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Vagus nerve stimulation (VNS) is an established treatment for selected patients with medically refractory seizures. Recent studies suggest that VNS could be potentially useful in the treatment of resistant depressive disorder. Although a surgical procedure is required in order to implant the VNS device, the possibility of a long-term benefit largely free of severe side effects could give VNS a privileged place in the management of resistant depression. In addition, VNS appears to affect pain perception in depressed adults; a possible role of VNS in the treatment of severe refractory headache, intractable chronic migraine and cluster headache has also been suggested. VNS is currently investigated in clinical studies, as a potential treatment for essential tremor, cognitive deficits in Alzheimer’s disease, anxiety disorders, and bulimia. Finally, other studies explore the potential use of VNS in the treatment of resistant obesity, addictions, sleep disorders, narcolepsy, coma and memory and learning deficits.

Vagus nerve stimulation (VNS) is the most widely used non-pharmacological treatment for medically intractable epilepsy and has been in clinical use for over a decade. It is indicated in patients who are refractory to medical treatment or who experience intolerable side effects, and who are not candidates for resective surgery. VNS used in the acute setting can both abort seizures and have an acute prophylactic effect. This effect increases over time in chronic treatment to a maximum at around 18 months. The evidence base supporting the efficacy of VNS is strong, but its exact mechanism of action remains unknown. A vagus nerve stimulator consists of two electrodes embedded in a silastic helix that is wrapped around the cervical vagus nerve. The stimulator is always implanted on the left vagus nerve in order to reduce the likelihood of adverse cardiac effects. The electrodes are connected to an implantable pulse generator (IPG) which is positioned subcutaneously either below the clavicle or in the axilla. The IPG is programmed by computer via a wand placed on the skin over it. In addition, extra pulses of stimulation triggered by a hand-held magnet may help to prevent or abort seizures. VNS is essentially a palliative treatment and the number of patients who become seizure free is very small. A significant reduction in the frequency and severity of seizures can be expected in about one third of patients and efficacy tends to improve with time. Vagus nerve stimulation is well tolerated and has few significant side effects. We describe our experience on the use of VNS on drug-resistant epilepsy in 90 patients treated in two departments (in Athens, Greece and Newcastle, England).

The failure of available antiepileptic medications to adequately control seizures in a substantial number of patients underscores the need to develop novel epilepsy therapies. Recent advancements in technology and the success of neuromodulation in treating a variety of neurological disorders have spurred interest in exploring promising therapeutic alternatives, such as electrical stimulation and gene-based synaptic control. A variety of different stimulation approaches to seizure control targeting structures in the central or peripheral nervous system have been investigated. Most studies have been based on uncontrolled observations and empirical stimulation protocols. Today the vagus nerve stimulator is the only FDA approved adjunctive treatment for epilepsy that utilizes electrical stimulation. Other potential strategies including direct stimulation of the epileptogenic cortex and deep brain stimulation of various targets are currently under investigation. Chronically implanted devices for electrical stimulation have a variety of limitations. First, they are susceptible to malfunction and infection. Second, most systems require battery replacement. Finally, electrical stimulation is incapable of manipulating neuronal function in a transmitter specific fashion. Gene delivery to epileptogenic targets or targets implicated in regulating seizure threshold has been investigated as an alternative means of neuromodulation in animal models. In summary, positive preliminary results and the lack of alternative treatment options provide the impetus for further exploration of electrical stimulation and gene-based therapies in pharmacoresistant epilepsy. Various specific targets and approaches to modulating their activity have been investigated in human studies.

Electrical stimulation of deep brain structures is a promising new technology for the treatment of medically intractable seizures. Performed and on animal models of epilepsy, electrical stimulation has shown to reduce seizure frequency. Preliminary results on humans are encouraging. However, such improvements emerge despite a lack of understanding of the precise mechanisms underlying electrical stimulation either delivered directly on the epileptogenic zone (direct control) or through an anatomical relay of cortico-subcortical networks (remote control). Anatomical targets such as the thalamus (centromedian nucleus, anterior thalamus, mamillary body and mamillothalamic tracts), the subthalamic nucleus, the caudate nucleus and direct stimulation of the hippocampal formation have been successfully investigated. Although randomized controlled studies are still missing, deep brain stimulation is a promising treatment option for a subgroup of carefully selected patients with intractable epilepsy who are not candidates for resective surgery. The effectiveness, the optimal anatomic targets, the ideal stimulation parameters and devices, as well as patient selection criteria are still to be defined.

Neurostimulation is an emerging treatment for neurological diseases. Different types of neurostimulation exist mainly depending of the part of the nervous system that is being affected and the way this stimulation is being administered. Vagus nerve stimulation (VNS) is a neurophysiological treatment for patients with medically or surgically refractory epilepsy. Over 30,000 patients have been treated with VNS. No clear predictive factors for responders have been identified. To date, the precise mechanism of action remains to be elucidated. Better insight in the mechanism of action may identify seizure types or syndromes that respond better to VNS and may guide the search for optimal stimulation parameters and finally improve clinical efficacy.

