosis calcifications. Seizure. 2005;14(2):85–88. 2018;1678:337–355.
85. Velasco TR, Zanello PA, Dalmagro CL, et al. Calcified cysticercotic 106. Fleury A, Carrillo-Mezo R, Flisser A, et al. Subarachnoid basal neu­
lesions and intractable epilepsy: a cross sectional study of 512 rocysticercosis: a focus on the most severe form of the disease.
patients. J Neurol Neurosurg Psychiatry. 2006;77(4):485–488. Expert Rev Anti Infect Ther. 2011;9(1):123–133.
86. Bianchin MM, Velasco TR, Wichert-Ana L, et al. Characteristics of 107. Cantú C, Barinagarrementeria F. Cerebrovascular complications of
mesial temporal lobe epilepsy associated with hippocampal sclero­ neurocysticercosis. Clinical and neuroimaging spectrum. Arch
sis plus neurocysticercosis. Epilepsy Res. 2014;108(10):1889–1895. Neurol. 1996;53(3):233–239.
 EXPERT REVIEW OF ANTI-INFECTIVE THERAPY 15

108. Hasan R, Iaia A, Flores C. Ischaemic stroke induced by neurocysti­ •• First study showing the presence of anti-brain protein auto­
cerosis, presenting as a clinical and radiological dilemma. BJR Case antibodies in NC patients
Rep. 2016;2(3):20150254. 132. Parkhouse RME, Sciutto E, Hernández M, et al. Extraparenchymal
109. Góngora-Rivera F, Soto-Hernández JL, Guevara P, et al. In neuro­ human neurocysticercosis induces autoantibodies against brain
cysticercosis, CSF cytokines correlate with cerebral blood flow tubulin and MOG35-55 in cerebral spinal fluid. J Neuroimmunol.
velocities. Neurology. 2008;71(14):1119–1122. 2020;349:577389.
110. Rodriguez-Carbajal J, Del Brutto OH, Penagos P, et al. Occlusion of 133. Klein RS, Hunter CA. Protective and pathological immunity during
the middle cerebral artery due to cysticercotic angiitis. Stroke. central nervous system infections. Immunity. 2017;46:891–909.
1989;20(8):1095–1098. 134. Zhang P, Lu Q. Genetic and epigenetic influences on the loss of
111. Monteiro L, Almeida-Pinto J, Leite I, et al. Cerebral cysticercus arteritis: five tolerance in autoimmunity. Cell Mol Immunol. 2018;15(6):575–585.
angiographic cases. Cerebrovasc Dis. 1994;4(3):125–133. 135. Höftberger R, Armangue T, Leypoldt F, et al. Clinical neuropathol­
112. Levy AS, Lillehei KO, Rubinstein D, et al. Subarachnoid neurocysti­ ogy practice guide 4-2013: post-herpes simplex encephalitis:
cercosis with occlusion of major intracranial vessels: case report. n-methyl-daspartate receptor antibodies are part of the problem.
Neurosurgery. 1995;36(1):183–188. Clin Neuropathol. 2013;32(7):251–254.
113. Aditya GS, Mahadevan A, Santosh V, et al. Cysticercal chronic basal 136. Sotelo J, Marin C. Hydrocephalus secondary to cysticercotic ara­
arachnoiditis with infarcts, mimicking tuberculous pathology in chnoiditis. A long-term follow-up review of 92 cases. J Neurosurg.
endemic areas. Neuropathology. 2001;24(4):320–325. 1987;66(5):686–689.
114. Garg RK, Karak B. Neurocysticercosis presenting as midbrain 137. Suastegui Roman RA, Soto-Hernandez JL, Sotelo J. Effects of pre­
syndrome. J Assoc Physicians India. 2000;48(5):533–535. dnisone on ventriculoperitoneal shunt function in hydrocephalus
115. Soto-Hernandez JL, Gomez-Llata Andrade S, Rojas-Echeverri LA, secondary to cysticercosis: a preliminary study. J Neurosurg.
et al. Subarachnoid hemorrhage secondary to a ruptured inflam­ 1996;84(4):629–633.
matory aneurysm: a possible manifestation of neurocysticercosis: • One of the first study showing the importance of corticoster­
case report. Neurosurgery. 1996;38(1):197–200. oid in improving the prognosis of patients with NC.
