Effect of Valproate on Serum BDNF and MMP-9 in Pediatric Epilepsy

Article information

J Epilepsy Res. 2025;15(2):104-113

Publication date (electronic) : 2025 December 10

doi : https://doi.org/10.14581/jer.25012

Anand Borisagar, MD ¹, Rachna Gupta, MD ¹, Manish Narang, MD ², Sumita Halder, MD ¹, Mohit Mehndiratta, MD ³

¹Department of Pharmacology, University College of Medical Sciences (University of Delhi) & GTB Hospital, New Delhi, India

²Department of Pediatrics, University College of Medical Sciences (University of Delhi) & GTB Hospital, New Delhi, India

³Department of Biochemistry, University College of Medical Sciences (University of Delhi) & GTB Hospital, New Delhi, India

Corresponding author: Rachna Gupta, MD, Department of Pharmacology, University College of Medical Sciences (University of Delhi) & GTB Hospital, New Delhi 110095, India, Tel. +91-11-22582972, E-mail; rgupta@ucms.ac.in

Received 2025 July 24; Revised 2025 November 7; Accepted 2025 November 17.

Abstract

Background and Purpose

In recent years, brain-derived neurotrophic factor (BDNF) and matrix metalloproteinase-9 (MMP-9) have garnered interest for their involvement in epilepsy. This study evaluated the serum levels of BDNF and MMP-9 in pediatric patients with epilepsy compared to healthy controls and assessed the effect of valproate on serum BDNF and MMP-9.

Methods

Children aged 1 year to 12 years, diagnosed with epilepsy (n=30), and age-matched healthy controls (n=30) were included. All participants were followed up for 16 weeks and assessed for changes in serum BDNF and MMP-9 levels.

Results

Children with epilepsy had significantly lower BDNF and higher MMP-9 levels compared to healthy controls at baseline. Following 16 weeks of treatment with valproate, BDNF levels were increased significantly (p<0.001), and MMP-9 levels decreased significantly (p<0.001).

Conclusions

The findings suggest the involvement of BDNF and MMP-9 in the pathogenesis of epilepsy. Serum BDNF and MMP-9 levels were increased and decreased, respectively, following valproate treatment in children with epilepsy. Hence, BDNF and MMP-9 could be potential biomarkers in pediatric epilepsy. Large sample sizes and long-term studies are warranted to confirm the findings.

Keywords: Epilepsy; Brain-derived neurotrophic factor; Matrix metalloproteinase 9; Valproic acid

Introduction

Epilepsy represents one of the most common chronic neurological disorders worldwide, characterised by recurrent, unprovoked seizures resulting from abnormal, excessive neuronal activity in the brain.1,2 Epilepsy affects over 65 million individuals globally, with approximately 10.5 million children living with epilepsy.3,4 The prevalence of pediatric epilepsy varies considerably across geographical regions, ranging from 4.6 to 16.5 per 1,000 children, influenced by interactions between genetic predisposition, environmental exposures, perinatal factors, and healthcare access.5,6

A substantial amount of evidence suggests that pathophysiology of epilepsy involves complex processes, including neuroinflammation, oxidative stress, blood-brain barrier dysfunction, and aberrant neuroplasticity. 7,8 These insights have increased interest in identifying biomarkers that could reflect these underlying processes, serving as objective indicators of disease progression, treatment response, and prognosis in epilepsy.9 Several studies have demonstrated that brain-derived neurotrophic factor (BDNF) has fundamental roles in neuronal survival, differentiation, and synaptic plasticity; processes integral to both normal neurodevelopment and epileptogenesis.10–12 Moreover, clinical investigations have shown altered BDNF levels in both serum and cerebrospinal fluid of epilepsy patients and which may vary across different epilepsy syndromes, age groups, and treatments.13,14

Alongside neurotrophic factors, inflammatory mediators have also been found to be involved in epileptogenesis. Matrix metalloproteinase-9 (MMP-9), a zinc-dependent endopeptidase involved in extracellular matrix remodelling, represents a critical intersection between inflammatory processes and structural neuroplasticity.15,16 Elevated MMP-9 activity has been implicated in blood-brain barrier disruption, leukocyte infiltration and propagation of inflammatory cascades within neural tissue.17,18 Studies have also reported increased MMP-9 levels in epilepsy patients, correlating with seizure frequency and severity.19 However, there is a lack of studies regarding serum levels of BDNF and MMP-9 in children with epilepsy.

