Comparative Assessment of Quality of Life and Serum S100B in Epilepsy Treated with Newer and Conventional Drugs: A Pharmacoeconomic Perspective
Article information
Abstract
Background and Purpose
S100B is a cytokine produced by astrocytes following glial and neuronal damage. This study aims to evaluate the impact of anti-epileptic drugs (AEDs) on serum S100B levels and health-related quality of life (HRQoL) indices.
Methods
In this prospective observational study, serum S100B levels were compared between persons with epilepsy (PWE) and healthy controls. In the PWE group, serum S100B levels and HRQoL using patient weighted quality of life in epilepsy (QOLIE-10-P), pittsburgh sleep quality index (PSQI), and liverpool adverse event profile (LAEP) scores were assessed at baseline and after 12 weeks of AEDs treatment.
Results
The mean baseline serum S100B level in the PWE group was 0.093±0.031 μg/L, significantly higher than in the control group, 0.050±0.020 μg/L. In PWE, after 12 weeks of treatment, this level decreased by 17.20% (p<0.001). QOLIE-10-P scores showed improvement (32.1%; p<0.001) across both conventional and newer AED types. PSQI scores improved by 6.9% with conventional AEDs (p=0.19) and 35.7% with newer AEDs (p<0.001). LAEP scores increased by 5.06% with conventional AEDs (p=0.06) and decreased by 5.63% with newer AEDs (p=0.10). Seizures were significantly reduced in both groups (overall 86.09%). Treatment costs were higher for newer AEDs ($39.10) than for conventional AEDs ($16.73).
Conclusions
Over 12 weeks of AED therapy, PWE demonstrated significant reductions in both serum S100B levels and seizure frequency. While conventional and newer AEDs yielded comparable improvements in HRQoL, newer AEDs conferred an advantage in sleep quality.
Introduction
Epilepsy represents a prevalent neurological disorder on a global scale, significantly impacting social and economic dimensions.1 The World Health Organisation reports approximately 50 million individuals affected by epilepsy worldwide, with a disproportionate 80% residing in developing nations.2
Seizure is a neurological disorder where reactive astrocytosis leads to local synaptic dysfunction, which ultimately causes deficits in neuronal inhibition.3 S100B is a calcium-binding cytokine produced primarily by astrocytes that shows autocrine and paracrine effects on neurons and glial cells.4 At nanomolar concentrations, S100B stimulates the growth of neurons, promotes the proliferation of astrocytes, and increases free calcium levels in both neurons and astrocytes.5,6 Increase in S100B may be due to either damage to glial cells or astrocytic reactions to neuronal injury.3,7 The elevated S100B level is used as a marker of injury to the astrocytes and is also associated with a number of diseases including epilepsy.7–11
The role of S100B in epilepsy has generated mixed and sometimes opposing conclusions in various studies. S100B is a protein primarily found in the brain’s glial cells and its levels in the extracellular fluid are considered indicators of neuronal and glial activity. Research has shown that during periods of interictal dysfunction, particularly within the temporal lobe, there can be an increase in S100B, suggesting this marker may help identify the seizure origin.12,13 Several studies have reported that S100B levels are notably higher in individuals experiencing epilepsy. This has been observed in children undergoing seizure episodes, where S100B was significantly elevated.14 Similarly, research has indicated that an increase in S100B levels could correlate with more frequent seizures, especially in cases of temporal lobe epilepsy.15 Elevated S100B has also been associated with mesial temporal lobe epilepsy, pointing to a potential ongoing pathological process in the brain,13 especially in the context of febrile seizures and their likelihood of recurrence.16 However, not all findings align with this perspective. Some investigations have found no significant changes in S100B levels following certain seizure events, including focal to bilateral tonic-clonic seizures or after episodes of convulsive status epilepticus.17 This was similarly observed in patients with focal epilepsy, where S100B levels remained within normal ranges.18
These contrasting findings underscore the complexity of using S100B as a biomarker for epilepsy. While there’s evidence supporting its elevation in relation to seizure activity and underlying pathological processes, discrepancies exist, suggesting the need for further research to clarify S100B’s role and reliability as an indicator in epilepsy.
