Handbook of Clinical Neurology, Vol. 108 (3rd series)Epilepsy, Part IIH. Stefan and W.H. Theodore, Editors# 2012 Elsevier B.V. All rights reserved

Chapter 58

Neurostimulation for epilepsy

KRISTL VONCK1*, VEERLE DE HERDT1, MATHIEU SPRENGERS1, AND ELINOR BEN-MENACHEM2

1Reference Center for Refractory Epilepsy, Department of Neurology, Ghent University Hospital, Ghent, Belgium2Institute of Clinical Neuroscience, Division of Neurology, G€othenburg University, G€othenburg, Sweden

INTRODUCTION

Neurostimulation is an emerging treatment for neuro-psychiatric disorders. Excitability-reducing neurostimu-lation is pursued as an alternative therapeutic strategyfor refractory epilepsy when drugs and surgery fail orare not indicated.

Various neurostimulation modalities for epilepsyhave been developed or are currently being investigatedfor efficacy and safety. Electrical stimulation of thetenth cranial nerve or vagus nerve stimulation (VNS)is an invasive but extracranial type of stimulation thatwas developed in the 1980s and is currently routinelyavailable in epilepsy centers worldwide. Through animplanted device and electrode, electrical pulses are ad-ministered to the afferent fibers of the left vagus nerveat the cervical level. VNS is indicated in patients withrefractory epilepsy who are unsuitable candidates forepilepsy surgery or who have had insufficient benefitfrom such a treatment (Ben-Menachem, 2002). Directintracerebral manipulation is avoided, as stimulation isapplied to that part of the vagus nerve that passesthrough the neck. Apart from the vagus nerve, thetrigeminal nerve is another cranial nerve that is beingtargeted to treat refractory seizures. Long-term resultswith trigeminal nerve stimulation (TNS) from an openpilot trial have recently become available (DeGiorgioet al., 2009).

Transcranial magnetic stimulation (TMS) is an ex-tracranial and noninvasive neurostimulation technique(Sparing and Mottaghy, 2008). In TMS a coil that trans-mits magnetic fields is held over the scalp and allows anoninvasive evaluation of excitatory and inhibitoryfunctions of the cerebral cortex. In addition, repetitiveTMS (rTMS) can modulate the excitability of corticalnetworks (Tassinari et al., 2003). This therapeutic form

*Correspondence to: Prof.Dr. Kristl Vonck, Department of Neurol

Belgium. Tel: þ32 933 24539, Fax: þ32 933 24971, E-mail: Kristl.

of TMS is currently being investigated as a treatmentoption for refractory epilepsy with varying results(Fregni et al., 2006). Transcranial direct current stimu-lation (tDCS) uses sponge electrodes attached to the pa-tient’s head to deliver electrical currents over longerperiods of time (minutes) to achieve changes in corticalexcitability that persist even after stimulation hasceased, hence with therapeutic potential in diseases char-acterized by a disturbed cortical excitability (Nitsche andPaulus, 2009).

For intracranial neurostimulation, stimulation elec-trodes are inserted into intracerebral targets in deepbrain stimulation (DBS) or placed over the cortical con-vexity for cortical stimulation (CS) to administer electri-cal pulses to central nervous system structures. Thesemodalities of neurostimulation are not entirely newfor neurological indications. Some have been exten-sively applied in movement disorders and pain(Nguyen et al., 2000; Pollak et al., 2002). Several new in-dications, such as obsessive compulsive behavior andcluster headache, are being investigated with promisingresults (Nuttin et al., 1999; Leone et al., 2003). In thepast, DBS and CS of different brain structures suchas the cerebellum, the locus coeruleus, and the thalamuswere performed mainly in patients with spasticity orpsychiatric disorders who had epilepsy as a comorbidity(Cooper, 1978; Wright et al., 1984; Upton et al., 1985;Feinstein et al., 1989). The vast progress in biotechnol-ogy, along with the experience in other neurological dis-eases in the past 10 years has led to a renewed interest inintracerebral stimulation for epilepsy. Several epilepsycenters around the world have recently reinitiated trialswith DBS in different intracerebral structures such asthe thalamus, the subthalamic nucleus, the caudatenucleus, and medial temporal lobe structures (Fisher

ogy, Ghent University Hospital, De Pintelaan 185, 9000 Ghent,

Vonck@UGent.be

K

et al., 1992; Velasco et al., 1995; Chkhenkeli andChkhenkeli, 1997; Chabardes et al., 2002; Hodaieet al., 2002; Boon et al., 2007). Also CS has recently beeninvestigated in a multicenter trial and incorporated in aso-called closed-loop system (the responsive neurosti-mulator system; RNS) (Morrell, 2011). Especially CSof eloquent cortex may be developed into a valuablealternative for resective surgery to treat refractorypartial focal motor seizures (Yao et al., 2008).

VNS on the one hand, and TNS, TMS, tDCS, DBS,and CS on the other are currently at different levelsof availability and clinical applicability. VNS is a widelyavailable therapy for refractory epilepsy with proven ef-ficacy and safety. For therapeutic TNS proof of concepthas been shown. Therapeutic TMS protocols for epi-lepsy have been developed in centers with a large expe-rience in diagnostic TMS but at this time TMS is not aroutinely available treatment in epilepsy centers, nor istDCS. DBS is under investigation in experimental trialsin several specialized epilepsy centers with a large expe-rience in refractory epilepsy and functional neurosur-gery. Apart from a group of patients who carryimplanted devices from the earlier era of neurostimula-tion for epilepsy, the more recent studies report resultsin no more than 600 patients worldwide. CS is consid-ered a therapeutic neurostimulation option for specifictypes of epilepsy, e.g., neocortical epilepsy, and more fi-nal results from the multicenter study in the USA haveto be awaited. This chapter focuses on the mechanism ofaction, safety, and efficacy of VNS and the differenttargets being investigated with DBS and CS.

VAGUSNERVESTIMULATION

Historical and anatomical background

The first vagus nerve stimulator was implanted inhumans in 1989. However, the historical basis of peri-pheral stimulation for treating seizures dates back cen-turies. In the 16th and 17th centuries physiciansdescribed the use of a ligature around the limb in whicha seizure commences to arrest its progress. This methodwas described by the ancient Greek author Pelops, forwhom this observation was proof that epileptic fits orig-inated from the limb itself. This hypothesis wasreviewed in the beginning of the 19th century whenOdier and Brown-Sequard showed that ligatures areequally efficacious in arresting seizures caused by or-ganic brain disease, e.g., a brain tumor (Odier, 1811).Later in this century Gowers (1881) attributed these find-ings to a raised resistance in the sensory andmotor nervecells in the brain that correspond with the limb involved.This would in turn arrest the spread of the discharge.Gowers (1881) also reported several other ways by whichsensory stimulation could prevent seizures from

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spreading, e.g., pinching of the skin and inhalation ofammonia. Almost 100 years later Rajna and Lona(1989) demonstrated that afferent sensory stimuli canabort epileptic paroxysms in humans.

