Professional Documents
Culture Documents
Q3: Can febrile seizures (simple or complex) be managed at first or second level care by non-specialist health care
providers in low and middle income country settings? What is the role of diagnostic tests in the management of febrile
seizures by non-specialists in low and middle income settings? For prophylaxis to prevent recurrence of simple or
complex febrile seizures, which of the pharmacological interventions when compared with placebo/comparator
produce benefit/harm in specified outcomes?
- continuous anticonvulsant therapy
- intermittent anticonvulsant therapy
- intermittent antipyretic treatment
Q3a): Can febrile seizures (simple or complex) be managed at first or second level care by non-specialist health care providers in low and
middle income country settings? What is the role of diagnostic tests in the management of febrile seizures by non-specialists in low and
middle income settings?
Background
Febrile seizures (FS) are common, with a life time prevalence of 2-6%. The definition of FS is controversial. The International League Against Epilepsy (ILAE)
defines FS as an epileptic seizure occurring in childhood associated with fever, but without evidence of intracranial infection or defined cause. Seizures
with fever in children who have experienced a previous non-febrile seizure are excluded (ILAE, 1993). British Paediatric Association suggested "an epileptic
seizure occurring in a child aged from six months to five years, precipitated by fever arising from infection outside the nervous system in a child who is
otherwise neurologically normal (Joint Working Group of the Research Unit of the Royal College of Physicians and British Paediatric Association, 1991).
Although it is important to distinguish "seizures with fever" and "febrile seizures" in terms of management and prognosis, this is often not possible in many
primary health facilities in resource poor countries (Joint Working Group of the Research Unit of the Royal College of Physicians and British Paediatric
Association, 1991). Seizures with fever include any seizure in a child of any age with fever of any cause.
For the purposes of this review, the following definitions are used:
First Level Care the first level contact with people taking action to improve health in a community. This includes General Practioners, nurses,
paramedics, clinical officers, medical officers attending the patient outside the hospital, such as at home, peripheral clinics or outpatient facilities.
Admission to hospital
Not stated
2. Complex FS
1. Simple FS none
2. A LP should be performed if:
consider LP
3. Complex FS
a. Blood chemistry
b. EEG
c. Neuroimaging
d. LP
Not stated
Not stated
Not stated
Prophylaxis against
recurrences
Not stated
1. If Simple FS none
2. Consider prophylaxis in
a. Recurrent FS with reliable parents
b. > 3 FS in 6 months
c. > 4 FS in 1 yr
Education
Not stated
1. Describe details of FS
2. Instructions for fever control
3. Discuss prophylactic drugs
3. Reassurance.
Recurrent seizures,
Focal seizures,
Table 2: Equipment and Supplies for the Diagnosis and Management of Febrile Seizures
Resource Rich Countries
Equipment
Oxygen
Diagnostic facilities
First Level
Second level
First Level
Second level
Syringes
Needles
Weighing scales
Refrigerator
()
Thermometer
Oxygen cylinder
()
Oxygen concentrator
Blood slide
()
()
()
()
Blood glucose
Electrolytes
Blood culture
Urine Microscopy
CSF Microscopy
()
and culture
()
CT scan
()
MRI scan
Drugs
Benzodiazepines
Phenytoin
Phenobarbital
()
The parents' attitudes to febrile seizures vary considerably around the world. This may effect the presentation and management of FS at primary and
secondary care facilities. In an Indian city 59% of parents did not recognize a convulsion and 91% did not perform any interventions before attending
hospital (Parmar et al, 2001), whilst in Turkey some parents administered rectal Diazepam (Yilmaz et al, 2008). Provision of leaflets with written instruction
to British parents did not appear to significantly improve their knowledge or reduce anxiety about FS (Paul et al, 2007).
Population/Intervention(s)/Comparison/Outcome(s) (PICO)
Population:
Interventions:
Comparison:
Outcomes:
Search strategy
The search strategy was conducted with the search terms outlined in Table 3.
7
Table 3: Search Strategy for the Management of Febrile Seizures in First and Secondary Level facilities
Breakdown of search remit provided:
Main question: Can (1) febrile seizure (2) be managed at (3) first and (4) second level care?
