Lennox-Gastaut syndrome (LGS) is one of the most severe epileptic encephalopathies and frequently patients with this syndrome respond poorly to antiepileptic drugs. The aim of this study was to evaluate the treatment outcomes of vagus nerve stimulation (VNS) in LGS patients with drug-resistant epilepsy.
We analyzed the clinical files, collected over 5 years, of children with LGS who received VNS treatment.
Seven children were included in this study (four males, three females; mean age of VNS insertion 12.4±3.5 years). All the patients had generalized tonic seizures and there were various other seizure types including myoclonic seizures, atonic seizures, and atypical absence seizures. Although two patients had normal imaging, five patients had abnormalities on imaging, including pachygyria, cortical dysplasia, kernicterus, and a chromosomal anomaly. Comparing the baseline seizure frequency to the frequency after the VNS surgery, the seizure frequency at the last follow-up showed a decrease of 57.2% (0% to 100%) on average (
In LGS patients with drug resistant epilepsy who are not candidates for a corpus callosotomy or resective surgery, VNS could be an effective, low-risk adjunct therapy for decreasing seizure frequency.
Lennox-Gastaut syndrome (LGS) is one of the most severe epileptic encephalopathies of childhood onset and accounts for approximately 3% to 10% of all childhood epilepsies [
LGS is regarded as one of the most challenging epilepsies to manage, due to a range of different seizure types which are mostly refractory to antiepileptic drugs (AEDs) [
Between January 2012 and May 2019, a total of 45 patients who met all the criteria of LGS visited the Department of Pediatrics at Chungnam National University Hospital [
In addition to demographic characteristics of the patients, some features, such as the patient age at the initial visit and during the follow-up period, were obtained retrospectively from the medical records. The clinical data were also collected retrospectively from the medical records and included the age at seizure onset, age at implant, latent period until surgery, post operation follow-up period, previous history of infantile spasms and diet therapy, seizure types, cognition, and etiology.
The study focused on assessing the change in seizure frequency of the predominant seizure type from baseline, meaning the 3-month period prior to implantation, to 24 months following implantation. The predominant seizure type was defined as the most disabling seizure type noted in the medical records, not necessarily the most frequent seizure type. This study utilized a six-point seizure frequency scale [
VNS (VNS pulse® 102·103, Cyberonics Inc., Houston, TX, USA) insertion was performed by otolaryngologists under general anesthesia and took approximately 2 hours and was done following standard surgical procedure [
The statistical analysis was done by SPSS version 17.0 (SPSS Inc., Chicago, IL, USA). The Wilcoxon Rank Sum test was applied to the data to compare non-parametric variables and a
This study protocol was reviewed and approved by the Institutional Review Board of Chungnam National University Hospital (2017-01-041). Due to its retrospective nature, the study was exempted from requiring informed consent from the participants.
A total of seven patients (four males, three females) with a VNS therapy device implanted were included in this study. The average patient age at seizure onset was 3.5±4.0 years (range, 0.0 to 12.0).
In our study patients had more than one seizure type, so there are a number of findings that overlap in
As can be seen in
In terms of complications, one patient was admitted to the intensive care unit (ICU) because of pneumonia that developed on day 4 postsurgery which was further complicated by atelectasis and a right-sided pleural effusion. The patient stayed in ICU for 17 days receiving the necessary treatment for the pneumonia and was discharged from the hospital in good condition on day 30 postsurgery. Apart from this patient, there were no other AEs relating to the surgery, including the more common neurological complications such as a hoarse voice.
The level of benefit, relating to quality of life (QOL), gained from adjunctive VNS therapy was assessed by the physician following at least 24 months of VNS treatment.
