Introduction

Epilepsy is one of the most prevalent pediatric neurological disorders globally, with a prevalence rate of 7.6 per 1000 children and an estimated annual incidence of 61.4 cases per 100,000 children. In Indonesia, the prevalence of epilepsy is estimated to be between 5 and 10 per 1000 children, with an annual incidence of 50 to 200 cases per 100,000 children.1 A significant proportion of children with epilepsy, ranging from 7% to 30%, develop Drug-Resistant Epilepsy (DRE).2–4 Drug-Resistant Epilepsy is characterized by the failure of adequate trials of two well tolerated, appropriately selected, and used anti-seizure medication (ASM) to achieve sustained seizure freedom.5–7

The quality of life (QoL) in children with epilepsy, particularly those with DRE, is profoundly impacted by uncontrolled seizures and associated psychological disorders, including behavioral issues, learning difficulties, memory degradation, identity disorders, and social interaction problems.8,9 This reduced QoL not only affects the patients but also extends to their parents and families. Drug-Resistant Epilepsy is associated with cognitive impairment, mood disorders, injury, and an increased risk of mortality, including sudden death in epilepsy.10–12

Various factors contribute to the decreased QoL in children with DRE, including the frequency and severity of seizures,13–15 and chronic epilepsy leading to increased neuroinflammation, cytokines, and other inflammatory biomarkers such as interleukin-1beta (IL-1β).16,17 Direct or indirect inflammation significantly impacts QoL. Comorbidities and radiological abnormalities also play crucial roles in affecting QoL in these children.8,18–20

Risk factors for DRE include high frequency of seizures in the early phase of the disorder, particularly due to hippocampal sclerosis.15,21 Previous studies indicate that half of DRE cases occur in children with focal idiopathic epilepsy, and frequent seizures occur at the onset of epilepsy.5,22

Neuroinflammation is a critical factor leading to DRE, characterized by an inflammatory response in the central nervous system involving glial cell activation and the release of inflammatory mediators.23–25 This inflammation affects the homeostatic function of astrocytes, microglia, and the blood–brain barrier thereby increasing seizure risk.26 Inflammatory molecules, including IL-1β, influence the nervous system in epilepsy. Elevated levels of IL-1β are associated with decreased QoL.27,28

Although it has been suggested that IL-1β influences the quality of life in children with epilepsy, it remains to be conclusively proven whether IL-1β indeed has a significant impact. Further research is necessary to verify the role of IL-1β in affecting the quality of life in children with epilepsy.

Low vitamin D status can adversely affect various components of QoL in children with DRE, such as cognitive function, executive function, emotions, behavior, and mood.29–31 This impact can be direct or indirect due to the DRE condition.32,33 Vitamin D plays a potential role in neuroinflammation in epilepsy, with several studies indicating a relationship between vitamin D deficiency and epilepsy.34–36 Vitamin D deficiency can lead to an imbalance of excitation and inhibition and a pro-inflammatory shift in the brain, increasing seizure risk.37,38

Comorbidities and radiological anomalies of the brain may also influence the QoL of pediatric patients with DRE.39 Comorbidities refer to preexisting medical conditions or congenital disorders present before the diagnosis of DRE,40 while radiological abnormalities include various structural brain irregularities identified through imaging techniques such as CT and MRI scans of the head.41–43

This research endeavor is directed toward evaluating the factors that exert the greatest influence on the quality of life experienced by children suffering from DRE.

Materials and Methods

This preliminary study used a cross-sectional design and was conducted at Adam Malik Hospital, Medan, Indonesia, from January 2024 until June 2024. The work included preparation of materials and equipment, administration of treatment, and the compilation of reports. The target population in this study was children with DRE. Specifically, the study targeted children with DRE who were attending the Pediatric Neurology Outpatient Clinic at Adam Malik Hospital, Medan.

Inclusion and Exclusion Criteria

Consecutive sampling was used in this study. The participants were pediatric patients with DRE who fulfilled specific criteria, including being aged between 4 and 18 years, taking chronic anti-seizure medication (ASM) for more than 24 weeks, still experiencing seizures within the last 12 weeks, not consuming vitamin D supplements for the past 24 weeks, and obtaining parental consent to participate in this study. Patients with cardiac, renal, hepatic, nutritional deficiencies, or other non-neurological chronic conditions were excluded from the study.

