Clinical Manifestations Associated with

Neurocysticercosis: A Systematic Review

He le` ne Carabin
1
*, Patrick Cyaga Ndimubanzi
1
, Christine M. Budke
2
, Hai Nguyen
1
, Yingjun Qian
3
, Linda
Demetry Cowan
1
, Julie Ann Stoner
1
, Elizabeth Rainwater
4
, Mary Dickey
5
1Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America, 2Department of
Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, United States of America,
3National Institute of Parasitic Diseases, Shanghai, Peoples Republic of China, 4Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City,
Oklahoma, United States of America, 5Department of Health Promotion Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United
States of America
Abstract
Background: The clinical manifestations of neurocysticercosis (NCC) are poorly understood. This systematic review aims to
estimate the frequencies of different manifestations, complications and disabilities associated with NCC.
Methods: A systematic search of the literature published from January 1, 1990, to June 1, 2008, in 24 different electronic
databases and 8 languages was conducted. Meta-analyses were conducted when appropriate.
Results: A total of 1569 documents were identified, and 21 included in the analysis. Among patients seen in neurology
clinics, seizures/epilepsy were the most common manifestations (78.8%, 95%CI: 65.1%89.7%) followed by headaches
(37.9%, 95%CI: 23.3%53.7%), focal deficits (16.0%, 95%CI: 9.7%23.6%) and signs of increased intracranial pressure (11.7%,
95%CI: 6.0%18.9%). All other manifestations occurred in less than 10% of symptomatic NCC patients. Only four studies
reported on the mortality rate of NCC.
Conclusions: NCC is a pleomorphic disease linked to a range of manifestations. Although definitions of manifestations were
very rarely provided, and varied from study to study, the proportion of NCC cases with seizures/epilepsy and the proportion
of headaches were consistent across studies. These estimates are only applicable to patients who are ill enough to seek care
in neurology clinics and likely over estimate the frequency of manifestations among all NCC cases.
Citation: Carabin H, Ndimubanzi PC, Budke CM, Nguyen H, Qian Y, et al. (2011) Clinical Manifestations Associated with Neurocysticercosis: A Systematic
Review. PLoS Negl Trop Dis 5(5): e1152. doi:10.1371/journal.pntd.0001152
Editor: Ana Flisser, Universidad Nacional Auto noma de Mexico, Mexico
Received December 10, 2010; Accepted February 24, 2011; Published May 24, 2011
Copyright: 2011 Carabin et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The World Health Organizations Foodborne Disease Burden Epidemiology Reference group (FERG) funded this project. PC Ndimubanzi received a
training grant from The Fulbright Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the
manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: [email protected]
Introduction
Neurocysticercosis (NCC) is primarily found in countries with
poor sanitation and hygiene and improper slaughterhouse services.
However, due to globalization and immigration, NCC is
increasingly being reported in developed countries [1]. Humans
become infected by ingesting Taenia solium eggs that later develop
into oncospheres. These larvae can migrate to any organ in the
body, but most reports have focused on cysts located in the Central
Nervous System (CNS), eyes, muscles or subcutaneous tissues. The
larvae have been found in several locations in the CNS. This
diversity of locations is believed to partly explain the range of
NCCs clinical manifestations. In addition, the signs and
symptoms associated with NCC depend on the larvaes number,
developmental stage (active, transitional or calcified), on the
duration of the infection and the hosts immune response [2].
Seizures and epilepsy are considered to be the most common
manifestations of NCC. However, several other neurological
disorders can also occur [3]. Unfortunately, these less common
manifestations are rarely recognized as being linked to NCC,
especially in low resource countries where imaging technology is
scarce [4]. Thus, data on the full range of clinical expression of
NCC are lacking, although such data are essential to accurately
estimate the burden of NCC on different communities. This
systematic review aims to estimate the frequency of the main
clinical manifestations associated with NCC.
Methods
A systematic search of the literature, including documents
published from January 1, 1990 to June 1, 2008, was conducted to
capture data on clinical manifestations associated with NCC.
Search strategy and data source
PubMed, Commonwealth Agricultural Bureau (CAB) Abstracts,
and 23 international databases were searched for data on NCC
manifestations. Articles published in Chinese, English, French,
Portuguese, Spanish, Italian, Romanian and German were
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searched. Two different searches were launched to cover both
clinical manifestations and mortality associated with NCC
infection. For the clinical manifestations, our search strategy in
PubMed included terms: "Cysticercosis/complications" [MeSH]
OR "Cysticercosis/history" [MeSH] OR Cysticercosis/pathol-
ogy" [MeSH] OR "Cysticercosis/psychology" [MeSH] OR
"Cysticercosis/radiography" [MeSH] OR "Cysticercosis/radionu-
clide imaging" [MeSH] OR "Cysticercosis/ultrasonography"
[MeSH]. CAB Abstracts and the international search engines
were queried using the following keywords: Taenia solium,
taeniasis or taeniosis, cysticercosis, and neurocysticerco-
sis. One Thesis in Medicine from Burkina Faso was identified
through contacts in Sub-Saharan Africa and was included.
