FOCUS ON EPILEPSY

Electrical brain stimulation for epilepsy Robert S. Fisher and Ana Luisa Velasco Abstract | Neurostimulation enables adjustable and reversible modulation of disease symptoms, including those of epilepsy. Two types of brain neuromodulation, comprising anterior thalamic deep brain stimulation and responsive neurostimulation at seizure foci, are supported by Class I evidence of effectiveness, and many other sites in the brain have been targeted in small trials of neurostimulation therapy for seizures. Animal studies have mainly assisted in the identification of potential neurostimulation sites and parameters, but much of the clinical work is only loosely based on fundamental principles derived from the laboratory, and the mechanisms by which brain neurostimulation reduces seizures remain poorly understood. The benefits of stimulation tend to increase over time, with maximal effect seen typically 1–2 years after implantation. Typical reductions of seizure frequency are approximately 40% acutely, and 50–69% after several years. Seizure intensity might also be reduced. Complications from brain neurostimulation are mainly associated with the implantation procedure and hardware, including stimulation-related paraesthesias, stimulation-site infections, electrode mistargeting and, in some patients, triggered seizures or even status epilepticus. Further preclinical and clinical experience with brain stimulation surgery should lead to improved outcomes by increasing our understanding of the optimal surgical candidates, sites and parameters. Fisher, R. S. & Velasco, A. L. Nat. Rev. Neurol. 10, 261–270 (2014); published online 8 April 2014; doi:10.1038/nrneurol.2014.59

Introduction

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, 300 Pasteur Drive, Room A343, Stanford, CA 94305‑5235, USA (R.S.F.). Clinica de Epilepsia, Hospital General de México OD, Calle Dr. Balmis No. 148, Col. Doctores, Cuauhtémoc, 06726 Mexico City, Mexico (A.L.V.). Correspondence to: R.S.F. robert.fisher@ stanford.edu

Neurostimulation represents an increasingly attractive treatment option for people with a variety of neurological conditions. By directly targeting a specific neural region or circuit, neurostimulation can modulate symptoms in a way that is adjustable, and reversible with removal of the implanted hardware. Additionally, neurostimulation avoids many adverse effects that are typically associated with medications. Treatment can take the form of peripheral nerve stimulation, such as vagus nerve stimulation (VNS); spinal cord stimulation; transcutaneous brain stimulation; or deep brain stimulation (DBS). VNS and responsive neurostimulation have both been approved by the FDA for the treatment of certain types of epilepsy in the USA. At the time of writing, DBS of the thalamus has been approved for the treatment of medicationresistant partial and secondarily generalized seizures in the European Union, Canada, Taiwan, Australia, New Zealand and Israel, and is also under consideration in other countries. The first use of DBS to treat epilepsy was probably in the 1950s.1,2 Subsequently, several case series showing antiseizure efficacy of this treatment were presented.3–6 The initial stimulation targets were the cerebellum3 and anterior thalamus.4 Benefits including seizure reduction Competing interests Stanford University received research funding from Medtronic to participate in the multicentre trial, but R.S.F. receives no personal support from either Medtronic or NeuroPace. R.S.F. has acted as a consultant for, or holds stock options in, ICVRx (cerebrospinal fluid perfusion of drugs), Cyberonics (vagus nerve stimulation), and Intelli-vision (seizure alert). A.L.V. declares no competing interests.

and minimal morbidity were reported, but these studies were not blinded and the outcomes were not quanti­ fied, so the degree of benefit remained uncertain. Sub­ sequently, negative results were reported for two small controlled studies of cerebellar stimulation,7,8 albeit in a total of only 17 patients, and DBS for epilepsy quickly fell out of favour. However, the success of DBS for movement disorders,9 and of VNS for epilepsy,10 re-established an atmosphere conducive to testing of DBS in people with epilepsy, and it is once again an option for treating refractory seizures. Various neurostimulation sites have been investigated for this purpose (Figure 1). Stimulus parameters, particularly frequency, have a profound impact on the effects of the stimulation.11 For example, antiseizure effectiveness of caudate stimulation in monkeys with seizures induced by alumina cream depended on whether 10 or 100 Hz stimulation was delivered, whether stimulation was continuous or intermittent, and the location of the stimulating electrode within the head or body of the caudate.12 Other potentially important stimulation variables include amplitude of stimulation, constant-voltage or constant-current stimulation, bipolar local versus wide-field referential stimulation, and whether stimulation is delivered automatically or in response to a detected event. Hypothetically, one set of parameters might be effective at one site whereas another set would be optimal at a different site. Clinical trials so far have made fortunate parameter choices, but the wide range of possible parameters emphasizes the need for ­laboratory experiments in advance of clinical trials. This Review focuses on electrical DBS to treat seiz­ures. It does not address peripheral neurostimulation such as