Furthermore, childhood represents a critical period of neurodevelopment characterised by extensive synaptogenesis, myelination, and neural circuit refinement. Epilepsy can significantly disrupt these processes, potentially leading to cognitive, behavioural, and psychosocial impairments beyond seizure manifestations in children.20,21 Research indicates that up to 70% of children with epilepsy experience some form of neurodevelopmental comorbidity, including intellectual disability, learning disorders, attention deficits, autism spectrum features, or behavioural problems.22,23

These adversities can hinder age-appropriate functioning in children with epilepsy, making early and systematic assessment essential. Standardised tools such as the vineland social maturity scale (VSMS) and the developmental screening test (DST) can help assess these developmental profiles, guide appropriate interventions, and provide a more holistic evaluation of treatment outcomes.24–26

In clinical practice, antiseizure medication (ASM) therapy is to be continued for a longer period in children to achieve seizure control. Valproate (valproic acid) is a widely used ASM due to its broad spectrum of efficacy across multiple seizure types in pediatric epilepsy.27

Hence, taking into consideration the above, the present study evaluated serum levels of BDNF and MMP-9 in pediatric patients with epilepsy compared to healthy controls and assessed the effects of valproate on serum BDNF and MMP-9. We also assessed cognitive and social development using standardised tools such as the VSMS and DST after valproate treatment in children with epilepsy.

Methods

Subjects and study design

This was an open-label prospective study. The children diagnosed as cases of ‘newly diagnosed epilepsy’, aged 1 year to 12 years, who were attending the outpatient and inpatient departments of pediatrics, were considered eligible for inclusion in the study. Children with a history of acute head trauma or post-traumatic epilepsy, known or suspected metabolic disorders, comorbid psychiatric illness, prior or current treatment with psychotropic medications within the past 6 months, and those with significant systemic illnesses such as liver or kidney disease, endocrine disorders, or febrile illness (n=18) were excluded from the study. The study had two groups: 1) children with epilepsy who were treated with valproate (n=30), which was initiated at a starting dose of 10 mg/kg/day in two divided doses (5 mg/kg twice daily), with titration up to 60 mg/kg/day depending on clinical response and tolerability. Dose adjustments were made by the treating pediatrician. If there was a reduction in frequency of seizures per month (≤1) after 16 weeks of therapy, it was taken as the response to drug treatment. 2) Age and sex-matched healthy children (n=30) served as the healthy control group. Written informed consent and assent were obtained from parents or legal guardians in the local vernacular language prior to recruitment. The study commenced after receiving ethical approval from the Institutional Ethics Committee for Human Research (registration number: ECR/1129/Inst/DL/2018).

Blood sample collection

Peripheral venous blood samples were collected under aseptic precautions from all participants on day 0 (baseline) and after 16 weeks of treatment. The samples were collected into plain test tubes and centrifuged at 4,000 rpm for 10 minutes to separate the serum. The extracted serum was stored at -20°C until biochemical analysis.

BDNF estimation

Serum BDNF levels were estimated using a commercially available human BDNF ELISA kit (GENLISA^TM; KRISHGEN BioSystems, Cerritos, CA, USA) according to the manufacturer’s protocol. In brief, 100 μL of standards and samples were added to pre-coated wells, followed by incubation with biotinylated antibody and streptavidin-horseradish peroxidase conjugate. After substrate addition, the reaction was stopped, and absorbance was measured at 450 nm using a microplate reader (Biotek Synergy H1 Hybrid Microplate Reader^®; BioTek Instruments, Winooski, VT, USA). All standards were run in duplicate to generate a standard curve.

MMP-9 estimation

Serum levels of MMP-9 were estimated using a commercially available human serum MMP-9 ELISA kit (GENLISA^TM; KRISHGEN BioSystems). The procedure followed the same general steps as the BDNF assay, including the use of precoated plates, serial dilutions of standards, sequential addition of detection antibodies, streptavidin-horseradish peroxidase conjugate, substrate incubation, and final absorbance reading at 450 nm.

