Refractory Epilepsy in Children Clinical Trial
Official title:
Does VNS Interact With the Serotonergic and Immune System in Children With Intractable Epilepsy? A Randomized Clinical Study.
Clinical randomized controlled observer blinded add-on design. Additionally there will be a
non-controlled follow-up phase of the study. Children (Age 4-18 years) with intractable
epilepsy, and not eligible for resective surgery will be treated with VNS.
Aim of the study:
1. To evaluate tolerability and effectiveness of VNS in children with intractable epilepsy
and cognitive and behavioural problems in a controlled study.
2. To evaluate the effect of VNS on the immune system which, in its turn, will lead to
changes in the serotonin metabolic pathway
3. To link the therapeutic effect of VNS to changes in the serotonin (5HT) metabolic
pathway.
In addition the investigators hope to detect some markers of immune and neurotransmitter
function that enable us to predict 1) Neuronal cell loss in relation to cognitive decline 2)
the response to therapeutic treatment of VNS.
Hypothesis:
The investigators aim to explore neuronal correlates for cognitive morbidity in children
with intractable epilepsy and to relate this to morphologic changes, biochemical markers,
and to epilepsy characteristics.
Correction of the "stressed" pro-inflammatory status of monocytes/macrophages via an
electrical stimulation of the vagus nerve will prevent/ameliorate seizures as well as
behavioural mood symptoms in children with refractory epilepsy, characterized by the
"pro-inflammatory monocyte signature"
Background information:
Repetitive seizures lead to an increase of pro-inflammatory cytokines in the peripheral
blood. Experimentally it has been shown that activation of inflammatory cytokines by the
peripheral administration of a toxic agents causes sickness behaviour. Pro-inflammatory
cytokines interfere with the catabolisation of a precursor of Serotonin (Tryptophan).
Tryptophan is catabolised to an endogen NMDA receptor agonist. NMDA (an excitatory
neurotransmitter) can lead to neuronal damage.
The Vagus Nerve (VN) plays an important role in the interaction between the neurotransmitter
and immune system in which cytokines are crucial. Vagus nerve stimulation (VNS) has an
effect on various amino-acid pools in the brain. Patients who respond to VNS show
significantly increased serotonin metabolites in their cerebrospinal fluid. VNS is also
associated with marked peripheral increases in pro-, and anti-inflammatory circulating
cytokines. Given the complexity of the serotonergic system and its interaction with multiple
neurotransmitter systems in the human brain it is not surprising to find that serotonin
plays a role in the etiology and the course of affective disorders. It is to be expected
that the serotonin-immune pathway also plays a role in the course of epilepsy.
Study population:
Children (Age 4-18 years) with intractable epilepsy, and not eligible for resective surgery
Study design:
Clinical randomized controlled observer blinded add-on design. Additionally, and as a
non-controlled follow-up of the study, the active control group will receive therapeutic
stimulation parameters. In a secondary analysis both VNS groups will be compared with the
pre-surgical period (baseline)
Intervention: VNS The generator is implanted beneath the subcutaneous tissue in the upper
chest region. The electrode is tunneled from the generator to the stimulation site in the
neck. The system is programmed with a computer. The pulse width, output current, signal
frequency and stimulation time are programmed telemetrically.
The study group is stimulated with the following parameters: Output current 0.25 milliampere
(to be ramped up to max. 1.75 milliampere), Pulse width 0.5 milliseconds, Frequency 30 Hz,
Duty cycle: 30 sec on 5 min off (duty cycle 10%).
The active control group is stimulated with: Output current 0.25 milliampere, Pulse width
0.1 milliseconds, Frequency 1 Hz, Duty cycle: 14 sec on 60 min off (duty cycle <0.5%)
Primary endpoint:
Seizure frequency reduction of 50% or more.
Main variables:
Demographics Epilepsy specific data (Seizure frequency (diary), Medication) Biochemical and
neuro-immunological assessments in in peripheral blood and CSF(serotonin metabolites,
Noradrenalin, GABA, Glutamate, pro-, and anti-inflammatory cytokines).
Neuropsychologic variables (mood, cognition, QoL )
;
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment