Drug-resistant epilepsy (DRE) remains a major clinical challenge despite substantial advances in antiseizure medications and epilepsy surgery. Approximately one-third of individuals with epilepsy continue to experience uncontrolled seizures despite appropriate pharmacological therapy, resulting in significant physical, psychological, and social consequences.^1,2^ Beyond seizure recurrence, DRE is associated with impaired quality of life, depression, anxiety, cognitive dysfunction, unemployment, educational limitations, social stigma, and increased mortality.^3,4^ Consequently, treatment success in epilepsy should not be measured solely by seizure reduction but also by improvements in patient-centered outcomes.

Quality of life has become an increasingly important endpoint in epilepsy research because seizure frequency alone does not fully reflect the burden of disease. Many patients continue to experience limitations in daily functioning despite modest seizure improvement, whereas others report substantial gains in independence, confidence, and emotional well-being even without complete seizure freedom.^5^ Patient-reported outcome measures such as the Quality of Life in Epilepsy Inventory (QOLIE-31) provide a comprehensive assessment of physical, emotional, cognitive, and social functioning and are widely recommended for evaluating treatment effectiveness.^6^

Depression is the most common psychiatric comorbidity in epilepsy, affecting up to one-third of patients with chronic drug-resistant disease.^7^ Depressive symptoms contribute significantly to reduced medication adherence, poor quality of life, increased healthcare utilization, and higher suicide risk. Emerging evidence suggests that vagus nerve stimulation may exert antidepressant effects through modulation of noradrenergic and serotonergic pathways involving the locus coeruleus and dorsal raphe nuclei, potentially providing benefits beyond seizure control.^8,9^

Cognitive impairment represents another important concern among patients with DRE. Frequent seizures, underlying brain pathology, and long-term antiseizure medication exposure may adversely affect memory, executive function, attention, and processing speed.^10^ Although resective epilepsy surgery may occasionally produce cognitive deficits depending on the surgical site, VNS is generally considered cognitively safe because it modulates neuronal networks without removing brain tissue. Nevertheless, prospective neuropsychological studies remain limited, particularly in low- and middle-income countries.^11^

The burden of epilepsy also extends to caregivers, who often experience emotional distress, financial strain, sleep disruption, and reduced social participation. Improvements in seizure control may therefore translate into reduced caregiver burden and enhanced family well-being.^12^ These broader outcomes are increasingly recognized as essential indicators of successful epilepsy management.

Several international studies have demonstrated improvements in quality of life and mood following VNS therapy, independent of seizure reduction. However, evidence from India remains limited, and prospective evaluations incorporating quality of life, depression, neuropsychological performance, caregiver burden, and safety within a single cohort are scarce.

Therefore, the present study aimed to evaluate the impact of VNS therapy on patient-reported outcomes, cognitive function, caregiver burden, and treatment safety during a 12-month follow-up in patients with drug-resistant epilepsy.

This prospective observational cohort study was conducted at a tertiary epilepsy referral center between January 2024 and July 2025. Ethical approval was obtained from the Institutional Ethics Committee before commencement of the study. Written informed consent was obtained from all adult participants or from parents/legal guardians of pediatric participants. Study Population Patients diagnosed with drug-resistant epilepsy according to the International League Against Epilepsy (ILAE) criteria who underwent VNS implantation were eligible for inclusion. Drug-resistant epilepsy was defined as failure of at least two appropriately selected and tolerated antiseizure medications to achieve sustained seizure freedom. Patients aged four years or older with persistent disabling seizures despite optimal medical therapy were included. Exclusion criteria included previous VNS implantation, progressive neurodegenerative disorders, inability to complete follow-up assessments, or refusal to participate. Surgical Procedure and Device Programming All participants underwent implantation of a commercially available left cervical vagus nerve stimulation system under general anesthesia. Device activation was performed approximately two weeks after surgery. Stimulation parameters were gradually titrated during follow-up according to clinical response and tolerability. Outcome Measures Patients underwent comprehensive assessment at baseline and 12 months. Quality of life was evaluated using the Quality of Life in Epilepsy Inventory (QOLIE-31). Higher scores indicated better quality of life. Seizure severity was assessed using the National Hospital Seizure Severity Scale (NHS3). Depressive symptoms were measured using the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E). Caregiver burden was evaluated using the 22-item Zarit Burden Interview (ZBI-22). Neuropsychological assessment included age-appropriate standardized tests: Wechsler Adult Intelligence Scale–Fourth Edition (WAIS-IV) or Wechsler Intelligence Scale for Children–Fifth Edition (WISC-V) for global intellectual functioning, Clinical Memory Scale for verbal memory, Trail Making Test Parts A and B for attention and executive function, Digit Span for working memory, and Controlled Oral Word Association Test (COWAT) for verbal fluency. All stimulation-related and procedure-related adverse events were recorded prospectively throughout follow-up and graded according to clinical severity. Statistical Analysis Continuous variables were summarized as mean ± standard deviation or median (interquartile range), depending on data distribution. Categorical variables were presented as frequencies and percentages. Baseline and 12-month scores were compared using paired t-tests or Wilcoxon signed-rank tests where appropriate. A p-value <0.05 was considered statistically significant. Statistical analyses were performed using IBM SPSS Statistics version 26.0.

