A Review on
effectiveness of different Antiepileptic Drugs in Pediatric Febrile Seizures
Anusha Mendem*, Mamatha Arma, Vinodkumar Mugada,
Raj Kiran Kolakota
Department of
Pharmacy Practice, Vignan Institute of Pharmaceutical
Technology, Duvvada, AP, India
*Corresponding Author E-mail: ponnyanushaa@gmail.com
ABSTRACT:
Febrile convulsions
(FCs) are defined as seizures that occur in children between 6 months and 5
years of age, associated with fever but without intracranial infection or
defined causes. The risk of developing epilepsy from a simple FC is 1.02.4%,
and from a complex FC is 4.16.0%. The aim of the study was to assess the
effectiveness of antiepileptic drugs in pediatric seizures. The data bases
searched are pub med, trip database, science direct and Cochrane library The
Type of study is observational studies and randomized control trails. In this
study considerable Study population are Infant (1 month) to 6 yrs children. Intervention related to effective treatment
of antiepileptic drugs in pediatrics. Patients with only febrile seizures and
there treatment are included. Interventional studies are excluded.
Children above 6 yrs age and adults are excluded.
Patients other than febrile seizures are also excluded. In
continuous anticonvulsant therapy, Phenobarbitone is most effective in
prevalence of reoccurrence of febrile seizures, Valproic acid is least
effective, Carbamazepine and phenytoin does not show any effective. In
intermittent anticonvulsant therapy Diazepam is most effective. The effective
dugs of antiepileptic drugs in pediatric seizures, Benzodiazepines given
intravenously, liquid Diazepam is a safe, effective, and rational alternative. Phenobarbital
is effective in recurrence of simple febrile seizures.
KEYWORDS: Pediatrics, febrile
seizures, antiepileptic drugs.
INTRODUCTION:
Epilepsy is a group
of neurologic conditions characterized by recurrent, unprovoked seizures. A
large proportion of epilepsy begins in childhood. The prevalence of epilepsy in
children has been estimated at 3.57.2 per 1000 children[1].
Febrile convulsions
and febrile seizures are synonymous terms and are defined as an event in
neurologically healthy infants and children between 6 months and 5 years
of age, associated with fever >38C, rectal temperature, but without
evidence of intracranial infection or a defined cause and with no history of
prior afebrile seizures[2]. Simple febrile seizures are
defined as generalized seizures, lasting <15 min, not recurring within 24 h,
and with no postictal neurologic abnormalities. Complex febrile seizures
or complicated febrile seizures are focal, prolonged, or recurrent within 24hr
or associated with postictal neurologic abnormalities, including Todd paresis[3].
A prolonged febrile seizure (PFS) is an important subtype of complex febrile
seizures. Together with focality and multiple seizures subtypes, complex
febrile seizures account for approximately 2530% of all febrile seizures[4].
TREATMENT:
Antiepileptic
drugs:
The drugs used were
antiepileptics (phenytoin, phenobarbitone, valproate, diazepam and clobazam),
antipyretics (diclofenac, acetaminophen and ibuprofen) and pyridoxine. The
following treatments were more effective for reducing seizures: intermittent
oral diazepam, continuous anti convulsant therapy and
intermittent antipyretics agents[5].
CONTINUOUS
ANTICONVULSANT THERAPY:
Phenobarbital:
Phenobarbital is
effective in preventing the recurrence of simple febrile seizures[6].
The adverse effects of phenobarbital include hyperactivity, irritability,
lethargy, sleep disturbances, and hypersensitivity reactions[7-10].
Valproic acid:
valproic acid seems
to be at least as effective in preventing recurrent, simple febrile seizures as
Phenobarbital and significantly more effective than placebo[7,11,12].
Drawbacks to therapy with valproic acid include its rare association with fatal
hepatotoxicity (especially in children younger than 3 years who also are at
greatest risk for febrile seizures), thrombocytopenia, weight loss and gain,
gastrointestinal disturbances, and pancreatitis[9].
Carbamazepine:
Carbamazepine was
not effective for febrile seizures [13,14]. Carbamazepine (20 mg/kg
per day in twice daily doses) vs phenobarbital (4 to 5 mg/kg per day) involving
children with complicated febrile seizures[7].
Phenytoin:
Phenytoin has not
been shown to be effective in preventing the recurrence of simple febrile
seizures (8 mg/kg per day)[9].
Primidone:
Primidone, in doses
of 15 to 20 mg/kg per day, has also been shown to reduce the recurrence rate of
febrile seizures [15,16] adverse effects include behavioral
disturbances, irritability, and sleep disturbances[16].