For mortality associated with NCC, PubMed was searched
using the terms: cysticercosis/mortality [MeSH] OR "neuro-
cysticercosis/mortality" [MeSH]. In CAB Abstracts and the
international search engines the keywords neurocysticercosis
and mortality were used.
Inclusion and exclusion criteria
Documents reporting valid (defined as an absence of major
biases, see later), original data on clinical manifestations associated
with NCC were eligible for inclusion. Books and conference
abstracts were excluded because they were unlikely to have
sufficient details on the methodology used.
All documents retrieved were screened based on the title and
the abstract. The exclusion criteria for phase I were: 1) wrong
agent; 2) animal data only; 3) no original data on the frequency of
NCCs clinical manifestations; 4) case series with less than 20
participants; 5) review article without original data; and
6) editorials or letters to the editors without original data.
Documents without abstracts were included in the next phase.
After phase I, all eligible full text documents were reviewed
qualitatively (phase II) and quantitatively (phase III). The
exclusion criteria for phase II were identical to those used in
phase I in addition to: 1) high potential for information bias
(defined as no neuroimaging (CT-scans or MRI) or autopsies used
for the diagnosis of NCC); 2) high potential for selection bias
(defined as the study of volunteers or less than 80% of patients with
imaging and NCC); or 3) all available data were from before 1990
or after June 1, 2008. The quantitative data from documents
included after phase II were extracted in phase III.
Articles reporting the proportion of epilepsy cases with lesions of
NCC were excluded from the current study and reported in
another article [5].
Data extraction
Data on studies characteristics, methodological quality and
frequency of clinical manifestations and mortality were collected.
Data extraction was conducted independently by at least two
investigators. A third investigator checked a random sample of
10% of all of the entries. Discrepancies were resolved through
discussion until a consensus was reached. The screening process
(phase I) was performed in an ExcelH spreadsheet (Microsoft
Corp., Redmond, WA). Methodological factors (phase II) and
frequency data (phase III) were recorded in standardized
electronic forms of a data extraction tool which was developed
in AccessH (Microsoft Corp., Redmond, WA) specifically for this
review (available from the authors on request). Authors of primary
studies were contacted when the article being reviewed contained
missing or unclear information on the study design or results.
Data synthesis and analysis
Whenever two or more different studies described the same
clinical manifestation, we conducted a meta-analysis and estimated
the pooled proportion of the given clinical manifestation among
people with NCC. For these analyses, studies reporting seizures
and those reporting epilepsy were combined, as most reports did
not discriminate between the two. The definition of epilepsy is the
occurrence of at least two unprovoked seizures separated by at
least 24 hours [6].
As there was great variability in the characteristics of the
included documents, results were expressed as random-effects
models using proportion with 95% confidence intervals (95% CI)
[7]. The Freeman-Tukey double arcsine transformation was used
for pooled estimates of proportion and corresponding 95% CI
from the random-effects model [89]. The Cochrans Q test was
used to assess homogeneity across studies and the I
2
index was
used to summarize the total variability in proportion due to
between-study variation [10]. Random-effect models were used
due to important heterogeneity between studies. A sensitivity
analysis was conducted by estimating the pooled proportion after
omitting one study at a time. The analysis was performed with the
R META package (Version 0.82; Guido Schwarzer in R-META
metagen function) from R statistical software (R Development
Core Team, www.R-project.org). No study had considerable effect
on the pooled estimate and results from the sensitivity analyses are
not presented. A mixed-effects regression model was used to
determine if the age group (children vs adults) significantly
influenced the estimated percentage of seizures and epilepsy
among people with NCC.
Results
Literature search
A total of 1569 documents were identified in phase I. Figure 1
shows the number of papers identified in each database and
included in each phase and the reasons for exclusions. After phase
I, nearly three-quarters of the articles were excluded. An
additional 383 articles were excluded during phase II, most of
which (n =200) did not have manifestation data or did not use
neuroimaging to diagnose NCC. Fourteen Chinese articles could
not be traced and were excluded. Finally, 11 articles were
Author Summary
Neurocysticercosis is an infection of the brain with the
flatworm Taenia solium which is normally transmitted
between humans and pigs. Sometimes, humans can infect
other humans and the larva of the parasite can go the
brain, causing the disease neurocysticercosis. There has
never been a systematic review of what clinical signs are
found among people with neurocysticercosis. We con-
ducted a thorough review of the literature to answer this
question. We reviewed 1569 and 21 were of a sufficient
quality to be included in the final analysis. Among
neurocysticercosis patients who are seeking care in
neurology clinics, about 79% have seizures/epilepsy, 38%
severe headaches, 16% focal deficits and 12% signs of
increased intracranial pressure. Several other symptoms
were also reported in less than 10% of patients. People
with neurocysticercosis who seek care in neurology clinics
show a whole range of manifestations. Clinicians should be
encouraged to consider neurocysticercosis in their differ-
ential diagnosis when a patient presented with one of the
symptoms described in this review. This would ultimately
improve the estimates of the frequency of symptoms
associated with neurocysticercosis.
