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Recurrence of Simple Febrile Seizure who follows Intermittent Prophylaxis: A

Comparative Study Between Clobazam and Diazepam

Article · July 2019

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 © 2019 Sufian A et al. This is an open access article distributed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0
Unported License (http://creativecommons.org/licenses/by-nc-sa/3.0/). ISSN 2518-6299 (print), 2520-5048 (online)

Original Article
Recurrence of Simple Febrile Seizure who follows
Intermittent Prophylaxis: A Comparative Study Between
Clobazam and Diazepam
Sufian A1, Ghosh UK2, Ahmed ATMF3, Hossain A4, Islam T5, Sultana A6
Abstract:
Background: Febrile seizures are common among children, with a prevalence of 2–5% aged less than 5 years.
The recurrence rate of febrile seizures 30–50%. Intermittent or continuous prophylaxis by using anticonvulsant
along with antipyretics have been prescribed rationally to prevent recurrence. Objective: To compare the
recurrence rate of simple febrile seizure who follows intermittent prophylaxis; between clobazam & diazepam
and adverse effects of each drug therapy. Methods: This prospective comparative observational study done in
children with aged 6–60 months with one or more than one episodes of simple febrile seizure. Children with
simple febrile seizure diagnosed after hospitalization were included in this study after exclusion of intracranial
infection, epilepsy and other causes of seizures. During discharge of that simple febrile seizure cases; intermittent
prophylaxis given rationally and proper counselling done. Among them 30 cases were given clobazam and 30
cases were given diazepam as both drugs can be used in prophylaxis. Clobazam 1 mg/kg/day once daily orally
and diazepam 0.5 mg/kg/day eight hourly orally for 3 days along with antipyretics were given. The children were
visited every 3 months for 6 months. Episodes of fever, recurrence of seizures and adverse effect of therapy noted.
Results: Seventeen (56.7%) male and 13 (43.3%) female, with mean age of 25.7±13.6 months, with mean weight
12.8±3.5 kilograms were in clobazam group. Fourteen (46.7%) male and 16 (53.3%) female, with mean age of
21.3±13.8 months, with mean weight 11.1±2.9 kilograms were in diazepam group. Since first attack of simple
febrile seizure; 115 episodes of fever occurred which included 55 (47.8%) episodes in the clobazam group and
60 (52.2%) episodes in the diazepam group. Eleven (36.7%), 9 (30.0%), 9 (30.0%) in the diazepam group and 4
(13.3%), 2 (6.7%), 1 (3.3%) cases in the clobazam group developed sedation, drowsiness and incoordination
respectively (P <0.05). Recurrence of seizures occurred in 10 (33.3%) cases in the clobazam group and in 3
(10%) cases in the diazepam group. (P = 0.029). Conclusions: Recurrence of simple febrile seizure who follows
intermittent prophylax is more in clobazam group but adverse effect like sedation, drowsiness & incoordination
more seen in diazepam group.

Key words: Febrile Convulsion, Intermittent Prophylaxis, Recurrence, Adverse effect, Clobazam, Diazepam

Received: July 10, 2019; Accepted: July 22, 2019

Introduction: More than one half of recurrences are experienced

Febrile seizures are common among children, with a during the first year and over 90% developed within
prevalence of 2–5%, aged less than 5 years. Mostly two years, following the first attack, with the higher
3 months to 5 years of age with peak age of febrile risk within the first 6 to 12 months. The likelihood
seizure of 14–18 months1,2,3. for recurrence is greater among infants who
convulse at temperatures below 40°C2.
It accounts 25% of childhood status epilepticus4.
Febrile seizures frequently recur, with a recurrence The risk of recurrence is about 30% for simple
rate of 50%, when the first attack occurs before one febrile seizure6. Treatment of febrile seizures
year of age. In general, one third of infants will consisting of controlling the convulsion by
develop a second attack following subsequent anticonvulsant, reduction of the body temperature
febrile illness; half of the latter group will by sponging and using paracetamol, treatment of the
experience a third febrile seizure as well5,6. Febrile acute infection responsible for the fever and
seizures recurs 3 or more times in 10% of cases4. prophylaxis to prevent recurrence2.

1
Dr. Abu Sufian, Assistant Professor, Dept. of Paediatrics, Eastern Medical College & Hospital, Cumilla, Bangladesh.
2
Dr. Uzzal Kumar Ghosh, Registrar, Dept. of Paediatrics, Dr. M R Khan Shishu Hospital & ICH, Mirpur-2, Dhaka, Bangladesh.
3
Dr. A T M Faruq Ahmed, Assistant Professor, Dept. of Paediatrics, Eastern Medical College & Hospital, Cumilla, Bangladesh.
4
Dr. Abir Hossain, Assistant Professor, Dept. of Paediatrics, Eastern Medical College & Hospital, Cumilla, Bangladesh.
5
Dr. Tithi Islam, Consultant Paediatrics, 250 bed Zilla Hospital, Manikgonj, Bangladesh.
6
Dr. Azmeri Sultana, Associate Professor, Dept. of Paediatrics, Dr. M R Khan Shishu Hospital & ICH, Mirpur-2, Dhaka, Bangladesh.

