|
|
|
Indian Pediatr 2021;58:857-860 |
 |
Zinc Supplementation for Prevention of
Febrile Seizures Recurrences in Children: A Systematic Review
and Meta-Analysis
|
|
Manish Kumar, 1 Swarnim
Swarnim2, Samreen Khanam3
From Department of Pediatrics, 1All India Institute of Medical
Sciences, Gorakhpur, Uttar Pradesh; 2Department of Pediatrics, Maulana
Azad Medical College, New Delhi; 3Guru Nanak Eye Center, Maulana Azad
Medical College, New Delhi.
Correspondence to: Dr Manish Kumar, Department of Pediatrics, All
India Institute of Medical Sciences, Kunraghat,
Gorakhpur, Uttar Pradesh 273 008.
Email:
[email protected]
Published online: August 02, 2020;
PII: S097475591600359
PROSPERO Registration Number: CRD42020190747
|
Background: Multiple studies have documented
lower serum zinc levels in patients with febrile seizures in comparison
to febrile patients without seizure. However, there is limited evidence
comparing the effects of zinc supplementation with placebo on recurrence
of febrile seizures in children. Objectives: To study the effects
of zinc supplementation on recurrence rate of febrile seizures in
children less than 60 months of age. Design: Systematic review
and meta-analysis of randomized and quasi-randomized controlled trials.
Data Source and selection criteria: We searched PubMed, EMBASE
and CENTRAL databases for articles reporting randomized or
quasi-randomized controlled trials comparing the effects of zinc
supplementation with placebo on recurrence of febrile seizures in
children aged less than 60 months. We performed a fixed effect
meta-analysis to provide pooled odds ratio of febrile seizure
recurrence. Quality of evidence was assessed using GRADE approach.
Participants: Children aged less than 60 months. Intervention:
Zinc supplementation Outcome measures: Odds of febrile seizure
recurrence. Results: Four clinical trials with a total of 350
children were included in the review. There was no statistically
significant difference between odds of febrile seizure recurrence during
one year follow up, in children on zinc supplementation compared to
those on placebo (OR 0.70; 95% CI 0.41 – 1.18, I2 = 0%). Conclusion:
Available evidence is very low quality and thus inadequate to make
practice recommendations.
Keywords: Epilepsy, Management, Outcome, Prevention,
Recurrence.
|
|
F
ebrile seizures are the most common
pediatric seizure disorder, primarily affecting children in the
age group of 6 months to 5 years, with a global prevalence of
2-5% [1]. The patho-physiology of febrile seizures is not well
understood and studies have identified various risk factors,
including family history, genetic factors, metabolic changes and
micronutrient deficiencies [2-5]. Putative role of zinc in the
pathogenesis of febrile seizures has been hypothesized [6-8]
with studies showing association of low zinc levels with higher
neuronal excitability through its interactions with multiple ion
channels and receptors [9-11]. A recent metanalysis found lower
serum zinc levels in patients with febrile seizure compared to
febrile cases without seizure [12]. However, there is limited
available evidence about the role of zinc supplementation in
prevention of febrile seizures recurrence, which this review
attempts to identify, appraise and synthesize.
METHODS
This systematic review has been conducted in
accordance to Preferred Reporting Items for Systematic Reviews
and Meta-Analyses (PRISMA) guidelines [13] The protocol was
registered in the International Prospective Register of
Systematic Reviews (PROSPERO) database.
Search strategy and search eligibility:
All authors independently searched the databases including
PubMed, Embase, Cochrane Central Register of Controlled Trials,
from inception to 28 September, 2020. Details of the electronic
search strategy and the results are given as
Web Table I.
Cross references of all articles whose full text was screened,
was also checked to find additional articles.
Inclusion criteria were original articles, in
any language, having randomized or quasi-randomized controlled
trial design; population included children less than 60 months
of age; intervention studied was zinc supplementation;
comparator being placebo; and outcome being febrile seizure
recurrences during 1year follow-up.
Data extraction and quality assessment:
Data were extracted by all authors independently using a
pre-designed form. Any disagreements were resolved with
consensus. The recorded details included lead author, year of
publication, country, sample size, inclusion and exclusion
criteria, gender distribution, mean age, type of zinc salt, dose
of zinc, number of recurrences of febrile seizure in
intervention and control group, and duration of follow-up.