As can be seen in
LGS is a severe childhood-onset epileptic syndrome characterized by multiple seizure types with high frequency, mental retardation and an EEG pattern of diffuse, slow spike-wave complexes and generalized fast activity. In most cases LGS responds poorly to AEDs [
VNS can be offered as one of these alternative therapies. It is a type of palliative surgery that was originally approved by the Food and Drug Administration in 1997 as an adjunctive therapy for adults and adolescents who are not eligible for resective surgery [
Recently, many studies have reported that VNS therapy might be helpful to decrease seizure frequency. Gonzalez et al. [
Our study aimed to add further evidence of VNS efficacy in Korean patients, especially after a relatively long period of more than 24 months. Seizure frequency at the last follow-up decreased by 57.2% on average compared with the baseline and with non-parametric statistics a
At the last follow-up visit one patient was completely seizure free, but one patient was reported as having a similar seizure frequency compared to the baseline. The first child stopped having seizures 18 months after the VNS surgery and remained seizure free for 12 months. According to Braakman et al. [
The second child with the similar seizure frequency compared to the baseline was a responder initially, directly after the VNS operation. The child’s baseline seizure frequency was 15 which is relatively low and there were continuous fluctuations in seizure frequency after the VNS surgery. Just 6 months before his last follow-up visit the patient was a responder. With the initial baseline seizure frequency low, one can argue that smaller changes in frequency may be more significant for this patient than in a patient with a high baseline frequency. Thus, it might not always be that important to assess the exact reduction in monthly seizures, but to rather evaluate the patient’s overall condition and subjective benefit, while monitoring changes in seizure frequency at regular intervals on a long-term basis.
VNS therapy has been reported to have a positive influence on QOL by several articles [
Several studies on the effects of VNS have also reported improvements of other factors related to QOL, including alertness, concentration, energy, memory, mood, verbal communication, progress with schoolwork and development of life skills [
By anchoring and stimulating the vagus nerve, the VNS system lets patients control over-excitabilities without damaging brain tissue, and depending on the symptoms, modulate stimulation intensity [
There were four retrospective studies on VNS efficacy published in South Korea. Thus, the present article briefly reviewed those studies with
Kang et al. [
Although there were some differences between those four studies and the present study, the conclusion that VNS appears to be effective and safe choice for VNS was common. Also, the four studies and the current study similarly examined the efficacy of VNS with seizure frequency reduction and mentioned complications of VNS therapy. Unlike the four articles which had relatively short minimum follow-up period or checked the seizure frequency for every 12 months, the present article indicated seizure frequency of each patient more specifically on
The present study has a few potential limitations. The study was based on the data of only seven patients at a single medical center. It would be of great help to recruit additional patients by cooperating with other hospitals to draw more universal conclusions and identify various etiologies. Although all the follow-up periods of seven patients was more than 24 months, performing consistent follow-up for each patient would also enable the collection of broader data. The other limitation is that our study mainly utilized caregivers’ reports to assess changes in seizure frequency. Considering the age of the patients and specificity of current equipment available used to monitor for seizures such as generalized tonic-clonic seizures, using a device like an epilepsy-recording bracelet might be helpful to gather more objective and accurate data.
Our study established that VNS therapy positively affects LGS patients in terms of decreasing seizure frequency and improving QOL. Apart from rare complications from the VNS surgery and vagal stimulation, VNS can be regarded as a relatively safe and effective treatment modality for patients with LGS, which is a very challenging epileptic encephalopathy to manage. In future, more multicenter studies with more objective data collection conducted over longer time periods are necessary for further evidence of VNS use in LGS. As mentioned before, most studies about VNS including the current study examine the medical records retrospectively. For establishing VNS as a safe and reliable option to pharmaco-resistant epileptic patients, it would be helpful to follow-up on patients who received VNS therapy decades ago in their childhood, and prospectively identify the current efficacy plus any late complications.
No potential conflicts of interest relevant to this article was reported.
This work was supported by the research fund of Chungnam National University (2018-1299-01). This work was presented at the Korean Pediatric Society Congress in 2017.
Seizure frequency before vagus nerve stimulation operation (OP), at 6, 12, 18, 24, 30, 36, 42, and 48 months after the operation. The frequency was reported by caregivers at the outpatient pediatrics clinic of Chungnam National University Hospital. PT, patient.