Manifestations of Neurocysticercosis
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Figure 1. Flowchart describing the number of papers remaining at different phases of the study.
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Table 1. Descriptive summary of the studies included for estimating the distribution of manifestations associated with
neurocysticercosis.
Reference
(language)
Country,
year(s) of
study
Population
Diagnosis of NCC
Type of
lesions
Measurement of
manifestations
Source Target
Study
sample size
[16] (Portuguese) Brazil,
198797
Autopsies of the Servico de
Anatomia Patolo gica do Hospital
de Cl nicas da Universidade
Federal do Parana, 198797
28 autopsies
(.15 years old)
27 (.1885
years old)
Autopsies 100% active Medical chart and
necropsy report
[15] (Portuguese) Brazil,
19956
Catchment population of the
Centro de Diagnostico por
Imagen do Parana (CEDIP),
Hospital das Nacoes, Curitiba,
PR, 199596
236 neurology
patients with
NCC (all ages)
236 CT-scan[49] 7.2% active Not specified
[11] (English) Brazil,
19934
People attending the Section of
Neuroinfectious Diseases at the
Clinicas da Faculdade de Medicina
da Universidade de Sao Paulo,
199394
38 neurology
patients with
NCC (18
60 years old)
38 CT-scan + positive
CSF immunological
test + MRI (cystic
lesions)
76.3% active Interview
(depression) and
medical charts
[25] (Portuguese) Brazil,
199001
Catchment population of
Ambulatorio de Neurologia do
Hospital Universitario Alcides
Caeneiro, Paraiba, 199001
44 neurology
patients with
NCC (all ages)
44 CT scan[50] +
CSF (33)+MRI (5)
52.3% active Standardized
medical chart
reviews
[21] (English) Ecuador,
198598
Catchment population of the
Department of Neurology of the
Eugenio Espejo Hospital in Quito,
198588
420 neurology
patients with a
stroke (17
86 years old)
420 CT scan, CSF,
immunologic tests,
other tests[51]
NR Stroke defined
according to Kotila,
1984 (neurological
examination)
[32] (English) Ecuador,
199496
Catchment population of the
Department of Neurology, Luis
Vernaza Hospital, and at the
Neuro-Oncology Service, Instituto
Oncologico Nacional, Guayaquil,
199496
43 neurology
patients with
cerebral glioma
(2086 years old)
43 CT-scan[5253] 100% inactive Histology of open
biopsy (presence
of malignant glial
cells)
[20] (English) Mexico,
198996
Catchment pediatric population
of the Neurology Department of
the Instituto Nacional de Pediatria
in Mexico City, 198996
122 neurology
patients with NCC
(14 months to 17
years old)
122 CT-scan, CSF
(n =71), MRI (n =20),
immunological tests
82.0% active Medical charts
[12] (English) Mexico,
199303
Catchment population of three
referral hospitals, Mexico City,
199303
206 neurology
treatment-free
NCC patients
(11 months -
62 years old)
206 CT-scan and/or MRI 75.7% active Direct
questionnaire
(adults, 1 year
prospective) or
hospital records
(children,
retrospective)
[33] (English) Mexico,
199396
People autopsied at the General
Hospital of Mexico, 199396
113 autopsies
with malignant
hematological
diseases (0
80 years old)
113 Pathological analysis
of the brain (autopsy)
NR Not provided
(autopsy)
[34] (Spanish) Mexico,
198698
Catchment population of the
neurological clinic of the Instituto
Nacional y Neurologia Manual
Velasco Suarez, 198698
63 patients with
non-aneurysmal
sub-arachnoid
hemorraghe (19
82 years old)
50 CT-scan and MRI
(no specific
definition provided)
NA Spontaneous
headache or
alteration of
consciousness w/o
trauma and
presence of blood
in the subarachnoid
space
[22] (English) USA,
198591
Catchment population of the Ben
Taug General Hospital of Houston,
Houston Texas, 198591
112 patients with
NCC (184 years
old)
112 Discharge diagnosis
of NCC (definite or
probable, no
reference)
80.4% active Medical charts
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excluded from this review and included in a study on the
proportion of epilepsy cases with NCC (see [5]).
