Epilepsy
Animal experiments and research in humans treated with VNS have collated electrophysiological studies (electromyography [EMG], evoked potential [EP], electroencephalography [EEG]) functional anatomical brain-imaging studies (positron-emission tomography [PET], single-photon-emission computed tomography [SPECT], functional magnetic resonance imaging [fMRI], c-fos, densitometry), and neuropsychological and behavioural studies. Furthermore, from the extensive clinical experience with VNS, interesting clues have arisen concerning the MOA of VNS. More recently, the role of the vagus nerve in the immune system has been investigated.
From the extensive body of research on the MOA, it has become conceivable that effective stimulation in humans is primarily mediated by afferent vagal A- and B-fibres.70,71
Unilateral stimulation
influences both cerebral hemispheres, as shown in several functional imaging studies.72,73
have been identified and include the locus coeruleus, the nucleus of the solitary tract and the thalamus and limbic structures.74–76 Neurotransmitters playing a role may involve not only the major inhibitory neurotransmitter γ-aminobutyric acid (GABA) but also the serotoninergic and adrenergic systems.77,78 the MOA of VNS can be found in Vonck et al.79
An extensive overview of Deep Brain Stimulation
Deep brain stimulation (DBS) is a more recently explored treatment modality in epilepsy. Compared with VNS it is a more invasive option. Parallel to VNS, the precise MOA and the ideal candidates for this treatment option are currently unidentified. Moreover, it is unknown which intracerebral structures should be targeted to achieve optimal clinical efficacy. Two major strategies for targeting have been followed. One approach is to target crucial central nervous system structures that are considered to have a ‘pacemaker’, ‘triggering’ or ‘gating’ role in the epileptogenic networks that have been identified such as the thalamus or the subthalamic nucleus. Another approach is to interfere with the ictal onset zone itself. This implies the identification of the ictal onset zone, a process that sometimes requires implantation with intracranial electrodes.
Targets
The selection of targets for DBS in humans partially resulted from progress in the identification of epileptogenic networks.80
Although the
cortex plays an essential role in seizure origin, increasing evidence shows that subcortical structures may be involved in the clinical expression, propagation, control and sometimes initiation of seizures. Consequently, several subcortical nuclei have been targeted in pilot trials for different types of epilepsy. The suppressive effects of pharmacological or electrical inhibition of the subthalamic nucleus (STN) in different animal models for epilepsy and the extensive experience with STN DBS in patients with movement disorders led to a pilot trial of high-frequency (130Hz) continuous STN DBS in five patients by a group from Grenoble.81,82
seizures had a >60% reduction in seizure frequency. Four other centres have reported STN DBS results. In one patient with Lennox-Gastaut syndrome, generalised seizures were fully suppressed and myoclonic and absence seizures reduced by >75%.83
seizure frequency reductions of >60% in two out of five patients treated with STN DBS.84
Crucial brainstem and intracranial structures
seizures in a patient with progressive myoclonic epilepsy in whom generalised seizures had been successfully treated with previous VNS.86
Thalamocortical interactions are known to play an important role in several types of seizure. Since 1984, Velasco et al. have investigated a large patient series (n=57) with different seizure types who underwent DBS of the centromedian (CM) nucleus, a structure that can be fairly easily stereotactically targeted due to its relatively large size, its spherical shape and its location on each side of the third ventricle.87,88 Intermittent (one minute on, four minutes off) high-frequency (60–130Hz) stimulation that alternated between the left and right centromedian (CM) thalamic nucleus was most effective in children (n=5) with epilepsia partialis continua, in whom full seizure control was reached between three and four months after stimulation. Secondary generalised seizures in these children were the earliest to respond, after one month of treatment. Atypical absences and generalised seizures (primary or secondary) responded significantly. Three out of 22 patients with Lennox-Gastaut syndrome became seizure-free. Complex partial seizures responded less successfully, although partial improvements were observed after long-term stimulation over one year, and patients tended to be satisfied with the treatment, which significantly decreased or abolished secondary generalised convulsions. In a separate report, Velasco et al. reported on 11 patients with Lennox-Gastaut syndrome, with an overall seizure reduction of 80% and two patients rendered seizure-free.89
In a double-blind cross-over protocol performed by Fisher et al., CM thalamic stimulation did not significantly improve generalised seizures in seven patients.90
An open extension phase of the trial using 24-hour stimulation resulted in a 50% decrease in half of the patients. It has become clear, especially from the experience with VNS but also from other studies, that increased efficacy may be observed after a longer duration of stimulation, possibly on the basis of neuromodulatory changes that take time to develop.91,92
There is sufficient evidence to suggest an equally important role of the anterior nucleus (AN) of the thalamus in the pathogenesis of seizure generalisation. Hodaie et al. performed bilateral AN thalamic DBS (one minute on, five minutes off, 100Hz, alternating between right and left AN) in five patients and showed a seizure frequency reduction of between 24 and 89%.93
Andrade et al. reported on the long-term follow-
up of six patients with AN DBS. After seven years of follow-up, five patients showed a more than 50% reduction in seizure frequency.94 Changes in stimulation parameters over the years did not further improve seizure control. Kerrigan et al. reported that four out of five patients who underwent high-frequency AN DBS showed significant decreases in seizure severity and in the frequency of secondary generalised seizures. Moreover, there was an immediate seizure recurrence when DBS was stopped.95
These studies all preceded a Three patients with symptomatic partial Loddenkemper et al. reported
Handforth et al. reported on one patient with bitemporal seizures in whom half of the seizures were suppressed and in one patient with frontal lobe epilepsy who experienced a one-third reduction of seizures.85
Vesper et al. described a 50% reduction in myoclonic 94
One hundred and ten patients were enrolled at 17 medical centres in the US. Half received stimulation and half received no stimulation during a three-month blinded phase; all then received unblinded stimulation. In the last month of the blinded phase, the stimulated group had a 29% greater reduction in seizures compared with the control group. Complex, partial and ‘most severe’ seizures were significantly reduced by stimulation. By two years, there was a median 56% reduction in seizure frequency, 54% of patients had a
multicentre double-blind randomised trial of bilateral AN stimulation (Stimulation of the Anterior Nucleus of the Thalamus in Epilepsy [SANTE] trial) in patients with partial-onset seizures with or without secondary generalisation.96
EUROPEAN NEUROLOGICAL REVIEW
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