Variable Determinant

The child’s age was ascertained based on the date of birth up to the time of the visit to the polyclinic and quantified in years. The patient’s age was categorized into two categories based on WHO classification and adjusted according to Indonesian law: children (aged 4–10 years old) and adolescent (aged 10–18 years old).

The severity of epilepsy was evaluated through the Hague Seizure Severity Scale (HASS) questionnaire, utilizing a scoring system. This questionnaire, completed by parents, consisted of 13 questions concerning the child’s seizures in the preceding 3 months. Each question was assigned a value from 1 to 4, with 1 denoting the most favorable response and 4 the least favorable; hence, the range of scores was from 13 to 52. Lower scores correspond to a milder perception of seizures by the parents. In this investigation, epilepsy severity was classified into two groups: mild (HASS score of 13–32) and severe (HASS score of 33–52).

Vitamin D status was assessed through the quantification of serum 25-hydroxy vitamin D (25(OH)D) levels in the bloodstream, denoted in picograms per milliliter (pg/mL). Vitamin D status was classified into three categories: sufficient (31–100 pg/mL); insufficient (20–30 pg/mL); or deficient (< 20 pg/mL).

Interleukin-1 beta (IL-1β) was a pro-inflammatory cytokine that could instigate seizures, quantified through the ELISA method in blood samples, with results reported in pg/mL units.

Comorbidities referred to preexisting conditions or congenital disorders experienced by the patient before the diagnosis of DRE. These comorbidities predominantly pertained to neurological and developmental issues, including but not limited to cerebral palsy, hemiparesis, global developmental delay (GDD), intellectual disability, attention deficit hyperactivity disorder (ADHD), autism, tuberculosis complex (TSC), and congenital rubella syndrome.

Radiological abnormalities encompassed irregularities in brain structure identified through head CT or MRI scans, such as cerebral atrophy, classification anomalies, hydrocephalus, pachygyria among others.

The evaluation of children’s quality of life was conducted through the Quality of Life in Childhood Epilepsy Questionnaire-55 (QOLCE-55), which generated a quantitative score. Parents completed this questionnaire consisting of 55 items, each rated on a scale of 1–6, in which 1 signified “very bad” and 6 indicated “very good.” Subsequently, the cumulative scores from all questions provided a total score, ranging from 55 to 330, with higher scores indicative of higher quality of life. The interpretation of this scoring system is classified into two categories, bad and good QoL with total score ranging from 55–220 and 221–330, respectively.

Data Analysis

The entire data was inputted into a central table and analyzed using Statistical Package for The Social Sciences (SPSS) software. Numerical data exhibiting a normal distribution was presented as mean + SD (standard deviation), whereas data not following a normal distribution was shown in median (minimum-maximum) values. Categorical data was depicted in quantities (percentages). The assessment of normality involved the application of the Kolmogorov–Smirnov test (for sample sizes exceeding 50). Evaluation of the connection between the variables of gender, age, epilepsy severity (HASS score), vitamin D-25OH levels, IL-1β, comorbidities, and radiological abnormalities with the QoL in children with DRE was conducted through bivariate analysis. The impact of the independent variables on the dependent variable was examined through multivariate analysis using the logistic regression test. Furthermore, a multivariate logistic regression analysis was conducted to evaluate numerous risk factors that significantly impact the quality of life of children with DRE. The correlation between the independent and dependent variables was determined using the Pearson test when the data adheres to a normal distribution, whereas the Spearman test was utilized for non-normally distributed data. Two-tailed p < 0.05 was considered statistically significant. The significant risk factors were further analyzed using ROC (Receiver Operating Characteristic) curve to analyze the sensitivity and specificity and determined the most optimal cut-off point.

Ethical Approval

The study was conducted in Medan, North Sumatra, Indonesia. The parents of the patients involved in this study were informed about the purpose of this study, in accordance with the Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects, Good Clinical Practice, and all applicable local regulatory requirements and laws. This study was approved by The Health Research Ethics Committee, Ministry of Education, Culture, Research, and Technology at the University of Sumatera Utara (protocol code: No. 1194/KEPK/USU/2023) and Adam Malik Hospital, Indonesia (protocol code: LB02.02/XV.III.2.2.2/85/2024). This study had been registered on ClinicalTrials.gov with the identifier NCT06053281.