The vagus nerve is a mixed cranial nerve that consistsof �80% afferent fibers originating from the heart,aorta, lungs, and gastrointestinal tract and of �20% ef-ferent fibers that provide parasympathetic innervationof these structures and also innervate the voluntarystriated muscles of the larynx and the pharynx (Foleyand DuBois, 1937; Agostini et al., 1957; Paintal, 1973).Somata of the efferent fibers are located in the dorsalmotor nucleus and nucleus ambiguus, respectively.Afferent fibers have their origin in the nodose ganglionand primarily project to the nucleus of the solitary tract.At the cervical level the vagus nerve mainly consists ofsmall diameter unmyelinated C-fibers (65–80%) and ofa smaller portion of intermediate diameter myelinatedB-fibers and large diameter myelinated A-fibers. Thenucleus of the solitary tract has widespread projectionsto numerous areas in the forebrain as well as the brain-stem, including important areas for epileptogenesis suchas the amygdala and the thalamus. There are direct neu-ral projections into the raphe nucleus, which is the majorsource of serotonergic neurons, and indirect projectionsto the locus coeruleus and A5 nuclei that contain nora-drenegic neurons. Finally, there are numerous diffusecortical connections. The diffuse pathways of the vagusnerve mediate important visceral reflexes such ascoughing, vomiting, swallowing, and control of bloodpressure and heart rate. Heart rate is mostly influencedby the right vagus nerve that has dense projectionsprimarily to the atria of the heart (Saper et al., 1990).Relatively few specific functions of the vagus nervehave been well characterized. The vagus nerve is oftenconsidered protective, defensive, and relaxing. This pri-mary function is exemplified by the lateral line system infish, the early precedent of the autonomic nervous sys-tem. The control of homeostatic functions by the centralnervous system in these earlier life forms was limited tothe escape and the avoidance of perturbing stimuli orsuboptimal conditions. Its complex anatomical distribu-tion has earned the vagus nerve its name, as vagus is theLatin word for wanderer. These two facts togetherinspired Andrews and Lawes (1992) to suggest the name“great wandering protector.”

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Mechanism of action

As for many antiepileptic treatments, clinical applica-tion of VNS preceded the elucidation of its mechanismof action (MOA). Following a limited number of animalexperiments in dogs and monkeys, investigating safetyand efficacy, the first human trial was performed

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(Uthman et al., 1990). The basic hypothesis on the MOAwas based on the knowledge that the tenth cranial nerveafferents have numerous projections within the centralnervous system and that in this way action potentialsgenerated in vagal afferents have the potential to affectthe entire organism (Berthoud and Neuhuber, 2000). Todate the precise mechanism of action of VNS and how itsuppresses seizures remains to be elucidated. Animalexperiments and research in humans treated with VNShave been performed by means of electrophysiologicalstudies (electroencephalography (EEG), electromyogra-phy, evoked potentials (EP), functional anatomic brainimaging studies (positron emission tomography (PET),single photon emission computed tomography (SPECT),functional magnetic resonance imaging (fMRI), c-fosimmunocytochemistry, densitometry), neuropsycholog-ical and behavioral studies. Also from the extensive clin-ical experience with VNS interesting clues concerningthe MOA of VNS have arisen.

NEUROSTIMULAT

EFFECTS OF VAGUS NERVE STIMULATION

ON FIBERS, INTRACRANIAL STRUCTURES,AND NEUROTRANSMITTERS

VNS inducesactionpotentialswithin thedifferent typesoffibers at the cervical level of the vagus nerve. The questionremains, what fibers are responsible or necessary for itsseizure-suppressingeffect.Unidirectional stimulation, ac-tivating afferent vagal fibers, is preferred as epilepsy isconsidered adiseasewith cortical origin and efferent stim-ulation may cause side-effects. From the extensive bodyof research on theMOA, it has become clear that effectivestimulation in humans is primarily mediated by afferentvagal A- and B-fibers (Zagon and Kemeny, 2000; Evanset al., 2004). Unilateral stimulation affects both cerebralhemispheres, as shown in several functional imagingstudies (Henry et al., 1998; Van Laere et al., 2002).

The next step is to identify central nervous systemstructures located on the anatomical pathways fromthe cervical part of the vagus nerve up to the cortex,which play a functional role in the MOA of VNS. Thesecould be central gateway or pacemaker function struc-tures such as the thalamus or more specific targets in-volved in the pathophysiology of epilepsy such as thelimbic system or a combination of both. Crucial brain-stem and intracranial structures have been identifiedand include the locus coeruleus, the nucleus of the sol-itary tract, the thalamus, and limbic structures (Naritokuet al., 1995; Krahl et al., 1998; Osharina et al., 2006;Cunningham et al., 2008).

Another issue concerns the identification of thepotential involvement of specific neurotransmitters.The intracranial effect of VNS may be based on localor regional GABA increases or glutamate and aspartate

decreases or may involve other neurotransmitters thathave been shown in the past to have a seizurethreshold-regulating role such as serotonin and norepi-nephrine (Proctor and Gale, 1999). Neurotransmittersplaying a role may involve the major inhibitoryneurotransmitter g-aminobutyric acid (GABA), but alsoserotonergic and adrenergic systems (Hammond et al.,1992; Ben-Menachem et al., 1995). More recently, Neeseand colleagues found that VNS following experimentalbrain injury in rats protects cortical GABAergic cellsfrom cell death (Neese et al., 2007). A SPECT studyin humans before and after 1 year of VNS showeda normalization of GABAA receptor density in theindividuals with a clear therapeutic response to VNS(Marrosu et al., 2003). Follesa et al. (2007) showed anincrease of norepinephrine concentration in the prefron-tal cortex of the rat brain after acute VNS. An increasednorepinephrine concentration after VNS has also beenmeasured in the hippocampus (Roosevelt et al., 2006)and the amygdala (Hassert et al., 2004).