Additional variation of terms for Boolean search: ((febrile seizures) OR (febrile convulsions)) AND ((first level) OR (primary healthcare) OR (primary
care)) AND ((secondary level care) OR (secondary healthcare) OR (secondary care))
Database
Boolean Search
Limits
Total
Pubmed
Complete Boolean = 3
Cochrane
45
WHO Eastern
Mediterranean
'febrile seizures' = 71
PsychInfo
Medline Plus
WHO Europe
'febrile convulsions' = 31
21
(febrile seizures) = 67
Total
10
performed
Pubmed
282
Total accessed
Pubmed
230
12
There are several hospital studies of variable validity looking at the probability of meningitis. The signs that were found to indicate an increased risk of
meningitis in a child with seizure and fever were: drowsy pre-seizure, neck stiffness, petechial rash, bulging fontanelle, a Glasgow Coma Scale of <15 (more
than one hour post seizure) (Offringa et al, 1992b; Offringa and Moyer, 2001). This was rated as Level III evidence and Delphi consensus, grade C
recommendation.
b)
No published evidence was found to address this issue. The need for a good urine sample collected without contamination was agreed in the first round of
a Delphi consultation carried out by the authors of the systematic review. The recommendation was that a child who has had a simple febrile seizure, where
no source for infection has been found clinically, should have a urine sample (clean catch, SPA or catheter specimen) taken for microscopy and culture. On
the second round two statements with equal weight were proposed, i.e., children with no focus for infection can be admitted for a short period of
observation (minimum two hours) or can be discharged home if the child looks well, as long as the parents/carers have ready access to health care and they
are happy with this decision. This was based on the Delphi consensus only, since there was no published evidence.
14
The literature suggests that complex febrile convulsions (defined above) are predictive of CNS infection (Green et al, 1993; Joffe et al, 1983; Offringa et al,
1992a; Offringa and Moyer, 2001). The risk of bacterial meningitis in children presenting with fever and seizure is about 3% (McIntyre et al, 1990) and with
a complex seizure is about 9%.
After the first Delphi round it was agreed that children with complex seizures should be admitted to hospital. After admission it was recommended that a
child presenting with a complex febrile seizure (defined above) with no clinical signs of meningitis should be observed closely and reviewed within two
hours by a paediatrician of at least Registrar/Resident level to decide on need for LP.
Referral from First level care
Seizures are one of the danger signs that the World Health Organizations Integrated Management of Childhood Illness (IMCI) suggests that the child should
be referred to a second level facility (WHO, 2005). In one study of 151 children aged 2 months to 5 years who presented with convulsions to first level care
facilities in three countries in Africa, it was suggested that only 12% needed to referred to a second level facility, since they had other signs such as lethargy,
impaired consciousness and/or unable to drink (Simoes et al, 2003). There have been no other studies that have addressed this question within this setting.
Education
Explanation and education about FS of the parents and/or guardians is an important component of the management of FS at all levels. This includes
explanation about the causes of FS, the diagnostic procedures that may be performed to exclude serious infections and the outcome of the FS. Further
advice about preventing recurrence and initiating treatment may be helpful in appropriate circumstances.
Methodological limitations
Most of the studies did not clearly state the facilities available for the diagnosis and management of FS in their reports.
Directness (in terms of population, outcome, interventions and comparison)
Most of the studies identified had been conducted in tertiary emergency departments, and none comprehensively examined the diagnosis and
management of FS in first or second level care. There were no audits of the management of FS in primary care settings.
Narrative Conclusion
15
Reference List
American Academy of Paediatrics (AAP) (1996). Practice parameter: the neurodiagnostic evaluation of the child with a first simple febrile seizure.
Provisional Committee on Quality Improvement, Subcommittee on Febrile Seizures. Paediatrics, 97:769-72.
Armon K Stephenson T, MacFaul R et al (2003). An evidence and consensus based guideline for the management of a child after a seizure. Emergency
Medicine Journal, 20:13-20.
Berg AT et al (1992). Classification of complex features of febrile seizures: interrater agreement. Epilepsia, 33:661-6.
Capovilla G et al (2009). Recommendations for the management of "febrile seizures": Ad Hoc Task Force of LICE Guidelines Commission. Epilepsia, 50(Suppl
1):2-6.