Address of Correspondence: Dr. Abu Sufian, Assistant Professor, Dept. of Paediatrics, Eastern Medical College & Hospital, Cumilla,
Bangladesh. Mobile: +8801718762595, Email: [email protected]

EMCJ. July 2019: 4 (2) (13)

Sufian A et al. Eastern Medical College Journal

The recurrence rate of 30–50% and family anxiety Results:

rationalize the prophylaxis6. Benzodiazepine agents Seventeen (56.7%) male and 13 (43.3%) female,
through oral, rectal route can be administered as with mean age of 25.7±13.6 months, with mean
intermittent prophylaxis7-9. Diazepam is the most weight 12.8±3.5 kilograms in clobazam group.
common agent used for this purpose but it has side Fourteen (46.7%) male and 16 (53.3%) female, with
effects such as drowsiness, ataxia and sedation8, 9. mean age of 21.3±13.8 months, with mean weight
11.1±2.9 kilograms in diazepam group. Since first
Clobazam is the first and only1,5 benzodiazepine in attack of simple febrile seizure; 115 episodes off
the management of seizures. It is used as effective ever occurred which included 55 (47.8%) episodes
antiepileptic agent in adults and children6, 7. in the clobazam group, 60 (52.2%) episodes in the
diazepam group (Table-I & II).
The side effects of clobazam are similar to other
benzodiazepines, but with lower severity3. In this Table-I: Age and weight distribution of the study
study, the authors compared the recurrence of population
simple febrile seizure who follows intermittent
prophylaxis and adverse effects of drugs between Group A Group B
P
Variable (n=30) (n=30)
clobazam and diazepam. value
Mean±SD Mean±SD
Materials & Methods: Age 21.3±
25.7±13.6 0.219ns
This prospective comparative observational study (months) 13.8
was conducted in children aged 6–60 months with Weight
12.8±3.5 11.1±2.9 0.054ns
one or more than one episodes of simple febrile (kg)
seizures. Study was done in Eastern medical ns= not significant
p value reached from unpaired t-test
College, Cumilla and Dr. M R Khan Shishu Hospital
& ICH, Mirpur 2, Dhaka from January 2019 to June
Table-II: Sex distribution and episode of fever in
2019.
the study population
Children with simple febrile seizure diagnosed after Group A Group B
hospitalization were included in this study. Presence P value
Variable (n=30) (n=30)
of neurological problems, progressive neurological n % n %
diseases, complex febrile seizures, other Male 17 56.7 14 46.7
symptomatic seizures, meningitis, encephalitis and Sex 0.303ns
Female 13 43.3 16 53.3
simple febrile seizure with abnormal Episode of fever 55 47.8 60 52.2 0.303ns
electroencephalogram findings were excluded. ns= not significant
During discharge of those simple febrile seizure p value reached from chi square test
cases, intermittent prophylaxis given rationally and
proper counselling done. Among them 35 cases Eleven (36.7%), 9 (30.0%), 9 (30.0%) in the
were given clobazam, 35 cases were given diazepam diazepam group and 4 (13.3%), 2 (6.7%), 1 (3.3%)
as both drugs can be used in prophylaxis. Clobazam cases in the clobazam group developed sedation,
1 mg/kg/day once daily orally and diazepam 0.5 drowsiness and incoordination respectively (P
mg/kg/day eight hourly orally for 3 days along with value<0.05%) (Table-III).
antipyretics were given.
Table-III: Side effects of drugs between the study
The children were visited every 3 months for 6 populations
months. Five cases in every group were lost of
follow up, but maximum cases followed intermittent Group A Group B
prophylaxis very cautiously with follow up Side effects (n=30) (n=30) P value
schedule. Outcome variables were occurrence of n % n %
febrile seizures and adverse effects of the drugs. On Nausea & vomiting 0 0.0 1 3.3 0.500ns
each visit, the frequency of febrile illness, Ataxia 2 6.7 7 23.3 0.073ns
recurrence of seizure and adverse effects of the Sedation 4 13.3 11 36.7 0.036s
therapy were evaluated. Data were collected by Drowsiness 2 6.7 9 30.0 0.021s
seeing previous discharge certificate, details history, Incoordination 1 3.3 9 30.0 0.006s
through examination and plotted in a preform data Insomnia 2 6.7 4 13.3 0.335ns
sheet. Finally total 60 cases, where 30 in clobazam Anorexia 0 0.0 2 6.7 0.246ns
(Group A) group and 30 in diazepam (Group B) Headache 0 0.0 2 6.7 0.246ns
group were found. Data were analyzed using chi- Abdominal pain 0 0.0 4 13.3 0.056ns
square and unpaired t-test with significance level s= significant, ns= not significant
<0.05. p value reached from chi square test

EMCJ. July 2019: 4 (2) (14)