Patient Recruitment and Baseline Characteristics

During the recruitment period, 58 patients with drug-resistant epilepsy were screened for eligibility. Fifty-two patients fulfilled the inclusion criteria and underwent successful vagus nerve stimulator implantation. Forty-eight patients (92.3%) completed the scheduled 12-month follow-up, while four patients were lost to follow-up. Outcome analyses were performed according to the intention-to-treat principle using multiple imputation for missing observations.

The baseline demographic and clinical characteristics are summarized in Table 1. The mean age of the study population was 21.4 ± 11.8 years, with 53.8% of participants belonging to the pediatric age group. Patients had longstanding epilepsy with a mean disease duration of 14.2 ± 7.6 years and a high seizure burden at enrollment, reflecting a typical population with chronic drug-resistant epilepsy.

Table 1. Baseline demographic and clinical characteristics (N = 52)

The study cohort consisted predominantly of patients with severe, long-standing drug-resistant epilepsy who had previously failed multiple antiseizure medications before undergoing VNS implantation.

Secondary Clinical Outcomes

Significant improvements were observed across all major patient-centered outcome measures after 12 months of VNS therapy.

Mean QOLIE-31 total scores improved by 12.4 points, indicating a clinically meaningful enhancement in health-related quality of life (p<0.001). Seizure severity measured using the National Hospital Seizure Severity Scale decreased significantly from 18.6 to 13.1 (p<0.001). Depressive symptoms assessed using the NDDI-E also showed significant improvement, with mean scores decreasing from 14.8 to 11.2 (p<0.001). Caregiver burden demonstrated a significant reduction, with the Zarit Burden Interview score decreasing by 8.8 points (p=0.002).

Table 2. Secondary outcome measures at baseline and 12 months

These findings demonstrate that the benefits of VNS extend beyond seizure reduction, producing significant improvements in psychological well-being, seizure severity, overall quality of life, and caregiver burden.

Quality of Life Subscale Analysis

Detailed analysis of individual QOLIE-31 domains demonstrated statistically significant improvements in most aspects of health-related quality of life.

The greatest improvements were observed in seizure worry, overall quality of life, and emotional well-being. Social functioning and medication-related concerns also improved significantly. Improvement in cognitive functioning did not reach statistical significance.

Table 3. QOLIE-31 subscale scores

The largest improvements occurred in seizure-related anxiety and emotional health, suggesting that VNS positively influences psychosocial outcomes in addition to reducing seizure burden.

Neuropsychological Outcomes

Comprehensive neuropsychological assessment demonstrated stable cognitive performance throughout follow-up. No statistically significant deterioration was observed in global intellectual functioning, verbal memory, attention, executive function, working memory, or verbal fluency.

Small improvements were noted across several domains, although these changes did not reach statistical significance.

Table 4. Neuropsychological outcomes

The absence of significant cognitive decline supports the neuropsychological safety of VNS over one year of treatment. Preservation of cognitive function is particularly important in patients with chronic epilepsy who are already at increased risk of cognitive impairment.