Results

This study involved 57 children with Drug-Resistant Epilepsy (DRE). All children and subjects included in this study met the inclusion criteria. The complete characteristics of the children were presented in Table 1. The gender distribution was almost equal with 52.6% male and 47.4% female. The majority of the subjects were adolescents (70.2%) with severe epilepsy (54.4%). More than 80% of the subjects had abnormal Vitamin D-25OH level: insufficiency (42.1%) and deficiency (40.4%). It was observed that about 50% of the subjects had comorbidities. Meanwhile, those with radiological abnormalities were fewer (31.6%) than those without (68.4%).

Table 1 Characteristics of Research Subjects and the Correlation of Gender, Age, Epilepsy Severity (HASS Score), Vitamin D (25(OH)D) Levels, IL-1β Levels, Comorbidities, and Radiologic Abnormalities to Quality of Life in Children with DREs

The correlation of gender, age, epilepsy severity (HASS score), vitamin D (25(OH)D) levels, IL-1β levels, comorbidities, and radiological abnormalities to quality of life in children with DRE showed a significant relationship between several factors and quality of life as shown in Table 1. The presence of comorbidities and radiological abnormalities were significantly associated with decreased QoL. Children with DRE without comorbidities tend to have a better QoL compared to those with comorbidities (p < 0.0001). Quality of life was also better in children without radiological brain abnormalities compared to those with abnormalities (p = 0.0002). The increased IL-1β levels were also associated with decreased QoL (p = 0.014).

There was a significant difference in IL-1 β levels in DRE children in the poor and good quality of life groups. So, we evaluated further using ROC curve analysis in Figure 1 to see the performance of IL-1β in predicting quality of life in epilepsy patients and to determine the most optimal cut-off point. The results of the ROC analysis showed that the area under the curve (AUC) is 0.699 with a standard error of 0.076 as shown in Figure 2. Table 2 shows result of ROC analysis for IL-1β levels which is the AUC value and had a significance of 0.014, with a 95% confidence interval ranging from 0.549 to 0.84. The AUC values obtained indicate that IL-1β levels had a fairly good ability to differentiate between good and poor quality of life in DRE patients. The IL-1β cut-off point of 282.14 pg/mL was found to be the optimal value based on ROC analysis, with an area under the curve (AUC) of 0.699 shown in Table 3. This suggests moderate accuracy of IL-1β as a biomarker in predicting quality of life. At this cutoff, the sensitivity and specificity of IL-1β were 64.9% and 65%, respectively. The sensitivity of 64.9% indicated that this cutoff could identify 64.9% of patients who have poor quality of life with IL-1β levels higher than 282.14 pg/mL. Meanwhile, a specificity of 65% showed that this cutoff could identify 65% of patients who had a good quality of life with IL-1β levels lower than 282.14 pg/mL. These results indicate that IL-1β levels could be used as a potential biomarker to evaluate the quality of life of children with epilepsy. Although the AUC value showed that IL-1β was not a very strong predictor, the combination of sensitivity and specificity obtained was sufficient to consider IL-1β levels as one of the parameters in assessing the quality of life of epilepsy patients.

Table 2 Area Under the Curve Test Result Variable (S): IL-1β Levels

Table 3 ROC Analysis for IL-1β Levels

Figure 1 ROC curve analysis.

Figure 2 ROC analysis of IL-1β levels and QoL with AUC of 0.699.

Table 4 showed the result of multivariate analysis of gender, age, epilepsy severity (HASS Score), vitamin D-25OH levels, IL-1 β levels, comorbidities, and radiological abnormalities on quality of life in children with DRE. Based on the results of the multivariate logistic regression analysis, several risk factors were proven to have a significant influence on QoL in children with DRE. Vitamin D levels, even if abnormal, had no statistically significant effect on quality of life. Comorbidities (OR = 24.98, p = 0.004, 95% CI) and high IL-1β levels (OR = 8.36, p = 0.022, 95% CI) were significant risk factors in reducing the QoL in children with DRE, indicating 24.98- and 8.36- times higher likelihood of decreased QoL, respectively. Other characteristics, albeit not statistically significant, appeared to impact quality of life.