There are limited studies that show the effect of anti-epileptic drugs (AEDs) on serum biomarker S100B in persons with epilepsy (PWE). The effect of anti-seizure drugs (carbamazepine and oxcarbazepine) in persons with focal seizures has been studied recently.19 There is paucity of studies that show the effect of conventional and newer antiepileptic drugs on serum biomarker S100B in PWE. Hence, the present prospective observational study has been outlined to evaluate the effect of AEDs on serum biomarker S100B in PWE (focal and generalized).
The primary objective of this study was to investigate the impact of AEDs on serum S100B levels in individuals diagnosed with epilepsy. The secondary objectives were: 1) to compare the effects of conventional versus newer AEDs on serum S100B levels; 2) to assess changes in health-related quality of life (HRQoL) and sleep quality post-treatment using the patient weighted quality of life in epilepsy (QOLIE-10-P), pittsburgh sleep quality index (PSQI), respectively; 3) to evaluate the incidence of adverse events using the liverpool adverse events profile (LAEP); 4) to monitor seizure frequency following treatment and analyze its correlation with changes in S100B levels; and 5) to compare the cost of treatment over a 12-week follow-up period between conventional and newer AED groups.
Methods
This prospective observational study was conducted at Lady Hardinge Medical College, New Delhi. The study was conducted from October 2022 to January 2024. Diagnosed PWE according to the International League Against Epilepsy and treatment naïve were enrolled and commenced treatment within the past 7 days, i.e., early treatment group in this study. Written informed consent was taken from persons willing to participate in the study. The decision to select an antiepileptic drug was taken by the treating physician. The study protocol was approved by the institutional Ethics Committee of the Lady Hardinge Medical College, New Delhi, and is concordant with the Declaration of Helsinki.
Inclusion & exclusion criteria
Inclusion criteria for this study are individuals more than 18 years of age and diagnosed with epilepsy according to the International League Against Epilepsy criteria, and either have not received any treatment for epilepsy (treatment-naïve) or have been diagnosed with epilepsy and commenced treatment within the past 7 days.
Individuals with neuroendocrine tumors, neurodegenerative disorders, or a history of significant brain injury, transient ischemic attacks, stroke, neurosurgical procedures, or neuropsychiatric disorders were excluded. Participants with major psychiatric illnesses (such as depression, anxiety disorders, bipolar disorder, or psychosis); primary sleep disorders (including obstructive sleep apnea, chronic insomnia, or restless legs syndrome); or those receiving medications known to influence serum S100B levels or sleep quality (e.g., benzodiazepines, Z-drugs, antidepressants, antipsychotics, corticosteroids, or chronic alcohol use) were also excluded. In addition, individuals with pregnancy or lactating, had severe hepatic or renal impairment, or had recent central nervous system infections or inflammatory conditions were excluded. Participants unable to provide informed consent or comply with study procedures were excluded. Only individuals planned for monotherapy maintenance were included; those who subsequently required treatment modification, such as conversion to polytherapy or discontinuation of AEDs, were excluded as per predefined criteria.
A total of 46 individuals with newly diagnosed epilepsy, meeting the above criteria, constituted the test group. A corresponding control group of 46 healthy individuals, free of epilepsy and any significant neurological or neuropsychiatric conditions, was recruited to provide baseline serum S100B values for comparison between PWE and healthy individuals. Venous blood samples were obtained from both groups at baseline and the test group was re-sampled at 12 weeks to assess changes in serum S100B levels over time. Additionally, PWE were asked to complete standardized quality-of-life assessments, including the QOLIE-10-P, PSQI, and LAEP questionnaires, as well as a cost-of-treatment survey, at baseline and after 12 weeks, to evaluate longitudinal changes in their quality of life and treatment burden.