Quality of each study was assessed using the
criteria outlined in the Risk of bias tool in Cochrane handbook
for systematic reviews of interventions [14]. Quality of
evidence was assessed using Grading of Recommendations
Assessment, Development and Evaluation (GRADE) approach [15],
and summary of findings table was generated on GRADEpro GDT
software [16].
Statistical analysis: We performed a
fixed effect meta-analysis to provide pooled odds ratio of
febrile seizure recurrence. Pooled odds ratio (OR) with 95%
confidence interval (CI) was calculated for primary outcome.
Heterogeneity was assessed using the I² statistics.
Statistical analysis was performed using Review Manager version
5.4 [17]. .
RESULTS
Our search strategy yielded 132 articles and
one additional article was included after manual search. Finally
four articles with a total of 350 children were included in
qualitative synthesis [18-21] (Fig. 1). Table I
summarizes the characteristics of the included studies.
Three of the included studies are from Iran [18-20], while one
study was conducted in India [21]. One article was in Persian
with English abstract [18]. Age of the children included varied
across the studies. Studies by Fallah, et al. [19] and Kulkarni,
et al. [21] included children with normal anthropometric
measurements. Though zinc sulfate was used as intervention in
all the four studies, the doses differed across the studies. All
the studies had a follow-up of one year. While in the study by
Ahmedabadi, et al. [18] and Fallah, et al. [19], follow up was
conducted every three months, children enrolled in study by
Kulkarni, et al. [21] were followed up on a monthly basis.
 |
|
Fig.1 PRISMA flow diagram
showing the study selection process.
|
Three studies (18,20,21) had high risk
of selection bias, performance bias and detection bias.
Web
Fig. 1 summarizes risk of bias for each included study and
Web Fig. 2 depicts risk of bias graph as percentages
across all studies. Publication bias was assessed with funnel
plot (Web Fig. 3); however, this analysis was limited by
small number of included studies. The pooled odds of recurrence
of febrile seizure during one year follow up was less in
intervention group, though it was not statistically significant
(OR 0.70; 95% CI 0.41 – 1.18, I 2
= 0%).
Fig. 2
depicts the Forest plot for this outcome.
 |
|
Fig. 2 Forest plot of effect of zinc
supplementation on rate of febrile seizure recurrence in
children less than 60 months of age.
|
The quality of evidence pooled from included
studies was assessed using GRADE approach and a summary of
findings table (Web Table II) was generated on GRADEpro
GDT software [16]. Due to inherent risk of bias of included
studies along with inconsistent and imprecise results from these
studies, the quality of evidence ranged from low to very low.
DISCUSSION
Available evidence from four
randomized/quasi-randomized trials, including a total of 350
children, did not find any significant difference between
recurrence rate of febrile seizure in children on zinc
supplementation compared to children on placebo.
However, there were differences across the
studies. While, Fallah, et al. [19] did not explain the reasons
for their assumption of such a large difference, while
calculating the sample size, the other three studies did not
mention their strategy for calculation of sample size. Further,
the study populations were not similar with respect to inclusion
and exclusion criteria. Age groups of children enrolled in
included studies had significant variation. Given the fact that
febrile seizures are an age-dependent phenomenon with reported
peak incidence between 12–18 months [22], such variations may
have important ramifications in rate of febrile seizure
recurrences across studies. Also, evolving evidence suggests
that serum zinc level is lower in patients with febrile seizure
[12]. In this light, variation in dose of zinc supplementation
in intervention groups of the included studies can affect
febrile seizure recurrences. Three of the included studies are
on Iranian population, which may affect the generalizability of
results for other population group.
Though we searched large and representative
databases for this review, we recognize the limitation of not
having searched other databases. Available evidence pertaining
to zinc supplementation for prevention of febrile seizures is of
low to very low quality and thus inappropriate to make a
practice recommendation. Included trials were inadequately
powered with high risk of bias. Further research, in the form of
methodologically robust, multi-centric randomized controlled
trials, is needed.
Acknowledgement: Dr Niraj Kumar,
Additional Professor, Department of Neurology, AIIMS Rishikesh
for his inputs in drafting the manuscript.
Note: Additional material related
to this study is available with the online version at
www.indianpediatrics.net
Contributors: MK: conceptualized the
review, literature search, data analysis and manuscript writing;
SS: literature search, data analysis and manuscript writing; SK:
literature search, data analysis and manuscript writing. All
authors approved the final version of manuscript, and are
accountable for all aspects related to the study.
