Effects of Vagus Nerve Stimulation and Ketogenic Diet on Quality of Life and Changes in EEG and Sleep

Abstract: When anti-epileptic drugs fail, and epilepsy surgery is found unfeasible or ineffective, there remains a group of at least 25% of children with epilepsy in whom seizure control cannot be achieved. Vagus nerve stimulation (VNS) is an adjunctive treatment for medically refractory epilepsy. It is an implantable, multi-programmable pulse generator that delivers current electrical stimulation to the vagus nerve for the purpose of suppressing and reducing the frequency and/or severity of epileptic seizures. Ketogenic diet (KD) is a high fat, low carbohydrate and low protein diet that has been used for childhood therapy resistant epilepsy since the1920s. It was developed to mimic the ketotic state of starvation. The general aim of this thesis was to evaluate effects of VNS on epileptiform activity, deltapower and sleep characteristics and to correlate these to clinical aspects on behaviour, mood and QOL in children with therapy resistant epilepsy. Initially, and after three and nine months of VNS-treatment, 15 children were investigated. Sleep characteristics and clinical correlations were also evaluated after 3 and 12 months in 18 children with KD. A diary of seizure frequency and the National Hospital Seizure Severity Scale (NHS3) were collected. In the first study (paper I) cognitive functioning was recorded, a Visual Analogue Scale for validating QOL, Child Behaviour Checklist (CBCL) for quantifying behaviour problems, Dodrill Mood Analogue Scale and Birleson Depression Self-Rating Scale were used. Six of fifteen children showed a 50% or more reduction in seizure frequency; one of these became seizure-free. Two children had a 25-50% seizure reduction. Two children showed increased seizure frequency. In 13 of 15 children there was an improvement in NHS3. The parents reported shorter duration of seizure and recovery phase. There were no changes in cognitive functioning. Twelve children showed an improvement in QOL. Eleven of these also improved in seizure severity and mood and 5 also in depressive parameters. In the second study (paper II) 24 hours ambulatory EEG monitoring for spike detection were used. This study shows that VNS reduces interictal epileptiform discharges (IEDs), especially in rapid eye movements (REM) and slow wave sleep, and the number of electrographic seizures. It also shows a concordance between reduction in IEDs and electrographic seizures. There was no correlation between the extent of improvement in clinical data and the degree of spike reduction. In the third and forth study (paper III and IV) children with VNS and KD were examined with ambulatory polysomnographic recordings. Sleep parameters, and in VNS, movement times (MTs), used to account for arousals were estimated. Our findings indicate that VNS counteracts known adverse effects of epilepsy on sleep and increases slow wave sleep. This possibly contributes to the reported improvement in wellbeing. We also see an increase in MTs. This arousal effect seems to be of minor importance for QOL and could possibly be related to the antiepileptic mechanisms in VNS. KD decreases night sleep and improves sleep quality. The improvement in sleep quality, with increased REM sleep, seems to contribute to the improvement in QOL. In the fifth study (paper V) the 24 hours ambulatory EEG monitoring were used to study immediate effects of VNS stimulation on epileptiform activity, arousals and background frequency in EEG. The findings lend no support to earlier studies suggesting immediate VNS stimulation related changes in IEDs och IEIs. There were no VNS stimulation related changes in background EEG frequency despite the significant increase in the number of MTs immediately related to the VNS stimulation periods.