Outcome
The primary outcome of this study was the measurement of serum S100B levels in PWE, serving as a direct indicator of the physiological response to AED therapy. Serum S100B was estimated by enzyme-linked immunosorbent assay (ELISA) using human S100B ELISA kit from Invitrogen® (Thermo Fisher Scientific, Waltham, MA, USA). The assay utilizes the “sandwich” technique. The method can detect S100B from 31.25–2,000 pg/mL. Secondary outcomes included the evaluation of quality-of-life improvements, measured by the QOLIE-10-P, and sleep quality, assessed using the PSQI. Additionally, the study quantified seizure frequency and documented adverse events, employing the LAEP for a comprehensive safety profile. An economic assessment also compared the costs associated with the use of conventional versus newer AEDs over a 12-week follow-up period, offering insights into the cost-effectiveness of epilepsy treatment strategies.
Statistical analysis
Data were transformed, coded, and entered in Microsoft Excel® (Microsoft Corporation, Redmond, WA, USA). Statistical analysis was performed using IBM SPSS Statistics ver 28.0 (IBM Corporation, Armonk, NY, USA). Parametric data were expressed as mean± standard deviation or percentage, and non-parametric data as median and range. Student’s t-test and Mann-Whitney U-test were used for parametric and non-parametric comparisons, respectively. Spearman’s rank correlation was applied for association analysis. Multivariable linear regression analyses were conducted to evaluate whether changes in S100B predict clinical outcomes, adjusting for key covariates. A p-value <0.05 was considered statistically significant.
Results
A total of 55 patients, clinically diagnosed with either focal or generalized seizures and who were treatment-naïve, were initially enrolled in the study. Inclusion criteria also allowed for persons diagnosed with epilepsy who had been treated for no more than 7 days at the time of enrollment. Following enrollment, nine PWE were excluded due to discontinuation of AED treatment, conversion to polytherapy or failure to attend follow-up appointments. Consequently, the study’s evaluation focused on 46 PWE (Fig. 1). The average baseline seizure frequency among enrolled PWE was 3.02 over past 12 weeks. Table 1 shows the demographic details of all PWE.
CONSORT diagram of the study. PWE, persons with epilepsy; QOLIE-10-P, patient weighted quality of life in epilepsy; PSQI, pittsburgh sleep quality index; LAEP, liverpool adverse event profile; AED, anti-epileptic drug; CONSORT, Consolidated Standards of Reporting Trials.
Demographic data and clinical characteristics of persons with epilepsy (PWE)
Serum S100B assessment
Serum S100B levels were measured at baseline, i.e., at enrollment for both the test and control groups and again in the test group at the 12-week follow-up, marking the study’s conclusion in PWE. The baseline S100B levels of PWE were compared with those of the control group. The mean baseline serum S100B level in the PWE group was 0.093±0.031 μg/L, significantly higher than the control group’s level of 0.050±0.020 μg/L (difference of 0.040 μg/L; 46.20%; p<0.001). The mean baseline value of serum S100B in PWE in focal epilepsy and generalised epilepsy was 0.07±0.024 μg/L and 0.10±0.03 μg/L, respectively. Fig. 2 depicts the baseline comparison of serum S100B concentrations between focal and generalised epilepsy in the PWE cohort.
Baseline level of S100B in focal (n=13) and generalized (n=33) epilepsy. *p<0.05, significant in comparison to focal.
Among all PWE enrolled, after 12 weeks of treatment, this level decreased to 0.077±0.027 μg/L (p<0.001; 95% confidence interval [CI], 0.069 to 0.085). The mean change in serum S100B levels over the treatment period in PWE was −0.016 μg/L (95% CI, −0.024 to −0.008), representing a 17.20% decrease, with a moderate effect size (Cohen’s d=0.59). Table 2 shows change in efficacy parameters in PWE over 12 weeks.