116. Tellez-Zenteno JF, Negrete-Pulido O, Cantú C, et al. Accidente 138. Sotelo J, Escobedo F, Rodriguez-Carbajal J, et al. Therapy of par­
cerebrovascular hemorrágico asociado a neurocisticercosis enchymal brain cysticercosis with praziquantel. N Engl J Med.
[Hemorrhagic stroke associated to neurocysticercosis]. Neurologia. 1984;310(16):1001–1007.
2003;18(5):272–275. 139. Sotelo J, Escobedo F, Penagos P. Albendazole vs praziquantel for
117. Kim IY, Kim TS, Lee JH, et al. Inflammatory aneurysm due to therapy for neurocysticercosis. A controlled trial. Arch Neurol.
neurocysticercosis. J Clin Neurosci. 2005;12(5):585–588. 1988;45(5):532–534.
118. Arauz A, Ruiz-Navarro F, Silos H, et al. Concurrent asymptomatic 140. Zhao BC, Jiang HY, Ma WY, et al. Albendazole and corticosteroids
inflammatory aneurysm and ischemic stroke due to cysticercal for the treatment of solitary cysticercus granuloma: a network
arteritis. Clin Neurol Neurosurg. 2013;115(12):2540–2543. meta-analysis. PLoS Negl Trop Dis. 2016;10(2):e0004418.
119. Vieira E, Faquini IV, Silva JL, et al. Subarachnoid neurocysticercosis 141. Tuckermann JP, Kleiman A, McPherson KG, et al. Molecular
and an intracranial infectious aneurysm: case report. Neurosurg mechanisms of glucocorticoids in the control of inflammation
Focus. 2019;47(2):E16. and lymphocyte apoptosis. Crit Rev Clin Lab Sci. 2005;42(1):71–104.
120. Mahale RR, Mehta A, Extraparenchymal RS. (racemose) neurocysti­ 142. Salvador E, Shityakov S, Förster C. Glucocorticoids and endothelial
cercosis and its multitude manifestations: a comprehensive review. cell barrier function. Cell Tissue Res. 2014;355(3):597–605.
J Clin Neurol. 2015;11(3):203–211. 143. White AC Jr, Coyle CM, Rajshekhar V, et al., Diagnosis and treat­
121. Ranjith MP, Divya R, Sahni A. Isolated third cranial nerve palsy: ment of neurocysticercosis: 2017 Clinical Practice Guidelines by the
a rare presentation of neurocysticercosis. Ir J Med Sci. 2011;180 Infectious Diseases Society of America (IDSA) and the American
(4):905–907. Society of Tropical Medicine and Hygiene (ASTMH). Am J Trop Med
122. Hamamoto Filho PT, Poliseli GB, Oliveira VA, et al. Unusual painful Hyg. 98(4): 945–966. 2018;
trigeminal neuropathy caused by racemose neurocysticercosis. •• Current guidelines for the diagnosis and treatment of NC.
Pain Med. 2016;17(5):992–994. 144. Nash TE, Mahanty S, Garcia HH, et al., Corticosteroid use in
123. Yang SY, Vásquez CM. Cysticercosis working group in perú. hemi­ neurocysticercosis. Expert Rev Neurother. 11(8): 1175–1183. 2011;
facial spasm secondary to arachnoiditis due to neurocysticercosis: •• Interesting review on the use of corticosteroids in NC.
clinical image. World Neurosurg. 2020;143:180–182. 145. Rice JB, White AG, Scarpati LM, et al. Long-term Systemic
124. Cuellar-Hernandez JJ, Valadez-Rodriguez A, Olivas-Campos R, et al. Corticosteroid Exposure: a Systematic Literature Review. Clin Ther.