INTERMITTENT
ANTICONVULSANT THERAPY:
Diazepam:
Administration of
oral diazepam (given at the time of fever) could reduce the recurrence of
febrile seizures. Children with a history of febrile seizures were given either
oral diazepam (0.33 mg/kg, every 8 hours for 48 hours) or a placebo at the time
of fever. Adverse effects of oral and rectal diazepam[17] and both
intranasal and buccal midazolam include lethargy, drowsiness, and ataxia.
Respiratory depression is extremely rare, even when given by the rectal route[18,19].
The combination of acetaminophen and low-dose diazepam did not reduce the
incidence of recurrence[17].
INTERMITTENT ORAL
THERAPY:
Antipyretic Agents:
Antipyretic agents,
in the absence of anticonvulsants, are not effective in preventing recurrent
febrile seizures [20,21]. Patients with a history of febrile
seizures demonstrated that administration of oral diazepam (given at the time
of a fever) could reduce the recurrence of febrile seizures[22]
Whether
antipyretics are given regularly (every 4 hours) or sporadically (contingent on
a specific body temperature elevation) does not influence outcome.
Acetaminophen was either given every 4 hours or only for temperature elevations
of more than 37.9°C in children. Prophylactic acetaminophen during febrile
episodes was ineffective in preventing or reducing fever and in preventing
febrile-seizure recurrence[23]. In general, acetaminophen and
ibuprofen are considered to be safe and effective antipyretics for children.
However, hepatotoxicity (with acetaminophen) and respiratory failure, metabolic
acidosis, renal failure, and coma (with ibuprofen) have been reported in
children after overdose or in the presence of risk factors[24,25].
METHODOLOGY:
Search strategy and
data bases:
We conducted a
systemic literature review with eligibility criteria. The data bases searched
are pubmed, trip database, science direct and cochrane library. The search included the following
keywords: Pediatrics, febrile seizures, antiepileptic drugs. This search was
conducted to identify effective treatment of pediatric seizures. Studies which
were published from 2000-2017 (7yrs) are searched and collected.
Selection criteria:
Inclusion criteria:
The Type of study
is observational studies and randomized control trails. In this study
considerable Study population are Infant (1 month) to 6 yrs
children. Intervention related to effective treatment of antiepileptic drugs in
pediatrics. Patients with only febrile seizures and there treatment are included.
Exclusion criteria:
The following were
excluded in this study and listed as follows.
1) Interventional studies
2) Patients aged above 6 yrs
and
3) Patients other than febrile seizures.
Data extraction:
Data extraction included
Information about
1)
Study information (demographic details and year),
2)
Type of study (observational studies and randomized control trails),
3)
Intervention (effective treatment of antiepileptic drugs in pediatrics),
4)
Participants (pediatrics from 1month to 6yrs),
5)
Search strategy (search terms, inclusion and exclusion criteria).
DISCUSSION:
The incidence of a single
febrile seizure is approximately 4% of all children younger than 5 years[26].
Febrile seizures are triggered by fever because of infection, but the diurnal
variation may be associated with the circadian rhythmicity of human body
temperature. They showed that the frequency of SFS was approximately five times
greater in the evening than in the early morning, with the maximum occurrence
of FS at 4:00 PM and the minimum occurrence at 4:00 AM. That study reported
that the first FS occurred most often in the evening (peaking between 6:00 and
10:00 PM) and least often between midnight and early morning hours (2:00 to
6:00 AM[27-29]. However, other causes of seizures, such as
intracranial infections, must be excluded before diagnosis, especially in
infants and younger children. The total number of febrile seizures has been
associated with an increase risk of unprovoked
seizures in previous studies, although each time the association was limited to
a subgroup of children. The duration of fever before the first febrile seizure
is the one factor clearly associated with both recurrent febrile seizures and
subsequent unprovoked seizures. This goes against the earlier notion that
seizures with fever that occur during the initial rise in temperature are the
most benign[30]. The risk of having recurrent simple febrile
seizures varies, depending on age. Children younger than 12 months at the time
of their first simple febrile seizure have approximately a 50% probability of
having recurrent febrile seizures[31]. Children with simple febrile
seizures have only a slightly greater risk for developing epilepsy by the age
of 7 years than the 1% risk of the general population[26,32].
Children who have had multiple simple febrile seizures and are younger than 12
months at the time of the first febrile seizure are at the highest risk[11].
