Enhanced steroid dosing reduces seizures during

antiparasitic treatment for cysticercosis and early after

*Hector H. Garcia, *Isidro Gonzales, Andres G. Lescano, Javier A. Bustos, #E. Javier
Pretell, *Herbert Saavedra, **Theodore E. Nash, and for The Cysticercosis Working Group in
Peru
Epilepsia, **(*):18, 2014
doi: 10.1111/epi.12739
Dr. Garcia directs the
Global Health Center,
Universidad Cayetano
Heredia and the
Cysticercosis Unit,
Institute of
Neurological Sciences,
in Lima, Peru.
SUMMARY
Objective: Neurocysticercosis (NCC) is a major cause of seizures and epilepsy in ende-
mic countries. Antiparasitic treatment of brain cysts leads to seizures due to the hosts
inammatory reaction, requiring concomitant steroids. We hypothesized that
increased steroid dosing will reduce treatment-associated seizures.
Methods: Open-label randomized trial comparing 6 mg/day dexamethasone for
10 days (conventional) with 8 mg/day for 28 days followed by a 2-week taper
(enhanced) in patients with NCC receiving albendazole. Follow-up included active sei-
zure surveillance and brain imaging. Study outcomes were seizure days and patients
with seizures, both measured in days 1142. Additional analyses compared days 110,
1121, 2232, 3342, 4360, and 61180.
Results: Thirty-two individuals were randomized into each study arm; two did not
complete follow-up. From days 11 to 42, 59 partial and 6 generalized seizure days
occurred in 20 individuals, nonsignicantly fewer in the enhanced arm (12 vs. 49,
p = 0.114). The numbers of patients with seizures in this period showed similar nonsig-
nicant differences. In the enhanced steroid arm there were signicantly fewer days
and individuals with seizures during antiparasitic treatment (days 110: 4 vs. 17,
p = 0.004, and 1 vs. 10, p = 0.003, number needed to treat [NNT] 4.6, relative risk
[RR] 0.1013, 95% condence interval [CI] 0.010.74) and early after dexamethasone
cessation (days 1121: 6 vs. 27, p = 0.014, and 4 vs. 12, p = 0.021, NNT4.0, RR0.33, 95%
CI 0.120.92) but not after day 21. There were no signicant differences in antiparasitic
efcacy or relevant adverse events.
Signicance: Increased dexamethasone dosing results in fewer seizures for the rst
21 days during and early after antiparasitic treatment for viable parenchymal NCC
but not during the rst 1142 days, which was the primary predetermined time of
analysis.
KEY WORDS: Cysticercosis, Neurocysticercosis, Seizures, Epilepsy, Taenia solium,
Cestodes, Peru.
Neurocysticercosis (NCC), a major cause of adult onset
seizures in endemic areas, is caused by infection with the
larval form of the pork tapeworm, Taenia solium. Humans
become infected and develop cysticercosis after the acci-
dental ingestion of ova released from the intestinal dwelling
adult tapeworm. Manifestations of NCC in humans are par-
ticularly varied, but the most common symptom is seizures
due to cysts lodged in the brain parenchyma.
1,2
Viable parenchymal cysts induce little inflammation.
However, during the natural evolution of the infection or as
a consequence of antiparasitic treatment, the host initiates a
Accepted June 23, 2014.
*Cysticercosis Unit, National Institute of Neurological Sciences, Lima,
Peru; Department of Microbiology, School of Sciences, Cayetano Heredia
Peruvian University, Lima, Peru; Center for Global Health Tumbes,
Cayetano Heredia Peruvian University, Lima, Peru; School of Public
Health, Cayetano Heredia Peruvian University, Lima, Peru; Department
of Parasitology and Public Health Training Program, US Naval Medical
Research Unit No. 6 (NAMRU-6), Lima, Peru; #Hospital National Alberto
Sabogal, ESSALUD, Callao, Peru; and **Gastrointestinal Parasites Sec-
tion, Laboratory of Parasitic Diseases, NIAID, NIH, Bethesda, Maryland,
U.S.A.
Address correspondence to Hector H. Garcia, Cysticercosis Unit, Insti-
tuto Nacional de Ciencias Neurologicas, Jr. Ancash 1271, Barrios Altos,
Lima 1, Peru. E-mail: hgarcia@jhsph.edu
Wiley Periodicals, Inc.
2014 International League Against Epilepsy
1
FULL-LENGTHORIGINAL RESEARCH
robust inflammatory response to degenerating cysts, which
frequently causes seizures.
35
Since the early use of antipar-
asitic treatment for NCC, corticosteroids have been
employed to suppress this response.