Intrasellar cysticercosis cyst treated with a transciliary supraorbital 2017;39(11):2216–2229.
keyhole approach– a case report. Surg Neurol Int. 2020;11:436. 146. Cronstein BN, Aune TM. Methotrexate and its mechanisms of action
125. Nash TE, O’Connell EM, Hammoud DA, et al. Natural history of in inflammatory arthritis. Nat Rev Rheumatol. 2020;16(3):145–154.
treated subarachnoid neurocysticercosis. Am J Trop Med Hyg. 147. Fautrel B, Borget C, Rozenberg S, et al. Corticosteroid sparing effect
2020;102(1):78–89. of low dose methotrexate treatment in adult Still’s disease.
126. Colli BO, Martelli N, Assirati JA Jr, et al. Results of surgical treatment J Rheumatol. 1999;26(2):373–378.
of neurocysticercosis in 69 cases. J Neurosurg. 1986;65(3):309–315. 148. Knarborg M, Hilberg O, Hoffmann HJ, et al. Methotrexate as an oral
127. Callacondo D, Garcia HH, Gonzales I, et al. High frequency of spinal corticosteroid-sparing agent in severe asthma: the emergence of
involvement in patients with basal subarachnoid a responder asthma endotype. Eur Clin Respir J. 2014;1(1):25037.
neurocysticercosis. Neurology. 2012;78(18):1394–1400. 149. Rathinam SR, Gonzales JA, Thundikandy R, et al. Effect of
128. Cárdenas G, Guevara-Silva E, Romero F, et al. Spinal Taenia solium corticosteroid-sparing treatment with mycophenolate mofetil vs
cysticercosis in mexican and indian patients: a comparison of methotrexate on inflammation in patients with uveitis:
30-year experience in two neurological referral centers and review a randomized clinical trial. JAMA. 2019;322(10):936–945.
of literature. Eur Spine J. 2016;25(4):1073–1081. 150. Keiser PB, Nash TE. Prolonged perilesional edema after treatment
129. Alsina GA, Johnson JP, McBride DQ, et al. Spinal neurocysticercosis. of parenchymal neurocysticercosis: methotrexate as a
Neurosurg Focus. 2002;12(6):e8. corticosteroid-sparing agent. Clin Infect Dis. 2003;36(10):e122–e6.
130. Pérez-Jacoiste Asín MA, Calleja-Castaño P, Hilario A. Lumbosacral 151. Mitre E, Talaat KR, Sperling MR, et al. Methotrexate as a
radiculopathy as the clinical presentation of neurocysticercosis. Am corticosteroid-sparing agent in complicated neurocysticercosis.
J Trop Med Hyg. 2020;102(6):1166–1167. Clin Infect Dis. 2007;44(4):549–553.
131. Parkhouse RME, Carpio A, Cortez MM, et al. Anti-brain protein 152. Anand P, Mukerji SS, Thon J, et al. Steroid-sparing agents for the
autoantibodies are detectable in extraparenchymal but not par­ treatment of inflammation in complicated neurocysticercosis.
enchymal neurocysticercosis. J Neuroimmunol. 2020;344:577234. Neurol Neuroimmunol Neuroinflamm. 2019;6(6):e606.
16 P. T. HAMAMOTO FILHO ET AL.

153. Aguilar-Rebolledo F, Cedillo-Rivera R, Cedillo-Rivera R, et al. 165. Jung H, Cárdenas G, Sciutto E, et al. Medical treatment for neuro­
Interleukin levels in cerebrospinal fluid from children with cysticercosis: drugs, indications and perspectives. Curr Top Med
neurocysticercosis. Am J Trop Med Hyg. 2001;64(1):35–40. Chem. 2008;8(5):424–433.