For a child who has experienced a simple febrile seizure, there are potentially
4 adverse outcomes that theoretically may be altered by an effective
therapeutic agent:
(1)
Decline in IQ
(2) Increased risk of epilepsy
(3) Risk of recurrent febrile seizures
(4) Death[33]
In contrast to the
slightly increased risk of developing epilepsy, children with simple febrile
seizures have a high rate of recurrence. The risk varies with age. Children
younger than 12 months at the time of their first simple febrile seizure have
an approximately 50% probability of having recurrent febrile seizures[34] high
rate of recurrence, no long-term adverse effects of simple febrile seizures
have been identified.
RECOMMENDATION:
On the basis of the
risks and benefits of the effective therapies, neither continuous nor
intermittent anticonvulsant therapy is recommended for children with 1 or more
simple febrile seizures.
Benefit:
prevention
of recurrent febrile seizures, which are not harmful and do not significantly
increase the risk for development of future epilepsy.
Harm:
adverse
effects including rare fatal hepatotoxicity (especially in children younger
than 2 years who are also at greatest risk of febrile seizures),
thrombocytopenia, weight loss and gain, gastrointestinal disturbances, and
pancreatitis with valproic acid and hyperactivity, irritability, lethargy,
sleep disturbances, and hypersensitivity reactions with Phenobarbital
lethargy, drowsiness, and ataxia for intermittent diazepam as well as the risk
of masking an evolving central nervous system infection.
Phenobarbital is effective in
preventing the recurrence of Simple febrile seizures[6]. Primidone,
in doses of 15 to 20 mg/kg per day, has also been shown to reduce the
recurrence rate of febrile seizures[15,16].
Valproic acid seems to be at
least as effective in preventing recurrent simple febrile seizures as
phenobarbital and significantly more effective than placebo[35-37].
Drawbacks to
therapy with valproic acid include its rare association with fatal
hepatotoxicity (especially in children younger than 2 years, who are also at
greatest risk of febrile seizures), thrombocytopenia, weight loss and gain,
gastrointestinal disturbances, and pancreatitis [9].
Carbamazepine has not been shown
to be effective in preventing the recurrence of simple febrile seizures.
Phenytoin has not been shown
to be effective in preventing the recurrence of simple febrile seizures, even
when the agent is in the therapeutic range[38,39].
Oral diazepam (given at the time
of fever) could reduce the recurrence of febrile seizures. A potential drawback
to intermittent medication is that a seizure could occur before a fever is
noticed[17]. No studies have demonstrated that antipyretics, in the absence
of anticonvulsants, reduce the recurrence risk of simple febrile seizures[32].
The authors determined that administering prophylactic acetaminophen during
febrile episodes was ineffective in preventing or reducing fever and in
preventing febrile-seizure recurrence[23].
Acetaminophen,
ibuprofen also has been shown to be ineffective in preventing recurrence of
febrile seizures [40-42]. Camfield and associates[23] randomized
79 children who had had a first simple febrile seizure to receive phenobarbital
at 5 mg/kg per day in a single dose or a placebo. In a controlled trial
comparing phenobarbital (5 mg/kg per day) with phenytoin (8 mg/kg per day) and
placebo, Bacon and associates[38] also found Phenobarbital to be
effective. Mamelle et al[36] compared
phenobarbital (3 to 4 mg/kg per day), valproate (30 to 40 mg/kg per day in
2 doses), and placebo in a randomized single-blind study of infants with
a first simple febrile seizure. Phenobarbital is associated with impairment of
short-term memory and concentration and worsening of behavior. Most data on the
effects of Phenobarbital have been obtained from adults or from children with
epilepsy. The drugs effect seems most prominent at the onset of therapy[43-45].
The study by Mamelle et al typifies the studies that
found valproic acid to be more effective than Phenobarbital[9,36].
Valproic acid therapy is associated with fatal hepatotoxicity, pancreatitis,
renal toxicity, hematopoietic disturbances, and other problems[46,50].
As with carbamazepine, preliminary studies showed no evidence that
phenytoin was effective for febrile seizures, so it has not been studied
extensively[39]. simple febrile seizures occur only in conjunction
with a fever, it has seemed logical to try to prevent these seizures by using
aggressive antipyretic therapy[20].
The recurrence rate is related to
various risk factors, which may include the type of treatment. Risk factors for
simple and complex recurrences are probably similar[51].
Offringa et al[51].
Besides young age at onset (I 2-24 months), a history of febrile or unprovoked
seizures in the first degree relatives and a temperature <40°C rectal at the
time of the first febrile seizure were associated with a significantly
increased recurrence rate.
Long-term PB
treatment appears to influence cognition and behavior (drowsiness, sleep
problems, aggression, hyperactivity, inattention)[10,12,45,52,53] a
large price for the prevention of a benign condition. VPA has in rare cases
been associated with hepatotoxicity[54,55].
