RESEARCH PAPER

Febrile seizure recurrence reduced by intermittent oral

levetiracetam
Lin-Yan Hu1,a, Li-Ping Zou1,a,, Jian-Min Zhong2, Lei Gao1, Jian-Bo Zhao3, Nong Xiao4, Hong Zhou5,
Meng Zhao1, Xiu-Yu Shi1, Yu-Jie Liu1, Jun Ju1, Wei-Na Zhang1, Xiao-Fan Yang1 & Patrick Kwan6,7
1
Department of Pediatrics, Chinese PLA General Hospital, Beijing 100583, China
2
Department of Neurology, Jiang-Xi Childrens Hospital, Jiangxi 330006, China
3
Department of Neurology, Beijing Childrens Hospital, Beijing 100045, China
4
Department of Neurology, Childrens Hospital of Chongqing Medical University, Chongqing 400014, China
5
The Beijing new century childrens Hospital, Beijing 100045, China
6
Departments of Medicine and Neurology, Royal Melbourne Hospital, University of Melbourne, Melbourne, Australia
7
Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong, China

Correspondence Abstract
Li-Ping Zou, Department of Pediatrics,
Chinese PLA General Hospital, Beijing Objective: Febrile seizure (FS) is the most common form of childhood sei-
100583, China. Tel: +86-10-55499016; zure disorders. FS is perhaps one of the most frequent causes of admittance
Fax: +86-10-66939770; to pediatric emergency wards worldwide. We aimed to identify a new, safe,
E-mail: zouliping21@hotmail.com and effective therapy for preventing FS recurrence. Methods: A total of 115
children with a history of two or more episodes of FS were randomly
Funding information
This study was supported by the National assigned to levetiracetam (LEV) and control (LEV/control ratio = 2:1) groups.
Natural Science Foundation of China (Nos. At the onset of fever, LEV group was orally administered with a dose of 15
30770747, 81071036, 81200463, 30 mg/kg per day twice daily for 1 week. Thereafter, the dosage was gradually
81201013) and the Beijing Municipal Natural reduced until totally discontinued in the second week. The primary efficacy
Science Foundation (Nos. 7081002 and variable was seizure frequency associated with febrile events and FS recurrence
7042024), Zhejiang Provincial Natural Science
rate (RR) during 48-week follow-up. The second outcome was the cost effec-
Foundation of China (NO. Y2100440).
tiveness of the two groups. Results: The intention-to-treat analysis showed
Received: 29 November 2013; Revised: 21 that 78 children in LEV group experienced 148 febrile episodes. Among these
December 2013; Accepted: 23 December 78 children, 11 experienced 15 FS recurrences. In control group, 37 children
2013 experienced 64 febrile episodes; among these 37 children, 19 experienced 32
FS recurrences. A significant difference was observed between two groups in
Annals of Clinical and Translational FS RR and FS recurrence/fever episode. The cost of LEV group for the pre-
Neurology 2014; 1(3): 171179 vention of FS recurrence is lower than control group. During 48-week follow-
up period, one patient in LEV group exhibited severe drowsiness. No other
doi: 10.1002/acn3.34
side effects were observed in the same patient and in other children. Interpre-
a
Co-first author. tation: Intermittent oral LEV can effectively prevent FS recurrence and reduce
wastage of medical resources.

wide.2 Considering that FS occurs in otherwise healthy

Introduction
children, an episode of generalized tonicclonic convul-
Febrile seizure (FS) is the most common form of child- sion represents an unfamiliar and terrifying event for
hood seizure disorders and accounts for 30% of seizures most parents/caregivers. Very few parents will hesitate to
in children. FS is a benign condition. Children who have dial 911 (120 in China) when witnessing a tonicclonic
or have not suffered FS before their fifth birthday have seizure. These children are typically transported by emer-
similar academic and social successes.1 Nevertheless, FS is gency medical services to the emergency department.
a traumatic experience and is a cause of panic for most Patients who have experienced FS will present more
parents. FS is also perhaps one of the most frequent emergently than febrile age-matched controls without
causes of admittance to pediatric emergency wards world- seizure.3,4 Parental anxieties are typically high, and