VSMS

The VSMS was used to evaluate social adaptability and maturity in the pediatric participants. This scale assesses social competence across various domains, including communication, self-help skills, socialisation, and locomotion. Based on the child’s performance across these domains, a “Social Age” was determined. The social quotient (SQ) was then calculated using the formula: SQ=(social age/chronological age)×100.28,29

DST

The DST was employed to assess neurodevelopmental functioning, covering socio-emotional, cognitive, motor, and language domains. The test consists of 88 age-specific items grouped by developmental milestones. Based on the successful completion of items, a “Developmental Age” was assigned. The developmental quotient (DQ) was then calculated using the formula: DQ=(developmental age/chronological age)×100.30

Outcome measures

The primary outcome measures were between-group comparison of baseline serum BDNF and MMP-9 levels in healthy controls and children with epilepsy and within-patient changes in serum BDNF and MMP-9 levels after 16 weeks of valproate therapy. The secondary outcome measure was the proportion of children with epilepsy who exhibited changes in VSMS and DST assessed at 8 weeks and 16 weeks following treatment.

Statistical analysis

Statistical analysis was performed using SPSS version 20 (IBM, Chicago, IL, USA). Continuous variables were expressed as mean±standard deviation, and categorical variables were summarised using frequencies and percentages. The data distribution was assessed for normality using the Shapiro-Wilk test. Paired t-tests were used to analyse changes in serum BDNF and MMP-9 levels before and after treatment within the valproate group. An independent t-test was used to compare BDNF and MMP-9 levels between the healthy control and valproate groups. Repeated measures analysis of variance followed by Tukey’s post hoc test was used to analyse within- and between-group differences in VSMS and DST scores over time. A p-value <0.05 was considered statistically significant. Correlation analysis between serum biomarker levels (BDNF and MMP-9) and neurodevelopmental scores (VSMS and DST) was performed using Pearson’s correlation coefficient (r). A p-value of less than 0.05 was considered statistically significant. The strength and direction of associations were interpreted based on correlation coefficients (ρ).

Results

Our study flowchart is depicted in Fig. 1. The mean age of children in healthy control group and valproate group was 6.52±1.28 and 6.75±1.11 years, respectively. The difference in the mean age between the groups was statistically non-significant (p-value >0.05). In both groups, 15 were males and 15 were females (Table 1).

Figure 1

Patient disposition and follow-up of the study. BDNF, brain-derived neurotrophic factor; MMP-9, matrix metalloproteinase-9; VSMS, vineland social maturity scale; DST, developmental screening test.

Table 1

Demographic and clinical profiles of healthy controls and valproate groups

The majority of children in the valproate group (90.0%) had generalised epilepsy, with generalised tonic-clonic seizures being the most common subtype (46.67%), followed by absence, myoclonic, atonic, and tonic seizures. A smaller proportion (10.0%) had focal epilepsy, including focal simple and focal complex types. At baseline, 18 of 30 patients (60.0%) had >3 seizures per week, seven (23.33%) had 1–3 seizures per week, and 5 (16.67%) had ≤1 seizure per week. In the valproate group, 29 patients (96.67%) responded to drug treatment, i.e., achieved the target clinical response of ≤1 seizure per month after 16 weeks of therapy; while one (3.33%) was a non-responder. Among the responders, 20 patients (66.67%) achieved target clinical response at a dose of 30 mg/kg per day of valproate given in two divided doses, while nine patients (30.0%) responded to a dose of 45 mg/kg per day given in two divided doses (Table 2).

Table 2

Clinical profile of the valproate group

BDNF levels in healthy control and valproate group

Serum BDNF levels in children with epilepsy were significantly (p<0.05) lower compared to healthy controls at 253.87±34.80 pg/mL, and they were significantly (p<0.05) increased from 222.98±23.22 pg/mL at baseline to 397.21±24.90 pg/mL after 16 weeks of treatment in valproate group (Fig. 2).

Figure 2

Effect of valproate on serum BDNF levels (mean±standard deviation) following 16 weeks of treatment in responders. BDNF, brain-derived neurotrophic factor. *p<0.001 (between groups at baseline); **p<0.001 (within valproate group between baseline and week 16).

MMP-9 levels in healthy control and valproate group

Serum MMP-9 levels in children with epilepsy were significantly (p<0.05) higher compared to healthy controls at 3.32±0.48 ng/mL, and they were significantly (p<0.05) decreased from 8.33±0.84 ng/mL at baseline to 6.11±0.91 ng/mL after 16 weeks of treatment in the valproate group (Fig. 3).