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EFFECTS OF VAGUS NERVE STIMULATION ON THE

IMMUNE SYSTEM

Recently, the important crosstalk between the vagus nerveand the immune system has been described. There isevidence that the vagus nerve controls and modulatesthe immune response under physiological conditions(Tracey, 2002). The vagus nerve innervates the principalinternal organs, including those that contain the reticulo-endothelial system (Berthoud and Neuhuber, 2000). Thevagus nerve signals the brain when inflammation occursin the body, and modulates the immune response byactivating different pathways, such as the cholinergicanti-inflammatory pathway, the hypothalamic–pituitary–adrenal (HPA) axis, and the sympathetic nervous system(Tracey, 2002).

The cholinergic anti-inflammatory pathway is a reflexresponse that activates vagal efferent fibers to releaseacetylcholine (Ach) in the vicinity of tissue macrophages,leading to an inhibition of cytokine release through inter-action with the macrophage nicotinic Ach receptors(Borovikova et al., 2000; Wang et al., 2003).

A second pathway activated by vagal nerve afferentscomprises theHPA axis, well known for its important rolein immunomodulation (John and Buckingham, 2003).

A third immunomodulatory pathway that is induced byvagal nerve afferents comprises the sympathetic nervoussystem (Elenkov et al., 2000). Activation of the vagusnerve fibers by electrical stimulation may control theseimmunological pathways (De Herdt et al., 2009a, b),pointing toward modulation of the immunological stateas one of the mechanisms of action of VNS that is cur-rently unexplored.

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ANTISEIZURE, ANTIEPILEPTIC, AND

ANTIEPILEPTOGENIC EFFECTS OF VAGUS

NERVE STIMULATION

When considering the efficacy of a given treatment inepilepsy, a certain hierarchical profile of the treatmentcan be distinguished. A treatment can have pure anti-seizure effects, meaning that it can abort seizures. Toconfirm such an effect the treatment ismost often admin-istered during an animal experiment in which the animalsare injected with a proconvulsant compound followed bythe administration of the treatment under investigation.A treatment can have a true preventative or a so-calledantiepileptic effect. Antiepileptic efficacy implies thatthe treatment prevents seizures, as themain characteristicof the disease, namely the unexpected recurrence ofseizures, is prevented from happening. A treatment canalso have antiepileptogenic properties. This implies thatthe treatment reverses the development of a pathologicalprocess that may have evolved over a long period of time.Such a treatment is clearly protective and may even beused for other neuroprotective purposes.

Early animal experiments in acute seizure modelssuggest an antiseizure effect of VNS. McLachlan(1993) found that applying VNS at the beginning ofa pentylenetetrazol (PTZ)-induced seizure significantlyshortened the seizure. Woodbury and Woodbury(1991) described the beneficial effect of VNS in prevent-ing or reducing PTZ-induced clonic seizures and electri-cally induced tonic–clonic seizures in rats. Zabara (1992)found that VNS interrupts or abolishes motor seizures incanines induced by strychnine. In our own group, VNSsignificantly increased the seizure threshold for focalmotor seizures in the cortical stimulation model (DeHerdt et al., 2006). Also in the human literature, evi-dence exists that VNSmay exert an acute abortive effect.The magnet feature allows a patient to terminate anupcoming seizure (Boon et al., 2001). Also, a few casereports describe the use of VNS for refractory statusepilepticus (SE) in pediatric and adult patients (Malikand Hernandez, 2004; De Herdt et al., 2009c). A recentstudy investigated the effects of acute VNS on corticalexcitability by using TMS (Di Lazzaro et al., 2004).However, in the clinical trials with VNS, many patientsdid not regularly self-trigger the device at the time of aseizure and still showed good response to VNS. More-over, VNS is administered in an intermittent way andit appears that seizures occurring during the VNS off-time are also affected. This intermittent way of stimu-lation is insufficient to explain the reduction of seizureson the basis of abortive effects alone and suggests a truepreventative or so-called antiepileptic effect of VNS.The fact that VNS influences seizures at a time whenstimulation is in the off-mode has also been shown in

many animal and human experiments. Already in1985, Zabara (1985, 1992) reported that seizure controlwas extended well beyond the end of the stimulation pe-riod. Stimulation for 1 minute could produce seizuresuppression for 5 minutes. Naritoku and Mikels (1996)showed that VNS pretreatment during 1 and 60 minutes,prior to administration of the seizure-triggering stimula-tion, significantly reduced the duration of behavioralseizures and the duration of afterdischarges in amyg-dala kindled rats. In a study by Takaya et al. (1996),VNS was discontinued before induction of PTZ seizuresthat were significantly shortened in duration. Moreover,repetition of stimuli increased VNS efficacy, suggestingthat efficacy of intermittent stimulation improves withlong-term use (Takaya et al., 1996). Zagon and Kemeny(2000) found that VNS-induced slow hyperpolarizationin the parietal cortex of the rat outlasted a 20-secondVNS train by 15 seconds. McLachlan (1992) found thatinterictal spike frequency was significantly decreasedor abolished after 20 seconds of VNS in rats for a var-iable duration, usually around 60 seconds to 3 minutesafter stimulation discontinuation. Recent data in humanEEG studies show a decrease in interictal epileptiformdischarges, both in an acute form and after long-termfollow-up (Koo, 2001; Santiago-Rodriguez et al.,2006; Carrette et al., 2007). The fact that seizures recurafter the end of battery life has been reached is a strongargument against VNS having an antiepileptogenic ef-fect. However, as progress in the development of morerelevant animal models for epilepsy has been made, theantiepileptogenic potential of neurostimulation in gen-eral is being fully explored and some promising resultshave been reported, e.g., in the kindling model (Naritokuand Mikels, 1996; Fernandez-Guardiola et al., 1999). Inthe human literature, one case report described long-lasting seizure control after explantation of the VNS de-vice (Labar and Ponticello, 2003). The basis for the com-bined acute andmore chronic effects of VNSmost likelyinvolves recruitment of different neuronal pathwaysand networks. The more chronic effects are thoughtto be a reflection of modulatory changes in subcorticalsite-specific synapses with the potential to influencelarger cortical areas. In the complex human brain theseneuromodulatory processes require time to build up.Once installed, certain antiepileptic neural networksmay be more easily recruited, e.g., by changing stimula-tion parameters that may then be titrated to the individ-ual need of the patient. This raises hope for potentialantiepileptogenic properties of VNS using long-term op-timized stimulation parameters that may affect and po-tentially reverse pathological processes that have beeninstalled over a long period of time. However, from aclinical point of view, up to now VNS cannot be consid-ered a curative treatment.