Chamberlain JM, Gorman RL (1988). Occult bacteraemia in children with simple febrile seizures. Amercian Journal of Diseases of Children, 142:1073-6.
Fetveit A (2008). Assessment of febrile seizures in children. European Journal of Paediatrics, 167:17-27.
Garvey M.A et al (1998). Emergency brain computed tomography in children with seizures: who is most likely to benefit? Journal of Paediatrics, 133:664-9.
Gerber MA, Berliner BC (1981). The child with a 'simple' febrile seizure. Appropriate diagnostic evaluation. Amercian Journal of Diseases of Children,
135:431-3.
Green SM et al (1993). Can seizures be the sole manifestation of meningitis in febrile children? Paediatrics, 92:527-34.
Hampers LC et al (2006). Febrile seizure: measuring adherence to AAP guidelines among community ED physicians. Paediatric Emergency Care, 22:465-9.
Hampers LC et al (2000). Setting-based practice variation in the management of simple febrile seizure. Academic Emergency Medicine, 7:21-7.
16
17
18
19
Q3b) In febrile seizures, which of the pharmacological interventions when compared with placebo/comparator produce benefit/harm in
specified outcomes?
- Continuous anticonvulsant therapy
- Intermittent anticonvulsant therapy
- Intermittent antipyretic treatment
Background
Febrile seizures (FS) are common, with a life time prevalence of 2-6%. The definition of FS is controversial. The International League Against Epilepsy (ILAE)
defines FS as an epileptic seizure occurring in childhood after 1 month of age associated with fever, but without evidence of intracranial infection or
defined cause. Seizures with fever in children who have experienced a previous non febrile seizure are excluded (ILAE ,1993). The Joint Working Group of
the Research unit of the Royal College of Physicians and the British Paediatric Association suggested "an epileptic seizure occurring in a child aged from six
months to five years, precipitated by fever arising from infection outside the nervous system in a child who is otherwise neurologically normal (Joint
Working Group of the Research Unit of the Royal College of Physicians and British Paediatric Association, 1991)." The Consensus in Medicine (1980)
definition of a febrile seizure is "an event in infancy or childhood usually occurring between 3 months and 5 years of age associated with a fever, but
without evidence of intracranial infection or defined cause for their seizure", after having excluded children with previous febrile seizures. For the purpose
of this profile, we follow the lower age limit of 6 months, given concerns regarding the possibility of an underlying serious but treatable infection in younger
infants masquerading as a febrile seizure (e.g. meningitis).
Although it is important to distinguish "seizures with fever" and "febrile seizures" in terms of management and prognosis, this is often not possible in many
primary health facilities in Low and Middle Income Countries (LMIC). Seizures with fever include any seizure in a child of any age with fever of any cause.
Febrile seizures are defined as simple if they are generalized, often tonic-clonic, self-limiting, of short duration (<15 minutes), without postictal pathology,
and do not recur within the next 24 hours. Febrile seizures are defined as complex if they have longer duration (>15 minutes), or have focal features, or if
they recur within 24 hours (multiple seizures). In developed countries, simple febrile seizures predominate but in developing countries, fever-associated
seizures are often complex febrile seizures. The literature suggests that complex febrile convulsions are predictive of CNS infection (Joffe et al, 1983;
Offringa et al, 1992; Offringa and Moyer, 2001; Green et al, 1993). In Australia, the risk of bacterial meningitis in children presenting with fever and seizure
is about 3% (McIntyre et al, 1990) and with a complex seizure is about 9%. In Kenya, a study found 84% of children with malarial fevers and seizures had
20
21
Population/Intervention(s)/Comparison/Outcome(s) (PICO)
Population:
Interventions:
Comparison:
no treatment
Outcomes:
22
Intermittent anticonvulsants
3
Intermittent diazepam vs. placebo
or no treatment
Outcomes
Adverse effects
Meremikwu, 2007
Prevention of
recurrence of
febrile seizures
Adverse effects
Risk of
subsequent
epilepsy
Prevention of
recurrence of
febrile seizures
No systematic review;
Knudsen et al, 1996 (RCT)
No systematic review, 2 RCTs
reported in BMJ clinical
evidence (Mewasingh 2008)
23
Adverse effects
Same as above
No systematic review or RCT
identified
Prevention of
recurrence of
febrile seizures
Continuous anticonvulsants
6
Continuous Phenobarbital vs.