Figure 3

Effect of valproate on serum MMP-9 levels (mean±standard deviation) following 16 weeks of treatment in responders. MMP-9, matrix metalloproteinase-9. *p<0.001 (between groups at baseline); **p<0.001 (within valproate group between baseline and week 16).

VSMS and DST scores in healthy control and valproate group

VSMS scores, i.e., SQ, in children with epilepsy were significantly (p<0.05) lower at 96.00 (90.75–100.00) compared to healthy controls and they were significantly (p<0.05) increased from 48 (47.00–65.75) at baseline to 73 (61.00–82.25) at 8 weeks and further to 87 (74.00–94.25) after 16 weeks of treatment in the valproate group (Fig. 4A).

Figure 4

(A) SQ (VSMS score) at 0, 8, and 16 weeks in groups 1 and 2. After valproate treatment, scores at 8 weeks and 16 weeks increased significantly in the valproate group. (B) DQ (DST score) at 0, 8, and 16 weeks in groups 1 and 2. After valproate treatment, scores at 8 weeks and 16 weeks increased significantly in the valproate group. VSMS, vineland social maturity scale; IQR, interquartile range; DST, developmental screening test; DQ, developmental quotient; SQ, social quotient. *p<0.001 (between groups at baseline); **p<0.001 (within valproate group between baseline and 8 weeks); ***p<0.001 (within valproate group between 8 weeks and 16 weeks).

DST scores, i.e., DQ, in children with epilepsy were significantly (p<0.05) lower at 95.50 (90.75–100.25) compared to healthy controls and they were significantly (p<0.05) increased from 76.50 (68.75–85.25) at baseline to 82.50 (76.00–91.00) at 8 weeks and further to 89.50 (83.00–98.00) after 16 weeks of treatment in the valproate group (Fig. 4B).

Correlation between serum biomarkers and neurodevelopmental scores in children with epilepsy

Serum BDNF levels were positively correlated with SQ (VSMS) (ρ=0.710; p<0.001) (Fig. 5A) and DQ (DST) (ρ=0.507; p<0.001) (Fig. 5B). While serum MMP-9 levels were negatively correlated with SQ (VSMS) (ρ=-0.646; p<0.001) (Fig. 5C) and DQ (DST) (ρ=-0.585; p<0.001) (Fig. 5D).

Figure 5

(A) Correlation between serum BDNF levels and social quotient (SQ; VSMS) in children with epilepsy (ρ=0.710; p<0.001). (B) Correlation between serum BDNF levels and developmental quotient (DST) in children with epilepsy (ρ=0.507; p<0.001). (C) Correlation between serum MMP-9 levels and SQ (VSMS) in children with epilepsy (ρ=-0.646; p<0.001). (D) Correlation between serum MMP-9 levels and developmental quotient (DST) in children with epilepsy (ρ=-0.585; p<0.001). VSMS, vineland social maturity scale; BDNF, brain-derived neurotrophic factor; DST, developmental screening test; MMP-9, matrix metalloproteinase-9.

Discussion

BDNF, a neurotrophic factor, is crucial for the survival, growth, and differentiation of neurons during central nervous system development. Studies have shown that BDNF supports nervous system function and promotes neuronal regeneration after injury, which is thought to be closely linked to the development of epilepsy.31