Table 4 Multivariate Analysis of Gender, Age, Epilepsy Severity (HASS Score), Vitamin D-25OH Levels, IL-1β Levels, Comorbidities, and Radiological Abnormalities on Quality of Life in Children with DRE

Discussion

This study showed that the presence of comorbidities and IL-1β levels were strongly correlated and significant on the quality of life in children with DRE. Children with comorbidities have a 24.98 times greater risk of decreased QoL than children without comorbidities. Children with high IL-1β levels have an 8.36 times greater risk of decreased QoL than children with low IL-1β levels.

Neurodevelopmental related comorbidities such as cerebral palsy, hemiparesis, GDD, intellectual disability, ADHD, autism, TSC, congenital rubella syndrome, etc. were the main contributor to the burden of disease experienced by children.44–47 Previous study revealed that almost 80% of children with epilepsy have one or more comorbidities, 55% with other medical disorders, 41% with additional neurological disorders, and 43% with developmental/psychiatric disorders. Children with either complicated or uncomplicated epilepsy had the highest rates of overall comorbidity leading to decreased quality of life, cognitive impairment, and other neurological and mental health disorders.48–52 Psychiatric comorbidities such as depression and anxiety were highly prevalent in children with epilepsy, further affecting their quality of life and functioning.53 These comorbidities could complicate treatment strategies, increased the risk of drug resistance, and necessitated a multidisciplinary approach to the management of children with DRE. Early identification and intervention are crucial to improve the overall well-being of children with epilepsy, emphasizing the importance of addressing these complex needs to enhance the outcomes and quality of life.49,54,55

IL-1β is a pro-inflammatory cytokine that played a role in facilitating and strengthening the inflammatory response in the body.56,57 IL-1β was produced by macrophages, monocytes, and dendritic cells as a proprotein, which was processed into its active form by caspase 1. IL-1β was also involved in the regulation of neurotransmission and had been linked to epileptogenesis and neuroinflammation in drug-resistant epilepsy.58,59 IL-1β might influence excitatory neurotransmission through changes in The N-methyl-D-aspartate (NMDA) receptor phosphorylation.60,61 Research suggested that IL-1β could aggravate seizures in epileptic individuals. IL-1β suppression might be a treatment option for DRE, according to many studies.60,62,63

Epilepsy’s pathogenesis was linked to elevated IL-1β levels.64 In the central nervous system (CNS), IL-1β was primarily produced by activated microglia but was also produced by neurons, astrocytes, and oligodendrocytes.65 In a healthy brain, IL-1β was present at low levels and played a role in the process of sleeping, learning, memorization, and neuromodulation. IL-1β levels in the patient’s peripheral blood could indicate the severity of the seizure.66 It could inhibit neurotransmission mediated by gamma-aminobutyric acid (GABA), inhibit glutamate uptake by astrocytes, and modulate neurons. Inhibition by IL-1RI antagonists or prevention of synthesis had neuroprotective effects.67

Interleukin 1 beta (IL-1β) played a significant role in affecting the quality of life of people with epilepsy. Studies had shown that IL-1β was acutely upregulated after ischemic stroke, leading to an increased risk of post-stroke seizures.68 Additionally, IL-1β had been linked to reduced neurogenesis in the epileptic human hippocampus, contributing to learning and memory difficulties in temporal lobe epilepsy patients.69 IL-1β signaling had been identified as a mediator of post-traumatic astrogliosis and seizure susceptibility after pediatric brain injury, highlighting its role in epileptogenesis and the potential for pharmacological intervention to improve QoL for individuals with epilepsy.70 Therefore, targeting IL-1β and its associated inflammatory responses might provide therapeutic benefits for managing epilepsy and improving the overall quality of life for affected individuals.

The results of this study suggested that IL-1β levels could serve as a potential biomarker for assessing the quality of life of children with DRE. Although the AUC value indicated that IL-1β may not be a very strong predictor on its own, the combination of sensitivity and specificity obtained was sufficient to consider IL-1β levels as one of the parameters in evaluating the QoL of children with DRE.