Phase III included 21 documents (1.3%) containing quantitative
data on various clinical manifestations associated with NCC
(Table 1).
Literature search on death rate associated with NCC
A total of 45 publications were identified. Of those, 27 were
excluded in phase I (seven case reports, 14 reviews or letters, two
animal studies, four without death data). Eighteen studies were
read in full. Of those, two were case reports, nine did not provide
an estimate of death rate and three were reviews. Table 2 reports
the four studies included.
Distribution of manifestations among people with NCC
attending neurology clinics
People diagnosed with NCC presented with a wide range of
clinical manifestations. Definitions and measurement methods for
manifestations were very rarely provided (Table 1).
Table 3 reports the random-effect model pooled estimates
(where applicable) of the percentage of manifestations among
symptomatic NCC patients by age group. Figures 2 and 3 report
the corresponding forest plots for epilepsy and headaches. Forest
plots for the other manifestations are shown in Figures 4, 5, 6, 7.
Each forest plot illustrates the estimated percentage and 95%CI of
NCC patients with the manifestation of interest found in each
study. The losange at the bottom of each plot corresponds to the
Reference
(language)
Country,
year(s) of
study
Population
Diagnosis of NCC
Type of
lesions
Measurement of
manifestations
Source Target
Study
sample size
[23] (English) USA,
198694
Catchment pediatric population
of the at Childrens Memorial
Hospitals emergency room,
Chicago, 198694
47 children with
NCC (115 years
old)
47 Biopsy or MRI/CT-
scan and serological
or CSF tests or MRI/
CT and epidemiological
link
56% active
from 45 CT-
scans
Medical records
(medical,
laboratory,
pathology,
outpatient records)
[18] (English) India,
198487
Pediatric catchment population
of the G.B. Pant Hospital, New
Delhi, 198487
27 children with
NCC (312 years
old)
27 CT-scan and positive
CSF ELISA and MRI
and histological exam
81.4% positive
for CSF ELISA
Not specified
[19] (English) India,
197990
Pediatric Neurology Clinic
patients, New Delhi, 197990
50 neurology
patients with
NCC (115 years
old)
50 CT-scan supported
by MRI (8), history,
serum or CSF
antibodies, histology
of nodules
80% active Medical charts
[24] (Chinese) PR China,
date?
Hospitalised population of
the department of neurology,
Guangdong Medical University
Hospital, Guangdong Province,
no dates
36 inpatients with
NCC (1460 years
old)
36 CT (31) or MRI (9)
of the brain[54]
78% with active
lesions
Not specified
[27] (Chinese) PR China,
199501
Catchment population of the
department of infectious disease,
Huaghan Hospital, Shangai,
199501
125 patients with
NCC (268 years
old)
125 MRI or CT scan
of the brain
showing lesions
of NCC (3 were
normal)
90 active, 4
inactive, 31
unknown
Not specified
[26] (Chinese) PR China,
199701
Catchment population of the
NCC institute of the Jilin
University, 199701
210 patients with
NCC (, 15 years
old)
210 MRI or CT scan
of the brain AND
immunological test
positive in the CSF
or serum
83.7% with
active lesions
Medical chart
reviews
[14] (English) Portugal,
198392
Catchment population of the
reference Hospital Geral de
San Antonio, district of Oporto,
198392
38 patients
referred for a
CT active NCC
(662 years old)
38 CT-scan (true or
probable)[55]
100% active Not specified
[13] (English) Portugal,
198389
Catchment population of the
reference Hospital Geral de
San Antonio, district of Oporto,
198389
231 symptomatic
patients referred
for a CT with NCC
(age unknown)
144 with
symptoms
CT-scan (divided
as true and
probable)[55],
MRI, CSF ELISA
20.0% active;
80.0% inactive
Not specified
[56] (French) Burkina
Faso,
200106
Catchment population of the
neurology and radiodiagnosis
of the Centre Universitaire Yaldago
Ouedraogo, Ouagadougou, 200106
35 symptomatic
patients referred
for a CT with NCC
(878 years old)
35 CT-scan 74.3% active,
25.7% inactive
Medical
examination
(prospective)
[17] (English) South
Africa,
198486
Catchment population of the
Garankuwa hospital, 198486
88 patients with
NCC (adults)
88 CT-scan 100% active Not specified
NA: Not applicable.
NR: Not Reported.
doi:10.1371/journal.pntd.0001152.t001
Table 1. Cont.