placebo or no treatment
Adverse effects
Risk of
subsequent
epilepsy
Prevention of
recurrence of
febrile seizures
No systematic review;
Wolf & Forsythe, 1989 (RCT)
Adverse effects
Risk of
subsequent
epilepsy
Prevention of
recurrence of
febrile seizures
Adverse effects
Temkin, 2001
24
Narrative description of the studies that went into the analysis (including a study-by-study table if appropriate):
Intermittent diazepam vs. placebo or no treatment:
*Masuko, 2003 and Temkin, 2001 - Study by Knudsen et al, 1985 included in the review by Temkin 2001 was excluded by Masuko 2003 because although
the authors describe the study as randomized, the description according to the systematic reviewers presented contrary evidence. Masuko et al, 2003 also
searched for articles in Portuguese and Spanish and included Mosquera, 1987, which is not included in Temkin, 2001. In Masuko et al, 2003, the recurrence
rates for this RCT are reported as 7/202 (3.5%) in children taking diazepam and 29/204 (14.2%) in children taking placebo; in Temkin, 2001, they are
reported as 37/202 (18.3%) in children taking diazepam compared with 53/204 (30%) in children taking placebo. These may explain how reviews with
predominantly the same included RCTs came to different conclusions. The mode, dose, and frequency of administration of diazepam varied in each RCT.
Most of the RCTs identified by the reviews had weak methods. The first RCT was small. In the second RCT, 50 children (25%) taking diazepam and 55
children (27%) taking placebo were lost to follow-up. The third RCT reported poor compliance in children taking diazepam, which was significantly different
from those taking placebo.
Pavlidou et al, 2006: In a prospective randomized cohort trial, 139 children who experienced a first febrile seizure were allocated to two groups: group A,
which received intermittent diazepam (n=68), and group B, which received no prophylaxis (n=71). All children had a 3-year follow-up. The inclusion criteria
were no personal history of afebrile seizures, normal neurodevelopment, no previous anticonvulsant therapy, and age between 6 months and 3 years.
Children with complex febrile seizures (approximately 19%) and febrile status epilepticus (approximately 3%) were also included. Each group was stratified
to low, intermediate, and high risk according to the available clinical data. The 36-month recurrence rates in the no-prophylaxis group were 83% in high-risk
patients, 55% in intermediate-risk patients, and 46% in low-risk patients. In the prophylaxis group, the recurrence rates were reduced in all risk groups:
38%, 35%, and 33%, respectively. Intermittent diazepam at times of fever reduced the recurrence risk significantly in high-risk children (P=0.005,
significant), whereas in low-risk (P=0.412, not significant) and intermediate- risk (P=0.341, not significant) patients, it had limited efficacy.
Adverse effects - The study reported that adverse effects with diazepam were mild and transient, and no long-term side effects were recorded during the 3year follow-up (no further numerical data or statistical analysis of adverse effects between groups reported).
25
Population
Adverse effects
Thilothammal et
al, 1993
Adverse effects necessitating withdrawal: 3/60 (5%) PB-treated children had intolerable
adverse effects (defined as effects persistent for longer than 1 month), including hyperkinetic
behaviour, extreme irritability, fussiness, aggressiveness, all of whom withdrew from the study
owing to the adverse effects. 1/30 (3.3%) of children taking placebo withdrew for unknown
reasons
Camfield et al,
Adverse effects necessitating withdrawal: 4/39 (10%) in both groups withdrew because of
26
febrile seizure
Bacon et al,
1981
Farwell et al,
1990
Negative effect on cognition: 2-year follow-up mean IQ, PB v placebo: 7.03 points, 95% CI 11.52
points to 2.5 points; P = 0.0068). 6 months after weaning and discontinuation of PB, mean IQ PB
v placebo: 5.2 points, 95% CI 10.5 points to 0.04 points; P = 0.052)
Camfield et al,
1979 (not
included in
systematic
review,
additional study)
Negative effects on behaviour (increased fussiness and sleep disturbance classed as transient,
dose related, or unacceptable): transient: 8/35 (23%) with PB v 7/30 (23%) with placebo; dose
related: 4/35 (11%) with PB v 0/30 (0%) with placebo; unacceptable: 3/35 (9%) with PB v 1/30
(3%) with placebo. Decreased comprehension: Children taking PB had lower scores on memory
concentration items on the StanfordBinet Intelligence scale at 8- to 12-month followup
compared with children taking placebo, although the difference between groups was not
significant (absolute numbers not reported; P = 0.07).