6,7
Despite their
apparent effectiveness in controlling inflammation, the use
of corticosteroids in viable NCC has never been studied in
randomized trials, and data are restricted to studies in
patients with a single degenerating parasite.
8
Therefore, the
comparative utility, safety, method of dosing, and choice of
steroid formulation are unknown. Clinicians use their own
judgment to choose from numerous and varied published
treatment regimens.
Seizures and other neurologic symptoms may increase
during antiparasitic therapy and during the first month after-
ward, even if steroids are used.
4,9
The most likely reason for
this relative increase is failure to fully suppress treatment-
induced inflammation because of inadequate corticosteroid
dosing. If this hypothesis is correct, enhanced regimens using
longer and higher doses of corticosteroids might prevent sei-
zure occurrences and lessen treatment-related morbidity. To
test this hypothesis we performed a randomized trial compar-
ing an enhanced corticosteroid (higher dose and extended
treatment duration) regimen to conventional dosing while
patients received antiparasitic therapy with albendazole.
Methods
Study design
Open-label randomized study comparing two dexametha-
sone (DXM) regimens in patients receiving albendazole
therapy for viable brain cysticercosis. The comparison
group (conventional steroid regimen) received 6 mg/day of
DXM for 10 days (2 mg every 8 h). The dose and length of
DXM therapy for this arm were taken from a prior random-
ized controlled trial.
9
To maximize the effect of steroids, the
intervention group (enhanced steroid regimen) received
8 mg/day of DXM (3 mg in the morning and afternoon;
2 mg in the evening) and this dose was maintained for
28 days and then tapered over the next 14 days (decreasing
doses every 2 days to 6, 4, 3, 2, and 1 mg, 0.5 mg for
4 days, and no drug thereafter). The 33% increase in the
dose of the enhanced steroid regimen was arbitrarily
selected to obtain a biologic effect without reaching doses
that were too high, and the 4-week duration was set so as not
to miss effects that occur during this period.
Study population
The study sample was obtained from patients who were
attending the Instituto Nacional de Ciencias Neurologicas
(INCN), a neurologic referral hospital in Lima, Peru, from
April 2006 to March 2010. Follow-up ended on March
2011. Participants were between 16 and 65 years of age
with a history of 10 years or less of seizures, had NCC with
<20 viable brain parenchymal cysts, and seizure activity
within the last 6 months. An epileptic seizure was defined
as a manifestation of excessive and/or hypersynchronous,
usually self-limited activity of neurons in the brain, and epi-
lepsy was defined as two or more unprovoked seizures more
than 24 h apart.
10
In addition, subjects were required to have a positive
Western blot for cysticercosis, and normal values for com-
plete blood count (CBC), glucose, and creatinine, as well as
alanine aminotransferase (ALT) and aspartate aminotrans-
ferase (AST) values (liver function tests, LFTs) <2.3 times
the defined normal range values. Viable cysts were defined
as hypodense on T
1
and fluid-attenuated inversion recovery
(FLAIR) magnetic resonance imaging (MRI) techniques,
hyperintense in T
2
, and may have some degree of enhance-
ment or edema.
Additional exclusions included other causes for seizures
or other central nervous system (CNS) conditions, history of
status epilepticus, permanent focal neurologic deficits, ven-
tricular or subarachnoid disease, intracranial hypertension,
cysts in critical regions such as the brainstem or eye, or cysts
larger than 2.5 cm in mean diameter. Patients who had
received albendazole treatment in the last 2 years were also
excluded, except for patients who received doses
<1,200 mg administered at least 2 months before evalua-
tion and demonstrated continued presence of viable cysts.
Furthermore, participants could not have used corticoster-
oids within the prior 2 weeks, or had received a course of
corticosteroids lasting more than 9 days within the past
6 months. Pregnant and nursing women were excluded.
Patients needed to be in relatively good health with stable
and normal vital signs in the absence of chronic diseases
including but not limited to diabetes, renal and hepatic
diseases, heart failure, and steroid dependent illness.
Patients were excluded if they had active tuberculosis (TB),
or had a history of TBin themselves or in close family mem-
bers. A chest x-ray consistent with TB excluded the patient
from the trial. All patients underwent purified protein deriv-
ative (PPD) testing, and if the induration was 10 mm they
were required to have three negative sputum examinations
for TB before treatment. HIV testing was requested but not
required. HIV positivity was not an exclusion criterion
unless PPD testing showed >5 mm reaction or the patient
had AIDS. Patients unable or unwilling to be hospitalized to
undergo MRI testing, or those with allergies or inability to
take study drug, antiepileptic drugs (AEDs), or to have other
required testing were excluded. Patients with strongyloides
or taeniasis required successful treatment before inclusion.