Sufian A et al. Eastern Medical College Journal

Ten patients (33.3%) in the clobazam group and 3 placebo controlled trial and reported 1.7%
patients (10%) in the diazepam group developed recurrence of seizure in the clobazam group vs
febrile convulsions in their febrile episodes. 12.5% in the placebo group (P=0.01)7.
(P=0.029) (Table-IV).
A randomized controlled trial among 75 children
Table-IV: Recurrence of seizure of the study compared efficacy of oral clobazam with oral
population diazepam for prophylaxis of febrile seizures. The
odds ratio of seizure recurrence was 2.3 in the
Group A Group B diazepam group as compared to clobazam group12.
Recurrence of
(n=30) (n=30) P value Recurrence of seizures occurred in 1.7% subjects in
seizure
n % n % the clobazam group, and in 3.1% cases in the
Yes 10 33.3 3 10.0 diazepam group (P value=0.474)14,18.
0.029s
No 20 66.7 27 90.0
s= significant Oral diazepam and clobazam are equally effective
p value reached from chi square and safe in the prophylaxis of recurrence of febrile
seizure3. The authors found that oral clobazam is
more effective in preventing febrile seizure
recurrence as compared to diazepam for this purpose
in children with history of at least one episode of
febrile seizure3.

Intermittent oral clobazam therapy is a very

effective measure in preventing recurrence of febrile
seizures. Ten (3.8%) in clobazam group and 38
(14.07%) in placebo group had seizure recurrence (p
value <0.001). The two groups were not
significantly different in terms of side effects (p
>0.05)15.One recurrence to a second or more are low
age at onset and especially positive family history of
febrile seizure. Additionally, low temperature prior
Figure-1: Bar diagram showing recurrence of to the initial seizure is a powerful predictor for three
seizure of the study population or more recurrences16; but our study did not match
with this study.
Discussion:
Role and efficacy of benzodiazepines in the In clobazam group, the frequencies of febrile seizure
prevention of recurrence of febrile seizures has been recurrence were 10%, 5% and 5% at 3, 6 and 12
well established2-4,6,8-10. months after the first attack. At the same time, the
frequencies of the recurrence in the diazepam group
The present study showed that recurrence of simple were 23.8%, 17.5% and 15%, respectively (p <
febrile seizure is more in oral clobazam group 0.05).
comparable to that of oral diazepam group
(P=0.029). Some studies done clobazam vs placebo The two groups were not significantly different in
as prophylaxis for febrile seizure7,10,11 and there are terms of the drug side effects (p = 0.194). The group
few studies comparing diazepam with clobazam in treated with clobazam experienced less febrile
this regard3,10,12. seizure recurrence in the 12 months follow-up. Thus,
clobazam can be used as an effective medication to
A double blind placebo-controlled study reported prevent febrile seizure recurrence in children17.
that recurrence of febrile seizure 30% in the
clobazam group and 83.3% in the placebo group. Some authors found reduced recurrence rates for
They concluded that clobazam is efficacious, well children with febrile seizures for intermittent
tolerated and superior to use of antipyretics alone as diazepam and continuous phenobarbitone
intermittent prophylaxis11. prophylaxis, with adverse effects up to 30%19.
A study on 50 children with febrile seizures and In present study adverse effects of clobazam were
found that clobazam is an effective prophylaxis for lower than diazepam like Sedation, drowsiness,
febrile seizures. Recurrence rate was 1.7% in the incoordination (P<0.0001). A study reported that
clobazam group and 22.9% in the antipyretic alone ataxia due to clobazam was much lower than that of
group (P<0.0001)13. Efficacy and safety of diazepam7. Fifty four percent in the diazepam group
intermittent clobazam prophylaxis for febrile and 14.2% cases in the clobazam group developed
seizures in a prospective randomized double-blind

EMCJ. July 2019: 4 (2) (15)

 Sufian A et al. Eastern Medical College Journal

drowsiness and sedation during the follow-up period 10. Akman CI. Febrile seizures: the role of
(P value=0.0001)14,18. intermittent prophylaxis. J Pediatr Neurol.
Treatment by clobazam has been caused recurrent 2005; 3: 1–3.
and complications like ataxia, drowsiness and other 11. Bajaj AS, Bajaj BK, Vinod P, Girish T.
side effects (vomiting, anorexia and irritability) less Intermittent clobazam in febrile seizures; an
than diazepam20. Indian experience. J Pediatr Neurol. 2005; 3:
19–23.
Single dose, fewer adverse effect of clobazam as 12. Gulati S, Saini D, Pandey RM, Kalra V.
compared the diazepam makes clobazam superior to Randomized controlled trial to compare
diazepam; but recurrence rate more in clobazam as efficacy of oral clobazam with oral diazepam
compared the diazepam makes clobazam inferior to for prophylaxis of febrile seizures.
diazepam for prophylaxis of simple febrile seizures. Neuropediatrics. 2006; 37: 13.
13. Manreza MLG, Gherpelli JLD, Machado HLR,
Conclusion: Pedreire CCC, Diament A, Heise CO.
Recurrence of simple febrile seizure who follows Treatment of Febrile seizures withintermittent
intermittent prophylaxis significantly more in clobazam. Arq Neuropsiquiatr. 2007; 55: 757–
clobazam group but adverse effect of drugs like 61.
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epilepsy could not be excluded in subsequent simple Clobazam for Intermittent Prophylaxis of
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