Continuous sodium valproate vs. placebo or no treatment - Temkin, 2001 identified three RCTs (278 children) comparing sodium valproate versus placebo
or no treatment. [26] It found no significant difference between groups in the proportion of children with febrile seizure recurrence. The authors of the
review suggest that, if only the small (48 children), placebo-controlled RCT is considered, there is a significant decrease in recurrent febrile seizures with
sodium valproate compared with placebo (1/22 [4%] with sodium valproate v 9/26 [35%] with placebo; RR 0.13, 95% CI 0.02 to 0.96, P = 0.01).
27
GRADE tables:
Table 1
Author(s): Dua T, Hyunh N, Bell G
Date: 2009-08-12
Question: Should Physical methods of temperature reduction vs. Antipyretic drugs be used in children with simple febrile seizures?
Settings:
Bibliography: Mewasingh LD (2008). Febrile seizures. Clinical Evidence, (Online). May 22;2008. pii: 0324.
Summary of findings
Quality assessment
No of patients
Effect
Antipyretic drugs
0/0 (0%)
0/0 (0%)
Importance
Relative
Absolute
(95% CI)
Quality
none
CRITICAL
Table 2
Author(s): Dua T, Hyunh N, Bell G
Date: 2009-08-12
Question: Should Antipyretic drugs vs. placebo be used in children with simple febrile seizures?
Settings:
Bibliography: El-Radhi AS, Barry W (2003). Do antipyretics prevent febrile convulsions? Archives of Diseases in Childhood, 88:641-2;
Meremikwu M, Oyo-Ita A (2002). Paracetamol for treating fever in children. Cochrane Database Systematic Reviews, (2):CD003676.
28
Summary of findings
Quality assessment
No of patients
No of
studies
Design
Limitations Inconsistency
Indirectness Imprecision
Other
considerations
serious2
none
Antipyretic
drugs
Effect
placebo
Relative
(95% CI)
Importance
Quality
Absolute
randomized
trials
serious1
no serious
inconsistency
no serious
imprecision
45/174
(25.9%)
45/166 (27.1%)
RR 1.05 (0.74 to
1.5)
0%
4/124 (3.2%)
LOW
CRITICAL
adverse effects
33
randomized
trials
serious4
no serious
inconsistency
serious5
serious6
none
RR 1.84 (0.65 to
5.18)
9/130 (6.9%)
0%
CRITICAL
0 more per 1000 (from 0 fewer to
0 more)
the 2 included studies double blind placebo controlled RCT; drop outs not described; pooled analysis done by self; BMJ clinical evidence describes the systematic review to have weak methods (inadequate search
methods difficult to replicate, no inclusion/exclusion criteria); however no additional RCT identified by BMJ clinical evidence.
2
No explanation was provided.
3
Meremikwu & Oyo-Ita, 2002, Cochrane review ; analysis 1.2, comparison 1.
4
The systematic review on antipyretic (both paracetamol and ibuprofen) vs. placebo in simple febrile seizures do not give information on adverse effects. This systematic review compares paracetamol vs. placebo in
children with fever.
5
95% CI 0.65 - 5.18 (crossing 1 and upper CI more than 2).
6
one study used ibuprofen and other paracetamol.