Study procedures
After enrollment, patients underwent a confirmatory
MRI, electroencephalogram, three stool exams including
Baermann tests to detect strongyloides (treated if positive),
pregnancy testing, phenytoin or carbamazepine drug level
testing, blood tests indicated earlier, and HIV testing if con-
sented for this. Patients who fulfilled inclusion criteria with-
out exclusions were randomized to the conventional or
Epilepsia, **(*):18, 2014
doi: 10.1111/epi.12739
2
H. H. Garcia et al.
enhanced DXM regimens using a computer-generated ran-
dom treatment allocation list in blocks of 4 and 6. Block
assignments were not stratified for prior number of seizures
or type of antiepileptic drug used before enrollment.
Patients were hospitalized for a minimum of 14 days
while receiving albendazole treatment. Patients in the
enhanced regimen who were stable were allowed to finish
the trial at home with daily visits by a study nurse who wit-
nessed the first daily dose of medication and reviewed the
seizure and symptoms diary.
All patients were required to have therapeutic AED levels
before treatment began and all received DXM and omepra-
zole 1 day prior to the onset of albendazole treatment
(15 mg/kg/day divided in two daily doses for 14 days).
Patients were reevaluated at 28, 42, 60, 90, 180, 270, and
360 days. Glucose levels were measured on days 1, 10, 14,
21, 28, 42, and 60, and antiseizure drug levels on days 42,
90, and 270. On day 180, patients had a follow-up MRI to
assess antiparasitic efficacy. Viable cysts were enumerated
and compared to the initial imaging, and patients with same
or worsening MRI findings were removed from the study
and retreated. On day 360, patients had both computed
tomography (CT; 64-slice scanner, Siemens, Erlangen,
Germany) and MRI (1.5 Tesla scanner, Siemens, Erlangen,
Germany) to assess lesion evolution. Those with viable
cysts on day 360 were also offered retreatment. All images
were read by a neuroradiologist who was unaware of the
treatment arm and the number of viable cysts remaining
confirmed by the study neurologist and staff. Discrepancies
were resolved by consensus among the study neurologist,
the reading neuroradiologist, and the principal investigators
of the study.
Special care was taken to validate and record every seizure
episode; this included intense staff training. The subjects
kept a seizure diary and were instructed to immediately
report every event compatible with a seizure. Suspected
events were evaluated by the study neurologist, including an
interview with the patient and/or witness to determine if the
event constituted a seizure as defined by International
League Against Epilepsy (ILAE) guidelines.
11
Multiple par-
tial seizures on a single day or multiple generalized seizures
on a single day were recorded as one seizure/day for each
type. Partial seizures with secondary generalization were
included in the generalized counts. Patients were evaluated
for side effects during the entire trial, with particular attention
to those effects that could be related to the use of steroids.
The protocol and consent forms were approved by the insti-
tutional review boards of the NIAID NIH, Universidad Peru-
ana Cayetano Heredia, Lima Peru, the INCN, Lima, Peru,
and the U.S. Naval Medical Research Unit No. 6. The trial is
registered at clinicaltrials.gov with number NCT00290823.
Sample size
The sample size was set to determine a comparative
reduction in the proportion of subjects who have seizures
between arms from 32% to 8%, a relative risk of 4. Assum-
ing a continuity-corrected chi-square test at a two-sided 5%
significance level, a sample size of 51 individuals assigned
to each treatment arm would have 80% power for demon-
strating the superiority of an extended schema of corticos-
teroids versus the traditional 10-day regimen in the clinical
outcome of the treatment of parenchymal cysticercosis. A
total of 110 individuals were to be enrolled to account for
potential losses to follow-up, according to the observed
rates of previous research in the site.
Primary data analysis
The study outcomes were the following: (1) the number
of seizure days, partial and generalized separately, and (2)
the proportion of patients who presented with seizures of
each type. The primary analysis of both outcomes included
only seizures occurring 1142 days (inclusive) after initia-
tion of therapy. The numbers of seizure days were compared
between arms using a nonparametric Mann-Whitney rank-
sum test to reduce the influence of outliers with multiple
seizures. The proportions of patients with seizures were
compared using a chi-square test with one degree of free-
dom or a Fishers exact test from the corresponding contin-
gency table. An intention-to-treat approach defining study
groups by the initial randomization was used.
Inspection of the seizure event data revealed an increase
in seizures occurring during antiparasitic treatment and soon
after. Therefore, prespecified secondary analyses compar-
ing other intervals defined in the protocol (days 110,
1121, 2232, 3342, 4360, and 61180) with the same
approach used for the main outcomes were also performed.