Deep brain stimulation (DBS) has been used extensively as a treatment for movement disorders. Several new indications such as obsessive compulsive behaviour and cluster headache are being investigated with promising results. The vast progress in biotechnology along with the experience in other neurological diseases in the past ten years has led to a renewed interest in intracerebral stimulation for epilepsy. Epilepsy centers around the world have recently reinitiated trials with deep brain stimulation in different intracerebral structures such as the thalamus, the hippocampus and the subthalamic nucleus.

We present the results of chronic electrical stimulation of the hippocampus (ESH) in 9 patients with complex partial seizures and at least 18 months follow-up. The magnetic resonance imaging (MRI) scan was normal in 5 while in 4 patients it showed hippocampal sclerosis. The seizure frequency ranged from 10 to 50 seizures per month. All patients were submitted to implantation of diagnostic 8-contact bilateral hippocampal depth electrodes to determine the location of epileptic foci. Once the focus was located, the diagnostic electrodes were replaced by deep brain stimulation (DBS) electrodes. Following DBS, all patients improved. With respect to outcome, patients were divided in two groups, one seizure-free (5 patients) and the other with residual seizures (4 patients). Both groups shared similar clinical features. However, the patients who were seizure free had normal MRI scan while those who had residual seizures were being stimulated on a sclerotic hippocampus. We conclude that electrical stimulation of the epileptic hippocampal formation can control mesial temporal seizures. Best results are obtained if we stimulate a hippocampus which does not show sclerosis in the MRI. In these cases, seizures are stopped and the recent memory tests improve even in patients with bilateral foci. This result is of extreme importance to patients who have either intractable seizures and normal MRI or bilateral epileptogenic foci, are excluded as candidates for temporal lobectomy and are left with no other alternative.

Deep brain stimulation (DBS), which mimics the effect of ablative surgery in movement disorders, is considered by analogy as potentially useful in the epileptic temporal lobe as an alternative to resection. It could be applied to patients in whom resective surgery is less beneficial, e.g. cases without memory impairment or with bilateral hippocampal involvement. In patients who undergo invasive presurgical analysis, the necessary intrahippocampal leads can serve for the application of DBS, provided that they are suited for chronic use. The hippocampus, in which the focus of epilepsy is detected, is stimulated continuously using high-frequency square-wave pulses. The reduction of interictal spike activity during a period of acute stimulation is the criterion for deciding whether the leads will be connected to an internal pulse generator. We are conducting a pilot study, with 16 patients enrolled so far, ten of whom have been followed up for more than one year. Some theoretical considerations are dedicated to hippocampal DBS.

Electrical stimulation (ES) of the thalamic centromedian nucleus (CMN) has been proposed as a minimally invasive alternative for the treatment of difficult-to-control seizures of multifocal origin and seizures that are generalized from the onset. ES intends to interfere with seizure propagation in a non-specific manner through the thalamic system. By adopting a frontal parasagittal approach and based on anterior-posterior (AC-PC) commissure intersection, deep brain stimulation (DBS) electrodes are stereotactically inserted. Electrophysiologic confirmation of electrodes position is accomplished by eliciting cortical recruiting responses and direct current (DC) shifts by low- and high-frequency stimulation through the electrodes. Cycling mode of bipolar stimulation has been used at 60–130 Hz, 0.45 msec, 2.5–3.5V, 1min ON in one side 4min OFF, 1min ON in the other side and 4min OFF forward and back for 24h. ES of CMN significantly decreases generalized seizures of cortical origin and focal motor seizures. Best results are obtained in non-focal generalized tonic clonic seizures and atypical absences of the Lennox-Gastaut syndrome. Experience has indicated that the most effective target for seizure control is the thalamic parvocellular centromedian subnucleus.

One option for treatment of medically refractory debilitating epilepsy is stimulation of the anterior thalamic nucleus, which projects via the cingulate gyrus to limbic structures and neocortex. In this chapter we describe the technique for anterior thalamic deep brain stimulation and report outcomes of early series of patients. The prospective double-blind randomized Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy (SANTE) trial will evaluate the efficacy of this technique for epilepsy treatment.

The present chapter describes the most important available experimental and clinical evidence on the role of electrical stimulation of the cerebellum or the thalamus in the control of epilepsy. Cerebellum serves as an integrator of sensory information and regulator of motor coordinating and training. The sole output of the cerebellum is inhibitory Purkinje cell projections to deep cerebellar nuclei in the brainstem. Cerebellar stimulation in animal models of epilepsy has given mixed results. Nevertheless, more than 130 epileptic patients have been subjected to cerebellar stimulation and the results from uncontrolled studies have been encouraging. The anterior thalamic nucleus (ATN) is part of the Papez circuit, a group of limbic structures with demonstrated role in epilepsy. The centromedian thalamic nucleus (CMN) is considered part of the thalamic reticular system. Stimulation of either of these nuclei in experimental animals has been associated with considerable antiepileptic effects. On the basis of the research evidence, numerous studies have been done on humans, which gave promising results. Currently, a multicenter trial on stimulation of the ATN, the SANTE trial is in progress in the USA. On the basis of the reported studies, the authors aim to provide insights into how the electrical stimulation of the above structures exerts an antiepileptic effect and also provide suggestions regarding the future progress in this field.