Table 3
Author(s): Tarun Dua, Nelly Huynh, Gail Bell
Date: 2009-08-13
29
Quality assessment
No of
Design
Limitations Inconsistency
studies
Recurrence of febrile seizure
41
randomized very
serious3
trials
serious2
Indirectness
Imprecision
no serious
indirectness
no serious
imprecision
Other
considerations
Summary of findings
No of patients
Intermittent diazepam
(during episodes of fever)
none
44/393 (11.2%)
placebo
68/398
(17.1%)
0%
Effect
Relative
(95% CI)
Absolute
Quality
Importance
OR 0.60 (0.4
to 0.9)
CRITICAL
CRITICAL
RR 0.9 (0.06
to 14.27)
CRITICAL
none
serious7
serious8
none
0/0 (0%)
1/152 (0.7%)
0/0 (0%)
1/137
(0.7%)
0%
Table 4
Author(s): Tarun Dua, Nelly Huynh, Gail Bell
Date: 2009-08-13
Question: Should Intermittent clobazam (during episodes of fever) vs. placebo be used in children with simple febrile seizures?
30
Summary of findings
Quality assessment
No of patients
No of
studies
Design
Limitations
Inconsistency
Indirectness
Imprecision
Other
considerations
Effect
Importance
Quality
Absolute
randomized
trials
very
serious2
no serious
inconsistency
no serious
indirectness
serious3
none
0/0 (0%)
0/0 (0%)
not
pooled4
0%
not pooled
not pooled
VERY
LOW
CRITICAL
VERY
LOW
CRITICAL
randomized
trials
very
serious2
no serious
inconsistency5
serious5
very
serious6
reporting bias
5/60 (8.3%)
0/48
(0%)
0%
RR 0 (0 to
0)
31
Quality assessment
No of
Design
Limitations
studies
Recurrence of febrile seizure
8
randomized
trials
very serious1
Inconsistency
serious2
Indirectness
no serious
indirectness
Imprecision
no serious
imprecision
Other
considerations
No of patients
Continuous
placebo
phenobarbital
none
90/483 (18.6%)
184/492
(37.4%)
0%
no serious
indirectness
serious5
reporting bias6
no serious
indirectness
no serious
imprecision
reporting bias6
7/99 (7.1%)
54/144 (37.5%)
5/69 (7.2%)
29/150
(19.3%)
0%
Summary of findings
Effect
Relative
Absolute
(95% CI)
Quality
Importance
RR 0.51 (0.32
to 0.82)
OOO
VERY
LOW
CRITICAL
RR 1.13 (0.36
to 3.48)7
OO
LOW
CRITICAL
RR 1.95 (1.33
to 2.87)
OOO
VERY
LOW
CRITICAL
CRITICAL
adverse effect (negative effect on cognition) (follow-up 2 years; Better indicated by lower values)
111
randomized no serious
no serious
trials
limitations4
inconsistency12
risk of subsequent epilepsy (follow-up mean 6.3 years)
19
randomized serious9,14
no serious
trials
inconsistency12
serious12
no serious
imprecision
reporting bias6
serious12,15
serious16
none
108
109
1/126
(0.8%)
CRITICAL
32
Table 6
Author(s): Tarun Dua, Nelly Huynh, Gail Bell
Date: 2009-08-14
Question: Should Continuous valproate vs. placebo be used in children with simple febrile seizures?
Settings:
Bibliography: Temkin NR (2001). Antiepileptogenesis and seizure prevention trials with antiepileptic drugs: meta-analysis of controlled trials. Epilepsia, 42:515-24.
Quality assessment
No of
Design
Limitations Inconsistency
Indirectness
studies
Recurrence of febrile seizure
3
randomized
very
serious3
no serious
1,2
trials
serious
indirectness
Imprecision
serious4
Other
considerations
No of patients
Continuous
placebo
valproate
none
29/102 (28.4%)
34/114
(29.8%)
0%
none
0/0 (0%)
0/0 (0%)
Summary of findings
Effect
Relative
Absolute
(95% CI)
78 fewer per 1000 (from 227
fewer to 367 more)
RR 0.74 (0.24 to
2.23)
0 fewer per 1000 (from 0 fewer to
0 more)
-
Quality
VERY
LOW
Importance
CRITICAL
CRITICAL
33
none
0/0 (0%)
0/0 (0%)
CRITICAL
2/3 studies not placebo controlled.
