Short course of albendazole therapy for
neurocysticercosis: A prospective randomized
trial comparing three days, eight days and the control group without albendazole
Dr.
Fernando Alarcón,* Dr. Gonzalo Dueñas,** Dr. Marcelo Diaz,* Dr. Nelson Cevallos,* Dr.
Galo Estrada,*
Department of Neurology*
and Neuroradiology**, Eugenio Espejo Hospital, Quito.
-----------------------------------------------------------------------
Correspondence
to: Dr.
Fernando Alarcón,
Department
of Neurology, Eugenio Espejo Hospital
P.O.
Box 17-07-9515, Quito, Ecuador
ABSTRACT:
Antihelminthic
therapy with albendazole for parenchymal cerebral cysticercosis, despite its widespread
acceptance, is still the subject of controversy. In this prospective, randomized clinical
trial, we compared the effectiveness of two regimens of albendazole therapy for
neurocysticercosis against each other and against symptomatic therapy alone. A first group
(27 patients) received albendazole for 3 days, a second group (27 patients) received
albendazole for 8 days, and a third group (29 patients) received only symptomatic
treatment. Effectiveness of albendazole was 85.8% with no difference between the 3 and
8-day groups of treatment. Improvement of the patients in the control group was 34.4%.
Complete resolution of cysts was obtained in 77.7% of the patients who received
albendazole. Two years after therapy, there was no difference in the number of patients
free of seizures, when comparing the three groups of treatment. The ultra-short course of
treatment with albendazole for 3 days was effective in our patients. Therapy with
albendazole for 8 days did not provide additional benefits.
RESUMEN:
Existe controversia en la efectividad del tratamiento antihelmíntico para la
cisticercosis, a pesar de su amplia utilización. En este estudio prospectivo y
randomizado, comparamos la eficacia de dos regimenes de albendazol contra un tratamiento
sintomático. Un grupo de 27 pacientes recibió albendazol por 3 días, un segundo grupo
(27 pacientes) recibió albendazol por 8 días y un grupo control (29 pacientes) no
recibió tratamiento específico. El porcentaje de reducción de quistes en los dos grupos
de pacientes que recibieron albendazol fue del 85.8%, sin diferencia significativa entre
ambos grupos. Por el contrario, solo el 34.4% de los quistes que no recibieron tratamiento
desaparecieron. Una resolución completa de los quistes se observó en el 77,7% de los
pacientes tratados con albendazol. Dos años luego del tratamiento, no hubo diferencia en
el número de pacientes libre de crisis convulsivas en los tres grupos de tratamiento.
Concluimos que el curso de 3 días con albendazol es eficaz para la destrucción de
cisticercos en el parénquima cerebral. Aumentar el curso de tratamiento a 8 días no
aumenta la eficacia del albendazol.
The first successful
medical treatment for human neurocysticercosis (NCC) was the administration of
praziquantel [1,2]. Albendazole appeared shortly thereafter as a sound therapeutic
alternative to praziquantel [3,4]. Albendazole
is considered the drug of choice for treatment of NCC [5], owing to its greater
effectiveness, higher tolerance, shorter time of treatment, and lower cost compared to
praziquantel [5-8]. The length of NCC
treatment with antiparasitic drugs has declined gradually, from 30 to 3 days [1-5]. A
single-day praziquantel therapy has been proposed as a regimen that exerts cysticidal
effects similar to those produced by longer courses of praziquantel [9]. Since evidence of
the results of effectiveness and duration of the NCC treatment with albendazole has been
inconclusive [10-13], we conducted a randomized clinical trial of albendazole treatment
for three and eight days, and compared their effectiveness with a control group that did
not receive antiparasitic treatment.