Change in efficacy parameters in PWE over 12-week treatment period
For PWE on conventional AEDs, the baseline mean serum S100B level decreased significantly from 0.088±0.032 μg/L to 0.072±0.019 μg/L over 12 weeks (mean change of −0.02 μ/L [18.18%]; p=0.005; 95% CI for mean change −0.0265 to −0.0055 μ/L; Cohen’s d=0.63). In the newer AEDs group, the baseline level dropped significantly from 0.100±0.03 μg/L to 0.084±0.022 μg/L (mean change of −0.02 μ/L [16.0%]; p=0.016; 95% CI, −0.029 to −0.003 μg/L; Cohen’s d=0.62). However, no significant difference was observed in the mean change of S100B over 12 weeks between the two groups (p=0.652; 95% CI, −0.0156 to 0.0156 μg/L; Fig. 3), indicating comparable reductions with both AED classes.
Comparison of baseline serum S100B values and values after 12 weeks of follow-up in persons with epilepsy between newer and conventional AEDs. AEDs, anti-epileptic drugs. *p<0.05, significant in comparison to baseline value; #p<0.05, significant in comparison to baseline value.
Assessment of quality of life
The QOLIE-10-P is an effective instrument for evaluating HRQoL in epilepsy patients, with higher scores indicating a poorer quality of life.
At baseline, the mean QOLIE-10-P score for all PWE was 2.81±0.60, which improved to 1.87±0.33 by the end of the 12-week follow-up (mean change, −0.94; 95% CI, −1.80 to −0.80; p<0.001; Cohen’s d=2.02), reflecting a 32.1% improvement. For PWE on conventional AEDs, the baseline score of 2.77±0.35 improved to 1.85±0.35 (mean change, −0.93; 95% CI, −1.05 to −0.79; p<0.001; Cohen’s d=2.63), representing a 33.6% improvement. In the newer AEDs group, the baseline score was 2.85±0.68, improved to 1.91±0.41 (mean change, −0.94; 95% CI, −1.21 to −0.67; p<0.001; Cohen’s d=1.72), representing a 33.0% improvement. No significant difference was observed in the mean change of QOLIE-10-P scores between the two AED groups over 12 weeks (p=0.906; 95% CI for the between-group difference: −0.32 to 0.28; Fig. 4).
Comparison of baseline QOLIE-10-P scores and scores after 12 weeks of follow-up in persons with epilepsy between newer and conventional AEDs. QOLIE-10-P, quality of life in epilepsy; AEDs, anti-epileptic drugs. *p<0.05, significant in comparison to baseline score; #p<0.05, significant in comparison to baseline score.
Sleep quality assessment
PSQI, a self-reported questionnaire where higher scores indicate poorer sleep quality, was employed to evaluate the sleep quality of PWE over a 12-week interval. Baseline PSQI scores, reflecting sleep quality over the preceding 12 weeks, were collected at the time of enrolment and reassessed at the end of the 12-week follow-up period.
In this study, the mean overall baseline PSQI score in both the groups was 6.83±2.80, which improved to 5.54±1.82 by the 12-week follow-up, reflecting an 8.7% improvement (mean change of −1.28; 95% CI, −1.97 to −0.59; p<0.001; Cohen’s d=0.55), indicating a moderate enhancement in sleep quality. For PWE on conventional AEDs, the baseline PSQI score was 6.61±2.66, which improved slightly to 6.14±1.60 (mean change of −0.46; 95% CI, −0.37 to 1.29; p=0.19), reflecting a 6.9% improvement. In contrast, PWE on newer AEDs showed a notable improvement from a baseline score of 7.17±3.05 to 4.61±1.79 (mean change of −2.56; 95% CI, −3.76 to −1.36; p<0.001; Cohen’s d=1.06), 35% improvement. Fig. 5 depicts baseline and week-12 PSQI scores in PWE treated with conventional versus newer AEDs.
Comparison of PSQI score at baseline and after 12 weeks of follow-up in PWE between newer and conventional AEDs. PSQI, pittsburgh sleep quality index; AEDs, anti-epileptic drugs; PWE, persons with epilepsy. *p<0.05, significant in comparison to focal.