Short-term
treatment of ongoing febrile seizures
BZDs given
intravenously are the drugs of choice in the immediate situation, but are often
unsuccessful in the small child. Rectal tubes containing liquid DZP is a safe,
effective, and rational alternative[56]. Antipyretic treatment
during febrile illnesses do not reduce the recurrence rate[20,21,23].
PB treatment during febrile episodes, the most widely used prophylaxis for
decades, is obsolete and ineffective[26] because of the long
half-life of the drug[57,58] .vinod et al
reported that Phenytoin was the most commonly prescribed antiepileptic
monotherapy drug (27.5%)[59] .Carbamazepine (CBZ)[7] and
phenytoin (PHT)[38] have not been shown to be effective.
|
Author (Year of publication) |
Sample size |
Age |
Outcome |
|
Martin et al., 2012 [5] |
2740 |
6months-7yrs |
No benefit was demonstrated for phenytoin, valproate, pyridoxine, intermittent phenobarbitone or antipyretics in the form of intermittent ibuprofen, acetaminophen or diclofenac in the management of febrile seizures. |
|
Hiroshi et al., 2017[9] |
462 |
21.6 months |
Our study suggests that the occurrence of patients with CFS needing hospitalization occurred more during evening and less during midnight hours. However, the severity of the seizure may not differ by the time of day. |
|
S Dunlop et al.,2005[13] |
288 |
25.74 months |
Although many children who present to the hospital with simple febrile convulsions are managed appropriately. In these cases, medical record documentation can be improved. |
|
Knudsen etal.,2015[17] |
195 |
6-30 months |
Diazepam is a safe and quickly absorbed anticonvulsant, virtually free from undesirable effects and there is little parental resistance to it. Diazepam may be an alternative prophylaxis in febrile convulsions. phenobarbitone of _ 16 mg/l effectively prevents new convulsions has not yet been substantiated in larger and more homogeneous groups of children. |
|
Eli Lahat et al., 2000[21] |
47 |
six months to five years |
Seizures were controlled more quickly with intravenous diazepam than with intranasal midazolam, although midazolam was as safe and effective as diazepam. |
|
Nevitt et al., 2017[24] |
17,961 |
---- |
carbamazepine and lamotrigine are suitable first treatment options for individuals with partial onset seizures and also show that levetiracetam, sodium valproate would also be a suitable treatment. |
|
Martin et al.,2013[25] |
2740 |
6, 12, 18, 24, 36 months and at age 5 to 6 years |
No benefit was demonstrated for phenytoin, valproate, pyridoxine, intermittent phenobarbitone or antipyretics in the form of intermittent ibuprofen, acetaminophen or diclofenac in the management of febrile seizures. |
|
Ebru et.al 2010 [31] |
225 |
018 years |
The efficacy and treatment failure rate of older antiepileptic drugs; valproate and carbamazepine and a newer antiepileptic drug; oxcarbazepine in a large group of pediatrics patients with newly diagnosed epilepsy. |
|
Yu et.al 2008 [33] |
203 |
6 months -5yrs |
A diazepam suppository after a febrile seizure will reduce the recurrence of febrile seizures during the same febrile illness. However, a diazepam suppository after a febrile seizure should be used only after carefully considering the benefits and potential adverse effects. |
|
Andrew L. Lux et.al 2009[36] |
230 |
1 and 4 years |
Antipyretic treatments are not proven to reduce the recurrence risk for febrile seizures, but they do help control fever and will usually make the child more comfortable during febrile illnesses.
|
|
Titilayo et.al 2012 [46] |
497 |
6 and 60 months |
Children today benefit from the remarkable changes in the epidemiology of infections in the febrile seizures age group, and from our understanding that risks of diagnostic procedures and of prophylactic medications outweigh their nominal benefits. |
CONCLUSION:
The effective dugs
of antiepileptic drugs in pediatric seizures, Benzodiazepines given
intravenously are the drugs of choice in the immediate situation, but are often
unsuccessful in the small child. Rectal tubes containing liquid Diazepam is a
safe, effective, and rational alternative. Phenobarbital is effective in
preventing the recurrence of simple febrile seizures.
ACKNOWLEDGEMENTS:
We are thankful for our
principal Dr. Y. Srinivasa Rao for his guidance and support in completing this
review.
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Received on 28.11.2018
Modified on 30.12.2018
Accepted on 21.01.2019
© A&V Publications All right
reserved
Asian J. Res. Pharm. Sci. 2019; 9(2):85-90.
DOI: 10.5958/2231-5659.2019.00013.4