Neurostimulation as a Treatment Option for Epilepsy Children
There are no controlled studies of VNS in children, but many epilepsy centres have reported safety and efficacy results in patients less than 18 years of age in a prospective way. All these studies report similar efficacy and safety profiles compared to findings in adults.20–25
In children with epileptic encephalopathies, suppressing effect of VNS,52 although another report described improved seizure control in this specific patient group.53 Side Effects and Tolerability Rare
adverse events unique to this age group included drooling and increased hyperactivity.24
efficacy may become evident after only >12 months of treatment.25 More recent reports show slightly better seizure control with VNS in children compared with adults. Fifty-four per cent of children in a series of 26 from Australia responded to VNS with ≥50% seizure frequency reduction. Status epilepticus episodes were reduced or ceased in four patients with recurrent status epilepticus.26
Seizure Types and Syndromes
The open-label longitudinal multicentre EO4 study also included patients with generalised epilepsy (n=24).27,28
described in a retrospective manner that primary generalised seizures and generalised epilepsy syndromes responded equally well to VNS compared with partial epilepsy syndromes. A prospective study by Holmes et al. in 16 patients with generalised epilepsy syndromes and stable antiepileptic drug (AED) regimens showed an overall mean seizure frequency reduction of 43% after a follow-up of at least 12 months.32
frequency reduction was 46%. Quintana et al.,29 Kostov et al.31
Ben-Menachem et al. included nine
patients with generalised seizures in a prospective long-term follow-up study. The patients with absence epilepsy in particular had a significant seizure reduction.17
A few studies are available specifically describing the use of VNS in patients diagnosed with Lennox-Gastaut syndrome. One prospective study in 16 patients with Lennox-Gastaut syndrome found that one- quarter of patients had a >50% reduction in seizure frequency after six months of follow-up, comparable to the response rates in the controlled studies, which included a few patients with leaky gut syndrome (LGS).33 Other prospective studies reported higher responder rates with a >50% seizure frequency reduction in half of the patients (n=13, six-month follow-up),34
in six out of seven patients (six-month follow-up )35 seven out of nine patients (one- to 35-month follow-up).36
and in A
retrospective multicentre study in 46 patients with LGS reported responder rates of 43%.37
Kostov et al. reported on 30 patients with
Lennox-Gastaut syndrome. The best effects were observed with atonic seizures (80.8% median reduction), followed closely by tonic seizures (73.3% median reduction). Additional positive effects included milder or shorter ictal or post-ictal phases in 16 patients. Improved alertness was reported in 76.7%.38
There have been many reports on various other seizure types and syndromes, such as seizures in patients with hypothalamic hamartomas,39 epilepsy,42,43
tuberous sclerosis,40,41 Landau Kleffner syndrome,44 epileptic encephalopathies39 disability and mental retardation46–49
progressive myoclonic Asperger’s syndrome,45
and syndromes with developmental and infantile spasms.50
All of the
studies reported were limited to reasonable efficacy in terms of controlling seizures and other disease-related symptoms, such as cerebellar dysfunction and behavioural and mood disturbances. A report on the efficacy of VNS in five children with mitochondrial electron transport chain deficiencies described no significant seizure reduction in any of the children.51
Furthermore, a study in patients with previous resective epilepsy surgery showed a limited seizure- EUROPEAN NEUROLOGICAL REVIEW Mechanism of Action
To date, the precise mechanism of action (MOA) of VNS and how it suppresses seizures remains to be elucidated. Research directed towards the identification of involved fibres, intracranial structures and neurotransmitter systems has been performed.
Following a limited number of animal experiments in dogs and monkeys investigating safety and efficacy, the first human trial was performed.2
Cardiac Side Effects
Despite the fact that the initial studies showed no clinical effect on heart rate, occurrence of bradycardia and ventricular asystole during intraoperative testing of the device (stimulation parameters: 1mA, 20Hz, 500μs, ~17 seconds) has been reported in a small number of patients. None of the reported patients had a history of cardiac dysfunction or abnormal cardiac testing after surgery. Tatum et al. reported on four patients who intraoperatively experienced ventricular asystole during device testing.64
In three patients, the implantation
procedure was aborted. Asconape et al. reported on a single patient who developed asystole during intraoperative device testing. After removal of the device, the patient recovered completely.65 described three similar cases.66
Ali et al. Andriola et al. reported on three patients
who experienced an aystole during intraoperative lead testing and who were subsequently chronically stimulated.67
Ardesch et al. reported on
three patients with intraoperative bradycardia and subsequent uneventful stimulation.68
Possible hypotheses in terms of the underlying
cause are inadvertent placement of the electrode on one of the cervical branches of the vagus nerve or indirect stimulation of these branches, reversal of the polarities of the electrodes, which would lead to primary stimulation of efferents instead of afferents, indirect stimulation of cardiac branches, activation of afferent pathways affecting the higher autonomic systems or of the parasympathetic pathway with an exaggerated effect on the atrioventricular node, technical malfunctioning of the device or idiosyncratic reactions. The contributing role of specific AEDs should be investigated further. One case report described late-onset bradyarrhythmia after two years of VNS.69
In these patients overall seizure Michael et al.30
and
Even at current low output levels, the most prominent and consistent sensation in patients when the vagus nerve is stimulated for the first time is a tingling sensation in the throat and hoarseness of the voice due to secondary stimulation of the superior laryngeal nerve.54–56
In long-term
extension trials, the most frequent side effects were hoarseness in 19% of patients and coughing in 5% of patients at two- year follow-up and shortness of breath in 3% of patients at three years.15
There was a clear
trend towards diminishing side effects over the three-year stimulation period. Ninety-eight per cent of the symptoms were rated mild or moderate by the patients and the investigators.57
Side effects can
usually be resolved by decreasing stimulation parameters. Central nervous system side effects seen typically with AEDs were not reported. After three years of treatment, 72% of the patients were still on the treatment.15
The most frequent reason for discontinuation was lack of efficacy. Initial studies on small patient groups treated for six months with VNS showed no negative effect on cognitive motor performance and balance.58–60
with a follow-up of two years.61,62
extensive neuropsychological testing in 36 patients treated for six months with VNS.63
These findings were confirmed in larger patient groups Hoppe et al. showed no changes in
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