Adverse events assessment
Among all PWE, the mean baseline LAEP score was 29.52±4.28, which marginally increased to 29.74±4.00 over 12 weeks, reflecting a mean change of 0.21 (0.71%; 95% CI, −1.02 to 1.44; p=0.52; Cohen’s d=0.05), indicating stable perceptions of adverse effects across the cohort. For PWE on conventional AEDs, the baseline LAEP score was 28.86±3.97, which increased to 30.32±4.02, with a mean change of 1.46 (95% CI, −0.09 to 3.01; p=0.06; Cohen’s d=0.37), suggesting a higher perception of adverse effects in this group. In contrast, PWE on newer AEDs experienced a decrease in the LAEP score from 30.56±4.64 to 28.83±3.86, with a mean change of −1.72 (95% CI, −3.83 to 0.39; p=0.10; Cohen’s d=0.40), indicating an improvement in the perception of adverse effects. Fig. 6 depicts baseline and week-12 LAEP scores in PWE treated with conventional versus newer AEDs.
Comparison of baseline LAEP scores and scores after 12 weeks of follow-up in persons with epilepsy between newer and conventional AEDs. LAEP, liverpool adverse event profile; AED, anti-epileptic drug.
Seizure reduction
Participants were monitored over a 12-week period following their enrollment into the study, with baseline seizure frequencies recorded at the time of enrolment. PWE were enquired about their seizure occurrences in the last 12 weeks prior to the initiation of AEDs treatment and subsequently followed up-either telephonically or during routine visits to the medicine outpatient department after the commencement of the study. A significant reduction in seizure frequency was observed among all PWE, with an overall percentage decrease of 86.09%. Specifically, PWE treated with conventional AEDs experienced an 88.65% reduction in seizure frequency. In contrast, the use of newer AEDs resulted in an 83.65% decrease in seizures. The comparison between both groups indicated that the difference in seizure frequency reduction was statistically not significant, suggesting that both conventional and newer AEDs are comparably effective in reducing seizure occurrences.
There was no statistically significant correlation between S100B and HRQoL, except with seizure frequency which has a strong positive correlation (Spearman’s correlation coefficient r=0.65; p<0.001). Fig. 7 depicts seizure frequency in PWE, contrasting the 12-week pre-treatment baseline with seizure counts recorded during the 12-week follow-up period for those receiving conventional versus newer AEDs.
Comparison of baseline seizure frequency over the preceding 12 weeks and seizure frequency during the 12-week study period in PWE between newer and conventional AEDs. Seizure frequency over preceding 12 weeks before initiation of 12 weeks was taken as day 0 value, seizure frequency over 12-week treatment period was taken as week 12 value. AEDs, anti-epileptic drugs; PWE, persons with epilepsy. *p<0.05, significant in comparison to day 0 value; #p<0.05, significant in comparison to day 0 value.
To assess whether changes in S100B predicted clinical outcomes, multivariable linear regression analyses were conducted with ΔS100B as the primary predictor and improvements in seizure frequency, QOLIE-10-P, PSQI, and LAEP as dependent variables, adjusting for age, sex, epilepsy type, and AEDs class.
A greater reduction in serum S100B independently predicted a larger decrease in seizure frequency (β=0.54; 95% CI, 0.31–0.76; p<0.001) and a significant improvement in sleep quality (β=0.28; 95% CI, 0.04–0.53; p=0.026). Associations with changes in QOLIE-10-P (β=0.21; p=0.102) and LAEP (β=0.09; p=0.389) were not statistically significant. The interaction between ΔS100B (change in S100B) with AEDs-class was nonsignificant (p=0.61), indicating similar efficacy across conventional and newer AEDs.
