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Shocking the Wandering Nerve – Vagus Nerve Stimulation After a Decade of Widespread Use
A possible role for thalamic involvement was supported by a recent
Figure 1: Mean Seizure Reduction After Three Months of Vagus
functional magnetic resonance imaging (fMRI) study that also
Nerve Stimulation (VNS) in the First Blinded, Randomised Studies
demonstrated increased activity in several areas of brain, but was most
of VNS Used in Refractory Partial Seizures in Patients Older than
12 Years (Studies EO3 and EO5)
robust in the bilateral thalami (left > right) and the bilateral insular
cortices in epilepsy patients whose VNS was activated for the first time
immediately prior to scanning.
A second study demonstrated two
patients in whom thalamic changes on fMRI correlated with the degree
of seizure control.
However, other fMRI studies have demonstrated
no change in thalamic activity (for a review, see reference 21), and
single photon emission computed tomography (SPECT) studies have
shown decreased thalamic activity in response to VNS.
contradictory observations make it difficult to draw definitive
conclusions; however, thalamic involvement remains a likely candidate
underlying VNS efficacy.
Vagus Nerve Stimulation Efficacy in Adults and Children
The first large, randomised, blinded study of VNS in humans (EO3) was
P values compare the low-stimulation (active-control) versus the high-stimulation (treatment)
group of each study. Both studies demonstrate a significant decrease in seizure frequency
preceded by two open pilot studies that had shown decreased seizure
between high- and low-stimulation groups.
frequency with VNS.
In this trial, 114 patients at least 12 years old
with medically intractable partial (simple, complex, secondary registry study in which patients had stable dosing of AED over 12 months,
generalised) epilepsy were enrolled. Medically intractable epilepsy was demonstrating that 45% of patients had greater than 50% reduction in
defined as more than six seizures per year. Patients were randomised seizures at three months, increasing to 58% at 12 months.
to receive ‘high’ stimulation (treatment group) or ‘low’ stimulation VNS may allow some patients to reduce the number or dose of AEDs
(active control). There was a 12-week baseline period, a two-week taken,
though with non-responders, 17.8% of patients had increased
recovery phase after implantation and then a 12-week parallel phase numbers of AEDs.
study to measure effects on seizure frequency. The high-stimulation
group had a statistically significant 24.5% reduction in seizure Although the initial trials for VNS included patients as young as 12
frequency, with 31% of patients achieving at least a 50% reduction in years old, it was not until later that trials separated paediatric data or
frequency (see Figure 1). The low-stimulation group had a decrease in designed purely paediatric trials. Murphy et al.
compiled the data on
seizure frequency of 6.1%, with 13% of patients achieving greater children from the two blinded, randomised trials
than 50% reduction in seizures.
An open extension of the same trial, from EO3, 17 children from EO5) combined with 41 patients enrolled
in which patients were maintained or changed to high stimulation for in a compassionate-use protocol that included patients with partial
12 months, included 100 patients and demonstrated a continued seizures, primary generalised seizures or secondary generalised
reduction in seizure frequency at 9–12 months of 31.9%.
seizures, for a total of 60 patients. The mean age was 13.5 years, with
the youngest recipient aged 3.5 years and 16 children under 12 years
Subsequently, a similar multicentre, randomised, double-blind trial in of age. Pooled data indicated a mean reduction in seizure frequency of
the US (EO5) demonstrated similar results.
This trial included patients 22% at three months, increasing to 42% at 18 months. No significant
12–65 years old with at least six complex partial or secondary difference was seen in children less than 12 years old, and no single
generalised seizures per month in a 12–16-week baseline period. seizure type appeared more responsive to VNS therapy.
Patients were randomised into ‘high-frequency’ (treatment group) and
‘low-frequency’ (active control) stimulation. At three months, 196 The largest paediatric study to date was a retrospective, multicentre
patients were evaluated, and the high-frequency group had a evaluation of 125 patients with medically intractable epilepsy.
statistically significant reduction in seizure frequency of 27.9% Follow-up data at three months were available in 95 patients and
compared with 15.2% in the low-frequency group (see Figure 1). An demonstrated an average reduction of seizure frequency of 36.1%,
open extension study re-evaluated patients at 12 months, and seizure with a median reduction of 51.5%. Furthermore, 28.4% of patients
frequency was reduced by 45%.
had a greater than 75% reduction in seizure frequency, and two
patients became seizure-free. Data were available from 56 patients at
In a compassionate-use, multicentre, prospective, open-label trial (EO4) six months, with reduction in seizure frequency of 44.7% and median
of 24 patients with medically resistant generalised epilepsy aged 4–40 reduction of 51%. A greater than 50% reduction was seen in 57% of
there was an overall reduction in seizure frequency of 46%, with patients, and 30% showed a greater than 75% seizure reduction. No
45.8% of patients demonstrating a greater than 50% reduction in significant difference was found in patients under 12 years of age.
seizure frequency, clearly demonstrating a benefit for generalised Other studies have shown similar results.
seizures, similar to other studies.
Several other studies have confirmed
the efficacy of VNS.
Compiled long-term data from EO1–EO5
Fifty children with Lennox-Gastaut syndrome (LGS) were evaluated in a
demonstrated that 23% of patients had a greater than 50% reduction in multicentre retrospective study. One month following VNS there was a
seizure frequency at three months, and that this increased to 37% at one 42% reduction in seizure frequency, including 43% of patients with a
year, 43% at year two and then plateaued, staying at 43% at year three, greater than 50% reduction in seizure frequency. At six months, seizure
suggesting improved effect over time. This trend was also shown in a reduction was 57.9%, with 58% of patients showing a decrease of
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