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 1.0–2.4%, and from a complex FC is 4.1–6.0%. 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 3.5–7.2 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 >38”C, 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 25–30% 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 drug’s 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

0–18 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