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NEUROSTIMULATIO

Randomized controlled trials

PILOT TRIALS EO1 AND EO2

The first descriptions of the implantable VNS system,the NeuroCybernetic Prosthesis System (CyberonicsW,Houston, USA) for electrical stimulation of the vagusnerve in humans appeared in the literature in the early1990s (Terry et al., 1990, 1991). At the same time, initialresults from single-blinded pilot trials (phase 1 trials EO1and EO2) in a small group of patients with refractorycomplex partial seizures who were implanted sinceNovember 1988 in three epilepsy centers in the USAwerereported (Penry and Dean, 1990; Uthman et al., 1990;Wilder et al., 1991). In 9/14 patients treated for3–22 months a reduction in seizure frequency of at least50% was observed. One of the patients was seizure freefor more than 7 months. Some patients reported lesssevere seizures with briefer ictal and postictal periods.Complex partial seizures, simple partial seizures, as well assecondary generalized seizures were affected. It was no-ticed that a reduction in frequency, duration, and intensityof seizures lagged 4–8 weeks after the initiation of treat-ment (Uthman et al., 1990). Uthman et al. (1993) reportedon the long-term results from the EO1 and EO2 study.Fourteen patients had now been treated for 14–35 months.There was a mean reduction in seizure frequency of 46%.Five patients had a seizure reduction of at least 50%, ofwhom two experienced long-term seizure freedom. Innone of the patients did VNS induce seizure exacerbation.It appeared that three types of responses to vagal stimula-tion occurred: rapid sustained, gradual, and nonresponse.

DOUBLE-BLIND RANDOMIZED TRIALS: EO3 AND EO5

In the meantime, two prospective multicenter (n¼ 17)double-blind randomized studies (EO3 and EO5) werestarted (Vagus Nerve Stimulation Study Group, 1995;Handforth et al., 1998). In these two studies patientsover the age of 12 with partial seizures wererandomized to a high- or low-stimulation paradigm.The parameters in the high-stimulation group (output:gradual increase up to 3.5 mA, 30 Hz, 500 ms, 30seconds on, 5 minutes off) were those believed to beefficacious based on animal data and the initial humanpilot studies. Because patients can sense stimulation, thelow-stimulation parameters (output: single increase topoint of patient perception, no further increase, 1 Hz,130 ms, 30 seconds on, 3 hours off) were chosen to pro-vide some sensation to the patient in order to protect theblinding of the study. Low-stimulation parameters werebelieved to be less efficacious and the patients in thisgroup represented an active control group. The resultsof EO3 in 114 patients were promising with a decreasein seizures of 24% in the high-stimulation group versus

6% in the low-stimulation group after 3 months of treat-ment (Vagus Nerve Stimulation Study Group, 1995). Thenumber of patients was insufficient to achieve US Foodand Drug Administration (FDA) approval leading to theEO5 study in the USA including 196 patients: 94 patientsin the high-stimulation group had a 28% decrease in sei-zure frequency versus 15% in patients in the low-stimulation group (Handforth et al., 1998).

Prospective clinical trials withlong-term follow-up

The controlled EO3 and EO5 studies had their primaryefficacy end-point after 12 weeks of VNS. Patientswho ended the controlled trials were offered enrolmentin a long-term (1–3 years of follow-up) prospectiveefficacy and safety study. Patients belonging to thelow-stimulation groups were crossed-over to high-stimulation parameters. In all published reports on theselong-term results increased efficacy with longer treat-ment was found (Holder et al., 1992; George et al.,1994; Salinsky et al., 1996; Morris and Mueller, 1999;DeGiorgio et al., 2000). In these open extension trialsthe mean reduction in seizure frequency increased upto 35% at 1 year and up to 44% at 2 years of follow-up. After that, improved seizure control reached a pla-teau (Morris and Mueller, 1999). In the following years,other large prospective clinical trials were conducted indifferent epilepsy centers worldwide. In Sweden, long-term follow-up in the largest patient series (n¼67) inone center not belonging to the sponsored clinical trialsat that time reported similar efficacy rates with a meandecrease in seizure frequency of 44% in patients treatedup to 5 years (Ben-Menachem et al., 1999). A joint studyof two epilepsy centers in Belgium and the USA included118 patients with a minimum follow-up duration of6 months. They found a mean reduction in monthly sei-zure frequency of 55% (Vonck et al., 2004). In China,a mean seizure reduction of 40%was found in 13 patientsafter 18 months of VNS (Hui et al., 2004).

Prospective clinical trials in children

There are no controlled studies on VNS in children, butmany epilepsy centers have reported safety and efficacyresults in patients less than 18 years of age in a prospec-tive way. All these studies report similar efficacy andsafety profiles to findings in adults (Lundgren et al.,1998a; Murphy, 1999; Zamponi et al., 2002; Buoniet al., 2004). Rare adverse events, unique to this agegroup, included drooling and increased hyperactivity(Helmers et al., 2001). In children with severe mental re-tardation and pre-VNS dysphagia, swallowing problemsmight occur. Switching off the stimulator by applyingthe magnet over the device during meals may be helpful

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in such events (Lundgren et al., 1998b). In children withepileptic encephalopathies efficacy may become evidentonly after>12 months of treatment (Parker et al., 1999).A Korean multicenter study evaluated long-term effi-cacy in 28 children with intractable epilepsy. In half ofthe children there was a >50% seizure reduction aftera follow-up of at least 12 months (You et al., 2007).

Safety, side-effects, and tolerability

Safety concerns with regard to VNS treatment can beapproached from different angles. A surgical interven-tion is required to perform the implant of the device.The effects of delivering current to nervous tissue needto be considered as thismight evoke changes in innervatedorgans and result in acute or chronic side-effects. Patientswith refractory epilepsy are often young people. The po-tential teratogenic effects have to be taken intoconsideration.

