Summary
Objective:
To determine the efficacy and safety of vagus nerve stimulation (VNS) for reducing the frequency of seizures and complications in drug-resistant epilepsy.
Methods:
This was a retrospective case series study conducted in King Abdullah Medical City from January 2015 to December 2021 hospital record. All patients undergoing VNS were enrolled according to inclusion and exclusion criteria. Patients were followed up for 12 months, and the seizure frequency and number of epileptic drugs used were evaluated. A paired sample t-test was applied to compare the outcome variables considering p-value < 0.05 as significant.
Results:
Among 9 enrolled patients, four were females, and five were males. The mean age of the patients was 23.9 ± 10.8 years. The average number of drugs used before VNS was 3, while it was 2 after VNS. However, a statistically significant (p = 0.08) reduction was not achieved. The mean seizure frequency before and after VNS was 14.4 ± 4.0 and 2.2 ± 3.2 at the 12-month follow-up visit (p < 0.05). The seizure frequency was statistically significantly reduced since the p-value was less than 0.05. No significant complications or death were observed.
Conclusion:
The VNS is a safe and effective adjuvant therapy for reducing the frequency of seizures in patients with drug-resistant epilepsy.
Keywords: Intractable epilepsy, Vagal nerve stimulation, Refractory epilepsy, Drug resistant epilepsy, VNS
Introduction
Epilepsy affects people around the world and has an impact on patient quality of life, especially for those with uncontrolled epilepsy with frequent seizures [1]. With the variety of currently available anti-epileptic drugs (AEDs), better control of seizures has been achieved; however, some patients unfortunately do not respond well to AEDs and develop drug-resistant epilepsy.
Drug-resistant epilepsy is defined by the International League Against Epilepsy (ILAE) as failure of adequate trials of two tolerated and appropriately chosen and used AED schedules (whether as a monotherapy or in combination) to achieve sustained seizure freedom [2].
Advances and better outcomes in the field of epilepsy and epilepsy surgery have been achieved by supporting evidence from several clinical trials involving patients with drug-resistant epilepsy that have shown that epileptic surgery is superior to medical therapy alone in treating drug-resistant epilepsy [3,4,5]. There are different surgical options for epilepsy including surgical resection including lobectomy (temporal, extratemporal), hemispherectomy, neurostimulation with either deep brain stimulation (DBS), responsive neurostimulation (RNS), or vagal nerve stimulation (VNS), palliative surgery such as corpus callosotomy, multiple subpial transection, and other surgical options including stereotactic radiosurgery and stereotactic laser ablation therapy. These surgical procedures have been shown to be effective in treating drug-resistant epilepsy [6].
Several clinical trials and studies enrolled patients with drug-resistant epilepsy those who received VNS therapy and showed the efficacy of VNS as an adjunctive therapy in treating drug-resistant epilepsy [7,8]. The United States Food and Drug Administration (US FDA) approved VNS as an adjunct therapy for treating drug-resistant epilepsy for those who failed medical therapy [9]. Similarly, the Saudi FDA approved VNS for drug-resistant epilepsy.
The VNS is a procedure in which a stimulation device is attached to the thoracic wall and connected to the vagus nerve in the neck to stimulate the vagus nerve and control seizures [6]. VNS has a neuromodulatory effect; however, its actual mechanism of action is not fully understood [6].
Many studies have been conducted on the effectiveness of VNS. However, to establish the efficacy and safety of the technique, more long-term studies are required to elucidate various aspects of VNS therapy in patients of different ethnicities [10] since the previous studies were mostly uncontrolled and had considerable variations in their study groups such as patient age and duration of follow-up [11]. No previous study on the efficacy of this technique has been conducted in our set-up in King Abdullah Medical City, Makkah. The purpose of this study was to evaluate the outcomes and efficacy of VNS in the patients with drug-resistant epilepsy in King Abdullah Medical City, Makkah, Kingdom of Saudi Arabia.