Patients and Methods
Between
January 1989 and December 1996, we identified and included all patients who came to the
Department of Neurology of Eugenio Espejo Hospital, Quito-Ecuador, with a new diagnosis of
NCC on the basis of characteristic CT findings. The designation of the patient to a
treatment group was made randomly, and allocated to one of the groups on a sequential
basis according to the admission number. All patients signed an informed consent prior to
being enrolled in the trial. Once treatment
was allocated, a neurologist administered the corresponding therapy, whereas a neurologist
blinded to treatment allocation conducted the follow-up. We included 95 patients in a
prospective, randomized clinical trial. Follow-up continued until December 1998. The study design had been previously approved by
the Ethics Committee of the Eugenio Espejo Hospital.
Inclusion Criteria: Men and women of
all ages, with neurological signs and symptoms for between one week and 3 years before
admission to our study, with CT showing one to six nonenhancing parenchymal brain cysts
without perisional edema, with or without calcifications. A positive CSF ELISA was not
required for inclusion.
Exclusion Criteria: We excluded
patients whose CT showed ringlike or nodular
enhanced cysts and/or edema surrounding the lesions, as well as those with subarachnoid or
intraventricular cysts or hydrocephalus. In addition, patients who had previously been
treated with either albendazole or praziquantel, pregnant women, and those with clinical
evidence of intracranial hypertension were excluded.
Evaluation:
All the patients had an initial assessment that included a neurological examination, plain
and contrast-enhanced CT of the brain, CSF analyses including cell count, glucose, total
proteins and ELISA for detection of anticysticercal antibodies, and a metabolic workup
including hematologic, biochemical and routine liver function tests. At the beginning of
the study, all patient had good general health. We explained patients that they could not
take albendazole or any other antiparasitic drug during the study. All the relatives
living with the patients were treated for tapeworm infection.
Treatment
Groups: All
patients were hospitalized for an initial evaluation. During hospitalization they received
symptomatic treatment for headache and epilepsy, until they were asymptomatic and
neurologically stable. Patients who were randomized for treatment with albendazole for 3
or 8 days remained in the hospital until 3 days after completing the treatment. Patients
who did not receive antiparasitic medication remained until all the complementary tests
were performed and they were asymptomatic.
After
informing the patients about the study and once they agreed to participate, we allocated
each patient to one of the following groups: Group
1, receiving 15 mg of albendazole per kilogram of body weight for 3 days; Group 2,
receiving 15 mg of albendazole per kilogram of body weight for 8 days; and Group 3, who
did not receive albendazole. In addition, all patients with seizures received
anticonvulsive drugs, including carbamazepine and phenytoin, administered as monotherapy.
None of the 95 patients received steroids.
Clinical
examination was performed every day during treatment and every month afterwards up to 3
months and afterwards at 3-month intervals for at least 2 years. CSF examinations were
performed on the day before the start of treatment and one day after the end of the trial.
Follow-up: The evolution of
parenchymal brain cyst was monitored by repeated CT scans. Mean and total numbers of cysts
were counted during the initial examination, at 3 months, and 12 months after treatment.
Patients were divided into two groups according to the number of cysts: those with a
single cyst, and those with 2 to 6 cysts. Evaluation
of the number of cysts on CT at baseline and at follow-up was performed by a single
neuroradiologist (GD) blinded to treatment allocation. Similar axial sections were taken
in initial and control CTs to assess the same cysts in subsequent follow-ups. In the
patients whose seizures recurred after the end of the study, brain CT-scan was repeated to
verify if a new infection had occurred.
Assessment of Treatment: We determined the
number of cysts as our primary outcome variable, and the number of patients who were free
of seizures as our secondary outcome variable. We established two independent indicators
for a successful therapeutic response: a) complete response with disappearance of all the
cysts on CT, and b) reduction or absence of seizures in the patients, with a follow-up of
more than two years.
Statistical Analysis: We performed the
chi-square test and ANOVA for demographic comparisons and the chi-square test for the
number of cysts before and after treatment. We
used the chi-square test and nonparametric Wilcoxon signed-rank test to analyze the
independent indicators of a therapeutic response among the groups of treatment. In
addition, we used ANOVA to compare the cells and proteins of the CSF in the 3 groups of
the study.