2014 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. 171
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and
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LEV Reduced FS Recurrences L.-Y. Hu et al.

prehospital interventions such as intravenous line place- were recruited from 31 October 2009 to 31 October 2011.
ments and supplemental oxygen can contribute to the The trial profile is summarized in Figure 1. Another
childs distress while also consuming medical resources. round of selection was performed in accordance with the
In previous years, interest has increased considerably in further assessment of their conditions. The criteria for
preventing FS and reducing its recurrence risk either by exclusion were as follows: episodes of previous seizures
continuous treatment with antiepileptic drugs (AEDs) without fever, intracranial infections or head trauma, or
such as phenobarbital and valproic acid (VPA) or with current use of AEDs. The criteria for diagnosis of com-
intermittent treatment with a drug such as diazepam. plex FS were FS duration longer than 15 min, repeated
Thus far, the evaluation of AEDs either administered con- convulsions within the same day, and focal seizure activ-
tinuously or intermittently during a febrile illness has ity or focal findings during the postictal period. Parents/
been limited to old patients. Although phenobarbital, caregivers were instructed to take a childs temperature
VPA, and primidone are considered effective in prevent- immediately when the child appears ill or feverish, such
ing the recurrence of FS when continuously adminis- as in cases of runny nose or nasal obstruction, hot flashes,
tered,5 long-term treatment with such drugs is associated sore throat, and constipation. Parents/caregivers were also
with a wide spectrum of adverse effects, including seda- instructed to administer promptly the study medication
tion, behavioral changes, gastrointestinal and hematologic when the temperature indicates a fever. Patients in the
toxicity, hypersensitivity reactions, and rare fatal hepato- LEV group received oral LEV at a dose of 1530 mg/kg
toxicity with VPA in young children. Although the inter- per day twice daily at the onset of fever (T > 37.5C) for
mittent administration of benzodiazepines (e.g., diazepam 1 week (therapy period), followed by dose tapering of
and midazolam) at the onset of fever is effective in pla- 50% every 2 days until complete withdrawal at the second
cebo-controlled trials,6 the effectiveness of this treatment week (decrement period) (Fig. 2). The parent/caregiver
is limited because sedative effects can mask the signs and was instructed to administer any other antipyretic drug to
symptoms of any evolving central nervous system infec- their child when T > 38.5C, with or without antibiotics
tion.5,7,8 Considering that the potential toxicities associ- as deemed appropriate by the attending pediatrician. The
ated with antiepileptic therapy outweigh the relatively study was approved by the Medical Ethics Committee of
minor risks associated with FS, the American Academy of the Chinese PLA General Hospital, Beijing, China. This
Pediatrics does not recommend continuous antiepileptic study was performed in accordance with the Declaration
therapy with phenobarbital or VPA and intermittent ther- of Helsinki, and written informed consent was obtained
apy with diazepam to prevent FS recurrences.5,9 If we can
explore a drug that is not only effective in preventing FS
recurrence but also safe, we can reduce the anxieties of
parents/caregivers and the unnecessary wasting of medical
resources.
Levetiracetam (LEV) is a novel AED with a unique
mechanism of action that primarily involves interactions
with the synaptic vesicle protein 2A.10,11 LEV has a favor-
able, dose-proportional pharmacokinetics in children,12,13
a relatively rapid onset of action (Cmax between 0.6 and
1.3 h), and a half-life of 68 h. In this study, we evalu-
ated the efficacy and tolerability of intermittent LEV
administration in preventing FS recurrence.

Subjects/Materials and Methods

Patients and study design

We performed a multicenter, randomized, controlled, 48-
week follow-up parallel-group outpatient study in chil- Figure 1. Trail profile: The 115 children who met the criteria for
inclusion and signed the informed assent were divided into LEV group
dren with FS from five hospitals in China. The criteria
and control group randomly by 2:1 ratio. During the 48-week follow-up
for inclusion were as follows: children with a history of period, 13 children were lost to follow-up, four were diagnosed with
two or more episodes of FS within the last 6 months, at epilepsy, five were noncompliant and discontinued their participation
least one seizure recurrence within the last 2 weeks, and in the study, and 93 achieved the treatment goal at the end of the
onset age between 3 months and 5 years. The participants follow-up period.