We compared serum BDNF in healthy controls and children with epilepsy before treatment and evaluated effect of valproate treatment on its level. We found that children with epilepsy exhibited significantly lower baseline serum BDNF levels compared to healthy controls. Literature lacks studies evaluating BDNF levels in children with epilepsy. However, our findings are in agreement with other studies performed in adults. One study evaluated BDNF levels in adult patients with acute generalised tonic-clonic seizures (n=50) and chronic epilepsy (n=93), and found a significant decrease in serum BDNF in patients with generalised tonic-clonic seizures compared to controls. This decrease was sustained at 1 hour and 72 hours after seizures. They did not find any association in BDNF and age, aetiology of epilepsy and duration of illness. However, the BDNF level was higher in women than in men in chronic epilepsy patients.32 McGonigal et al.,33 in adult patients with epilepsy, observed that serum BDNF levels were not associated with epilepsy severity or psychiatric comorbidities such as depression and anxiety. Use of ASM was associated with higher BDNF levels in patients, especially valproate and perampanel as compared to patients without ASM. Another study has shown that serum BDNF levels in patients with epilepsy (n=135; age 11 years to 65 years) were not different from those of healthy controls (n=34). Serum BDNF concentrations were measured using Luminex technology in their study. They found gender, but not age, to be a significant factor related to serum BDNF levels in controls and people with epilepsy. Serum BDNF levels in people with epilepsy (mean, 8,798.5; standard error [SE], 321.5 pg/mL) were not different from those of controls (mean, 8,919.5; SE, 709.0 pg/mL). Seizure frequency (p<0.001) and epilepsy duration (p=0.025) were negatively correlated with serum BDNF levels. Hence, they recommended that concentration of BDNF in serum is associated with disease severity in people with epilepsy.34 Whereas our study included newly diagnosed children with epilepsy and healthy controls and found a positive correlation between BDNF and social as well as DQs.

Another study reported that patients with focal epilepsy (n=57) exhibited lower serum BDNF levels compared to healthy controls (n=35).35 Studies performed in adult epilepsy patients had some differences from our study, including study design, inclusion and exclusion criteria, epilepsy duration and use of other ASMs while measuring baseline BDNF.

In contrast to our study, one study found no significant differences in serum BDNF levels between adult patients with mesial temporal lobe epilepsy (n=28) and healthy controls (n=21).36

In our study, following 16 weeks of valproate therapy, BDNF levels were increased. Similarly, one study demonstrated that sodium valproate and its combination with lamotrigine significantly increased serum BDNF levels, with the combination therapy showing even greater elevations. The study involved children with refractory epilepsy (n=110) who were treated either with sodium valproate alone (n=51) or in combination with lamotrigine (n=59).37 Moreover, one study has reported higher serum BDNF levels in patients with focal epilepsy (n=78) compared to healthy individuals (n=13), with a negative correlation between new ASM (including lamotrigine, oxcarbazepine, zonisamide and lacosamide) levels and serum BDNF.38 In our study, post-treatment serum BDNF levels in the valproate group were higher than those of the healthy control group. This indicates that compensatory neuroplasticity and drug-induced BDNF upregulation could possibly be associated with valproate treatment, consistent with previous findings that ASMs such as valproate upregulate BDNF expression via neuroprotective mechanisms.37,39

Furthermore, MMP-9 has been shown to possess a critical role in synaptic remodelling and neuronal circuit reorganisation.40 Elevated MMP-9 levels have been implicated in the pathogenesis of epilepsy via multiple mechanisms including disrupting the blood-brain barrier, promoting neuroinflammation, and facilitating aberrant synaptic plasticity.41

We compared serum MMP-9 in healthy controls and children with epilepsy before treatment and after valproate treatment. Our study found significantly elevated baseline serum MMP-9 levels in children with epilepsy compared to healthy controls, which significantly reduced after following 16 weeks of valproate therapy. The modulatory effect of valproate on MMP-9 observed in our study is aligned with other studies. One study reported significantly elevated serum MMP-9 levels in patients with infantile epileptic spasms syndrome (n=22) compared to age-matched healthy controls (n=12).42 Another study found that monotherapy of topiramate (n=58) and a combination therapy of levetiracetam and topiramate (n=66) significantly reduced serum MMP-9 levels and improved cognitive function in children with intractable epilepsy after 6 months of treatment.39 Hence, the reduction in MMP-9 levels following valproate treatment in our study may indicate normalisation of extracellular matrix remodelling and synaptic plasticity, potentially contributing to seizure control and improved neurological function.