Seizure frequency was not compared after day 180 because
of the variability in the procedures after that date. Subjects
who showed no decrease in the number of viable cysts at
day 180 were retreated, resulting in nonsimilar groups that
could not be fairly compared. Comparisons of seizure days
were additionally confirmed with the more robust Fishers
exact permutation test (data not shown). In addition, an
exploratory analysis of the factors potentially associated
with partial seizures during study days 1180 was con-
ducted including baseline characteristics and clinical vari-
ables. The analysis of side effects was limited to the first
60 days of therapy. All analyses were conducted using
STATA v12.1 (Stata Corporation, College Station, TX,
U.S.A.). Two-sided p-values < 0.05 were considered statis-
tically significant.
Secondary analyses
For secondary analyses, stratified analysis was used to
explore the influence of baseline differences in the protec-
tive effect of enhanced DXM. Further secondary analyses
also compared resolution of all cysts as assessed by MRI at
day 180, the number of patients requiring re-treatment at
days 180 and 360 and the number of adverse events within
the first 60 days of treatment. All of these analyses followed
Epilepsia, **(*):18, 2014
doi: 10.1111/epi.12739
3
Steroids during Neurocysticercosis Treatment
the same approach used to test the main objective. Continu-
ous outcomes such as number of viable cysts at baseline and
the proportion of viable cysts that resolved were compared
between groups using a Mann-Whitney test. Further proto-
col details are available at www.clinicaltrials.gov.
Results
Eighty nine (53 male and 36 female) people met inclusion
criteria and were enrolled into the study. Further testing led
to the exclusion of 25 individuals who failed to meet study
entrance criteria. Six patients had concurrent taeniasis, and
two had strongyloidiasis; all of them were successfully trea-
ted. None of the enrolled patients had active TB. The trial
was voluntarily stopped because of slow enrollment, with
64 individuals randomized, 32 into each arm (Fig. 1). The
statistical power of the sample attained for the study out-
come was 55%, and no interim analyses of early effect/futil-
ity were conducted. There were no differences between
arms with regard to age or sex. Patients in the enhanced
treatment arm had symptoms for a longer period and had
experienced generalized seizures in a higher proportion, but
neither difference was statistically significant. In addition,
carbamazepine was prescribed significantly more often in
the enhanced treatment arm (p = 0.044). There were four
patients with a history of only partial seizures (without gen-
eralization), all allocated to the conventional DXM arm.
Three of the patients were receiving phenytoin and one was
receiving carbamazepine. The patients levels of carbamaz-
epine and phenytoin were all in therapeutic range by the
time of antiparasitic treatment. Individuals with a prior his-
tory of generalized seizures had disease for a much longer
period (34 vs. 11 months, p 0.001) and subjects who
received carbamazepine had disease for a slightly longer
period (33 vs. 21 months, p = 0.128). Patient characteris-
tics by treatment arm are provided in Table 1.
All patients completed treatment with albendazole and
dexamethasone. All but two male patients who were lost to
follow-up, one in each arm, underwent an evaluation for
efficacy on about day 180. These two patients were
excluded from any analyses of seizures or cysticidal effi-
cacy after day 60. In addition, one female and two male
patients were lost to follow-up between days 180 and 270;
they had no remaining viable cysts and had been treated in
the conventional DXM arm.
Over the first 180 days of the trial, subjects in the study
cohort had 175 seizure relapse episodes (seizure days)
occurring in 31 individuals. There were many more epi-
sodes of partial seizures (n = 167) compared to generalized
seizures (n = 12) (four episodes had both partial and gener-
alized seizures in the same day, Table S1). Twenty subjects
(31%) had at least one seizure during days 1142.
Seizure frequency
Although the numbers of seizures in the enhanced arm
compared to the conventional arm were decreased for most
time periods, the difference did not reach significance for
days 1142, the primary predetermined analysis period.
Further analysis along prespecified protocol periods demon-
Figure 1.
Flow diagram: open-label randomized trial comparing a conven-
tional versus an enhanced dexamethasone regimen in patients with
neurocysticercosis receiving albendazole.