Methods
This was a retrospective case series study conducted in King Abdullah Medical City in Makkah, Saudi Arabia. Institutional review board permission was provided (registration no. H-02-K-001). The study was governed by the Helsinki Declaration. We included all patients older than 12 years with drug-resistant epilepsy who were not fit for surgical resection or had multifocal seizures or seizures in eloquent cortex and were given VNS as an adjuvant therapy between January 2015 and December 2021. All patients younger than 12 years of age and those who were treated with surgical resection alone without VNS were excluded from the study. A chart review of the hospital data recorded from January 2015 to December 2021 was performed, and data from the selected patients were shifted to an electronic form that did not reveal the patient's identity. The collected data were given study codes that were related to the patients' names that were kept confidential and safe.
Twelve patients were identified from the record review. Three of them could not be followed up and were excluded from the analysis. Demographic characteristics such as age and gender were noted. The detailed history of epilepsy and risk factors was also recorded. This included a history of neonatal brain insult, head trauma, central nervous system (CNS) infection, brain lesions, brain surgery, family history, and developmental delay, the duration of epilepsy, seizure frequency, and number of AEDs. Patients were followed up at three, six, nine, and 12 months after the procedure. The primary objective was to assess for a reduction in seizure frequency after 12 months. The secondary objective was to assess for a reduction in the number of AEDs and complications of the procedure.
All the data collected were analyzed using IBM SPSS Statistics for Windows, version 23 (IBM Corp., Armonk, N.Y., USA). All the categorical variables such as gender and risk factors in the history are reported as frequencies and percentages. Quantitative variables such as age, frequency of seizures, and number of medications are reported as the mean and standard deviation. These variables were compared before and after treatment using a paired sample t-test. A p-value of < 0.05 was considered significant.
Results
There were 12 patients who were enrolled in the study. Out of these, three patients who were lost to follow-up were excluded from the final analysis. The final analysis was performed on nine patients. Of these, four (44.45%) were males, and five (56.6%) were females. The mean patient age was 23.89 ± 10.8 years (minimum: 15 years; maximum: 50 years). The mean duration of disease at the time of the procedure was 15.7 ± 11.1 years. Among various risk factors in the patient history, 11.1% (1) had a neonatal brain insult, history of head trauma, and history of developmental delays. A history of a CNS infection was present in two (22.2%) patients. There were four (44.4%) patients with a history of febrile seizures and four with a family history of epilepsy. A detailed description of these factors is given in Table 1.
Table 1.
Frequencies of risk factors in the patient history.
| Risk Factors in the History | Present | Absent |
|---|---|---|
| Neonatal Brain Insult | 1 (11.1%) | 8 (88.9%) |
| Head Trauma | 1 (11.1%) | 8 (88.9%) |
| CNS Infections | 2 (22.2%) | 6 (77.8%) |
| Developmental Delay | 1 (11.1%) | 8 (88.9%) |
| Febrile Seizures | 4 (44.4%) | 5 (55.6%) |
| Family History of Epilepsy | 4 (44.4%) | 5 (55.6%) |
No complications of the procedure observed or any deaths. The average number of drugs used before VNS was 3. This was reduced to an average of two AEDs. This reduction was not statistically significant (p = 0.08). The mean seizure frequency (primary outcome) at the 12-month follow-up visit was 14.4 ± 4.0 before VNS, compared to 2.2 ± 3.2 after VNS. There was a statistically significant reduction in the frequency of seizures one year after the procedure (p = 0.0001). The mean seizure frequency decreased over time after the procedure, from 6.4 ± 5.0 at three months, to 4.9 ± 3.5 at 6 months, and finally to 3.1 ± 3.4 at 9 months (p < 0.05). This reduction was also statistically significant since the p-value was <0.05. These findings are elaborated in Table 2. The procedure was well tolerated, with only one patient (11.1%) complaining of cough and voice hoarseness.
Table 2.