Results
Over
a period of 8 years, 95 patients with NCC met the criteria to become part of the study.
Six patients, two in each group, were excluded because they could not guarantee good
compliance and two patients because they had a concomitant stroke; one of these patients
patient was allocated to the group that would receive albendazole for 3 days and the other
to the group receiving albendazole for 8 days. Eighty-seven patients started treatment
after the randomization. Four patients dropped out of the study, because we were unable to
obtain complete information from them for at least 2 years after therapy was started. One
patient belonged to the 3-day albendazole group, two to the 8-day albendazole, and the
other to the control group. The results of the remaining 83 patients are presented (Table
1). ELISA test in CSF was positive in 60 patients (72%). No differences were found when
the treatment groups were compared with respect to age, sex, the total number of cysts,
number of single cysts and of two to six cysts, and the number of patients with seizures.
The average age of the 83 patients was 33.4 ± 15.2 years (age range, 12 to 80 years). The
mean duration of follow-up during the trial was 31.4 months. We found 147 viable cysts in the 83 patients
(Table 2). The average number of cysts in the 54 patients who received albendazole was 1.8
whereas the average number of cysts of the 29 patients who did not receive the drug was
1.9.
At
the first follow-up evaluation, 3 months after antiparasitic treatment (Table 2), 30
(36.1%) of the 83 patients were without cysts (p < 0.001). At the second follow-up
evaluation, 52 (62.6%) of the patients were without cysts (p < 0.05). Thirteen (61.9%)
of the 21 patients with single cysts who received albendazole were without cysts in the
first evaluation and 17 (80.9%) in the second evaluation. Two patients (20%) of the
control group with single cysts were without cyst in the first evaluation and five (50%)
in the second. Fifteen (45.4%) of the 33 patients with multiple cysts who received
albendazole were without cysts in the first follow-up evaluation and 25 patients (75.7%)
in the second evaluation. Three (15.7%) of the 19 patients of the control group with
multiple cysts were without cysts in the first evaluation and 5 (26.3%) in the second.
Twenty-eight of the 54 patients (51.8%) who received albendazole were without any cyst at
the first follow-up and 42 (77.7%) at the second. Two of the 29 patients (6.8%) of the
control group were without any cysts at the first assessment and 10 (34.4%) at the second.
In
the two evaluations, when comparing the patients with single cysts, who received
albendazole for 3 and 8 days, we did not find a statistical difference in the number of
patients who were without cysts (Table 2). When comparing each one and the two groups of
treatment who received albendazole with the control group, we found significant
differences in the number of patients with single cysts who were without cysts, in both
the first (p < 0.001) and the second evaluations (p < 0.05). In the patients with
multiple cysts who received albendazole for 3 and 8 days, we did not find differences in
the number of patients who were without cysts, in the first and second evaluations. There
was a significant difference when comparing the two groups of treatment who received
albendazole and the control group, in both the first (p < 0.001) and the second (p <
0.05) evaluations (Table 2). When comparing the total number of cysts in the three study
groups, there was no difference between the two groups that received albendazole, but
there was a significant difference when comparing the two groups that received
antiparasite treatment with the control group, in both the first (p < 0.001) and the
second evaluations (p < 0.05).
Fifty-eight
(69.8%) of the patients included in the study had seizures. Eighteen patients (21.6%) had
more than one seizure per month (Table 3). All
the patients with seizures received anticonvulsive treatment for more than 2 years.
Twenty-seven patients (46.5%) with epilepsy were without seizures two years after the
antiparasitic treatment (Table 3). We did not find significant differences in the number
and percentage of the patients who were free of seizures for at least 2 years when
comparing the three groups of the study.
During
the antiparasitic treatment, 8 patients (29.6%) of the group with albendazole for 3 days,
and 6 patients (22.2%) of the group with albendazole for 8 days suffered headaches.