Epilepsy in childhood often disrupts normal brain development, leading to cognitive, behavioural, and social difficulties. Recurrent seizures and altered neuroplasticity can impair learning, attention, and social functioning.20,21 Tools such as the VSMS and DST help quantify these effects by assessing SQ and DQ, providing valuable insight into the broader impact of epilepsy and treatment outcomes.25,30

We found that children with epilepsy had significantly lower VSMS scores compared to healthy controls. This finding aligns with an earlier study, which showed that preschool children with epilepsy (n=26) exhibited significantly lower social competence compared to age- and gender-matched healthy controls (n=26), particularly among those with complicated epilepsy. These children showed fewer age-appropriate social skills and increased attention and behavioural problems, underscoring the impact of early-onset epilepsy on socio-behavioural development.43 Following valproate treatment, we observed improvements in VSMS scores, though they remained below those of healthy controls. These findings complement one study in which improvements in social age following ASM optimisation were observed in children with epilepsy.44

We observed DST scores were significantly lower in children with epilepsy compared to healthy controls. Post-treatment improvements in DST scores suggest that seizure control may positively influence developmental trajectories, though longer follow-up would be necessary to assess sustained effects. Our findings regarding developmental parameters align with the observations of İpek et al.45 who reported lower developmental scores across all domains in children with seizure disorders compared to controls.

Therefore, the results of our study indicate that BDNF and MMP-9 can be used as potential biomarkers for epilepsy. Changes in serum BDNF and MMP-9 biomarkers are associated with clinical response to valproate treatment. Hence, antiseizure/clinical efficacy of valproate could partly be attributed to its BDNF-increasing effect, thus providing neurotrophic support. Therefore, our study corroborates other studies that valproate might upregulate BDNF/neurotrophic signalling as part of its therapeutic effect.46 Using BDNF and MMP-9 as biomarkers can help clinicians develop more personalised treatment plans in pediatric epilepsy, which may lead to improved care and outcomes. In addition, improvements were observed in social and developmental scores, highlighting the age-appropriate neurocognitive and socio-behavioural development in children with epilepsy with valproate. Thus, initiation of valproate therapy can positively influence developmental outcomes and social behavioural functioning in children with epilepsy, along with serum BDNF and MMP-9 levels.

Our study had some limitations, including a small sample size and an open-label design. Additionally, participants were recruited from a single centre and the follow-up duration was relatively short. Apart from that, potential bias may arise on account of using VSMS and DST scores, as these are subjective in nature and they may not reflect the actual social and behavioural development in children with epilepsy after treatment.

The results of our study revealed that BDNF and MMP-9 levels were increased and decreased, respectively, following valproate treatment in children with epilepsy. BDNF and MMP-9 could be potential biomarkers of treatment response in pediatric epilepsy. Valproate therapy also enhanced cognitive and social development in children with epilepsy. These findings indicate that, in addition to seizure control, valproate may contribute to improved developmental outcomes in children with epilepsy. Further long-term studies are warranted to confirm these findings.

Notes

Conflict of Interest

The authors declare no conflicts of interest related to this manuscript.

Acknowledgments

The authors acknowledge Dr Edelbert Antonio Almeida for his assistance in biochemical analysis.

References

1. Fisher RS, Cross JH, French JA, et al. Operational classification of seizure types by the International League Against Epilepsy: position paper of the ILAE commission for classification and terminology. Epilepsia 2017;58:522–30.

2. Fiest KM, Sauro KM, Wiebe S, et al. Prevalence and incidence of epilepsy: a systematic review and meta-analysis of international studies. Neurology 2017;88:296–303.

3. Aaberg KM, Gunnes N, Bakken IJ, et al. Incidence and prevalence of childhood epilepsy: a nationwide cohort study. Pediatrics 2017;139:e20163908.

4. Ngugi AK, Bottomley C, Kleinschmidt I, Sander JW, Newton CR. Estimation of the burden of active and life-time epilepsy: a meta-analytic approach. Epilepsia 2010;51:883–90.

5. Biset G, Abebaw N, Gebeyehu NA, Estifanos N, Birrie E, Tegegne KD. Prevalence, incidence, and trends of epilepsy among children and adolescents in Africa: a systematic review and meta-analysis. BMC Public Health 2024;24:771.

6. Camfield P, Camfield C. Incidence, prevalence and aetiology of seizures and epilepsy in children. Epileptic Disord 2015;17:117–23.

7. Vezzani A, French J, Bartfai T, Baram TZ. The role of inflammation in epilepsy. Nat Rev Neurol 2011;7:31–40.

8. Scharfman HE, MacLusky NJ. Sex differences in the neurobiology of epilepsy: a preclinical perspective. Neurobiol Dis 2014;72(Pt B):180–92.

