European Journal of Cardiovascular Medicine

Epilepsy is one of the most common chronic neurological disorders, characterized by recurrent, unprovoked seizures due to excessive electrical activity in the brain. It affects approximately 50 million people worldwide, with a considerable proportion residing in low- and middle-income countries (1). Despite significant advances in antiepileptic drug (AED) development, nearly one-third of patients fail to achieve adequate seizure control with pharmacological therapy alone and are classified as having drug-resistant epilepsy (DRE) (2,3).

DRE not only increases the risk of physical injury and comorbid psychiatric conditions but also leads to significant impairments in quality of life (QoL), daily functioning, and social participation (4). For such individuals, alternative therapeutic approaches, including surgical resection and neuromodulatory techniques, are considered. However, not all patients are candidates for resective surgery due to multifocal or poorly localized seizure foci, making neuromodulation a valuable adjunct in treatment strategies (5).

Vagus nerve stimulation (VNS), approved by the U.S. Food and Drug Administration in 1997 for refractory epilepsy, involves the delivery of intermittent electrical impulses to the left vagus nerve via an implanted device (6). The proposed mechanisms by which VNS exerts antiepileptic effects include modulation of neurotransmitter release, alteration of cortical excitability, and enhancement of thalamocortical inhibition (7,8). Multiple studies have reported reductions in seizure frequency and improvements in mood, alertness, and overall QoL following VNS therapy (9,10).

Despite its established safety profile, long-term prospective data assessing both clinical and psychosocial outcomes in diverse populations remain limited. Therefore, this multicenter prospective study was designed to evaluate the efficacy of VNS in reducing seizure burden and improving QoL among patients with DRE across multiple tertiary care centers in India.

A total of 120 patients aged between 12 and 60 years who were clinically diagnosed with DRE, as defined by failure of adequate trials of two or more tolerated and appropriately chosen antiepileptic drugs (AEDs), were included. Inclusion criteria required a minimum seizure frequency of four episodes per month over the previous 6 months. Patients with progressive neurological disorders, prior epilepsy surgery, or contraindications to VNS implantation were excluded.

Procedure
After obtaining written informed consent, eligible participants underwent VNS device implantation. The VNS system was surgically placed under general anesthesia, with the stimulating electrode wrapped around the left cervical vagus nerve. Following a 2-week post-operative recovery period, device activation and stimulation parameter adjustments were performed under neurologist supervision.

Data Collection
Seizure frequency was documented using patient-maintained seizure diaries at baseline and at monthly intervals. Quality of life was assessed using the validated Quality of Life in Epilepsy Inventory-31 (QOLIE-31) questionnaire administered at baseline, 6 months, and 12 months. Adverse effects related to the device or stimulation were also recorded at each follow-up.

Outcome Measures
The primary outcome was the reduction in mean monthly seizure frequency at 12 months compared to baseline. Secondary outcomes included changes in QOLIE-31 scores and incidence of stimulation-related side effects.

Statistical Analysis
All data were entered into Microsoft Excel and analyzed using SPSS version 26.0. Paired t-tests were applied to compare pre- and post-intervention seizure frequencies and QOLIE-31 scores. A p-value <0.05 was considered statistically significant.

A total of 120 patients with drug-resistant epilepsy were enrolled in the study. The mean age of participants was 28.6 ± 9.4 years, with 68 (56.7%) males and 52 (43.3%) females. The majority of patients (70%) had focal seizures, while 30% had generalized seizure types. Demographic and baseline clinical characteristics are summarized in Table 1.

Following VNS implantation, a statistically significant reduction in mean monthly seizure frequency was observed. At baseline, the mean seizure frequency was 12.4 ± 3.1 episodes per month, which declined to 7.1 ± 2.9 episodes at 6 months and further to 5.2 ± 2.8 at 12 months (p<0.001). These findings are detailed in Table 2.

In terms of quality of life, the mean QOLIE-31 score improved from 48.7 ± 6.5 at baseline to 62.4 ± 6.0 at 6 months and reached 69.2 ± 5.8 by the 12-month follow-up (p<0.001). Improvements were observed across all domains, including seizure worry, emotional well-being, and cognitive functioning (Table 3).

Regarding responder rates, 65% of patients (n=78) achieved a ≥50% reduction in seizure frequency by the end of the study. Additionally, 20 patients (16.7%) were classified as seizure-free for at least 3 consecutive months during the follow-up period (Table 4).

Adverse events associated with VNS therapy were generally mild and transient. The most frequently reported side effects were voice alteration (11%), throat discomfort (9%), and coughing during stimulation (5%). No patient required device removal or discontinuation due to complications (Table 5).

Table 1: Baseline Demographic and Clinical Characteristics (n=120)

Table 2: Change in Mean Monthly Seizure Frequency

Table 3: Quality of Life (QOLIE-31) Scores Over Time

Table 4: Clinical Outcome Categories at 12 Months

Table 5: Reported Adverse Effects Following VNS

This multicenter prospective study evaluated the efficacy and safety of vagus nerve stimulation (VNS) as an adjunctive treatment in patients with drug-resistant epilepsy (DRE). The findings demonstrated a significant reduction in seizure frequency and notable improvements in quality of life (QoL), corroborating earlier reports that support the clinical utility of VNS in refractory epilepsy cases (1,2).

The observed ≥50% seizure reduction in 65% of patients aligns with previous studies, which reported responder rates between 50% and 70% following one year of VNS therapy (3,4). While complete seizure freedom remains rare, sustained reductions in seizure frequency can lead to better psychosocial adjustment and reduced risk of injury or status epilepticus (5). This outcome was particularly meaningful in our study population, most of whom had a long history of uncontrolled seizures despite multiple anti-seizure medications.

In terms of quality of life, QOLIE-31 scores improved significantly post-VNS implantation. Enhancements were noted across domains such as emotional well-being, cognitive functioning, and seizure worry. These findings are consistent with literature suggesting that VNS has positive neuromodulatory effects on mood and cognition, independent of seizure control (6,7). Improvements in QoL following VNS have also been attributed to increased autonomy and reduced social stigma, which often accompany better seizure control (8,9).

The mechanism of VNS remains incompletely understood; however, it is hypothesized to involve activation of afferent vagal fibers that project to the nucleus tractus solitarius and subsequently modulate widespread cortical and subcortical structures via noradrenergic and serotonergic pathways (10,11). Functional imaging studies have demonstrated changes in thalamic and limbic activity following chronic VNS, supporting the hypothesis of a broader neuromodulatory role (12,13).

Adverse events in our study were mild and reversible, with hoarseness and throat discomfort being the most frequently reported, mirroring earlier clinical trials (14). Importantly, no serious device-related complications occurred, highlighting the procedure's favorable safety profile when performed in experienced centers.

Nevertheless, this study has some limitations. First, the absence of a control group limits direct attribution of outcomes solely to VNS. Second, the follow-up period of 12 months, although adequate for short-term evaluation, may not capture the full therapeutic potential of VNS, which is often delayed and cumulative over time (15). Future randomized controlled studies with longer follow-ups and objective biomarkers may help further elucidate patient-specific predictors of favorable response.

In conclusion, VNS appears to be a valuable adjunctive therapy for patients with DRE, leading to meaningful reductions in seizure frequency and significant improvements in quality of life. Its minimally invasive nature, coupled with a strong safety profile, makes it an attractive option for patients not eligible for resective epilepsy surgery.

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