Seizures were recorded in one patient from the group with albendazole for 3 days, and in
one patient from the group with albendazole for 8 days. Two patients displayed focal motor
deficit during treatment, one in the group that received albendazole for 3 days and one in
the group that received albendazole for 8 days. There was vomiting and dizziness among 14
patients who received albendazole. These symptoms appeared between the second and third
day of treatment, both in patients who received 3 days and in those who received 8 days of
albendazole. In these two groups, the rise in cells and proteins was similar in the CSF
analysis one day after treatment (Table 4). CSF
in the control group did not show significant modifications during the study. During the
follow-up, one patient from the group with albendazole for 8 days required a ventricular
shunt due to obstructive hydrocephalus.
Discussion
Praziquantel
and albendazole are effective drugs for the treatment of cysticercosis of the brain
parenchyma [7,14,15]. Currently, albendazole is considered the drug of choice for
treatment of NCC [5]. Owing to the terms used to select the patients and the selection and
measurement of outcome variables that were used in the studies conducted with these
anti-parasitic drugs [5,7,14-16], their results have been considered inconclusive [11,12].
Albendazole
was initially administered at daily doses of 15 mg/kg/day for 30 days; nevertheless,
further studies showed that, at similar doses, the length of therapy could be shortened,
from 30 days to 8, 7 and 3 days without lessening the efficacy of the drug [4,7,8,15,-17].
Most of these studies were open-ended, with a short duration of follow-up and similar
effectiveness. Owing to the need to reduce the dose and the cost of the therapy,
ultra-short treatments involving a single-day administration of praziquantel for NCC have
been applied and they have proven to be effective [9].
When
we compared the results of the first follow-up CT (3 months after treatment) with a
baseline CT, we found that a high number of the patients who received albendazole for 3
and 8 days, were without cysts, and there was a significant difference with the control
group. When comparing the number of patients with total disappearance of cysts, we did not
find any difference between the two groups that received albendazole, but there was a
significant difference when comparing them with the control group. This difference was
maintained in the second follow-up CT. When comparing the first and second follow-up (3
and 15 months after treatment), between the two groups that received albendazole we found
no statistical difference in the number of patients that were without cysts. These findings suggest that albendazole produces
the death and disappearance of parenchymal brain cysticercus, and confirms our previous
findings that the ultra-short treatment of 3 days with albendazole is as effective as the
8-day treatment [17].
In
most studies on drug therapy for NCC, clinical variables were not well defined. Of the
many signs and symptoms of NCC, epilepsy is the most frequent and the most easily
identified and quantified. Improvement in
seizure control has been used as an outcome variable to evaluate the effectiveness of
antiparasitic drugs [18,19]. In those studies, seizures have persisted in the control
group that was untreated with antiparasitic drugs, even though a concurrent control group
selected in a manner similar to those treated was not identified (1-4,7,8,15-19). Our
study, in concordance with a previous study [13], showed that the control of the seizures
in these patients is not modified by albendazole therapy. These results, along with the
lack of sufficient evidence in pathological studies, suggest that antiparasitic drugs do
not produce a more profound cerebral cicatrix than symptomatic therapy [20].
Our
study showed a statistically significant difference in the radiological prognosis, when
comparing the groups treated with albendazole with the control group, in the number of
patients without cysts, or with decline in the number of cysts by group of treatment, and
in the mean reduction in cysts per patient. We did not find differences in the
radiological prognosis when comparing the previously indicated parameters between the
patients who received albendazole for 3 and 8 days. Our study did not show any statistical
difference in the clinical prognosis; the number of patients who were free of seizures, in
the three groups, was similar.
