TREATMENT OF EOSINOPHILIC MENINGITIS WITH A COMBINATION OF
PREDNISOLONE AND MEBENDAZOLE
VERAJIT CHOTMONGKOL,* KOOKWAN SAWADPANITCH, KITTISAK SAWANYAWISUTH,
SITICHOKE LOUHAWILAI,
AND
PANITA LIMPAWATTANA
Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
Abstract.
To study the efficacy of the combination of prednisolone and mebendazole for the treatment of eosino-
philic meningitis, we conducted a pilot study among Thai patients with eosinophilic meningitis. Patients were given a
two-week course of prednisolone, 60 mg/day, and mebendazole, 10 mg/kg/day. The primary observation parameter was
the number of patients who still had headaches after the two-week course of treatment. Forty-one patients were enrolled
in the study. Four (10%) patients still had headaches after the two-week course of treatment and the median length of
time until complete disappearance of headaches was three days. Serious side effects were not detected. Treatment for
two weeks with the combination regimen of prednisolone and mebendazole is safe and beneficial in relieving headaches
in patients with eosinophilic meningitis.
INTRODUCTION
Worldwide, the commonest cause of eosinophilic meningi-
tis is the rat lung worm Angiostrongylus cantonensis. Acute to
subacute severe headaches with nonfocal neurologic findings,
with the exception of occasional involvement of a cranial
nerve, are the most common symptoms.
1
There is no specific
treatment for this infection. Symptomatic treatment is indi-
cated for symptoms such as headache, nausea, and vomiting.
A two-week course of prednisolone, 60 mg/day, was shown to
be beneficial in relieving headache.
2
Repeat lumbar puncture
is performed in patients with increased intracranial pressure.
A trial of specific treatment is still inconclusive. Thiabenda-
zole, mebendazole, and albendazole have some effect in ani-
mal infections.
3?5
Thiabendazole was ineffective in treatment
of human angiostrongyliasis.
6
Albendazole or the combina-
tion of prednisolone and albendazole have been used clini-
cally with good results.
7,8
Treatment with the combination of
mebendazole and dexamethasone appeared to shorten the
course of infection, but details of the trial were not demon-
strated.
9
To our knowledge, this is the first report of the out-
come of the treatment of eosinophilic meningitis with the
combination of prednisolone and mebendazole.
MATERIALS AND METHODS
Study population. Adult patients (
15 years of age) who
had eosinophilic meningitis and who came to Srinagarind
Hospital, Muncha Khiri Hospital, and Nampong Hospital
(Khon Kaen, Thailand) were studied. The diagnosis of eosin-
ophilic meningitis was based on findings of
10% eosino-
phils in the cerebrospinal fluid (CSF), with negative results
for Gram, acid-fast bacilli, and India ink staining, cryptococ-
cal antigen testing, and culture. Patients were excluded if they
had undergone a previous lumbar puncture or if they were
pregnant or nursing, or had concomitant conditions such as
serious infections.
The severity of headache was classified by using a visual
analog scale: 0
no pain; 1?3, mild pain; 4?7, moderate pain;
and 8?10, severe pain (with 10 indicating the worst pain imag-
inable). A CSF opening pressure
300 mm of H
2
O after the
patient was fully relaxed was defined as high CSF pressure.
The study protocol was reviewed and approved by the in-
stitutional review board and the ethics committee of Khon
Kaen University.
Treatment. Subjects gave written informed consent before
beginning the study and were given prednisolone, 60 mg/day
orally in three divided doses, and mebendazole, 10 mg/kg/day
orally in two divided doses, after meals for two weeks.
Studies to monitor efficacy and toxicity. Before treatment,
the following studies were performed: complete blood count;
measurements of blood glucose, electrolytes, serum blood
urea nitrogen, and creatinine; and liver function tests. CSF
samples were obtained for India ink, Gram, and Ziehl-
Neelsen staining; culture for bacteria; determination of open-
ing pressure; total and differential blood cell counts; glucose
and protein levels; and cryptococcal and bacterial antigen
tests. Chest radiographs was also obtained.
During treatment, two tablets of acetaminophen (500 mg
each) were given to relieve headache every 4?6 hours if the
headache persisted or recurred. Repeat lumbar puncture was
done for patients with severe headaches that was not relieved
by acetaminophen.
Evaluation. After a baseline evaluation, patients were
evaluated at the end of treatment and every two weeks until
they completely recovered. At each visit, a physical examina-
tion was done and any adverse events were assessed and re-
corded. During treatment and until the headache completely
disappeared, the frequency of acetaminophen use and repeat
lumbar puncture was also recorded. Compliance was checked
by the pill-count method.
The day of complete recovery was defined as the first day
that the patient thought the headache had disappeared and
had taken no acetaminophen nor undergone lumbar punc-
ture, if the headache did not recur within one month. For the
patients who had post-lumbar headaches, the day of complete
recovery was defined as the first day that the patient thought
the headache had disappeared while the patient was supine
and had taken no acetaminophen.
The primary observation parameter in this study was the
number of patients who still had headaches after the two-
week course of treatment. The secondary parameter was the
length of time until the complete disappearance of headache.
Information obtained from the subjects and laboratories were
* Address correspondence to Verajit Chotmongkol, Department of
Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen,
Thailand. E-mail: chotmongkolverajit@yahoo.com
Am. J. Trop. Med. Hyg., 74(6), 2006, pp. 1122?1124
Copyright © 2006 by The American Society of Tropical Medicine and Hygiene
1122
recorded on case-record forms. Data was analyzed by descrip-
tive statistics.