Neuromodulatory effects after VNS.
| Paired Difference | ||
|---|---|---|
|
|
||
| Paired variables | Mean ± SD | P-Value |
| Seizure frequency before VNS - Seizure frequency 12 months after VNS | 12.2 ± 4.6 | 0.000 |
| Seizure frequency before VNS - Seizure frequency 3 months after VNS | 8.0 ± 6.1 | 0.004 |
| Seizure frequency before VNS - Seizure frequency 6 months after VNS | 9.55 ± 4.9 | 0.000 |
| Seizure frequency before VNS - Seizure frequency 9 months after VNS | 11.3 ± 4.8 | 0.000 |
| No. of AEDs before VNS - No. of AEDs 12 months after VNS | 0.7 ± 1.0 | 0.081 |
Discussion
Among recently developed therapies for treating epilepsy, VNS is an important neuromodulatory therapy that has been and is being studied for its effectiveness and safety in patients with epilepsy that is not responding well to AEDs [12]. This treatment remains an adjuvant therapy that is used along with AEDs in drug-resistant epilepsy. We conducted this study to observe the effects of VNS therapy in patients with drug-resistant epilepsy at a tertiary care center in King Abdullah Medical City, Saudi Arabia.
There were 2 observed outcomes in our study. One was a reduction in the number of AEDs used from an average of three before VNS therapy to an average of 2 after therapy (p = 0.08). However, this reduction was not statistically significant since the p-value was greater than 0.05. The other outcome was a reduction in the seizure frequency (primary outcome). The seizure frequency before (14.4 ± 4.0) and after VNS therapy was compared at 3, 6, 9, and 12 months of follow-up, with mean values of 6.4 ± 5.0, 4.9 ± 3.5, 3.1 ± 3.4, and 2.2 ± 3.2, respectively. The p-value for each of these findings was less than 0.05. This finding was statistically significant. Similar results were seen by Hamilton et al [13]. They observed that implantation of VNS in 51 patients reduced the number of seizures (p < 0.001). At least 59% of patients had ≥50% reduction in seizures. Using the same device, Kawai et al [14]. found similar results of a reduced seizure frequency. A randomized controlled trial by Rong et al [15]. showed that eight-week VNS therapy in patients with epilepsy showed a reduction of 42.6% in seizure frequency, while the control group showed an 11.5% reduction. These findings were statistically significant (p < 0.05) between the two groups. A number of other studies have shown the effectiveness of this therapy in reducing seizure frequency [16,17].
While we considered a reduction in number of AEDs in patients treated with VNS therapy, we identified studies that indicated that a change in the number of AEDs is acceptable or at least not harmful in patients undergoing VNS therapy. A systematic review and meta-analysis by Batson et al [18]. showed that with VNS therapy, patients may reduce the use of concomitant AEDs without losing seizure control. Revesz et al [19]. found that 57 patients out of total 110 patients (51.8%) did not require more AEDs post-implantation; they had required fewer, or the same number of AEDs as compared with before VNS therapy. On the other hand, a study by Lim et al [20]. reported that there was no change in the number of AEDs used in patients who underwent VNS therapy. However, the results of a study by Muthiah et al [21]. showed that the reduction in the number of AEDs was not statistically significant, which is quite similar to our results. There is also a possibility that the change in the number of AEDs in our population was not considerable due to the small sample size.
Some adverse effects that were observed with VNS therapy are voice hoarseness [10]. However, in our study, only one patient developed voice hoarseness. Furthermore, no patient died during the study. Although febrile seizures and a past family history of epilepsy were the most frequent risk factors (44.4% each) among those mentioned in the results, these factors did not seem to affect the prognosis of the patients. The VNS technique, as a whole, was found to be a good treatment option for patients with refractory and drug-resistant epilepsy [22,10,11,12,13].
There are few limitations in our study. These include the small sample size and single-center study design. This study was observational; therefore, it was not controlled, which leaves room for effectively establishing the efficacy and safety of the treatment procedure. We recommend a multi-center study with a large sample size. A randomized controlled trial would be the study methodology of choice in this view.
In conclusion, VNS is an effective adjuvant therapy for patients with epilepsy that fail to respond appropriately to AEDs. In our study, VNS therapy significantly reduced the seizure frequency in most of our patients. To effectively establish the efficacy of VNS, a multi-centered study with a large sample size involving patients with different types of seizures that considers patient comorbidities is needed.
Acknowledgment
None.
Conflict of interest
The authors declare no conflict of interest.
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