PERIOPERATIVE SIDE-EFFECTS

The classic surgical technique has been described indetail by several authors (Reid, 1990; Landy et al.,1993; Kemeny, 2003). Surgical techniques using a singlecervical incision and subpectoral placement have alsobeen described resulting in favorable cosmetic outcomein adults and children without prolonging the durationof the procedure (Glazier et al., 2000; Patil et al.,2001; Zamponi et al., 2002). Cosmetic side-effects havealso been improved since the production of the smallerModel 101 and will be greatly improved once the Model103 Generator Demipulse (CyberonicsW, Houston,USA) and Model 104 Generator Demipulse Duo (Cyber-onicsW, Houston, USA) become widely available.Surgical complications and difficulties are rare. Fluidaccumulation at the generator site with or without asso-ciated infection occurs in 1–2% of patients and mayrespond to aspiration and antibiotics. Incisional infec-tions are unusual and usually respond to oral antibi-otic therapy and occur in 3–6% of the patients(Ben-Menachem, 2002). Unilateral vocal cord paralysisoccurred after approximately 1% of the implants in thecontrolled studies with full recovery after a few weeksin most cases. This may be due to intraoperative manip-ulation of the vagus nerve and subsequent damage to thevagal nerve vascularization (Fernando and Lord, 1994).One study systematically evaluated vocal fold mobilityin subjects before and after implantation. Thirteen pa-tients underwent preimplantation laryngeal electromy-ography and videolaryngoscopy. Two weeks afterimplantation and 3 months after implantation and acti-vation of the device all subjects were re-evaluated. Periop-erative vocal fold paresis occurred in approximately50% of subjects (Shaw et al., 2006).

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RAMPING UP AND LONG-TERM STIMULATION

For therapeutic purposes, VNS aims at stimulating vagalafferents. There are widespread connections from thevagus nerve to the central nervous system. Throughthese connections efficacious stimulation parametersmay also induce other central nervous system side-effects. Moreover, selectively stimulating afferents isdifficult and approximately 20% of the fibers in thecervical part of the vagus nerve are efferent fibers.These fibers innervate thoracoabdominal organs, whichexplains the potential side-effects when these fibers arestimulated (Ramsay et al., 1994).

Pharyngeal and laryngeal effects

The most prominent and consistent sensation in patientswhen the vagus nerve is stimulated for the first time,even at low output current levels, is a tingling sensationin the throat and hoarseness of the voice. The tinglingsensation may be due to secondary stimulation of the su-perior laryngeal nerve that branches off from the vagusnerve superior to the location of the implanted electrodebut travels along the vagus nerve in the carotid sheath(Claes and Jaco, 1986). The superior laryngeal nervecarries sensory fibers to the laryngeal mucosa. Stimula-tion of the recurrent laryngeal nerve that branches offdistally from the location of the electrode and carriesmotor (Aa) fibers to the laryngeal muscles causes thestimulation-related hoarseness (Banzett et al., 1999;Charous et al., 2001). Fiberoptic laryngoscopy andvideo-stroboscopic examination have shown left vocalcord adduction (tetanic contraction) during stimulationat 30 Hz or higher (Ristanovic et al., 1992; Lundy et al.,1993; Zumsteg et al., 2000; Charous et al., 2001; Kersinget al., 2002). These stimulation-related side-effects aredose dependent, which means that higher amplitudes,higher frequencies, and wider pulse widths are associ-ated with more intense sensations and voice changes(Uthman et al., 1993).

Side-effects reported by the patients in the EO1 andEO2 study were almost always related to the stimulationon-time and consisted of hoarseness and tingling sensa-tion, left anterior neck muscle movement, hiccup, cough,and shortness of breath during exercise (Uthman et al.,1993). In the EO3 study stimulation-related hoarsenesswas present in one-third of the patients; coughing andthroat pain also gained statistical significance (Ramsayet al., 1994). Hoarseness was significantly more presentin the high-stimulation group.

A survey of 20 patients who responded to a question-naire specifically addressing the issue of voice changeshowed that 95% of the patients experience some kindof voice change but that 100% would have a stimulator

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reimplanted despite knowing the vocal side-effects theyhave (Charous et al., 2001). Three studies investigatedwhether the effect on the vocal cord and laryngealmuscles influenced swallowing in the sense that orallyingested material could enter the subepiglottal larynx(Heck et al., 1998; Lundgren et al., 1998b; Schallertet al., 1998). This could lead to aspiration and pneumo-nia. Using therapeutic VNS parameters there were noclinically significant swallowing problems. However,patients with severe mental and motor impairment,pre-existing dysphagia, and benzodiazepine treatmentmight be at risk for swallowing problems during VNSon-time (Lundgren et al., 1998b).

NEUROSTIMULAT

Effects on thoracoabdominal organs

With regard to side-effects related to stimulation of vagalefferents, effect on heart rate, pulmonary function, andgastrointestinal digestion are of major concern. Stimula-tion of the efferent fibers may induce bradycardia andhypersecretion of gastric acid. The stimulation electrodeis always implanted on the left vagus nerve, which isbelieved to contain fewer sinoatrial fibers than the right(Janes et al., 1986; Banzett et al., 1999).

In the initial pilot trials and controlled randomizedtrials extensive internal investigations were performed,including continued monitoring in the long-term exten-sion phases. In the EO1 and EO2 studies there were noeffects on heart rate after 3 months of stimulation asmeasured by electrocardiography and Holter monitor-ing and no effects on gastric acid output as measuredby fasting acid output during 1 hour. There were nochanges in the physical examinations, specifically sys-tolic and diastolic blood pressure and body weight;24-hour Holter monitoring in 28 patients (11 from thehigh-stimulation group, 17 from the low-stimulationgroup) showed no VNS-related abnormalities (VagusNerve Stimulation Study Group, 1995). There were noreports of gastric ulcers and no significant changes inpulse, respiration, blood pressure, temperature, orweight (Ramsay et al., 1994). Pulmonary function testingin a subgroup of 15 patients showed no influence of VNSon the forced expiratory volume after 3 and 9 months ofstimulation (Lotvall et al., 1994). Holter monitoring in asample of patients of the EO4 study showed no clinicallysymptomatic changes. Pulmonary function testing wasperformed in 124 patients with no change between base-line and long-term treatment (Salinsky et al., 1996).Malow et al. (2000) reported that patients with pre-existing obstructive sleep apnea are at risk for increaseof nightly apneas. One study investigated the effects ofchronic VNS on visceral vagal function and found no sig-nificant adverse effect on gastrointestinal vagal function(Tougas et al., 1992).