2
American Academy of Paediatrics, 1999 practice parameter systematic review included valproate vs. phenobarbital/ vs. placebo studies. One of the included studies in that review (Wallace and Smith, 1980) is not
included in Temkin, 2001 systematic review. Reason for exclusion not clear.
3
I square not provided, however tests for statistical heterogeneity was found significant. Visual investigation of forest plot also suggests heterogeneity.
4
95% CI crossing 1 and upper CI more than 2.
5
There are known rare, serious adverse effects of sodium valproate include hepatotoxicity and haematological toxicity. Although valproate hepatotoxicity may be dose dependent, it can, more rarely, be an
idiosyncratic phenomenon which means that it is often irreversible and difficult to predict on the basis of laboratory monitoring. Blood disturbances can also be dose dependent, with direct bone marrow
suppression leading to aplastic anaemia or peripheral cytopenia affecting one or more cell lines, or even fatal bone marrow failure.
1
Table 7
Author(s): Tarun Dua, Nelly Huynh, Gail Bell
Date: 2009-08-14
Question: Should Continuous phenobarbital vs. Continuous valproate be used in children with simple febrile seizures?
Settings:
Bibliography: Masuko AH et al (2003). Intermittent diazepam and continuous phenobarbital to treat recurrence of febrile seizures: a systematic review with meta-analysis. Arquivos de Neuro-Psiquiatria, 61:897-901.
Epub 2004 Jan 6.
Summary of findings
Quality assessment
No of patients
No of
studies
Design
Limitations
Inconsistency
Indirectness Imprecision
Other
considerations
serious2
none
Continuous
phenobarbital
Effect
Continuous
valproate
Relative
(95% CI)
Importance
Quality
Absolute
randomized
trials
no serious
limitations1
no serious
inconsistency2
very
serious3
4/21 (19%)
1/22 (4.5%)
0%
CRITICAL
34
none
0/0 (0%)
0/0 (0%)
CRITICAL4
none
0/0 (0%)
0/0 (0%)
CRITICAL
check drop out rate and outcome assessment from the original paper.
single study.
3
sample size less than 100, 95% CI wide with no effect and appreciable benefit.
2
Reference List
American Academy of Paediatrics (1999). Practice parameter: long-term treatment of the child with simple febrile seizures. Committee on Quality
Improvement, Subcommittee on Febrile Seizures. Paediatrics, 103(6 pt 1):1307-9.
Armon K et al (2003). An evidence and consensus based guideline for the management of a child after a seizure. Emergency Medical Journal, 20:13-20.
Autret E et al (1990). Double-blind, randomized trial of diazepam versus placebo for prevention of recurrence of febrile seizures. Journal of Paediatrics,
117:490-4.
Bacon CJ et al (1981). Behavioural effects of phenobarbitone and phenytoin in small children. Archives of Disease in Childhood, 56:836-840.
Bajaj AS et al (2005). Intermittent clobazam in febrile seizures: an Indian experience. Journal of Paediatric Neurology, 3:19-23.
Berg AT et al (1992). Classification of complex features of febrile seizures: interrater agreement. Epilepsia, 33:661-6.
Camfield S et al (1979). Side effects of phenobarbital in toddlers; behavioral and cognitive aspects. Journal of Paediatrics, 95:361-5.
Capovilla G et al (2009). Recommendations for the management of "febrile seizures": Ad Hoc Task Force of LICE Guidelines Commission. Epilepsia, 50(Suppl
1):2-6.
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Explanation
Narrative
summary of
the evidence
base
Febrile seizures are defined as simple if they are generalized, often tonic-clonic, self-limiting, of
short duration (<15 minutes), without any after effects, and do not recur within the next 24 hours.
Febrile seizures are defined as complex if they have longer duration (>15 minutes), or have focal
features, or if they recur within 24 hours (multiple seizures).
Although no data on this is available regarding the capacity of non-specialist health care providers
from low-and middle-income countries (LAMIC) health care settings, there are clinical criteria to
differentiate simple from complex febrile seizure.
In simple febrile seizures, local standards for diagnosis and management of fever should be
followed.