RESULTS
Study population. From October 2002 through November
2004, 45 patients were enrolled in the study. Four patients
were excluded from the study because they were lost to fol-
low-up and the clinical data were incomplete. Therefore, 41
patients were studied. The clinical and laboratory features of
the patients are shown in Tables 1 and 2. Before illness de-
veloped, 36 had eaten raw pila snails, and 5 had eaten raw
freshwater shrimp.
Outcome. Thirty-four patients reported complete disap-
pearance of headaches 7 days after treatment, 37 at 8?14 days
after treatment, and 41 at 15?21 days after treatment. The
details of clinical outcomes are shown in Table 3. No gastro-
intestinal bleeding, hyperglycemia, or altered mental status
was seen, and there were no cases of recurrent meningitis.
DISCUSSION
In humans, infection by A. cantonensis is caused by eating
third-stage larvae in raw or inadequately cooked interme-
diate hosts, such as snails and slugs, or transport hosts such
as freshwater prawns, frogs, and the yellow tree monitor.
When third-stage larvae are ingested, they penetrate the
blood vessels of the intestinal tract and are carried to the
meninges, where they usually die. A presumptive diagnosis
may be made for patients who have symptoms of meningitis
with CSF eosinophilia and a history of consumption of raw
snails.
A number of serologic tests have been used to support
the diagnosis of angiostrongyliasis. We found that a specific
29-kD antigen from young adult female worms may serve
as a reliable marker for the diagnosis of human angio-
strongyliasis.
10
In our patients, immunoblot analysis for de-
tecting the 29-kD antigen showed low positive results. How-
ever, A. cantonensis was most likely the causative agent of
eosinophilic meningitis because most patients had a history
of ingestion of raw snails or raw freshwater shrimp before
this illness and had clinical manifestations that were simi-
lar to those in the patients described by Punyagupta and
others.
1
Although headache is not fatal, it is a distressing symptom
that interferes with the personal and professional lives of pa-
tients. Supportive treatment, such as analgesic drugs and re-
peat lumbar puncture are recommended. Punyagupta and
others reported that after 14 days of treatment with analgesics
alone, approximately 60% of 284 patients who had eosino-
philic meningitis probably caused by A. cantonensis still had
headaches.
1
A recent study demonstrated that a two-week
course of prednisolone was beneficial in relieving headache,
shortened the median time until resolution of headache, and
reduced the need for repeat lumbar puncture. The number of
patients who still had headaches after 14 days of treatment
was 9.1% and the median length of time until complete dis-
appearance of headache was 5 days.
2
The role of antihelmintic agents is still inconclusive. Me-
bendazole was effective in the treatment of infection with A.
cantonensis in mice and rats.
4
Theoretically, the neurologic
symptoms should be exacerbated as a result of the death lar-
vae. However, the combination of mebendazole and dexa-
methasone was used clinically without serious side effects.
9
In
our study, we demonstrated good results with a combination
of mebendazole and prednisolone. In addition, no harmful
effects of treatment were demonstrated. The results of our
previous study of the treatment of this disease with a combi-
nation of albendazole and prednisolone showed that 11.5% of
the patients still had headaches after 14 days of treatment
with a median time of four days until complete disappearance
of headaches.
8
In summary, treatment for two weeks with a combination
of mebendazole and prednisolone is safe and effective for the
treatment of eosinophilic meningitis. Further study is neces-
sary to prove the efficacy of this regimen compared with pred-
nisolone alone and a combination of albendazole and pred-
nisolone.
T
ABLE
1
Initial clinical features of the study patients*
Feature
N
41
Age, years, mean ± SD (range)
37.3 ± 11.90 (18?67)
Sex, male (%)
31 (75.6)
Incubation, day, median (range)
30 (1?365)
Signs or symptoms
Headache
Duration, day, median (range)
7 (1?30)
Degree
Mild
1
Moderate
7
Severe
33
Vomiting
12
Stiff neck
12
Fever (temperature
38°C)
0
CNP
0
* CNP
cranial nerve palsy.
T
ABLE
2
Initial laboratory features of the study patients*
Feature
N
41
Blood eosinophilia (
700 cells/mm
3
)
31
Positive serologic result for antibody against
the 29-kD specific antigen of Angiostrongylus
cantonensis on immunoblotting?
2
CSF abnormalities
High opening pressure (
300 mm H
2
O)?
4
WBC/mm
3
, median (range)
850 (12?3,520)
Eosinophilia, %, median (range)
57 (12?84)
Protein content, mg/dL, median (range)
71 (17?320)
Glucose ratio, CSF: blood, %, median (range)
53 (27?100)
* CSF
cerebrospinal fluid; WBC
white blood cells.
? N
10 patients.
? N
17 patients.
T
ABLE
3
Clinical variables of study patients
Variable
N
41
Headache after 14 days of treatment, no. (%)
of patients
4 (9.75)
Time until complete disappearance of headache,
day, median (range)
3 (1?20)
Repeat lumbar puncture, no. (%) of patients
4 (9.75)
Frequency of acetaminophen use in patients who
had complete disappearance of headache within
14 days of treatment, median no. of times
5
TREATMENT OF EOSINOPHILIC MENINGITIS
1123
Received March 30, 2005. Accepted for publication August 23, 2005.
Authors? address: Verajit Chotmongkol, Kookwan Sawadpanitch,
Kittisak Sawanyawisuth, Sitichoke Louhawilai, and Panita Limpa-
wattana, Department of Medicine, Faculty of Medicine, Khon Kaen
University, Khon Kaen, Thailand, E-mail: chotmongkolverajit@
yahoo.com.
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CHOTMONGKOL AND OTHERS
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