172 2014 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.
L.-Y. Hu et al. LEV Reduced FS Recurrences

48-week follow-up. The second variable in efficacy was

the side effects associated with the drugs. These variables
were analyzed at the end of the evaluation period, and
the LEV and control groups were compared. For tolera-
bility assessment, vital signs were assessed by multiparam-
eter patient monitoring, including conditions such as
mental state (e.g., changes in temper, lethargy), gastroin-
testinal symptoms (e.g., poor appetite, stomachache, vom-
iting), skin-related changes (e.g., rashes, pruritus), and
Figure 2. Study medication: Patient of LEV group received oral LEV
body temperature observed at home. Upon admission to
1530 mg/kg per day twice daily at the onset of fever (T > 37.5C)
for 1 week (therapy period), then followed by dose tapering of 50% the study, parents/caregivers were instructed on what and
every 2 days until complete withdrawal at the second week how to observe vital signs. The parents/caregivers were
(decrement period). assigned to assess treatment tolerability in accordance with
the designed follow-up observation table. We measured the
primary and secondary endpoints after all follow-up infor-
from a parent/caregiver of each child before trial-related mation on the patients were collected.
procedures were conducted.
Statistical analysis
Randomization and masking
All results are presented for the intention-to-treat (ITT)
The sample size was obtained by calculating with SAS 9.1 population. All available data were used. Patients who
(SAS, Cary, NC). A total of 115 patients were enrolled in discontinued the treatment early completed all end-of-
the study. Randomization was computer generated with a study assessments. Descriptive statistics were used in the
block size of 3. The randomization code was managed by analysis of all efficacy, demographic, and baseline vari-
a centralized control. The center gathered and assigned ables. Chi-square and Fishers exact test were used to ana-
the patients to the LEV and control groups in accordance lyze the constituent ratio of gender, family convulsion
with the mechanism of competitive enrollment. The history, FS type, number of patients lost to follow-up,
responder of each site informed the study coordinator diagnosed epilepsy, noncompliant cases, and temperature
once a patient who met the criteria for inclusion signed degree. Age of onset, visiting age, course of disease, and
the informed assent. Thereafter, the study coordinator FS frequency before admittance to the study showed a
opened the envelope corresponding to the order of the skewed distribution, which was described with the median
individual. The group wherein the patient was assigned (Q1Q3). The Wilcoxon rank-sum test was applied to
was indicated inside the envelope. compare the differences in these indexes between the LEV
and control groups. Logistic regression analysis was per-
formed to analyze seizure frequency associated with fever
Procedures
episodes and FS RR in the LEV and control groups. The
In accordance with the protocols, birth and development odds ratio (OR) for FS recurrence relative to LEV with a
history, FS and seizure family history, liver and kidney 95% confidence interval (CI) was estimated. All statistical
function, neuroimaging (computer tomography [CT] or analyses were conducted by using SPSS 13.0 (SPSS Inc.,
MRI), and electroencephalogram (EEG) (regular EEG or Chicago, IL), and P < 0.05 was considered statistically
V-EEG) were taken. Pediatric neurology examination was significant. This study was registered as an International
performed outside an FS attack for all patients. Parents/ Standard Randomized Controlled Trial (No. ChiCTR-
caregivers were fully informed about the nature and man- OCC-11001874). The formula for calculating the cost sav-
agement of FS. Follow-up observation tables were also ing of LEV for the prevention of FS recurrence was
distributed to the parents/caregivers for the recording of described as follows:
febrile and seizure events, temperature peaks, and adverse
X
n
effects after medication at home. Parents/caregivers were f1 10:14%  F  f2 50%  F;
contacted by telephone every 12 weeks to reinforce the i1
study program. At each episode of febrile illness, parents/
caregivers called the study site staff and provided all the where i is the FS frequency of one patient in 1 year, f1 is
necessary information about recurrence. The primary var- the one-time fee of LEV for the prevention of FS recur-
iable in efficacy was seizure frequency associated with rence, f2 is the one-time fee for the prevention of FS
febrile events and FS recurrence rate (RR) during the recurrence in the control group (considering that no