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estimated pooled estimate based on the random-effects model. In all
age groups, seizures/epilepsy was by far the most common
manifestation followed by headaches, focal deficits and signs of
increased intracranial pressure. All other manifestations were
estimated to occur in less than 10% of symptomatic NCC patients
presenting for care. The estimated proportion of seizures/epilepsy
among children NCC patients was 15.9% (95%CI: 2.3%29.5%)
higher than in adult NCC patients. All other manifestations, except
for altered mental state, occurred in a similar proportion of pediatric
and adult NCC patients. One study focusing on psychiatric
symptoms among NCC patients [11] was an outlier, which explains
the very large 95% confidence interval for this estimate among
adults.
The distribution of manifestations in patients with active and
inactive lesions was presented in three studies [1214] (Table 4).
There was a considerably higher proportion of patients with
inactive NCC who presented with seizures/epilepsy (.88%) as
compared with patients with active lesions (6063%). Conversely,
the proportion with signs or symptoms of intracranial hypertension
was approximately 25% in patients with active lesions but was not
found in patients with inactive NCC lesions. Hydrocephalus and
meningitis were reported by only one author and were more
frequent with active lesions.
Distribution of manifestations in people with NCC
attending an imaging clinic
In one study from Brazil [15], 236 patients seen at an imaging
clinic had lesions suggestive of NCC of which 219 were inactive
lesions. Lesions suggestive of other pathologies were found in 48
(20.3%) of the cases with suspected NCC. The distribution of
manifestations was 30% with epilepsy, 51% with headaches, 8%
with focal motor/sensory deficits. There were 35% with other
symptoms found among patients with a CT-scan due to suspected
neoplasia or stroke.
Among 231 patients with NCC lesions seen in a neuroradiology
department, 87 (38%) were asymptomatic, incidental findings in
trauma patients and cases of suspected cerebrovascular disease
[13]. All of these 87 had inactive lesions. This study is unique
because it reports on the possible clinical spectrum of NCC.
Distribution of manifestations among autopsied patients
In a review of 901 autopsies conducted in a department of
pathology and anatomy at the University Hospital of Parana,
Brazil, the authors reported on 28 cases of NCC, with medical
charts available for 27 of the cases [16]. Of those, 13 were
asymptomatic, nine had seizures as a complicating factor of the
clinical picture prior to death, four had increased intracranial
pressure, one had meningitis, one had a cerebrovascular form and
Table 2. Descriptive summary of the studies included for estimating the death rate associated with neurocysticercosis.
Reference
(language)
Country, year(s)
of study Denominator Source of death data Measure of mortality
[28] (English) USA, 199002 Population of the United States
199002
National Center for Health
Statistics (NCHS)
Age adjusted annual mortality rate
[29] (English) Brazil, 198504 Population of the state of Sao
Paolo, 198504
Death certificates Over 20 years age- standardized
mortality rates
[30] (English) USA, 198900 Population of California 198900 State of California, Center for Health
Statistics, Office of Vital Records
Crude 12 years mortality rate
[31] (English) USA, 199500 Population of Oregon 199500 State of Oregon Death certificates Crude 6 years mortality rate
doi:10.1371/journal.pntd.0001152.t002
Table 3. Pooled estimates of the percentage of manifestations among symptomatic NCC patients using random-effect binomial
models.
Manifestation
Age group
All Children Adults
Seizures/epilepsy 78.8% (65.1%; 89.7%) 78.9% (70.5%; 86.2%) 63.2% (51.9%; 73.8%)
Headaches 37.9% (23.3%; 53.7%) 27.7% (20.7%; 35.2%) 25.9% (10.7%; 45.0%)
Signs of Intracranial Pressure/Hydrocephalus/Papilledema 11.7% (6.0%; 18.9%) 22.7% (10.2%; 38.5%) 16.3% (5.3%; 31.8%)
Meningitis symptoms 7.9% (2.7%; 15.5%) 11.2% (5.2%; 19.0%) 5.6% (1.9%; 12.8%)*
Cranial nerve palsy 2.8% (0.1%; 14.5%)* 6.0% (0.6%; 16.2%) NA
Gait abnormality/ataxia 6.0% (1.9%; 12.1%) 2.4% (0.2%; 7.2%) 5.6% (1.9%; 12.8%)*
Focal deficits 16.0% (9.7%; 23.6%) 12.5% (7.6%; 18.4%) 11.8% (4.1%; 22.9%)
Visual changes 5.6% (1.1%; 13.5%) 3.5% (1.3%; 6.7%) NA
Altered mental state/psychiatric symptoms 4.5% (1.5%; 9.0%) 4.0% (0.5%; 13.4%)* 28.1% (0.5%; 74.9%)
Pyramidal signs NA 11.6% (0.0%; 42.9%) NA
*One study with binomial 95%CI.