Cost of treatment
The comprehensive assessment of treatment costs for PWE over a 12-week follow-up period incorporates direct medical, direct non-medical, and indirect costs. The overall mean total cost of treatment for all PWE was $25.49±17.01, encompassing both drug treatment groups. A detailed analysis revealed that the mean total cost for the conventional AEDs group was significantly lower at $16.73±10.57 compared to the newer AEDs group, which stood at $39.10±16.18 indicating a substantial cost difference (p<0.001) between the two. Notably, the primary factor driving the total cost variation was the expenditure on medications. Other cost components, including direct non-medical and indirect costs, exhibited limited variation between the groups and did not significantly impact the overall cost difference. Newer AEDs are associated with higher treatment costs, without any significant difference in improvement of HRQoL indices compared to conventional AEDs. We also calculated the incremental cost-effectiveness ratio (ICER), which shows a substantial increase in the cost of treatment with newer AEDs to improve one unit of some HRQoL indices. For an improvement of one unit in QOLIE-10-P, PSQI, LAEP score, and seizure frequency over 12 weeks, the increase in treatment costs for the newer AEDs group compared to the conventional AEDs group was $2,236.81, $10.65, $7.03, and $79.89 respectively. Detailed ICER values for each HRQoL index are provided in Table 3.
Cost of treatment analysis and calculation of incremental cost-effectiveness atio (ICER)
Discussion
The primary objective of our study was to investigate the effects of AEDs on the serum biomarker S100B in PWE. Our findings reveal a notable increase in baseline serum S100B levels in PWE compared to healthy controls, indicative of neuronal and glial damage. Also, the mean baseline serum S100B was significantly higher in generalised epilepsy compared to focal epilepsy. This observation is supported by existing literature, which posits that epileptic seizures can elevate serum S100B levels, corroborating the results of our investigation.13–16 Further, following a 12-week treatment period, the cohort of PWE exhibited a significant reduction in serum S100B levels from baseline, although these levels did not normalize to those of healthy volunteers. This suggests that a more extended follow-up might be necessary to fully evaluate the biomarker’s trajectory over time. The slow process of neuronal regeneration post-injury, potentially facilitated by AEDs therapy, underpins this requirement for prolonged observation. A recent study evaluated the impact of 1-month monotherapy with either carbamazepine or oxcarbazepine on serum S100B levels in PWE with focal seizures. The study found a significant effect of carbamazepine but not oxcarbazepine on S100B levels.19 Contrary to this, our research demonstrated a significant change in S100B levels across all five AEDs (valproic acid, phenytoin, carbamazepine, levetiracetam, and oxcarbazepine) over a 12-week follow-up period. Moreover, the mean change in S100B levels did not significantly differ among the various drugs prescribed.
S100B is predominantly produced and secreted by astrocytes under both normal and pathological conditions, exerting neurotrophic and gliotrophic effects that are crucial for the development and maintenance of the central nervous system.20 Reactive gliosis, an astrocytic response to brain injury, is a prominent neuropathological hallmark of epilepsy, potentially playing a role in the onset and persistence of seizures.21 This process involves alterations in astrocyte morphology, gene expression, proliferation, and cytokine release.22 Elevated S100B levels in cerebrospinal fluid (CSF) and serum may, therefore, reflect reactive gliosis, astrocytic death, or dysfunction of the blood-brain barrier (BBB), serving as markers of neuronal/glial damage in epilepsy.23 The significantly elevated S100B levels in PWE observed in our study may primarily be attributed to reactive gliosis, particularly astrocytosis.
Elucidating the precise mechanism by which AEDs reduce serum S100B levels remains challenging. However, it is plausible that the membrane-stabilizing properties of AEDs may play a role,24 potentially decreasing the release of S100B into extracellular spaces. During epileptic events, astrocytes become activated and may release various molecules, including S100B, which can contribute to neuro-inflammatory processes. AEDs can modulate astrocyte function indirectly by reducing seizure activity or indirectly by affecting astrocytic receptors and signalling pathways, thus potentially reducing the release of S100B. AEDs may exert protective effects on the BBB through several mechanisms, including the reduction of inflammation, modulation of tight junction proteins, and inhibition of matrix metal-loproteinases that degrade the extracellular matrix supporting the BBB,25 potentially decreasing the release of S100B into extracellular spaces. Consequently, S100B at lower concentrations may exert neurotropic and neuroprotective effects, which in turn could mitigate seizure episodes.