Epilepsia ILAE
Table 1. Demographic, clinical, and radiologic
characteristics of enrolled patients
Conventional
steroids
Enhanced
steroids p-Value
Sex 22 male (69%) 21 male (66%) 0.790
10 female (31%) 11 female (34%)
Age
(mean SD)
31.4 10.7 years 30.1 123 years 0.650
Range 1861 Range 1765
Duration
of symptoms
21.7 25.4 months 31.5 32.4 months 0.179
Range 178 Range 1112
Type of
prior seizures
Partial 22 (69%) Partial 15 (47%) 0.076
Generalized
28 (88%)
Generalized
32 (100%)
0.057
Antiepileptic
drug
Carbamazepine
10 (31%)
Carbamazepine
19 (59%)
0.044
a
Phenytoin 21 (66%) Phenytoin 13 (40%)
Valproate 1 (3%) Valproate 0 (0%)
a
Fisher
0
s exact test.SD, standard deviation.
Epilepsia, **(*):18, 2014
doi: 10.1111/epi.12739
4
H. H. Garcia et al.
strated significantly fewer seizures in the enhanced steroid
arm compared to conventional steroids during antiparasitic
treatment, from days 1 to 10 (4 vs. 17, p = 0.004), and
immediately after cessation of DXM in the comparison arm
from days 11 to 21 (6 vs. 27, p = 0.014 mostly occurring in
days 1116 [data not shown]) (Table 2). In contrast, the
numbers of seizure days in intervals after day 21 were not
significantly different between groups. Aggregating the
periods between days 2232 and 3342 together did not
alter the findings. The low number of generalized seizure
occurrences precluded meaningful analyses for all intervals.
Proportions of patients with seizures
The number of persons with seizures also differed
between steroid treatment arms. Similar to the data for sei-
zure days, even though the number of individuals with par-
tial and total seizures was lower at nearly all time periods in
the enhanced arm compared to the conventional arm, the
number of persons with seizures failed to reach significance
between the arms over the default analysis period (11
42 days) (relative risk [RR] 0.67, 95% confidence interval
[CI] 0.321.41) (Table 2). However, the number of individ-
uals in the enhanced arm was significantly decreased for
persons with seizures on days 110 (RR 0.10, 95% CI 0.01
0.74, p = 0.024), 1121 (RR 0.33, 95% CI 0.120.92,
p = 0.035, also clustered in days 1116), and days 1180
(RR 0.48, 95% CI 0.270.84, p = 0.010), respectively, indi-
cating that the difference in numbers of seizures between
arms was not unduly influenced by seizures occurring in a
few individuals (Table 2). Overall, only 10 (32%) of 31
individuals in the enhanced DXM arm had at least one sei-
zure of any type during the 180 days of follow-up, com-
pared with 21 (68%) of 31 in the conventional arm (odds
ratio [OR] 0.23, 95%CI 0.080.66, p = 0.005).
Eleven patients had an unplanned change in corticoste-
roid dosing. In four patients (all in the enhanced DXM arm),
the dosing was lowered. The amount was decreased in two
subjects in an attempt to shorten the duration of insomnia
and herpes labialis. The other two patients forgot to take
their assigned drug dose. DXM was increased in seven
patients (four in the enhanced arm and three in the conven-
tional arm) to control treatment-related neurologic symp-
toms including headache (n = 1), vomiting (n = 1),
intracranial hypertension (n = 1), partial seizures (n = 2),
and/or generalized seizures (n = 2).
Efficacy of treatment
Analyses using different statistical approaches consis-
tently showed no significant differences in efficacy of anti-
parasitic treatment between arms (11/31 individuals with
complete cyst resolution in the enhanced steroid arm versus
14/31 in the standard steroid arm, OR 1.50, 95% CI 0.54
4.15, p = 0.437). Before treatment, both arms had similar
burdens of disease in average and total number of cysts. At
day 180, there were no significant differences in total viable
cysts remaining, percent cyst reduction, mean number of
viable cysts remaining, or rates of complete cyst resolution
(Table 3). Similar low rates of complete cyst resolution
were previously noted in prior treatment trials.
9,12,13
Analysis of potential modifying factors
The DXM regimen was the only factor that accounted for
differences in the proportion of subjects with partial
seizures between days 1 and 180. No differences were
associated with antiepileptic drugs (AEDs), prior partial sei-
zures, duration of symptoms, or complete cyst resolution,
among other variables examined (Table 4). Although the
two arms were not balanced regarding AEDs, the decrease
in partial seizures in patients in the enhanced arm remained
after adjusting for AED use, and was present both in
subjects receiving phenytoin (23% vs. 55%, p = 0.070) or
carbamazepine (39% vs. 60%, p = 0.283). However, there
were at least twice as many subjects with generalized
seizures in the phenytoin group regardless of the arm
(enhanced arm 15% vs. 6%, p = 0.376; conventional arm
20% vs. 10%, p = 0.449), but not significantly so.