NA: No data Available.
doi:10.1371/journal.pntd.0001152.t003
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Figure 2. Forest plots of the proportion of symptomatic neurocysticercosis cases presenting with seizures/epilepsy. The forest plots
represent A) all age groups, B) Children (019 years old) and C) Adults (.19 years old). N/A represents the period of study missing.
doi:10.1371/journal.pntd.0001152.g002
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Figure 3. Forest plots of the proportion of symptomatic neurocysticercosis cases presenting with headaches. The forest plots
represent A) all age groups, B) Children (019 years old) and C) Adults (.19 years old). N/A represents the period of study missing.
doi:10.1371/journal.pntd.0001152.g003
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Figure 4. Forest plots of the proportion of symptomatic neurocysticercosis cases presenting with increased intracranial pressure
symptoms. The forest plots represent A) all age groups, B) Children (019 years old) and C) Adults (.19 years old). N/A represents the period of study
missing.
doi:10.1371/journal.pntd.0001152.g004
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one had dementia noted at some point during the course of the
disease. Only two of the 27 patients had been diagnosed with
NCC prior to death, which suggests that NCC is often
undiagnosed among patients with neurological symptoms.
Proportion of NCC cases seeking care who died
The proportion of cases of NCCwho sought care and subsequently
died were 2.3% (2/88) of adult patients with active lesions in South
Africa [17], 18.5%(5/27), 2.0% (1/50) and 1.6%(2/122) of pediatric
patients in India [1819] and Mexico [20], respectively, 3.2% (1/31)
of adult patients with stroke in Ecuador [21], 5.3% (2/38) of patients
with active lesions in Portugal [14], and 0.9% (1/112) of patients in
Houston, Texas [22]. Most deaths were associated with complica-
tions of shunt surgery for the treatment of hydrocephalus. The
duration of patient follow-up and referrals to other facilities were not
reported, which limits the interpretation of the data. In a study of 27
autopsied patients in Brazil, the NCC lesions were considered the
cause of death in 30% of the autopsied cases [16].
Duration of disease at the time of seeking medical care
Several of the studies reported the time from the onset of
symptoms to seeking medical care, with an average of 56.8 weeks
in adult patients in South Africa [17], a median of 3.5 months
(range 0492 months) in patients in the United States [22], a
median of 2 days (range ,1 day to 8.75 years) in children
presenting to the emergency room in the United States [23], and
a range of 5 days to 20 years in inpatients seeking care in China
[24]. Percentages of 77.3% [25] and 80% [26] of patients had
sought care within one year, 92.8% within three years [27]. The
time from onset of symptoms to seeking and receiving medical
care will also vary depending on the type of manifestations and
the local medical services capacity.
Death rate due to NCC
One study in the United States [28] and another in the State of
Sao Paolo [29], Brazil, reported age-adjusted annual mortality
rates of 0.06 (95% CI: 0.050.07) and 1.68 (95% CI: 1.581.78)
deaths per million population, respectively. The other studies from
California [30] and Oregon [31] in the United States reported
annual crude mortality rates of 0.33 (95% CI: 0.27 0.38) and
0.29 (95%CI: 0.110.64) deaths per million population.
Proportion of NCC cases among people with specific
manifestations
In people presenting with glioma [32], malignant hemato-
logical disease [33], or non-aneurysmal subarachnoid hemor-
rhage [34], the proportions with NCC were 18.6%, 6.2% and
4.0%, respectively (Table 5). The proportion of NCC reported
in people with stroke was 7.4% [21]. Some correlation between
the location of the cyst and the focal neurological deficit was
found in all NCC cases. These studies can only be used to
encourage physicians to add NCC to their list of differential
diagnoses when such a manifestation occurs, especially in
endemic countries.
Association between manifestation and NCC
The odds ratio of NCC and cerebral glioma was estimated to be
7.63 (95%CI: 2.0331.09) when cases of glioma were compared to
Figure 5. Forest plots of the proportion of symptomatic neurocysticercosis cases presenting with focal deficits. N/A represents the
period of study missing.
doi:10.1371/journal.pntd.0001152.g005
Figure 6. Forest plots of the proportion of symptomatic neurocysticercosis cases presenting with visual changes. N/A represents the
period of study missing.
doi:10.1371/journal.pntd.0001152.g006
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age-sex-socioeconomic status matched, previously healthy, head
trauma controls [32]. The odds ratio of the relation between NCC
and malignant hematological diseases was estimated to be 3.54
(95%CI: 1.179.79) when autopsied cases were compared to
autopsied cases without any type of neoplasm [33].
Discussion
This study is the first systematic review of clinical manifestations
associated with NCC, which can have a wide spectrum of
neurologic and psychiatric manifestations including seizures,
epilepsy, headache, cerebrovascular disorders, motor deficits and
depression [35].