Bradycardia

Despite the fact that the initial studies showed no clinicaleffect on heart rate, occurrence of bradycardia and ven-tricular asystole during intraoperative testing of the de-vice (stimulation parameters: 1 mA, 20 Hz, 500 ms, �17seconds) have been reported in a few patients. None ofthe reported patients had a history of cardiac dysfunc-tion, nor did they show abnormal cardiac testing aftersurgery (Asconape et al., 1999; Tatum et al., 1999;Andriola et al., 2000; Ali et al., 2004; Ardesch et al.,2007). Possible hypotheses with regard to the underlyingcause are inadvertent placement of the electrode on oneof the cervical branches of the vagus nerve or indirectstimulation of these branches, reversal of the polaritiesof the electrodes, which would lead to primary sti-mulation of efferents instead of afferents, indirectstimulation of cardiac branches, activation of afferentpathways affecting higher autonomic systems or ofthe parasympathetic pathway with an exaggerated ef-fect on the atrioventricular node, technical malfunc-tioning of the device, or idiosyncratic reactions. Thecontributing role of specific antiepileptic drugs (AEDs)should be further investigated. Suggested steps to be takenin the operating room in case of bradycardia or asystoleduring generator and lead impedance testing have beenformulated by Asconape et al. (1999). Adverse cardiaccomplications at the start or during ramping-upof the stim-ulation intensity have not been observed (Ramsay et al.,1994). One case report described a late onset bradyarrhyth-mia after 2 years of VNS (Amark et al., 2007).

Retention rate and tolerability

Ninety-nine percent of patients completed the EO5study, indicating high tolerability for the treatment(Handforth et al., 1998). A notable increase of the per-ceived well-being during VNS treatment was foundusing a global rating scale for quality of life scoredby the patient, the investigator, and a companion. Inthe patient series of 118 patients, four patients requestedthe stimulator to be turned off because of lack of effi-cacy. In none of the patients did the device have to beturned off because of stimulation-related side-effects.In the long-term extension trials, the most frequentside-effects were hoarseness in 19% of patients andcoughing in 5% of patients at 2 years of follow-up,and shortness of breath in 3% of patients at 3 years(Morris and Mueller, 1999). There was a clear trend to-wards diminishing side-effects over the 3-year stimula-tion period. Ninety-eight percent of the symptoms wererated mild or moderate by the patients and the investiga-tors (Ben-Menachem, 2001). Side-effects can usually beresolved by decreasing stimulation parameters. After

K

3 years of treatment, 72% of the patients were stillon the treatment (Morris and Mueller, 1999). The mostfrequent reason for discontinuation was lack ofefficacy.

Central nervous system effects

Central nervous system side-effects typically seen withAEDs were not reported. Initial studies on small patientgroups treated for 6 months with VNS showed nonegative effect on cognitive motor performance andbalance (Clarke et al., 1992a, b, c). These findings wereconfirmed in larger patient groups with a follow-up of2 years (Clarke et al., 1997a, b). Hoppe et al. (2001)showed no changes in extensive neuropsychological test-ing in 36 patients treated for 6 months with VNS.

In patients treated for 3 months with VNS who under-went polysomnography and multiple sleep latency testingthere was no change in sleep architecture and a markeddecrease in daytime sleepiness was noticed (Malow et al.,2001). After that, several studies investigated the effectof VNS on sleep and respiration and found nomajor respi-ratory changes (Banzett et al., 1999), hypocapnia (Salinskyet al., 1996; Holmes et al., 2003b), apneas (Malow et al.,2000; Holmes et al., 2003a; Marzec et al., 2003; Khuranaet al., 2007; Papacostas et al., 2007), a decrease in SaO2

(Zaaimietal., 2005),andmodificationof thesleepstructure(Rizzo et al., 2004).

SUDDEN UNEXPECTED DEATH IN EPILEPSY

Annegers et al. (1998) have reported on 25 deaths in 1819patients treated with VNS. Sudden unexpected death inepilepsy (SUDEP) rates were 4.1 in the VNS group versus4.5 per 1000 for patients with refractory epilepsy. Withinthe VNS-treated patients, SUDEP rates dropped from5.5 per 1000 for the first 2 years of treatment to 1.7per 1000 for the subsequent years, suggesting a trend to-wards lower SUDEP rates in refractory epilepsy patientstreated with VNS.

MISCELLANEOUS SIDE-EFFECTS

In the literature there are several case reports on isolatedadverse events (Leijten and Van Rijen, 1998; Gatzoniset al., 2000; Koutroumanidis et al., 2000; Iriarte et al.,2001; Kim et al., 2001; Kalkanis et al., 2002; Sanossianand Haut, 2002; Guilfoyle et al., 2007; Rauchenzauneret al., 2007). Psychiatric side-effects have been reportedby Blumer et al. (2001), who found an exacerbation ofpre-existing dysphoric disorders in patients with a>75% reduction in seizure frequency after treatmentwith VNS. This “forced normalization” appeared tooccur more often than with AED treatment and canbe successfully treated with antidepressant medication.

962 K. VONC

It might also be related to the VNS-induced increase ofalertness that is often reported and is unrelated tochanges in seizure frequency. In patients with pre-existing psychiatric disorders decreased sedation and in-creased alertness may manifest itself as psychosis withhallucinations. Also De Herdt et al. (2003) reported onfour cases of psychosis after VNS treatment. In contrastto an increase in psychiatric disturbances, Koutroumani-dis et al. (2003) suspected a potential antipsychoticeffect in patients with postictal psychosis. These symp-toms disappeared in two patients who were treated withVNS following unsuccessful epilepsy surgery. There areclear indications that VNS can interfere with psychiatricsymptoms and that specific VNS-induced “positive”side-effects exist.

ET AL.

TERATOGENIC EFFECTS OF VAGAL NERVE STIMULATION

Teratogenic effects in the sense of deleterious effectson the development of an embryo or fetus seem unlikelyto be due to an implanted device. One study investigatedteratogenicity of VNS in rabbits (Danielsson and Lister,2008). There was no effect of VNS on any reproductiveparameter. Ben Menachem et al. (1998) reported oneight pregnancies in patients treated with VNS after ret-rospective analysis of over 1000 patients. All patientswere taking concomitant AEDs. Five pregnancies wentfull term resulting in unremarkable and healthy deliver-ies, including one set of twins. Two elective abortions,one owing to unplanned pregnancy and one to abnormalin utero fetal development, were performed. The abnor-mal development was attributed to AEDs. One patientreported spontaneous abortion although the actual preg-nancy was never confirmed. It appears that VNS doesnot inhibit conception.