2014 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. 173
LEV Reduced FS Recurrences L.-Y. Hu et al.

special medicine was used in the control group; thus, f2 and 75.68% (28 of 37) were patients with simple FS.
was hypothesized as zero), and F is the medical costs Tables 1, 2 summarize the demographics and characteris-
produced after the failed prevention (direct medical tics of the sample.
costs = transport expenses of ambulance + outpatient or No significant differences were found in visiting age,
inpatient expenses; indirect medical costs = charge for disease cause, gender constitution (male/female), FS type
loss of working time). (simple/complex), and patients with family convulsion
history between the two groups (P > 0.05). However, a
significant difference was found between the LEV and
Results
control groups (P < 0.05) in terms of FS onset age and
Random sampling resulted in a sample size of 115 chil- FS frequency before enrollment. Hence, the FS onset age
dren (89 males and 29 females). From this sample, 78 and FS frequency before enrollment were considered con-
children (61 males and 17 females) received oral LEV founding factors for efficacy assessment.
(1530 mg/kg per day twice daily), whereas 37 children EEG was performed on all children. No abnormal find-
(25 males and 12 females) did not receive LEV in the pri- ings were found among the 86 children who underwent
mary analysis. The ranges of FS onset age, FS course, and regular EEG. However, 21 abnormal findings were
visiting age in the LEV group were 355, 189, and 9 recorded from the 29 children who underwent V-EEG or
94 months, respectively. The medians (Q1Q3) were 16 active-EEG. The characteristics of abnormal EEG were
(1122.75), 15 (927.5), and 33.5 (2448.75), respectively. summarized as bilateral leads paroxysmal or sporadic
The range of FS frequency before enrollment was 215 spikes and waves, slow waves, sharp waves, spike waves,
times. The median (Q1Q3) was 4 (35.75). Among the or sharp waves during sleep. Eight children had abnormal
sample, 38.46% (30 of 78) had a family history of seizure birth histories, and two children had mild mental or
disorder, 17.95% (14 of 78) were patients with complex motor retardation. Among the 100 children who under-
FS, and 82.05% (64 of 78) were patients with simple FS. went cranium imaging, 32 consented to MRI; a total of
In the control group, the ranges of FS onset age, FS six abnormal findings were observed. Among the 68 chil-
course, and visiting age were 659, 0.543, and 12 dren who underwent CT, one abnormal finding was
79 months, respectively. The medians (Q1Q3) were 22 observed. Table 3 presents the essential information.
(1330), 12 (619), and 36 (2545), respectively. The Thirteen children (11.3%) (11 in the LEV group and
range of FS frequency before enrollment was 212 times. two in the control group) were lost to follow-up. More-
The median (Q1Q3) was 3 (25). Among the sample, over, four children (3.5%) (three in the LEV group and
21.62% (eight of 37) had a family history of seizure disor- one in the control group) discontinued their participation
der, 24.32% (nine of 37) were patients with complex FS, in the study because of diagnosed epilepsy, and five

Table 1. Demographics and characteristics of the enrolled children.