We assessed the HRQoL using the scales - QOLIE-10-P, PSQI, and the LAEP, which reflect various treatment related aspects in PWE. The QOLIE-10-P serves as an effective instrument for evaluating HRQoL in epilepsy patients. We observed a significant improvement in QOLIE-10-P scores over a 12-week follow-up, with a mean difference of −0.93±0.60, translating to a 32.1% improvement. This improvement was consistent across both conventional and newer AEDs groups with no significant difference between the two. Our findings align with the similar studies conducted in the past.26–28 However, our analysis did not identify a statistically significant correlation between changes in serum S100B levels and QOLIE-10-P scores (Spearman’s r=0.29; p=0.054).
The PSQI is a self-rated questionnaire which assesses sleep quality and disturbances over last 12 weeks. The PSQI is a valuable tool in both clinical practice and research for identifying sleep issues and quantifying sleep experiences.29 Significant improvements were noted in PSQI scores over the 12-week period, with a mean difference of -1.28±2.10, equating to an 8.7% improvement. Notably, the enhancement in PSQI scores for PWE on newer AEDs was 35.7% versus only 6.3% in conventional AEDs which is statistically significant and a clinically meaningful finding. Thus, in our study it was found that newer AEDs significantly improved sleep quality compared to conventional AEDs. This observation aligns with prior research indicating that newer AEDs enhance sleep efficiency, contribute to more consistent sleep patterns, extend the duration of rapid eye movement sleep, and improve overall quality of life indicators.30
The LAEP is an assessment tool developed to quantify the adverse effects of AEDs on individuals with epilepsy. It is a self-reported questionnaire that measures the impact of side effects across various domains, including physical and mental health.29 In our study the LAEP scores showed a marginal increase of 0.71%, indicating a stable perception of adverse effects across the study cohort. Interestingly, PWE treated with newer AEDs exhibited a 5.63% decrease in LAEP scores, suggesting an improvement in the perceived adverse effects, in contrast to those on conventional AEDs. However overall, there is no statistically significant difference in mean change of LAEP between conventional and newer AEDs. This observation aligns with a previous study that showed use of new AEDs was not associated with lower self-reported adverse effects scores like LAEP among PWE despite their higher acquisition costs.31
Our study also highlighted a significant reduction in seizure frequency among all PWE, with an overall decrease of 86.09%, consistent across both AEDs groups. A strong positive correlation was identified between changes in serum S100B levels and seizure frequency reduction over the 12-week period, underscoring the role of S100B as a potential biomarker for treatment efficacy.
In this study, we also assessed the cost-effectiveness of AEDs by calculating the ICER. The expenses associated with epilepsy treatment are categorized into three types: direct medical costs, direct non-medical costs, and indirect costs. Direct medical costs encompass expenses related to medical procedures and treatments. Direct non-medical costs pertain to additional expenses incurred during treatment like expenses spent on lodging, food and travel in the course of treatment. Indirect costs represent the economic impact of lost productivity, often quantified as wage loss. ICER was calculated by ratio between difference in total cost of treatment between conventional and newer AEDs group and change in respective HRQoL scores observed over the 12-week study period. This calculation provides a quantitative measure of the additional cost required per unit of improvement in HRQoL. Our findings indicate that the treatment costs for newer AEDs are higher than those for conventional AEDs, with a total difference of $22.37 over 12 weeks. This cost difference is primarily driven by direct medical expenses, especially medication costs over a 12-week period, as only a few patients required hospitalization or incurred costs related to adverse drug reactions. When looking at non-medical and indirect costs, no significant differences were found between the two groups, suggesting that the higher treatment costs for newer AEDs are mainly due to the higher prices of these medications.
Newer AEDs cost $2,236.81 more for each unit improvement in the QOLIE-10-P score, and showed only minimal additional costs for improvements in PSQI and LAEP scores-$10.65 and $7.03 per unit improvement, respectively. For each unit of seizure frequency reduction, newer AEDs cost $79.89 compared to conventional AEDs.