More than three-quarters of symptomatic NCC patients seen in
neurological clinics present with seizures or epilepsy. Although
definitions of these conditions were very rarely provided, the estimate
was surprisingly consistent across studies as a result of including only
studies of a certain quality, making them more comparable to one
another and the results more valid. Several recent review papers
have reported percentages of NCC cases presenting with seizures
and epilepsy varying from 70% to 90% [3642].
The proportion of NCC cases seen in neurological clinics with
seizures/epilepsy was higher in children than adults. In a review
paper of NCC in childhood from India, the authors reported that
from 70% to 90% of children with NCC present with seizures
[43], which agrees very well with our finding. However, these
results may also reflect the fact that more children with seizures/
epilepsy are referred to facilities with CT as compared to adults. In
addition, if adults tend to be referred to neurology clinics for a
larger spectrum of neurological disorders, this would reduce the
proportion of seizure/epilepsy observed.
The next most common manifestation was headaches, at a
frequency of approximately one-third of symptomatic NCC
patients. The between-study estimates were more variable than
what was seen for seizures/epilepsy, but were still reasonably
consistent. This is surprising, since no study provided a definition
for headaches. The proportion of pediatric patients with
headaches was similar to that in adults but lower than the
estimate for all ages combined. Measuring headaches in toddlers
and young children is especially challenging since most of them
cannot communicate their symptoms [44].
The effect of NCC on altered mental state and psychiatric
symptoms remains poorly described. However, in the studies that
were included here, they were the presenting manifestations in
about 5% of cases of NCC, except for one study [11], where 52%
were found to have depression at presentation. Had the studies
also included psychiatry clinics, these estimates may have been
higher. The proportion of NCC cases with symptoms of or
increased intracranial pressure was similar between children and
adults. This could be due to the fact that papilledema, which is
more common among children, was included in this category of
symptoms.
All of the publications found in this review reported on patients
with symptomatic NCC seen in neurology clinics where imaging
Figure 7. Forest plots of the proportion of symptomatic neurocysticercosis cases presenting with altered mental state.
doi:10.1371/journal.pntd.0001152.g007
Table 4. Percentage of manifestations reported in symptomatic NCC patients with active and inactive lesions.
Reference Country, year(s) of study Manifestation Type of lesions Percentage 95%CI
[14] Portugal, 198392 Seizures/Epilepsy Active 60.5% 43.4%76.0%
[12] Mexico, 199303 Seizures/Epilepsy Active 62.8% 54.7%70.4%
[13] Portugal, 198389 Seizures/Epilepsy Inactive 98.3% 92.6%99.5%
[12] Mexico, 199303 Seizures/Epilepsy Inactive 88.0% 75.7%95.5%
[14] Portugal 198392 Intracranial Hypertension Active 23.7% 11.1%40.2%
[12] Mexico, 199303 Intracranial Hypertension Active 28.8% 21.9%36.6%
[13] Portugal, 198389 Intracranial Hypertension Inactive NA NA
[12] Mexico, 199303 Intracranial Hypertension Inactive 0.0% 0.0%7.1%
[14] Portugal, 198392 Hydrocephalus at CT Active 23.7% 11.4%40.2%
[13] Portugal, 198389 Hydrocephalus at CT Inactive 3.5% 1.0%8.7%
[14] Portugal, 198392 Meningitis Active 5.3% 1.7%21.4%
[13] Portugal, 198389 Meningitis Inactive 0.9% 0.0%4.7%
doi:10.1371/journal.pntd.0001152.t004
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was available. Therefore, the distribution of manifestations over-
estimates the true frequency of NCC-associated disease, since
patients who are asymptomatic or with only mild symptoms are
unlikely to be seen in neurology clinics. Indeed, in two studies
which were conducted in neuroimaging departments, about 35%
of all NCC cases were asymptomatic [1415]. In an autopsy
study, nearly 50% of cases of NCC did not have symptoms noted
in their medical charts [16]. There is a lack of knowledge on the
proportion of NCC cases who will develop symptoms, when in
the course of disease specific symptoms occur, and the frequency
with which the manifestations change over time. In a study
conducted in Mexico, 9.1% of randomly-selected residents
without neurological symptoms were found to have NCC based
on CT-scan examinations [45]. In another study conducted in
Honduras with sampling based on EITB results, 31 of 148
participants (21%) had lesions of NCC. Of these, 26 (18%)
showed no manifestations, two had headaches, two had epilepsy,
and one had dizziness [46]. The authors demonstrated that EITB
had very poor accuracy in detecting NCC, which would suggest
that sampling based on EITB may not introduce any important
selection bias. If this is the case, then we could conclude that
16.1% (5/31) of people in that community had prevalent NCC
symptoms. Unfortunately, in none of those studies was the history
of manifestations reported.