Variable LEV group (N = 78) Control group (N = 37) Values P value (two-sided)

Male/female 61/17 25/12 1.5061 0.2542

Onset age, months
Range 355 659
M (Q1Q3) 16 (1122.75) 22 (1330) 2.6793 0.0074
Visiting age, months
Range 994 1279
M (Q1Q3) 33.5 (2448.75) 36 (2545) 0.3273 0.7444
Course of disease, months
Range 189 0.543
M (Q1Q3) 15 (927.5) 12 (619) 1.8533 0.0644
FS frequency before enrollment
Range 215 212
M (Q1Q3) 4 (35.75) 3 (25) 2.0293 0.0424
Family convulsion history 30 8 3.2171 0.0912
The type of seizures
Complicated/simple 14/64 9/28 0.6381 0.4602

v value.
1 2

2
Fisher exact test.
3
Z value.
4
Wilcoxon rank-sums test.

174 2014 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.
L.-Y. Hu et al. LEV Reduced FS Recurrences

Table 2. The distribution of simple FS and complex FS. Table 4. The comparison of constituent ratio of discontinued
patients.
The number of patients
Discontinued LEV group Control group P value1
The type of FS LEV group Control group
reasons (N = 78) (N = 37) v2 (two-sided)
Simple FS 64 28
Lost/not lost 11/67 2/35 1.893 0.218
Complex FS 14 9
Epilepsy/nonepilepsy 3/64 1/34 0.160 1.000
Prolonged duration (>15 min) 5 1
Noncompliance 4/60 1/33 0.502 0.656
Recurrent seizures within 6 8
the same febrile illness 1
Fisher exact test.
over a 24-h period
Focal onset 3 0

Table 5. The comparison of constituent ratio of fever episodes during

follow-up.
Table 3. Essential information of the enrolled children.
Temperature LEV Control P value1
No. of peak (C) group (N) group (N) v2 (two-sided)
Investigations children Abnormal findings
40 1 3 6.791 0.064
EEG 115 3939.9 46 24
Regular EEG 86 No 3838.9 91 30
V-EEG 29 21 3737.9 10 7
Bilateral leads paroxysmal or
sporadic spike and waves, 1
Fisher exact test.
slow waves, sharp and waves,
spike waves, or sharp waves
during sleep During the 48-week follow-up, ITT analysis showed
Cranium 100
148 and 64 fever episodes in the LEV and control groups,
imaging
MRI 32 6
respectively. The highest body temperatures were divided
Cornu posterius ventriculi into four degrees: 40, 3939.9, 3838.9, and 3737.9C.
lateralis lamellar long T2 signal No significant difference was found between the two
with dilated lateral cerebral ventricle groups in the constituent ratio of the maximum tempera-
Bilateral cerebral periventricle ture (P = 0.064) (Table 5).
long T2 signal In the LEV group, 78 children experienced 148 febrile
Bilateral temporal lobe multiple
episodes. Among these 78 children, 11 experienced 15 FS
punctiform long T2 signal
Right hippocampus long T2 signal
recurrences. In the control group, 37 children experienced
Right postoccipital neuroepithelial cyst 64 febrile episodes. Among these 37 children, 19 experi-
Left temporal pole arachnoid cyst enced 32 FS recurrences during the 48-week follow-up, as
CT 68 1 indicated by the ITT analysis. The FS onset age and FS
Cyst of pellucid septal cave frequency before enrollment were divided into two strati-
Liver function 115 No fications. The ranges in the first and second stratifications
Birth history 115 8
of the FS onset age were <18 and 18 months, respec-
Low birth weight (SGA) 3
Premature infant associated 5
tively. Before enrollment, the FS frequency had a range
with low birth weight 24 times in the first stratification. The second stratifica-
Developmental 115 2 tion exhibited a range 515 times. The FS RR was 14.10%
history Mild mental retardation IQ = 71 1 (11 of 78) in the LEV group and 51.35% (19 of 37) in
Mild motor development retardation 1 the control group (P < 0.001) (Fig. 3). The OR of FS RR
with LEV treatment was 0.089, and the 95% CI was
0.0290.268. The FS recurrence/fever episode was 10.14%
(15 of 148) in the LEV group and 50.00% (32 of 64) in
children (4.3%) (four in the LEV group and one in the the control group (P < 0.001) (Fig. 4). The RR of FS
control group) were noncompliant. No significant differ- recurrence/fever episode with LEV treatment was 0.113,
ence was found between the LEV and control groups in and the 95% CI was 0.0550.233 (Tables 6, 7).
the constituent ratio (P > 0.05). This proportion of chil- We calculated the cost saving of LEV for the preven-
dren did not affect the constituent ratio of the two tion of FS recurrence in a child weighing 20 kg with FS.
groups (Table 4). When presenting with fever, the one-time fee of LEV for

2014 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. 175
LEV Reduced FS Recurrences L.-Y. Hu et al.