The
evidence of medical treatment of NCC has been persuasive but inconclusive [10], and this
has led some authors to doubt its effectiveness [11-13]. Some revisions have been critical
with the trials of NCC, especially the way of selecting the patients and the selection and
measurement of outcome variables. Our study is a controlled randomized trial conducted
during 8 years and based on our previous study of a short treatment for 3 days [17], which
demonstrated an effectiveness similar to the more prolonged treatments. None of our
patients received corticosteroids along with albendazole, and therefore their results were
not affected by interactions with this drug [13].
The
results of our controlled trial, with a follow-up of more than 2 years, show that the
ultra-short course of treatment with albendazole for 3 days for parenchymal brain cysts is
similar to, and is not significantly different from, the 8-day course of treatment. In
addition, our study shows that, when comparing the groups treated with albendazole with
the control group, the rate of disappearance of cystic lesions, and the number of patients
without cysts were significantly higher after albendazole therapy. Our study also shows
that the control of seizures is not modified by albendazole.
In
conclusion, although the size of the sampling of our study is small, its suggests that the
3-day course of albendazole therapy is safe, effective, and has the obvious advantage of
better patient compliance and reduced costs of therapy. New controlled studies, with
larger numbers of patients are needed to accumulate further evidence that short courses of
albendazole are effective.
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Table 1. Demographic, imaging, and clinical
characteristics of 83 patients with NCC.
|
Albendazole
3-day
group
(n
= 27)
|
Albendazole
8-day
group
(n
= 27) |
Control
group
(n
= 29)
|
Age
years (mean ± SD) |
33.6
± 15.6 |
33.9
± 16.1 |
32.9
± 14.1
|
Sex
(man/woman)
|
12/15 |
12/15 |
12/17 |
Average
follow-up during trial (months)
|
33.1
± 11.9 |
31.1
± 6.4 |
30.2
± 10.8 |
Total
cysts (mean) |
49
(1.8) |
43
(1.7) |
55
(1.9)
|
Single
cyst |
9 |
12 |
10
|
Two
to six cysts |
40 |
31 |
45
|
Total
patients with seizures |
18 |
20 |
20 |
Nonsignificant
difference (chi-square test)
Nonsignificant
difference (ANOVA)
Table 2. Number
of patients, number of cysts and mean at baseline and follow-up at 3 and 12 months after treatment
Evaluations
|
Albendazole 3-Day Group
|
Albendazole 8-Day Group
|
Control Group
|
No. patients |
No. cysts
Total (mean±SD) |
No. patients |
No. cysts
Total (mean±SD) |
No. patients |
No. cysts
Total (mean±SD) |
At baseline CT scan |
|
|
|
|
|
|
Total |
27 |
49
(1.8±0.7) |
27 |
43
(1.7±0.7) |
29 |
55
(1.9±0.7) |
Single cyst |
9 |
9 |
12 |
12 |
10 |
10 |
Multiple
cysts |
18 |
40 |
15 |
31 |
19 |
45
|
First follow-up (3 months) |
|
|
|
|
|
|
Total |
27 |
18
(0.6±0.7) |
27 |
13
(0.4±0.5) |
29 |
47*
(1.6±0.8) |
Single
cyst |
10 |
10 |
11 |
11 |
11* |
11 |
Multiple
cysts |
4 |
8 |
1 |
2 |
16* |
36 |
Without cysts
|
13 |
- |
15 |
- |
2* |
-
|
Second follow-up (12 months) |
|
|
|
|
|
|
Total |
27 |
7
(0.2±0.5) |
27 |
6 (0.2±0.4) |
29 |
28*
(0.9±0.8) |
Single cyst |
5 |
5 |
6 |
6 |
12* |
12 |
Multiple
cysts |
1 |
2 |
- |
- |
7* |
16 |
Without cysts
|
21 |
- |
21 |
- |
10* |
- |
Statistically significant when comparing the number of
patients with cysts and the number of cysts of the groups that received albendazole with
the control group in the first evaluation (p < 0.001) and the second evaluation (p <
0.05) after treatment (chi-square test and Wilcoxon test).
Autor:
Ecuadorian
magazine of neurology