Assessing the distribution of manifestations among people with
active and inactive lesions can inform us somewhat about the
natural history of NCC. Seizures and epilepsy were more frequent
among patients with calcified lesions. Those with active lesions
were more likely to present with increased intracranial pressure,
hydrocephalus or meningitis. If properly defined, the term
epilepsy would be used to include only persons with unpro-
voked, recurrent seizures [6]. Thus, any cases of epilepsy that were
a result of NCC would, by definition, have to occur in persons with
inactive lesions, otherwise they would be acute symptomatic
seizures. The higher proportion of seizures/epilepsy in those with
inactive lesions may also reflect that NCC and epilepsy may be co-
occurring conditions rather than be causally linked.
The duration of NCC-associated disease remains unknown.
This review of the literature only allowed the estimation of the
time between the first recorded or reported symptom and medical
care. Some patients will never seek care and the duration of
disease will remain unknown since NCC can only be accurately
diagnosed with imaging. Once patients are in care, in case of
active disease, cysticercosis will be treated and the symptoms will
most likely disappear, although in the case of seizures, they may
persist beyond the period of active disease.
Death was reported in only a few studies. It has been reported that
neurologic deterioration in patients with NCC may be a life-
threatening event with numerous causes and diverse clinical
presentations [40]. In one study, the principal concurrent conditions
listed as contributing to death included hydrocephalus, cerebral
edema, cerebral compression, and epilepsy/convulsions [28]. The
methods to estimate death rates were so heterogeneous that they could
not be combined. Inorder toestimate the global burdenof NCC, using
a country-specific case fatality rate would be more helpful.
Various uncommon clinical manifestations have been reported in
numerous case reports, illustrating that clinical manifestations
associated with NCC are non-specific and pleomorphic [35,40].
However, in this review, only case series that had more than 20
participants were included meaning that rarer manifestations are not
included. Another important limitation is the lack of definitions of the
outcomes of interest. In addition, it is possible that some researchers
chose to report on only a certain set of symptoms and not on others.
Alertness of medical staff is needed to better recognize and
diagnose NCC, including providing symptoms definitions to
improve our knowledge of its clinical spectrum. Other limitations
are inherent to NCC itself and result from the difficulty of
diagnosing NCC even with neuro-imaging [47]. Brain calcifica-
tions or granulomas which represent the most frequently observed
feature in NCC are also common in tuberculosis, sarcoidosis and
toxoplasmosis [48]. These lesions may lead to false positive NCC
diagnoses and biased estimates of symptoms distribution [46].
This systematic review of the literature shows that NCC imposes
a heavy burden in endemic communities causing a wide range of
neurological, neuropsychological and psychiatric manifestations
and even premature death. Some clinical manifestations have an
insidious onset and a slow progression, making their diagnosis
difficult and often delayed. Hence, NCC should be kept in mind
when confronted with any neurological manifestation in patients
with histories of residing in endemic areas. When the clinical
presentation suggests NCC infection, it is critical to perform a
neuroimaging examination. The development of modern, afford-
able, valid diagnostic procedures and tests is needed to improve
understanding of all the clinical manifestations of NCC and its
epidemiology. A highly sensitive, specific and inexpensive
diagnostic tool will represent a big step in gaining insight into
the morbidity and mortality caused by NCC and will help to
accurately estimate its global burden.
Acknowledgments
We wish to thank Jinying Zhao for her help with the Chinese papers. We
also thank the members of the parasitic task force of FERG for their helpful
comments. Finally, we thank Stephanie Reynolds with her help in the final
steps of the reviews.
Author Contributions
Conceived and designed the experiments: HC CMB PCN MD. Performed
the experiments: HC PCN CMB HN YJQ ER MD. Analyzed the data:
HC PCN JAS. Contributed reagents/materials/analysis tools: HC PCN
HN JAS. Wrote the paper: HC PCN CMB LDC JAS.
Table 5. Percentage of NCC among people presenting in specific populations.
Reference Country, year Clinical presentation
Number of people
with NCC
Number of people
with manifestations % NCC (95% CI)
[32] Ecuador, 199496 Cerebral Glioma 8 43 18.6% 7.0%30.2%
[33] Mexico, 199396 Malignant hematological disease 7 113 6.2% 1.8%10.6%
[19] Ecuador 198588 Stroke 31 420 7.4% 5.1%10.3%
[34] Mexico 198698 Non-aneurysmal subarachnoid
hemorrhage
2 50 4.0% 0.1%11.6%
doi:10.1371/journal.pntd.0001152.t005
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