154. Nash TE, Ware JM, Coyle CM, et al. Etanercept to control inflamma­ 166. Toledo A, Osorio R, Matus C, et al. Human extraparenchymal neu­
tion in the treatment of complicated neurocysticercosis. Am J Trop rocysticercosis: the control of inflammation favors the host . . . but
Med Hyg. 2019;100(3):609–616. also the parasite. Front Immunol. 2018;9:2652.
155. Agapejev S. Neurocysticercosis: the enigmatic disease. Cent Nerv •• The first study clearly addressing the potential risks of corti­
Syst Agents Med Chem. 2011;11(4):261–284. costeroid therapy in patients with NC.
156. Sotelo J, Jung H. Pharmacokinetic optimisation of the treatment of 167. Mahanty S, Orrego MA, Cangalaya C, et al. TNF-α blockade suppresses
neurocysticercosis. Clin Pharmacokinet. 1998;34(6):503–515. pericystic inflammation following anthelmintic treatment in porcine neu­
157. Garcia HH, Gonzales I, Lescano AG, et al. Enhanced steroid dosing rocysticercosis. PLoS Negl Trop Dis. 2017;11(11):e0006059.
reduces seizures during antiparasitic treatment for cysticercosis 168. Singh AK, Singh SK, Singh A, et al. Immune response to Taenia
and early after. Epilepsia. 2014;55(9):1452–1459. solium cysticerci after anti-parasitic therapy. Int J Parasitol. 2015;45
158. Sáenz B, Ruíz-Garcia M, Jiménez E, et al. Neurocysticercosis: clinical, (12):749–759.
radiologic, and inflammatory differences between children and 169. Palomares-Alonso F, Toledo A, Palencia Hernández G, et al. Effect of
adults. Pediatr Infect Dis J. 2006;25(9):801–803. dexamethasone on albendazole cysticidal activity in experimental
159. Garg RK, Malhotra HS. Solitary cysticercus granuloma. Expert Rev cysticercosis by Taenia crassiceps in BALB/c mice: in vitro and
Anti Infect Ther. 2012;10(5):597–612. in vivo evaluation. Exp Parasitol. 2020;208:107801.
160. Del Brutto OH. Neurocysticercosis among international travelers to 170. Herrera Vazquez O, Romo ML, Fleury A. Neurocysticercosis and HIV
disease-endemic areas. J Travel Med. 2012;19(2):112–117. infection: what can we learn from the published literature? Arq
161. Mejia R, Nash TE. Corticosteroid withdrawal precipitates perile­ Neuropsiquiatr. 2019;77(5):357–365.
sional edema around calcified Taenia solium cysts. Am J Trop 171. Fernández-Ruiz M, Aguado JM. Risk of infection associated with
Med Hyg. 2013;89(5):919–923. anti-TNF-α therapy. Expert Rev Anti Infect Ther. 2018;16
162. Lowe LH, Morello FP, Jackson MA, et al. Application of transcranial (12):939–956.
doppler sonography in children with acute neurologic events due 172. Lühder F, Reichardt HM. Novel drug delivery systems tailored for
to primary cerebral and west nile vasculitis. AJNR Am J Neuroradiol. improved administration of glucocorticoids. Int J Mol Sci. 2017;18(9):1836.
2005;26(7):1698–1701. 173. Parida SK, Poiret T, Zhenjiang L, et al. T-cell therapy: options for
163. Gundamraj S, Hasbun R. The use of adjunctive steroids in central infectious diseases. Clin Infect Dis. 2015;15(61):S217–S22
nervous infections. Front Cell Infect Microbiol. 2020;10:592017. 174. Idris MI, Tai SML, Tan CT, et al. Streptococcus pneumoniae menin­
164. Carpio A, Kelvin EA, Bagiella E, et al. Effects of albendazole treat­ gitis and intracranial vasculopathy: clinical correlation with improv­
ment on neurocysticercosis: a randomised controlled trial. J Neurol ing transcranial doppler hemodynamics. Case Rep Neurol. 2020;12
Neurosurg Psychiatry. 2008;79(9):1050–1055. (Suppl. 1):106–109.