Discussion
FS is a convulsion associated with a significant rise in
body temperature and pediatric emergency. However, an
optimal strategy for preventing FS has not been estab-
lished because the potential toxicities associated with an-
tiepileptic therapy outweigh the relatively minor risks
associated with FS. The patients who enrolled in the trial
had at least two recent occurrences of FS, thus indicating
that the patients have a high possibility for FS recurrence,
which may cause accidental injuries and induce typically
high panic among parents. Nevertheless, prophylactic
therapy for FS recurrence should provide improved sei-
zure protection but not at the expense of added toxicity
and adverse effects. LEV has demonstrated good tolerabil-
Figure 3. The FS recurrence rate in the LEV group and control group. ity and efficacy against seizures as adjunctive therapy or
The FS recurrence rate was 14.1% (11/78) in the LEV group and
monotherapy in children, including children aged
51.4% (19/37) in the control group (P < 0.001).
1 month to <4 years.1418 In this study, we found that
intermittent oral LEV can effectively prevent FS recur-
rence. With regard to safety, just one patient experienced
drowsiness after taking LEV once. Nevertheless, we cannot
tell whether the symptom was caused by the medicine or
was merely one of the signs of fever because no side
effects had previously occurred in this patient. Further-
more, no other adverse effects occurred in the other
patients. Post hoc, intermittent LEV therapy was safe for
FS patients at the same time.
The rationale behind the 2-week study design and
the drug treatment is described as follows. Early and
regular treatments for FS recurrence are consistently
emphasized. However, 21% of the children experienced
seizures prior to or within 1 h of the onset of fever,
57% had a seizure after 124 h of fever, and 22%
experienced FS more than 24 h after the onset of
Figure 4. The FS recurrence or free frequency/fever episode in the
fever.19 The fever of a child is not always recognized
LEV group and control group. The FS recurrence/fever episode was
10.14% (15/148) in the LEV group and 50.0% (32/64) in the control
on time; this situation is one of the drawbacks of
group (P < 0.001). intermittent prophylaxis.20 FS is mostly caused by a
variety of common infectious diseases. Acute upper
respiratory tract infection or other viral illnesses, signs,
the prevention of FS recurrence (f1) was 90 RMB; the and symptoms often last for 714 days, and the fever
dosage is 25 mg/kg and the outpatient and inpatient usually lasts 34 days.2123 Given that the onset of
medical costs after failed prevention (F) were 998 and symptoms typically occurs 13 days after viral or bacte-
5780 RMB on average, respectively, according to the for- rial infection,23,24 we designed an LEV therapy period
mula described previously. LEV can save 308 RMB in the for 1 week when a child appeared ill or feverish (pre-
outpatient department and 2339 RMB in the inpatient senting runny nose or nasal obstruction, hot flashes,
department on average (Table 8). sore throat, and constipation). Parents/caregivers imme-
On the basis of the complaints of the parents/caregivers diately took the childs temperature and administered
of children who took the study medication during the the study medication promptly when febrile tempera-
course of fever, only one child experienced severe drowsi- ture was reached. The common mechanism of all AEDs
ness after taking LEV once. Aside from this case, no other is to inhibit paradoxical discharge from brain cells.
side effects were observed in the other children. Of the Thus, unexpectedly stopping the medication may cause
five noncompliant children, no one missed the dosage the abrupt removal of the inhibition of brain cells, thus
because of the side effects. making patients uncomfortable. Moreover, the V-EEG

176 2014 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.
L.-Y. Hu et al. LEV Reduced FS Recurrences

Table 6. Logistic regression analysis of FS recurrent rate between LEV group and control group.