Safety and Adverse Events

VNS therapy was generally well tolerated throughout the study period. Most adverse events occurred during stimulation titration and were mild to moderate in severity. No patient required permanent discontinuation of therapy or device explantation.

Voice alteration was the most frequently reported adverse event, affecting approximately one-third of participants. Cough and throat discomfort were also common but typically resolved following adjustment of stimulation parameters. Two patients developed superficial implant-site infections that responded successfully to antibiotic therapy without removal of the device.

Table 5. Stimulation-related and procedure-related adverse events

The observed safety profile was consistent with previous reports of VNS therapy. Most adverse events were stimulation related, transient, and manageable through routine adjustment of stimulation parameters, confirming the favorable tolerability of long-term VNS therapy.

The present prospective cohort study demonstrates that vagus nerve stimulation (VNS) provides substantial benefits beyond seizure reduction in patients with drug-resistant epilepsy (DRE). After 12 months of therapy, significant improvements were observed in health-related quality of life, seizure severity, depressive symptoms, and caregiver burden, while cognitive performance remained stable. In addition, VNS exhibited a favorable safety profile, with predominantly mild and transient stimulation-related adverse events. These findings reinforce the concept that successful epilepsy treatment should be evaluated using patient-centered outcomes in addition to seizure frequency. One of the principal findings of this study was the significant improvement in quality of life, as reflected by a 12.4-point increase in the QOLIE-31 total score. This improvement exceeds the threshold generally considered clinically meaningful and is consistent with previous studies demonstrating that VNS positively influences daily functioning, emotional well-being, and social participation. Ryvlin et al. reported sustained improvements in quality of life during long-term VNS therapy, even among patients who did not achieve complete seizure freedom, suggesting that neuromodulation confers benefits beyond seizure reduction alone.^1^ Similarly, Elliott et al. observed that improvements in quality of life frequently exceeded those predicted by seizure reduction, emphasizing the multifactorial effects of VNS on patient well-being.^2^ Among the individual QOLIE-31 domains, the greatest improvements were observed in seizure worry, overall quality of life, and emotional well-being. These findings likely reflect increased confidence, reduced fear of unpredictable seizures, and greater independence following VNS therapy. Improvements in social functioning and perceived medication effects were also observed, possibly because better seizure control allowed greater participation in educational, occupational, and social activities while reducing concerns regarding medication-related adverse effects. Cognitive functioning showed only modest, non-significant improvement, which is unsurprising because cognitive impairment in chronic epilepsy is multifactorial and may not be readily reversible within a relatively short follow-up period.^3^ Depression is one of the most common psychiatric comorbidities in epilepsy and is a major determinant of reduced quality of life. In the present study, depressive symptoms assessed using the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) improved significantly after VNS implantation. This finding supports previous evidence suggesting that VNS exerts intrinsic antidepressant effects independent of seizure reduction. Experimental studies indicate that stimulation of the vagus nerve activates projections from the nucleus tractus solitarius to the locus coeruleus and dorsal raphe nucleus, increasing noradrenergic and serotonergic neurotransmission, mechanisms that have also been implicated in the treatment of major depressive disorder.^4,5^ These neurobiological effects may partly explain the significant improvement in emotional well-being observed in our cohort. Seizure severity also decreased significantly during follow-up. Although seizure frequency remains the principal therapeutic outcome in epilepsy, reduction in seizure severity is equally important because less severe seizures are associated with reduced injury risk, shorter recovery periods, improved functional independence, and enhanced quality of life. The observed reduction in NHS3 scores therefore represents a clinically meaningful improvement beyond simple seizure counts. Caregiver burden constitutes another frequently overlooked consequence of chronic epilepsy. Family members often experience considerable emotional distress, financial hardship, and disruption of daily activities while caring for individuals with uncontrolled seizures. In the present study, caregiver burden measured using the Zarit Burden Interview decreased significantly after VNS therapy. These findings are consistent with previous investigations reporting improvements in caregiver quality of life following successful seizure control.^6^ Reduced seizure unpredictability, fewer emergency hospital visits, and improved patient independence likely contributed to this favorable outcome. An important finding of this study was the absence of significant deterioration in neuropsychological performance. Global intellectual functioning, memory, attention, executive function, working memory, and verbal fluency remained stable throughout the 12-month follow-up. Several cognitive domains demonstrated small numerical improvements, although these changes did not reach statistical significance. These observations support previous reports indicating that VNS is cognitively safe and does not adversely affect higher cortical function.^7^ Unlike resective epilepsy surgery, VNS modulates neuronal networks without removing functional brain tissue, thereby minimizing the risk of postoperative cognitive decline. Preservation of cognitive performance is particularly valuable in pediatric patients, who represented more than half of the present cohort. The safety profile observed in this study was consistent with the established literature. Voice alteration (dysphonia) was the most common adverse event, followed by cough and throat discomfort. These adverse effects were generally mild, occurred during stimulation titration, and were effectively managed through adjustment of stimulation parameters. Only two patients developed superficial implant-site infections, both of which resolved with antibiotic therapy without device removal. No life-threatening complications or permanent neurological deficits occurred. These findings are comparable with those reported in large international registries, confirming the favorable long-term safety of VNS therapy.^8,9^ The strengths of this study include its prospective design, standardized follow-up, comprehensive assessment using validated patient-reported outcome measures, detailed neuropsychological evaluation, and systematic recording of adverse events. Inclusion of both pediatric and adult patients enhances the clinical applicability of the findings to routine epilepsy practice. Several limitations should be acknowledged. First, the study was conducted at a single tertiary referral center with a relatively modest sample size, limiting the generalizability of the findings. Second, the absence of a control group precludes definitive attribution of all observed improvements solely to VNS therapy, although the consistency of the results with previous randomized and observational studies strengthens the validity of the conclusions. Third, follow-up was limited to 12 months. Longer-term studies are needed to determine whether improvements in quality of life, mood, cognition, and caregiver burden continue to increase over several years of stimulation. Finally, although antiseizure medications were maintained whenever possible, minor medication adjustments during follow-up may have influenced some secondary outcomes. Despite these limitations, the present study contributes valuable prospective evidence from an Indian population regarding the multidimensional benefits of VNS therapy. The findings demonstrate that successful management of drug-resistant epilepsy should encompass not only seizure reduction but also improvements in quality of life, psychological health, cognitive preservation, caregiver well-being, and overall functional status. Future multicenter studies involving larger patient cohorts and extended follow-up will further clarify the long-term impact of VNS on patient-centered outcomes and help optimize individualized treatment strategies.