9. Jeromin A, Bowser R. Biomarkers in neurodegenerative diseases. Adv Neurobiol 2017;15:491–528.

10. Xu X, Miller EC, Pozzo-Miller L. Dendritic spine dysgenesis in Rett syndrome. Front Neuroanat 2014;8:97.

11. Leal G, Bramham CR, Duarte CB. BDNF and hippocampal synaptic plasticity. Vitam Horm 2017;104:153–95.

12. LaFrance WC Jr, Leaver K, Stopa EG, Papandonatos GD, Blum AS. Decreased serum BDNF levels in patients with epileptic and psychogenic nonepileptic seizures. Neurology 2010;75:1285–91.

13. AlRuwaili R, Al-kuraishy HM, Al-Gareeb AI, et al. The possible role of brain-derived neurotrophic factor in epilepsy. Neurochem Res 2024;49:533–47.

14. De Assis GG, Murawska-Ciałowicz E. BDNF modulation by microRNAs: an update on the experimental evidence. Cells 2024;13:880.

15. Mizoguchi H, Yamada K. Roles of matrix metalloproteinases and their targets in epileptogenesis and seizures. Clin Psychopharmacol Neurosci 2013;11:45–52.

16. Rempe RG, Hartz AMS, Bauer B. Matrix metalloproteinases in the brain and blood-brain barrier: versatile breakers and makers. J Cereb Blood Flow Metab 2016;36:1481–507.

17. Yabluchanskiy A, Tarantini S, Balasubramanian P, et al. Pharmacological or genetic depletion of senescent astrocytes prevents whole brain irradiation-induced impairment of neurovascular coupling responses protecting cognitive function in mice. Geroscience 2020;42:409–28.

18. Wilczynski GM, Konopacki FA, Wilczek E, et al. Important role of matrix metalloproteinase 9 in epileptogenesis. J Cell Biol 2008;180:1021–35.

19. Doll DN, Barr TL, Simpkins JW. Cytokines: their role in stroke and potential use as biomarkers and therapeutic targets. Aging Dis 2014;5:294–306.

20. Holmes GL. Effect of seizures on the developing brain and cognition. Semin Pediatr Neurol 2016;23:120–6.

21. Reilly C, Atkinson P, Das KB, et al. Neurobehavioral comorbidities in children with active epilepsy: a population-based study. Pediatrics 2014;133:e1586–93.

22. Shimizu H, Morimoto Y, Yamamoto N, Tayama T, Ozawa H, Imamura A. Overlap between epilepsy and neurodevelopmental disorders: insights from clinical and genetic studies. In : Czuczwar SJ, ed. Epilepsy 1st edth ed. Brisbane (AU): Exon Publications; 2022. p. 41–54.

23. Berg AT, Langfitt JT, Testa FM, et al. Global cognitive function in children with epilepsy: a community-based study. Epilepsia 2008;49:608–14.

24. Berg AT, Zelko FA, Levy SR, Testa FM. Age at onset of epilepsy, pharmacoresistance, and cognitive outcomes: a prospective cohort study. Neurology 2012;79:1384–91.

25. Sparrow SS. Vineland adaptive behavior scales. In : Kreutzer JS, DeLuca J, Caplan B, eds. Encyclopedia of Clinical Neuropsychology 2nd edth ed. New York, NY: Springer; 2011. p. 2618–21.

26. Chung HJ, Yang D, Kim GH, et al. Development of the Korean developmental screening test for infants and children (K-DST). Clin Exp Pediatr 2020;63:438–46.

27. Perucca E. Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience. CNS Drugs 2002;16:695–714.

28. Doll EA. The Measurement of Social Competence: A Manual for the Vineland Social Maturity Scale 1st edth ed. Minneapolis: Educational Test Bureau; 1953. p. 39–54.

29. Yang S, Paynter JM, Gilmore L. Vineland adaptive behavior scales: II profile of young children with autism spectrum disorder. J Autism Dev Disord 2016;46:64–73.

30. Bellman M, Byrne O, Sege R. Developmental assessment of children. BMJ 2013;346:e8687.

31. Wang X, Hu Z, Zhong K. The role of brain-derived neurotrophic factor in epileptogenesis: an update. Front Pharmacol 2021;12:758232.

32. Poniatowski ŁA, Cudna A, Kurczych K, Bronisz E, Kurkowska-Jastrzębska I. Kinetics of serum brain-derived neurotrophic factor (BDNF) concentration levels in epileptic patients after generalized tonic-clonic seizures. Epilepsy Res 2021;173:106612.