DEEPBRAINSTIMULATION

DBS is a more recently explored field in epilepsy. Com-pared with VNS it is a more invasive treatment option.Parallel to VNS, the precise mechanism of action andthe ideal candidates for this treatment option arecurrently unknown. Moreover, it is unknown whichintracerebral structures should be targeted to achieveoptimal clinical efficacy. Two major strategies forthe identification of brain targets have been followed.One approach is to target crucial central nervoussystems structures that are considered to have a“pacemaker,” “triggering,” or “gating” role in theepileptogenic networks that have been identified, suchas the thalamus or the subthalamic nucleus (Proctorand Gale, 1999). Another approach is to interfere withthe ictal onset zone itself.

NEUROSTIMULATIO

Targets

CEREBELLUM

The earliest reports on intracranial neurostimulation in-volved stimulation of cerebellar structures. In most in-stances electrical current was administered throughelectrodes bilaterally placed on the superior medial cere-bellar cortex (Davis, 2000). Intermittent (1–8 minuteson, 1–8 minutes off) high-frequency (150–200 Hz) cere-bellar stimulation was initially investigated for the treat-ment of spasticity due to cerebral palsy or stroke inseveral hundreds of patients with implantation durationtimes of up to 20 years. Some of these patients also hadrefractory seizures that were completely abolished in60% of patients. Two controlled studies in small patientgroups (n¼5, n¼ 12) did not, however, show significanteffects (Van Buren et al., 1978; Wright et al., 1984). Inview of this controversy and with the advent of fully im-plantable and programmable pulse generators, Velascoet al. (2005) performed a double-blind study in fivepatients showing significant decreases in tonic–clonicseizures after 1–2 months of stimulation.

SUBCORTICAL NUCLEI

The selection of other targets for DBS in humans partiallyresulted from the progress in the identification of epilep-togenic networks (Proctor and Gale, 1999). Although thecortex plays an essential role in seizure origin, increasingevidence shows that subcortical structures may beinvolved in the clinical expression, propagation, control,and sometimes initiation of seizures. Consequently, sev-eral subcortical nuclei have been targeted in pilot trials fordifferent types of epilepsy.

Subthalamic nuclei

The suppressive effects of pharmacological or electricalinhibition of the subthalamic nucleus (STN) in differentanimal models for epilepsy and the extensive experiencewith STN DBS in patients with movement disorders ledto a pilot trial with high-frequency (130 Hz) continuousSTN DBS in five patients by the group from Grenoble,France (Benabid et al., 2002; Chabardes et al., 2002).Three patients with symptomatic partial seizures had a>60% reduction in seizure frequency. Four other cen-ters have reported STN DBS results. In one patient withLennox–Gastaut syndrome, generalized seizures werefully suppressed and myoclonic and absence seizures re-duced with >75% (Alaraj et al., 2001). Loddenkemperet al. (2001) reported seizure frequency reductions ofmore than 60% in two out of five patients treated withSTN DBS. Handforth et al. (2006) reported on one pa-tient with bitemporal seizures in whom half of the

seizures were suppressed and in one patient with frontallobe epilepsy who experienced a one-third reduction ofseizures. Vesper et al. (2007) described a 50% reductionin myoclonic seizures in a patient with progressive myo-clonic epilepsy in whom generalized seizures had beensuccessfully treated with previous VNS.

N FOR EPILEPSY 963

Centromedian thalamic nuclei

Thalamocortical interactions are known to play an im-portant role in several types of seizures. Since 1984,Velasco et al. (2001, 2002) have investigated a large pa-tient series (n¼57) with different seizure types whounderwent DBS of the centromedian (CM) nucleus, astructure that can be stereotactically targeted fairly eas-ily owing to its relatively large size, its spherical shape,and location on each side of the third ventricle. Intermit-tent (1 minute on, 4 minutes off) high-frequency(60–130 Hz) stimulation that alternated between the leftand right CM thalamic nucleus was most effective inchildren (n¼5) with epilepsia partialis continua in whomfull seizure control was reached between 3 and 4 monthsafter stimulation. Secondary generalized seizures inthese children were the earliest to respond after 1 monthof treatment. Atypical absences and generalized seiz-ures (primary or secondary) responded significantly.Three out of 22 patients with Lennox–Gastaut syndromebecame seizure free. Complex partial seizuresresponded less successfully, although after long-termstimulation over 1 year partial improvements were foundand patients tended to be satisfied with the treatment thatsignificantly decreased or abolished secondary general-ized convulsions. In a separate publication Velascoet al. (2006) reported on 11 patients with Lennox–Gastautsyndrome with an overall seizure reduction of 80% andtwo patients rendered seizure free.

In a double-blind crossover protocol performed byFisher et al. (1992), CM thalamic stimulation did not sig-nificantly improve generalized seizures in seven pa-tients. Bilateral intermittent (1 minute on, 5 minutesoff during 2 hours per day) high-frequency (60 Hz)stimulation was performed in blocks of 3 months alter-nating between on and off stimulation in a double-blinded manner. A reduction of 30% of tonic–clonicseizures had been observed during blocks with the stim-ulation on versus 8% in blocks with stimulation off. Anopen extension phase of the trial using 24-hour stimula-tion resulted in a 50% decrease in three out of six of thepatients. It has become clear, especially from the expe-rience with VNS, but also from other studies, that in-creased efficacy may be observed after longerduration of stimulation, possibly on the basis of neuro-modulatory changes that take time to develop(DeGiorgio et al., 2000; Velasco et al., 2002).

964 K. VONCK

Anterior thalamic nuclei

There is sufficient evidence to suggest an equally impor-tant role of the anterior nucleus (AN) of the thalamus inthe pathogenesis of seizure generalization. Hodaie et al.(2002) performed bilateral AN thalamic DBS (1 minuteon, 5 minutes off, 100 Hz, alternating between right andleft AN) in five patients and showed a seizure frequencyreduction of 24–89%. Andrade et al. (2006) reported onthe long-term follow-up of six patients with AN DBS.After 7 years of follow-up five patients showed a morethan 50% reduction in seizure frequency. Changes instimulation parameters over the years did not furtherimprove seizure control. Kerrigan et al. (2004) reportedthat four out of five patients who underwent high-frequency AN DBS showed significant decreases inseizure severity and in the frequency of secondarily gen-eralized seizures. Moreover, there was an immediateseizure recurrence when DBS was stopped.

These studies all preceded a multicenter randomizedtrial with AN DBS (SANTE; Stimulation of the AnteriorNucleus of the Thalamus for Epilepsy) in 110 patients withpartial onset seizures with or without secondary general-ization (Fisher et al., 2010). Unadjustedmedian declines atthe end of the 3 month blinded phase were 14.5% in thecontrol group and 40.4% in the stimulated group. In anopen-label follow-up study median seizure frequencyreduction further increased up to 56% after two years.