The number of patients

Onset age FS frequency Patients with Patients without

(months) before enrolled Group FS recurrence FS recurrence v2 OR (95% CI) P value (two-sided)

<18 24 LEV 4 17 18.397 0.089 (0.0290.268) <0.001

Control 5 2
515 LEV 6 15
Control 4 2
18 24 LEV 0 25
Control 8 10
515 LEV 1 10
Control 2 4

OR, odds ratio; CI, confidence interval.

Table 7. Logistic regression analysis of FS frequency/febrile episode between LEV group and control group.

Fever episodes

Onset age FS frequency FS-free P value

(months) before enrolled Group FS frequency frequency v2 OR (95% CI) (two-sided)

<18 24 LEV 6 35 34.840 0.113 (0.0550.233) <0.001

Control 11 9
515 LEV 7 53
Control 5 3
18 24 LEV 0 27
Control 11 13
515 LEV 2 18
Control 5 7

OR, odds ratio; CI, confidence interval.

Table 8. All kinds of medical costs and cost saving of LEV for prevention of FS recurrence one time in different center.

Jiang-Xi Beijing Chonging The Beijing New

Chinese PLA Childrens Childrens Childrens Century
All kinds of medical costs General Hospital Hospital Hospital Hospital Childrens Hospital Average

Direct medical costs (RMB)

Transportation expenses 150 120 150 120 150 138
of ambulance
Expenses of outpatient 500 400 500 400 800 520
Expenses of inpatient 5000 3000 5000 3000 8000 4800
Indirect medical costs (RMB)
Charge for loss of working time
Outpatient 400 200 400 200 500 340
Inpatient 1000 600 1000 800 1500 998
Fee of LEV for prevention of FS 90 90 90 90 90 90
recurrence one time (RMB)
Cost saving of LEV for prevention
of FS recurrence one time (RMB)
Outpatient 329 197 329 197 488 308
Inpatient 2401 1483 2401 1563 3847 2339

2014 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. 177
LEV Reduced FS Recurrences L.-Y. Hu et al.

of some patients presented bilateral leads paroxysmal or authors in relation to the submission. The corresponding
sporadic slow waves, as well as sharp waves, spike author had full access to all the data in the study and had
waves, or sharp waves during sleep. Unexpectedly stop- final responsibility for the decision to submit for publica-
ping the medication may adversely affect electrocerebral tion. Li-Ping Zou initiated the research program and super-
activity. To prevent the adverse effect caused by the vised the project. Lin-Yan Hu, Li-Ping Zou, and Patrick
sudden removal of LEV administration, the 1-week Kwan wrote the manuscript. Lin-Yan Hu, Lei Gao, Jian-
therapy was followed by a slow decrement period. A 1- Min Zhong, Jian-Bo Zhao, Nong Xiao, Hong Zhou, Xiu-
week therapy period plus a 1-week decrement period is Yu Shi, Yu-Yie Liu, Jun Ju, Wei-Na Zhang, Xiao-Fan Yang,
inconvenient for patients because the duration is long and Li-Ping Zou participated in recruitment of patients
and noncompliance may be possible. Given that FS and data collection. Meng Zhao participated in statistical
appears to occur consistently in the first 3 days, a com- analysis. Patrick Kwan has received speakers honoraria
parison of the effects during a short medication period from GlaxoSmithKline and UCB Pharma, and has served
may be performed in the future. on scientific advisory boards for GlaxoSmithKline and
The range of LEV dosage was set at 1530 mg/kg per day Eisai. Other coauthors report no disclosures.
taken twice daily. This range was large enough to be
divided into high-dose and low-dose LEV groups. How- References
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Conflict of Interest 11. Lynch BA, Lambeng N, Nocka K, et al. The synaptic
vesicle protein SV2A is the binding site for the
Foundation sponsors of the study had no role in study
antiepileptic drug levetiracetam. Proc Natl Acad Sci USA
design, data collection, data analysis, data interpretation, or
2004;101:98619866.
writing of report. There is no conflict of interest of any

178 2014 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.
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2014 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. 179