33. McGonigal A, Becker C, Fath J, et al. BDNF as potential biomarker of epilepsy severity and psychiatric comorbidity: pitfalls in the clinical population. Epilepsy Res 2023;195:107200.

34. Hong Z, Li W, Qu B, et al. Serum brain-derived neurotrophic factor levels in epilepsy. Eur J Neurol 2014;21:57–64.

35. Chen SF, Jou SB, Chen NC, et al. Serum levels of brain-derived neurotrophic factor and insulin-like growth factor 1 are associated with autonomic dysfunction and impaired cerebral autoregulation in patients with epilepsy. Front Neurol 2018;9:969.

36. Filimonova EA, Pashkov AA, Moysak GI, et al. Brain but not serum BDNF levels are associated with structural alterations in the hippocampal regions in patients with drug-resistant mesial temporal lobe epilepsy. Front Neurosci 2023;17:1217702.

37. Zhang D, Qiu L, Zhang Y, Sang Y, Zheng N, Liu X. Efficacy and safety of sodium valproate plus lamotrigine in children with refractory epilepsy. Exp Ther Med 2020;20:2698–704.

38. Demir M, Akarsu EO, Dede HO, et al. Investigation of the roles of new antiepileptic drugs and serum BDNF levels in efficacy and safety monitoring and quality of life: a clinical research. Curr Clin Pharmacol 2020;15:49–63.

39. Pan D, Li X, Jiang J, Luo L. Effect of levetiracetam in combination with topiramate on immune function, cognitive function, and neuronal nutritional status of children with intractable epilepsy. Am J Transl Res 2021;13:10459–68.

40. Kuzniewska B, Rejmak K, Nowacka A, et al. Disrupting interaction between miR-132 and MMP9 3’UTR improves synaptic plasticity and memory in mice. Front Mol Neurosci 2022;15:924534.

41. Bronisz E, Kurkowska-Jastrzębska I. Matrix metalloproteinase 9 in epilepsy: the role of neuroinflammation in seizure development. Mediators Inflamm 2016;2016:7369020.

42. Matsuura R, Hamano SI, Koichihara R, et al. Serum matrix metallopeptidase-9 levels in infantile epileptic spasms syndrome of unknown etiology. Epilepsy Res 2024;207:107454.

43. Rantanen K, Timonen S, Hagström K, Hämäläinen P, Eriksson K, Nieminen P. Social competence of preschool children with epilepsy. Epilepsy Behav 2009;14:338–43.

44. Rangarajan A, Mundlamuri RC, Kenchaiah R, et al. Efficacy of pulse intravenous methylprednisolone in epileptic encephalopathy: a randomised controlled trial. J Neurol Neurosurg Psychiatry 2022;93:1299–305.

45. İpek R, Makharoblidze K, Polat BG, et al. Developmental evaluation in children experiencing febrile convulsions. Turk J Pediatr 2021;63:602–11.

46. Shpak AA, Guekht AB, Druzhkova TA, Rider FK, Gulyaeva NV. Brain-derived neurotrophic factor in blood serum and lacrimal fluid of patients with focal epilepsy. Epilepsy Res 2021;176:106707.

Article information Continued

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Parameter	Healthy control (n=30)	Valproate group (n=30)
Age (years)	6.52±1.28	6.75±1.11
Gender
Male	15	15
Female	15	15
Parental education ≥10th grade	23 (76.66)	21 (70.0)
Employment of parents (employed)	27 (90.0)	26 (86.66)

	Value
Epilepsy type
Generalised epilepsy	27 (90.0)
Focal epilepsy	3 (10.0)
Seizure type
Generalised tonic–clonic	14 (46.67)
Absence	5 (16.67)
Myoclonic	4 (13.33)
Atonic	3 (10.0)
Tonic	1 (3.33)
Focal simple	2 (6.67)
Focal complex	1 (3.33)
Seizure frequency (at baseline)
>3 per week	18 (60.0)
1–3 per week	7 (23.33)
≤1 per week	5 (16.67)
Responders	29 (96.67)
At the dose of 30 mg/kg per day	20 (66.67)
At the dose of 45 mg/kg per day	9 (30.0)
Non-responder	1 (3.33)