TEMPORAL LOBE

The choice of targeting the medial temporal lobe regionfor a pilot trial in humans at Ghent University Hospital,Ghent, Belgium, was based on several considerations.This region often shows specific initial electroencephalo-graphic epileptiform discharges as a reflection of seizureonset in human temporal lobe epilepsy. These findingshave been recordedwith implanted depth electrodes in pa-tients with refractory epilepsy in whom the ictal onsetzone could not be identified on the basis of noninvasiveevaluations. Subsequent to the localization of the ictal on-set zone, patients may undergo resective surgery to treatseizures. Temporal lobectomy and, more specifically,selective amygdalohippocampectomy are effective inreducing seizures with a well-defined mesiobasal limbicseizure onset (Wiebe et al., 2001). Basic research involvingevoked potential excitability studies in humans and ana-tomic studies with tracer injections and single-unit record-ings with histological studies in animals have alsoconfirmed the involvement of the amygdala and the hippo-campus in the epileptogenic network (Wilson and Engel,1993; Bragin et al., 2000; Kemppainen et al., 2002). Somestudies have applied electrical fields to in vitro hippocam-pal slices with positive effects on epileptic activity (Lianet al., 2003; Su et al., 2008).Also in vivo studies in rats have

shown that high-frequency stimulation affects seizures inthe kindling model (Wyckhuys et al., 2007). Bragin et al.(2002) described repeated stimulation of the hippocampalperforant path in rats showing spontaneous seizures4–8 months after intrahippocampal kainate injection. Dur-ing perforant path stimulation spontaneous seizures weresignificantly reduced. In humans, preliminary short-termstimulation of hippocampal structures showed promisingresults on interictal epileptiform activity and seizure fre-quency (Velasco et al., 2000). Not all patients with tempo-ral lobe epilepsy who underwent resective epilepsy surgeryremain seizure free in the long term. Moreover, temporallobe resection, especially left-sided,may be associatedwithmemory decline and temporal lobe resection is contraindi-cated in patients with bilateral ictal onset. In an initial pilottrial atGhentUniversityHospital, 10 patients scheduled forinvasive video-EEG monitoring of the medial temporallobe were offered high-frequency medial temporal lobeDBS following ictal onset localization (Boon et al.,2007). Long-term follow-up in all 10 of these patientsshowed that 1/10 stimulated patients was seizure free(>1 year); 1/10 patients had a >90% reduction in seizurefrequency; 5/10 patients had a seizure frequency reductionof>50%; 2/10 patients had a seizure frequency reductionof 30–49%; 1/10 patients was a nonresponder. None of thepatients reported side-effects. In one patient MRI showedasymptomatic intracranial hemorrhages along the trajec-tory of the DBS electrodes. None of the patients showedchanges in clinical neurological testing.

Two other groups have reported on long-term hippo-campal stimulation. In four patients with complex par-tial seizures based on left-sided hippocampal sclerosishigh-frequency stimulation was performed in a random-ized, double-blind protocol with periods of 1 month offor on by Tellez-Zenteno et al. (2006). During the stimu-lation on periods seizures decreased by 26% comparedwith baseline. During the off periods seizures increasedby 49%. Neuropsychological testing revealed no differ-ence between on or off periods, not even in one patientwho was stimulated left-sided following previous right-sided temporal lobectomy.

Velasco et al. (2007) reported results in 11 patients after18 months of hippocampal high-frequency stimulation(uni- or bilateral, with or without hippocampal sclerosisonMRI). Patients with normalMRIs showed optimal out-come, with four of them being becoming seizure freeafter 2months of stimulation.Noneof the patients showedneuropsychological decline with a trend toward improval.

ET AL.

NEOCORTEX

An implanted responsive neurostimulator has recentlybeen evaluated for safety and efficacy in a multicenter,double-blind randomized trial (n¼191) (Morrell, 2011).The device used in this study, the RNSW System

IO

(NeuroPace, Mountain View, USA), records EEG sig-nals by means of subdural and/or depth electrodesand delivers responive cortical stimulation. At the endof the three month blinded evaluation period, meanseizure frequency reduction in the treatment groupwas 42%, compared to 9% in the sham stimulated group.

NEUROSTIMULAT

CONCLUSION

The lack of adequate treatments for all refractory epi-lepsy patients, the general search for less invasive treat-ments in medicine, and the progress in biotechnologyhave led to a renewed and increasing interest in neuro-stimulation as a therapeutic option.

For all types of neurostimulation currently being in-vestigated, major issues remain unresolved. The idealtargets and stimulation parameters for a specific typeof patient, seizure, or epilepsy syndrome are unknown.The characterization of the full and long-term side-effects profile needs to be further investigated. Theelucidation of the mechanism of action of different neu-rostimulation techniques requires more basic research inorder to demonstrate its potential to achieve long-termchanges and true neuromodulation.

It can be concluded that VNS is an efficacious andsafe treatment for patients with refractory epilepsy.VNS appears to be a broad-spectrum treatment; identi-fication of responders on the basis of type of epilepsyor specific patient characteristics proves difficult.Large patient groups have been examined and identify-ing predictive factors for response may demand morecomplex investigations. VNS is a safe treatment andlacks the typical cognitive side-effects associated withmany other antiepileptic treatments. Moreover, manypatients enjoy a positive effect of VNS on mood, alert-ness, and memory. In contrast to many pharmacologi-cal compounds, treatment tolerance does not developin VNS. In contrast, efficacy tends to increase withlonger treatment.

However, on the basis of currently available data theresponder rate in patients treated with VNS is notsubstantially higher than recently marketed AEDs.Efforts to decrease the number of nonresponders mayincreasingly justify implantation with a device. Toincrease efficacy, research towards the elucidation ofthe mechanism of action is crucial. In this way rationalstimulation paradigms may be investigated. With a rap-idly evolving biomedical world, various neurostimula-tion modalities will be applied in patients withrefractory epilepsy. Future studies will have to showthe precise position of VNS in comparison with treat-ment such as deep brain stimulation and transcranialmagnetic stimulation.

Deep brain stimulation is still an experimentaltreatment option for patients with refractory epilepsy.

The finalization of several pilot trials in different epilepsycenters has led to the initiation of randomized controlledtrials, of which the outcome will be available in thenext year.

N FOR EPILEPSY 965

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