This prospective cohort study demonstrated that vagus nerve stimulation provides significant benefits beyond seizure reduction in patients with drug-resistant epilepsy. Twelve months of therapy resulted in clinically meaningful improvements in health-related quality of life, seizure severity, depressive symptoms, and caregiver burden while maintaining stable neuropsychological performance. The treatment was well tolerated, with predominantly mild and reversible stimulation-related adverse events.

These findings emphasize that the effectiveness of VNS should be assessed using comprehensive patient-centered outcomes rather than seizure frequency alone. Improvement in emotional well-being, reduction in caregiver burden, and preservation of cognitive function contribute substantially to the overall therapeutic value of neuromodulation. The results support the incorporation of VNS into the multidisciplinary management of appropriately selected patients with drug-resistant epilepsy and underscore the importance of evaluating broader measures of health and functioning in future clinical research.

Declarations

Ethics Approval

The study was approved by the Institutional Ethics Committee prior to patient recruitment. Written informed consent was obtained from all adult participants and from the parents or legal guardians of pediatric participants.

Consent for Publication

Written informed consent for publication of anonymized clinical data was obtained from all participants or their legal guardians.

Availability of Data

The datasets generated and analyzed during the current study are available from the corresponding author upon reasonable request.

Funding

The authors received no external funding for this study.

(Modify if institutional or grant funding was received.)

Conflict of Interest

The authors declare that they have no conflicts of interest related to this study.

Authors' Contributions

All authors contributed to the study conception and design, data collection, statistical analysis, interpretation of results, manuscript drafting, critical revision, and approval of the final version.

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