Table 2. Seizure frequency, numbers, and percents of
individuals with seizure episodes per period and
compared between treatment arms
Days
Seizure days
Conventional
(n = 32)
Enhanced
(n = 32) p-Value
a
Primary analysis period (1142) 49 12 0.114
Secondary period analyses
110 17 4 0.004
1121 27 6 0.014
2232 10 3 0.644
3342 12 3 0.708
4360 21 6 0.441
61180
b
57 9 0.154
Overall study period (1180)
b
144 31 0.007
Period days
Individuals with seizures
Conventional
(n = 32)
Enhanced
(n = 32)
p-
Value
c
Primary analysis period (1142) (%) 12 (38) 8 (25) 0.281
Secondary period analyses (%)
110 10 (31) 1 (3) 0.003
1121 12 (38) 4 (13) 0.021
2232 3 (9) 2 (6) 0.500
3342 2 (6) 3 (9) 0.500
4360 5 (16) 3 (9) 0.354
61180
d
10 (32) 5 (16) 0.138
Overall study period (1180)
d
21 (68) 10 (32) 0.005
a
Mann-Whitney test.
b
Two subjects, one in each arm, were lost to follow-up after day 60 without
having experienced any seizures until then. Two individuals, both in the stan-
dard DXM arm, presented 61 and 22 partial seizure-days, respectively.
c
Chi-square/Fishers exact tests.
d
Two subjects, one in each arm, were lost to follow-up after day 60 without
having experienced any seizures until then.
Bold type indicates statistical signicance.
Epilepsia, **(*):18, 2014
doi: 10.1111/epi.12739
5
Steroids during Neurocysticercosis Treatment
Adverse events
There were no significant differences in the prospectively
recorded adverse events (AEs) between the arms (808 vs.
689 in the initial 60 days, p = 0.819), including neurologi-
cally based AEs, common corticosteroid side effects, and
putative treatment induced side effects (Table 5). There
were no statistically significant differences among the 16
reportable serious adverse events (SAEs, seven in the con-
ventional arm vs. nine in the enhanced arm), which were all
due to prolonged hospitalizations. Severe adverse events
that did not meet the criteria for SAE were almost exclu-
sively abnormal laboratory results with elevated liver
function tests (9 of 11: 3 in the conventional arm and 6 in
the enhanced arm), all of which resolved soon after tempo-
rary suspension of ABZ therapy (Table 5).
Discussion
Our findings demonstrated significantly decreased fre-
quency of seizure days and numbers of persons experienc-
ing seizures in the enhanced DXM arm from days 1 to 21
(during antiparasitic treatment and up to 11 days following
cessation of DXM treatment in the conventional arm), with-
out a significant decrease in efficacy or undue severity of
side effects. This decrease results mostly from partial sei-
zures, since only few generalized seizures occurred in this
cohort. This significantly heighted period of seizures
decreased after day 21, thereby diluting the significance for
the 1142 day period, the primary period of study. In fact
the choice of 1142 days for the primary analyses was not
based on prior knowledge of the most appropriate period to
compare seizure occurrences, which is the rationale for
other periods for analyses that were also included. The
decrease in seizures in the enhanced steroid arm during the
initial 10 days when both were receiving DXM (either 6 or
8 mg/day) was unexpected. The 2 mg increase in DXM was
enough to significantly protect against seizures in this per-
iod. Our standard comparison regimen used 0.1 mg/kg/day
for 10 days (approximately 6 mg/day), with no drug taper,
and approximates most of the multiple steroid regimens
reported in the literature. It is likely that the lack of tapering
resulted in a rebound effect accounting for more seizures
in days 1116. Because the choice of the enhanced dosing
regimen employed in this study was not based on precise
information but was prolonged to maximize the protective
effect, it is likely that it can be shortened and improved.
Despite the duration and higher dose of dexamethasone,
there were no differences in adverse events commonly
observed with corticosteroids.
Randomization did not control for prior seizure history or
the type of antiseizure medication, and subjects in the
enhanced steroid group had had seizures for a longer period,
had fewer prior partial seizures, and had more prior general-
ized seizures, but these differences were not statistically
significant (p = 0.179, p = 0.076, and p = 0.057, respec-
tively), perhaps due to the sample size (Table 4). We cannot
rule out a contribution of prior partial seizures to the
detected differences between groups, although the magni-
tude of this effect would have been small and probably did
not alter the important reduction of seizures due to the effect
of enhanced steroids.