Patients demographical and clinical profiles
Variable | Value |
---|---|
Gender, male/female | 4 (57.1):3 (42.9) |
Age at seizure onset (yr) | 3.5±4.0 (0.0–12.0) |
<1 | 3 (42.9) |
3–6 | 3 (42.9) |
>6 | 1 (14.2) |
Age at surgery (yr) | 12.4±3.5 (5.3–16.5) |
<6 | 1 (14.2) |
>10–16 | 5 (71.6) |
>16 | 1 (14.2) |
Latent period of surgery (yr) | 9.0±5.2 (1.7–14.9) |
Postoperation follow-up period (mo) | 38.8±6.4 (29.7–49.7) |
Seizure types | |
Generalized tonic | 7 (100.0) |
Myoclonic | 5 (71.4) |
Atonic | 4 (57.1) |
Atypical absence | 1 (14.2) |
Etiology | |
Symptomatic | 5 (71.4) |
Pachygyria | 2 (28.6) |
Diffuse cortical dysplasia | 1 (14.3) |
Kernicterus | 1 (14.3) |
Chromosome abnormality | 1 (14.3) |
Unknown | 3 (42.9) |
Previous history of infantile spasms | 2 (28.6) |
Previous history of diet therapy | 3 (42.9) |
Values are presented as number (%) or mean±standard deviation (range).
Changes on seizure frequency and numbers of AED
Patient no. | Baseline seizure frequency (/mo) | Seizure frequency at last follow-up (/mo) | Baseline AED no. | AED no. at last follow-up |
---|---|---|---|---|
1 | 240 | 120 (50.0↓) | 5 | 5 |
2 | 15 | 16 (6.7↑) | 5 | 5 |
3 | 600 | 180 (70.0↓) | 6 | 6 |
4 | 150 | 45 (70.0↓) | 7 | 4 |
5 | 50 | 0 (100.0↓) | 4 | 4 |
6 | 90 | 30 (67.0↓) | 3 | 4 |
7 | 120 | 60 (50.0↓) | 3 | 5 |
Total | 180.7 | 64.4 (57.2↓) | 4.7 | 4.7 |
Values are presented as number (%).
AED, antiepileptic drug.
Level of benefit achieved with vagus nerve stimulation therapy
Patient no. | Severity of illness | CGI-I | Efficacy index | |
---|---|---|---|---|
Before | After | |||
1 | 7 | 7 | 4 | Unchanged |
2 | 5 | 4 | 2 | Moderate |
3 | 5 | 4 | 3 | Minimal |
4 | 6 | 2 | 1 | Marked |
5 | 4 | 4 | 3 | Minimal |
6 | 4 | 4 | 3 | Minimal |
7 | 7 | 5 | 3 | Minimal |
Description of the grades | 0=Not assessed | 0=Not assessed | Marked | |
1=Normal, not at all ill | 1=Very much improved | Moderate | ||
2=Borderline mentally ill | 2=Much improved | Minimal | ||
3=Mildly ill | 3=Minimally improved | Unchanged or worse | ||
4=Moderately ill | 4=No change | Not assessed | ||
5=Markedly ill | 5=Minimally worse | |||
6=Severely ill | 6=Much worse | |||
7=Among the most extremely ill patients | 7=Very much worse |
CGI-I, Clinical Global Impression of Improvement.
Retrospective studies on vagus nerve stimulation efficacy South Korea
Study | Study population | No. of centers | Total no. | Patients with VNS | Patients with LGS | Follow-up period | Patients with greater than 50% reduction (%) |
---|---|---|---|---|---|---|---|
Kim et al. (2004) [ |
Intractable pediatric epilepsy | Multiple | 12 | 12 | 9 | 3–57 mo | 67 |
You et al. (2005) [ |
Intractable pediatric epilepsy | Single | 7 | 7 | 2 | 12–44 mo | 71 |
Kang et al. (2005) [ |
Intractable pediatric epilepsy | Single | 297 | 5 | 2 | 6–88 mo | 40 |
Yum et al. (2007) [ |
Lennox-Gastaut syndrome | Single | 79 | 7 | 7 | 5.0±3.3 yr | 29 |
Current study | Lennox-Gastaut syndrome | Single | 7 | 7 | 7 | 3.2±0.5 yr | 86 |
VNS, vagus nerve stimulation; LGS, Lennox-Gastaut syndrome.