Intervention/Compar
ator
Recurrence of
febrile seizure
Adverse effects
Risk of subsequent
epilepsy
Physical methods of
temperature
reduction vs.
antipyretic
drugs/placebo
2 RCTs, No
significant effect
No significant difference,
very wide confidence
intervals
RR 1.05 (0.74-1.50)
No difference
(The evidence is
inconclusive and so it is
not possible to determine
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Single RCT, no
significant difference
RR 0.9 (0.06 -14.27)
(self calculation)
(very wide CI)
Intermittent
clobazam vs. placebo
or no treatment
2 RCTs , RR 0.31
(0.18-0.55) (self
calculation)
favouring active
treatment
Significantly increased
ataxia in one study
Intermittent vs.
continuous
anticonvulsant
Continuous
Phenobarbital vs.
placebo or no
treatment
Statistically
significant
difference RR 0.51
(0.32-0.82),
favouring active
treatment
Adverse effect
necessitating withdrawal
(may be significant
difference in one study,
other study - no significant
difference) (RR 1.13 (0.363.48); negative effect on
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No significant
difference RR 0.74
(0.24-2.23)
Continuous
Phenobarbital vs.
continuous valproate
No significant
difference
RR 0.24 (0.03-1.96)
In LAMIC settings, febrile seizures presenting to the health facilities are often complex. Complex
febrile seizures (CFS) indicate entities with variable etiology, semiology, and prognosis. Therefore,
treatment depends upon the etiologic and nosographic picture. A CFS may result from an acute
disorder of the CNS (such as cerebral malaria, bacterial meningitis, encephalitis) or could be simply
a prolonged febrile seizure. Admission is recommended for observation because of the wide
variability of conditions underlying this event. Search for underlying etiology is recommended in
case of CFS. The risk of bacterial meningitis in children presenting with fever and seizure is about
3% and in a complex seizure about 9%. Children with following features - at least 3 days of illness,
seen by GP in previous 24 hours, drowsiness at home, vomiting at home, CFS, petechaie, suspected
nuchal rigidity, bulging fontanelle, and focal neurological signs - have an increased risk of
meningitis.
The vast majority of children who present with febrile seizures do not develop epilepsy. However,
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Intervention/Compar
ator
Recurrence of
febrile seizure
Adverse effects
Risk of subsequent
epilepsy
Physical methods of
temperature
reduction vs.
antipyretic
drugs/placebo
Very low
Very low
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Balance of
benefits
versus harms
Intermittent
clobazam vs. placebo
or no treatment
Very low
Very low
Intermittent vs.
continuous
anticonvulsant
Continuous
Phenobarbital vs.
placebo or no
treatment
Very low
low
Continuous valproate
vs. placebo or no
treatment
Very low
Continuous
Phenobarbital vs.
continuous valproate
moderate
Intermittent antipyretics may be no more effective than placebo in treating episodes of fever to
prevent seizure recurrence in children with one or more previous simple febrile seizures.
Intermittent anticonvulsant (diazepam or clobazam) are may be more effective at reducing the risk
of febrile seizure recurrence in children with a history of simple or complex febrile seizures.
However diazepam has been associated with increased hyperactivity, lethargy, irritability, and with
difficulties with speech, activity level, or sleep. Clobazam is also associated with adverse effects
such as ataxia. Phenobarbital may be more effective at reducing febrile seizure recurrence in
children with a history of simple or complex febrile seizures. Phenobarbital is may be associated
with cognitive impairment, and with behavioural problems including hyperactivity, irritability, and
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For febrile seizures, prophylactic therapy is advocated by some because of the concerns that such
seizures lead to additional febrile seizures, to epilepsy, and perhaps even to brain injury. Moreover,
they note the potential for such seizures to cause parental anxiety. Addressing parental anxiety
should a key part of the management of febrile seizures, as parents' (unspoken) worry with a first
seizure is that their child might have died.
Costs and
resource use
and any other
relevant
feasibility
issues
The non-specialist health care provider can be trained to recognize and manage febrile seizures.
Final recommendation(s)
Children with simple febrile seizures can be diagnosed and managed by non-specialist health care providers in low
and middle income countries. In simple febrile seizures, local standards for diagnosis and management of fever
should be followed and children should be observed for 24 hours. Integrated Management of Childhood Illnesses
(IMCI) guidelines should be used for management of fever.
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