Albendazole was administered for 14 days instead of 10
days in an attempt to increase the incomplete efficacy regu-
larly found with albendazole treatment. AEDs were admin-
istered to all participants, and levels had to be therapeutic
before starting albendazole; levels were also measured peri-
odically during follow-up. The close supervision of AED
Table 3. Cysticidal efcacy of albendazole treatment by
steroid dose groups
Feature
Arm 1 (n = 32)
conventional
Arm2
(n = 32)
a
enhanced p-Value
Viable cysts at baseline 151 153 0.859
Average per patient
(mean SD)
4.7 4.7 4.8 4.9 0.959
Range 120 118
Viable cysts at day 180
a
69 86 0.837
Average per patient
(mean SD)
2.2 3.5 2.8 4.8 0.608
Percent cyst reduction
a
53.7 43.4 0.578
Patients with all cysts
resolved (%)
a
11/31 (35.5) 14/31 (45.2) 0.437
Required retreatment
at day 180 (%)
b
6/20 (30.0) 6/17 (35.3) 0.732
Required retreatment
at day 360 (%)
c
9/14 (64.3) 8/11 (72.3) 0.493
a
Analysis with 62 subjects. Two participants, one in each arm, were lost to
follow-up before the MRI at day 180.SD, standard deviation.
b
Analysis with 37 subjects, only those that were still under follow-up on day
180 and had not resolved all cysts by that time.
c
Analysis with 25 subjects, only those that were still under follow-up on day
360 and had not resolved all cysts by that time.
Table 4. Factors associated with proportion of subjects
having partial seizures in days 1180
Seizures % p-Value
a
Arm Conventional 18/31 58 0.041
Enhanced 10/31 32
Prior partial seizures No 9/26 35 0.156
Yes 19/36 53
Prior generalized seizures No 2/4 50 0.617
Yes 26/58 45
Duration of symptoms 112 months 12/30 40 0.429
13112 months 16/32 50
Complete cyst resolution No 17/37 46 0.880
Yes 11/25 44
Antiepileptic drug Carbamazepine 13/28 46 0.754
Phenytoin 14/33 42
Baseline cysts 12 13/30 43 0.779
320 15/32 47
a
Fisher
0
s exact test.
Bold type indicates statistical signicance.
Epilepsia, **(*):18, 2014
doi: 10.1111/epi.12739
6
H. H. Garcia et al.
intake and levels may have been responsible for the rela-
tively low number of generalized seizures that occurred in
both groups.
Our study has several limitations. It was an open label,
single site study with early termination of enrollment, and
the analysis along the primary selected study period showed
only a nonsignificant reduction in seizures. However, sig-
nificant reduction was observed in prespecified and clini-
cally relevant study periods. In addition, all the results
consistently suggest lower seizure frequency in the
enhanced steroid arm, regardless of outcome, study period,
and statistical test. Early study termination was not due to
nonparticipation, losses to follow-up, or side effects, but
instead resulted from reduced patient enrollment due to
other trials competing for the same patients and therefore
should not have resulted in biases. Insufficient power could
have prevented detecting a true lower rate of seizures in
the study period. Additional, smaller reductions in the
frequency of seizures may have also been missed for the
same reason, but were probably not clinically relevant.
Two potential detrimental complications could mitigate
the usefulness of enhanced corticosteroids in reducing sei-
zures: a decrease in efficacy and/or an increase in harmful
side effects. In particular corticosteroid side effects were
consistently sought, and although increased in some did not
significantly differ between arms. No significant differences
in efficacy or side effects were detected between the two
arms.
Corticosteroids are commonly used to modify antipara-
sitic-induced inflammatory responses during treatment of
NCC.
7
The only randomized studies of the utility of corti-
costeroids in NCC
8,1419
are limited to their use in single
enhancing lesions (SELs), which result from a single
inflammatory focus consisting of a degenerating cysticer-
cus.
20
Although four of five studies showed significant
decreases in seizures in corticosteroid-treated patients, the
results are not conclusive.
19,21
Furthermore, SELs behave
differently in many ways compared to viable cysts and mul-
ticystic disease,
21,22
and thus the benefit of enhanced corti-
costeroid treatment in this trial cannot be extrapolated to
patients with SELs.
This is the first randomized study of the utility of adjunct
corticosteroids in the treatment of viable NCC. Our data
demonstrate that better control of inflammation by
increased doses of steroids along the initial 3 weeks after
treatment onset is associated with a decreased likelihood of
seizures during and early after antiparasitic treatment of via-
ble intraparenchymal NCC. More precise estimations of
dose and length of steroid treatment are required to maxi-
mize the benefit of antiparasitic treatment and avoid harm-
ful side effects of treatment and drug.