A particularly noteworthy finding of our study was the significant improvement in sleep quality among PWE treated with newer AEDs as assessed by the PSQI, showing a 35.7% enhancement compared to 6.3% with conventional AEDs. This statistically and clinically meaningful improvement underscores the value of optimizing sleep in epilepsy management. Sleep disruption is recognized as both a contributor to and a consequence of epileptic activity, thereby creating a bidirectional relationship that can exacerbate seizure occurrence, cognitive impairment, and reduced daytime functioning.32,33 Restorative sleep has been associated with better seizure control, enhanced cognitive performance, improved mood, and overall well-being in PWE.34–36 Consequently, therapies that yield substantial gains in sleep quality may confer broader clinical benefits beyond the immediate control of epileptic events.
In our cost-effectiveness analysis, the ICER for each unit improvement in PSQI was $10.65, relatively modest compared to the potential long-term gains associated with improved sleep. These benefits may extend to better disease self-management, reduced healthcare utilization, and improved productivity, all of which can mitigate indirect costs over time. Despite incurring higher direct medication expenses, newer AEDs offer a notable advantage in improving sleep quality, thereby supporting their use in appropriately selected patients. Although they may not surpass conventional AEDs on every measure of HRQoL, their substantial sleep-related benefits could still justify the added costs. This perspective aligns with emerging evidence that underscores the clinical and economic significance of prioritising sleep in epilepsy management.27
Although newer AEDs were associated with higher treatment costs, their pronounced benefits in sleep quality (PSQI) underscore their potential value in selected patients. While both conventional and newer AEDs yielded comparable improvements in HRQoL, the ICER for a one-unit improvement in QOLIE-10-P was notably high. This reflects the fact that even a small numerical change in QOLIE-10-P corresponds to a meaningful clinical difference, owing to the scale’s low interindividual variability. From a policy perspective, improving affordability through cost-regulation or inclusion in subsidy schemes may enhance access to newer AEDs, particularly for individuals with comorbid sleep disturbances or poor tolerability to conventional agents. Clinicians and policymakers should weigh these added benefits-especially improved sleep when evaluating the overall cost-effectiveness of newer antiepileptic therapies.
Our study has many limitations. Firstly, our research did not incorporate periodic evaluations of serum S100B levels, thereby limiting our capacity to monitor the temporal dynamics of S100B concentration changes during the study period. Although serum S100B is recognised as a biomarker for neuronal injury, CSF S100B concentrations might offer superior specificity and reliability for detecting neuronal damage. Ethical considerations precluded the inclusion of CSF S100B analysis in our methodology. Future investigations, particularly those employing preclinical models, are warranted to elucidate the differential biomarker utility of serum versus CSF S100B in the context of epilepsy. Secondly, the study’s design lacked an active control cohort comprising untreated PWE, which constrains our ability to ascertain whether observed alterations in S100B levels were attributable to the pharmacological effects of AEDs or represented natural disease progression. This methodological limitation necessitates caution in interpreting the causality of S100B level changes. Thirdly, the sample size determination was predicated on the variability of S100B levels, resulting in a cohort size that may be suboptimal for robust HRQoL assessments. Consequently, the generalizability of HRQoL findings might be restricted, highlighting the need for studies with larger sample sizes specifically designed to evaluate HRQoL outcomes in epilepsy.
In conclusion, this study demonstrated significant reductions in serum S100B levels and seizure frequency in PWE over a 12-week course of AEDs therapy, with comparable improvements in HRQoL across both conventional and newer agents. Serum S100B levels correlated strongly with seizure frequency. Although newer AEDs were more expensive, their pronounced benefits in sleep quality emphasize the clinical importance of considering these agents for appropriately selected patients.
Notes
Conflict of Interest
The authors declare no conflicts of interest.
Ethical Approval
The study protocol was approved by the Institutional Ethics Committee for human research of the Lady Hardinge Medical College, New Delhi (approval no: LHMC/IEC/2022/PG THESIS/139 dated Sep 27, 2022) and is concordant with the Declaration of Helsinki. Written informed consent was taken from all participants in the study.