Funding: None; Competing interests:
None stated.
REFERENCES
1. Steering Committee on Quality
Improvement and Management, Subcommittee on Febrile Seizures
American Academy of Pediatrics. Febrile seizures: Clinical
Practice Guideline for the Long-Term Management of the Child
with Simple Febrile Seizures. Pediatrics. 2008;121:1281-6.
2. Audenaert D, Van Broeckhoven C, De
Jonghe P. Genes and loci involved in febrile seizures and
related epilepsy syndromes. Hum Mutat. 2006;27:391-401.
3. Kang J-Q, Shen W, Macdonald RL. Why
does fever trigger febrile seizures? GABAA receptor gamma2
subunit mutations associated with idiopathic generalized
epilepsies have temperature-dependent trafficking
deficiencies. J Neurosci. 2006;26:2590-7.
4. Dubé C, Vezzani A, Behrens M, et al.
Interleukin-1â Contributes to the Generation of Experimental
Febrile Seizures. Ann Neurol. 2005;57:152-5.
5. Reid AY, Galic MA, Teskey GC, Pittman
QJ. Febrile seizures: current views and investigations. Can
J Neurol Sci. 2009;36:679-86.
6. Reid CA, Hildebrand MS, Mullen SA, et
al. Synaptic Zn2+ and febrile seizure susceptibility. Br J
Pharmacol. 2017; 174:119-25.
7. Tütüncüoğlu S, Kütükçüler N, Kepe L,
et al. Proinflam-matory cytokines, prostaglandins and zinc
in febrile convulsions. Pediatr Int. 2001;43:235-9.
8. Hildebrand MS, Phillips AM, Mullen SA,
et al. Loss of synaptic Zn2+ transporter function increases
risk of febrile seizures. Sci Rep. 2015;5:17816.
9. Marger L, Schubert CR, Bertrand D.
Zinc: An under-appreciated modulatory factor of brain
function. Biochem Pharmacol. 2014;91:426-35.
10. Paoletti P, Vergnano AM, Barbour B,
Casado M. Zinc at glutamatergic synapses. Neuroscience.
2009;158:126-36.
11. Khosravani H, Bladen C, Parker DB, et
al. Effects of Cav3.2 channel mutations linked to idiopathic
generalized epilepsy. Ann Neurol. 2005;57:745-9.
12. Heydarian F, Nakhaei AA, Majd HM,
Bakhtiari E. Zinc deficiency and febrile seizure: A
systematic review and meta-analysis. Turk J Pediatr.
2020;62:347-58.
13. Liberati A, Altman DG, Tetzlaff J, et
al. The PRISMA statement for reporting systematic reviews
and meta-analyses of studies that evaluate healthcare
interventions: Explanation and elaboration. BMJ.
2009;339:b2700.
14. Assessing risk of bias in a
randomized trial. Accessed September 29, 2020. Available
from: https://training.
cochrane.org/handbook/current/chapter-08
15. RevMan. Accessed September 29, 2020.
Available from:
https://training.cochrane.org/online-learning/core-soft
ware-cochrane-reviews/revman
16. GRADE handbook. Accessed September
29, 2020. Available from:
https://gdt.gradepro.org/app/handbook/handbook.html
17. GRADEpro. Accessed September 29,
2020. Available from: https://gradepro.org/
18. Ahmadabadi F, Mirzarahimi M,
Samadzadeh M, et al. The efficacy of zinc sulfate in
prevention of febrile convulsion recurrences. J Isfahan Med
Sch. 2014;31:1910-8.
19. Fallah R, Sabbaghzadegan S, Karbasi
SA, Binesh F. Efficacy of zinc sulfate supplement on febrile
seizure recurrence prevention in children with normal serum
zinc level: A randomised clinical trial. Nutrition. 2015;31:
1358-61.
20. Shiva S, Barzegar M, Zokaie N, Shiva
S. Dose supple-mental zinc prevents recurrence of febrile
seizures? Iran J Child Neurol. 2011;5:11-4.
21. Kulkarni S, Kulkarni M. Study of zinc
supplementation in prevention of recurrence of febrile
seizures in children at a tertiary care center. MedPulse Int
J Pediatr. 2020;13:1-4.
22. Leung AK, Hon KL, Leung TN. Febrile seizures: an
overview. Drugs Context. 2018;7:21253.
|
|
|
 |
|