Acknowledgments
Funding: Supported in part by the Intramural research Program of the
National Institute of Allergy and Infectious Diseases, the National Institutes
of Health (NIH), and by the Fogarty International Center/NIH (training
grants D43 TW001140 and D43 TW007393). H.G. is supported by a Well-
come Trust Senior International Research Fellowship in Public Health and
Tropical Medicine and receives additional support from the NIH (NINDS
R01 NS054805 [PI] and D43 TW001140 [PI]), the Gates Foundation, and
The Wellcome Trust. The funders had no role in study design; data collec-
tion, analysis, or interpretation; in writing the report, or in the decision to
submit the article for publication.
Co-investigators Manuel Martinez, Manuel Alvarado, Miguel Porras,
Alfredo Cjuno, Victor Vargas (neurologists); Diego Escalante (neuroradi-
ologist); Monica Vera (head clinical monitor), all associated with The Insti-
tuto Nacional de Ciencias Neurologicas, Jr. Ancash 1271, Barrios Altos,
Lima, Peru.
Disclosures
Dr. Garcia serves as an editorial consultant for The Lancet, an Associate
Editor of PLoS Neglected Tropical Diseases, and on the editorial boards of
the American Journal of Tropical Medicine and Hygiene, Experimental
Parasitology, World Journal of Gastroenterology, Annals of Neurosciences
Table 5. Analysis of adverse events related to NCCand
steroids
Individuals with adverse events
Conventional
(n = 32)
Enhanced
(n = 32) p-Value
NCC-related (%) 30 (94) 28 (88) 0.391
Mean standard deviation 2.4 1.4 1.8 1.1 0.078
Blurred vision 1 (3) 0 (0) 0.500
Focal sensory symptoms:
Burning sensation,
paresthesia
or hypoesthesia
14 (44) 13 (41) 0.800
Dizziness 15 (47) 11 (34) 0.309
Headache 27 (84) 24 (75) 0.351
Intracranial hypertension 2 (6) 1 (3) 0.500
Memory loss 2 (6) 0 (0) 0.246
Myoclonus 1 (3) 1 (3) 0.754
Myokymia 2 (6) 0 (0) 0.246
Focal motor symptoms:
Paresis, paraparesis or
hemiparesis
4 (13) 2 (6) 0.336
Somnolence 4 (13) 2 (6) 0.391
Tinnitus 1 (3) 4 (13) 0.177
Tremor 4 (13) 1 (3) 0.177
Steroid-related (%) 21 (66) 24 (75) 0.412
Mean SD 13 13 17 14 0.230
Anxiety 4 (13) 6 (19) 0.491
Depression 0 (0) 1 (3) 0.500
Mood alteration 0 (0) 1 (3) 0.500
Insomnia 5 (16) 11 (34) 0.083
Psychogenic syncope 0 (0) 0 (0) 1.000
Increased glucose 1 (3) 0 (0) 0.500
Cushingoid appearance 0 (0) 3 (10) 0.119
Weight gain 1 (3) 5 (16) 0.098
Nausea 11 (34) 8 (25) 0.412
Vomiting 6 (19) 7 (22) 0.756
Abdominal Pain 14 (44) 13 (41) 0.800
a
The percent of subjects with adverse effects was compared with a chi-
square test. The average number of adverse effects per person was compared
with Students t-tests.
Epilepsia, **(*):18, 2014
doi: 10.1111/epi.12739
7
Steroids during Neurocysticercosis Treatment
(India), and Journal of Neuroparasitology; and receives research support
from the NIH (NINDS R01 NS054805 [PI] and D43 TW001140 [PI]), the
Gates Foundation, and The Wellcome Trust. Dr. Lescano receives research
support from the NIH (D43 TW 007393 [PI]). The remaining authors have
no conflict of interests to disclose. All the authors confirmthat we have read
the Journals position on issues involved in the ethical publication and
affirmthat this report is consistent with those guidelines.
Disclaimer/Copyright Statement
The views expressed in this article are those of the authors only and do
not necessarily reflect the official policy or position of the U.S. Department
of the Navy, U.S. Department of Defense, or the U.S. Government. T.N.
and A.L. are employees of the U.S. Government. This work was prepared
as part of their duties. Title 17 U.S.C. 105 provides that Copyright pro-
tection under this title is not available for any work of the United States
Government. Title 17 U.S.C. 101 defines a U.S. Government work as a
work prepared by a military service member or employee of the U.S. Gov-
ernment as part of that persons official duties.
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Supporting Information
Additional Supporting Information may be found in the
online version of this article:
Table S1. Seizure frequency and numbers and percents
of individuals with seizure episodes per period and com-
pared between treatment arms.
Epilepsia, **(*):18, 2014
doi: 10.1111/epi.12739
8
H. H. Garcia et al.