Several other factors also showed a tendency to affect quality of life in this study. Patients with radiological abnormalities tended to have an 8.21 times greater risk of experiencing a decreased QoL.

Brain structure abnormalities in epilepsy could significantly impact the quality of life of individuals with the condition. Research highlighted that alterations in neuronal dynamics, such as abnormal oscillation patterns, played a crucial role in cognitive impairment in epilepsy, independent of seizures and interictal epileptiform activity.71,72 The correlation between cerebral atrophy, calcification, hydrocephalus, and pachygyria, as seen in conditions like Sturge-Weber syndrome and primary familial brain calcification, could lead to dysfunctional communication between the hippocampus and prefrontal cortex, contributing to cognitive deficits and psychiatric manifestations.73–75 This impaired communication could affect behavior and cognitive functions even without structural damage. Underlying brain dysfunction, particularly in the hippocampus, served as a significant predictor of depression in epilepsy, impacting subjective health status and quality of life.76,77 This present research showed that brain radiology abnormalities were a significant risk factor for quality of life at the beginning of bivariate analysis. However, after multivariate analysis, the significance of radiological abnormalities as a risk factor was not as strong as comorbidities and IL-1β.

Vitamin D deficiency was a significant concern for children with epilepsy.78 Parents of children with DRE experience significantly higher levels of stress compared to those with controlled epilepsy, impacting their QoL.79 The Quality of Life in Childhood Epilepsy Questionnaire (QOLCE) had been validated as a reliable measure for assessing the quality of life in children with DRE, providing valuable insights into their well-being.80 Studies had shown that children on ASM were prone to vitamin D insufficiency, with enzyme-inducing ASM affecting vitamin D metabolism.78,81 Furthermore, pediatric epilepsy patients on non-enzyme-inhibiting ASM therapy and those reaching puberty were at a higher risk of hypovitaminosis D.81,82

Studies had shown that prolonged use of ASM had been linked to hypovitaminosis D, which affects bone mineral density, leading to an increased risk of fractures and osteoporosis, especially in those resistant to medication, which significantly impacts QoL.82–85 Children with epilepsy have a higher prevalence of vitamin D deficiency compared to healthy controls, with a strong negative correlation between vitamin D levels and the duration of epilepsy treatment.78 Vitamin D deficiency was also correlated with neuroinflammation. Neuroinflammation played a crucial role, especially in DRE, affecting immune, pathophysiological, and biochemical processes, leading to aberrant neural connections and hyperexcitable neural networks.67,86 Vitamin D played a crucial role in the quality of life of children with DRE by potentially upregulating the vitamin D receptor (VDR) and influencing transcriptional activity.87

In this study, there was no significant effect of vitamin D levels, either normal or abnormal, on the quality of life of children with DRE. Future studies may need to evaluate the impact of vitamin D levels after supplementation with vitamin D on improving the quality of life of children with DRE. Monitoring and supplementation of vitamin D are essential in managing epileptic children on long-term ASM to mitigate the adverse effects on bone health and the impact of neuroinflammation on their quality of life and overall health.

Limitation

This is preliminary research. This research is a single-center study with a small sample size, limited by the research duration, rendering the necessity of larger sample size and multi-center study to increase the validity of this research. Duration and types of anti-seizure medications were disregarded in this study.

Conclusion

This study showed no impact of vitamin D on the quality of life of children with DRE, but overall, the results of this study provided important information regarding risk factors that need to be considered in the management of patients with drug-resistant epilepsy, especially those related to the presence of high levels of IL-1β and comorbidities. These findings will help develop more comprehensive and targeted management strategies to improve the QoL of children with DRE.

Acknowledgments

We sincerely thank all individuals and institutions who contributed to this research, for their expertise and guidance throughout the project, and for their technical support. This work would not have been possible without the dedication and contributions of each individual mentioned.

Author Contributions

Each author has made substantial contributions to this study, encompassing various areas such as conceptualization, study design, implementation, data collection, analysis, and interpretation. All authors have been involved in drafting, revising, and critically reviewing the article. They have provided their final approval for the version to be published and have participated in the decision regarding the choice of journal for submission. Furthermore, all authors agree to take responsibility for every aspect of the work.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Disclosure

The authors report no conflicts of interest in this work.

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