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REVIEWS Key points ■■ Electrical brain stimulation is an increasingly utilized therapy for medicationresistant seizures ■■ Randomized controlled trials have demonstrated the efficacy and safety of intermittent (on a clock cycle) thalamic deep brain stimulation, and responsive neurostimulation at the site(s) of seizure origin ■■ Stimulation to control seizures has been investigated in brain regions including the cerebellum, centromedian thalamus, hippocampus, anterior nucleus of the thalamus, motor cortex, caudate, subthalamic nucleus, and other seizure foci ■■ Despite several laboratory studies, the mechanisms by which electrical brain stimulation ameliorates epilepsy remain poorly understood ■■ Additional experience will be needed to individualize neurostimulation therapy for patients with drug-resistant seizures, determine which type of neurostimulation to first employ, and decide when to intervene

Anterior thalamus

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Figure 1 | Sites in the human nervous system where stimulation has been attempted as a method of controlling seizures. Highlighted sites have been documented to be beneficial in large randomized trials of neurostimulation. Permission obtained from Elsevier © Lockman, J. & Fisher, R. S. Neurol. Clin. 27, 1031–1040 (2009).

VNS13 or trigeminal nerve stimulation,14 transcranial magnetic brain stimulation,15 or stimulation to map regional brain functions before epilepsy surgery,16 all of which have been reviewed elsewhere. Animal studies,17,18 and a detailed clinical summary of regional stimulation for seizures,19 have also been featured in other publications.

DBS targets for epilepsy Cerebellum Cerebellar outflow is inhibitory to most target structures, so stimulation of the cerebellum might seem a logical approach to the treatment of epilepsy. However, such logic is questionable because stimulation of the cerebellar cortex—the site used in the early cerebellar stimulation studies—­predominantly inhibits the deep cerebellar nuclei from which cerebellar outflow tracts originate. In some animal studies, stimulation of both deep cerebellar nuclei20 and the cerebellar cortex 21 inhibited seizures. Other animal studies showed no benefit of cerebellar stimulation.22,23 Overall, these studies showed little consistency in reported outcomes, although cerebellar cortex stimulation seemed to be beneficial for generalized and certain 262  |  MAY 2014  |  VOLUME 10

focal seizures in laboratory models of epilepsy, whereas stimulation of the deep fastigial nuclei a­ meliorated limbic seizures.24 Irving Cooper first implanted stimulating electrodes over the anterior vermis and lateral cerebellar cortex in human patients in 1972.25 The first patient remained seizure-free for 13 weeks,3 encouraging Cooper to repeat the procedure in a further 32 patients. 26,27 Details of seizure classifications, medication changes and concurrent medical conditions were not provided, but improvement in seizure frequency by at least 50% occurred in 18 patients.26,27 Other investigators published 11 non­ controlled studies with favourable findings, 28 and two controlled studies with unfavourable findings.7,8 A controlled study with a blinded lead-in design found a statistically significant benefit of stimulating the cere­ bellar cortex in five patients with generalized seizures.29 However, no large controlled trial of cerebellar stimulation for epilepsy has been published. A systematic review of the existing studies showed inconsistent outcomes.30

Centromedian thalamus The centromedian thalamic nucleus (CM) is considered to be part of the so-called nonspecific thalamic activating system,31 which influences wide regions of the cortex and has strong anatomical ties to the basal ganglia and insular cortex.32 In 1951, researchers showed desynchronization in cortical EEG scans in response to CM stimulation in cats.31 Seizures are characterized by synchronization of neural structures, so disruption of synchrony seemed to be a potential way to inhibit seizures. Extrapolation from laboratory work done on this region from animals to humans is, however, difficult. For example, the CM– parafascicular complex in rats is only partially analogous to the human CM. In 1987, DBS electrodes were implanted bilaterally in the CM of five patients with refractory tonic–clonic seizures.33 Stimulation was delivered for 2 h daily, in cycles consisting of 1 min of 0.1 ms pulses at 0.8–2.0 mA, 60–100 Hz, followed by 4 min off stimulation, alternating between the left and right electrodes. Generalized seizure frequencies decreased by more than 80% in response to this inter­vention.33 A subsequent study showed similar improvements in 13 patients with Lennox–Gastaut syndrome, which is a condition characterized by frequent, medication-resistant seizures of various types. A double-blind, crossover design was employed to further test the effects of CM stimulation in seven patients with medication-refractory seizures.34 Stimulation was delivered via cycles of 1 min of 90 μs pulses of approximately 5 V at 65 Hz followed by 4 min off stimulation for 2 h daily. Treatment was randomized to on or off stimulation for the first 3 months, followed by a 3‑month washout, before crossing over to the other treatment. During the on-stimulation segments, seizure frequency decreased from baseline by approximately 30%, whereas reductions from baseline during off-stimulation segments were only 8%.34 This between-group difference in seizure frequency was not statistically significant, but two problems hindered interpretation of this result. First, after the



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FOCUS ON EPILEPSY initial on-stimulation phase, one patient with marked benefit from stimulation did not consent to the stimulator being turned off and, therefore, could not be included in the data analysis. Second, the duration of carry-over effects from stimulation might have been long enough to confound the placebo segment of the trial. Another study closely followed this crossover protocol34 in five patients with mixed (generalized tonic– clonic, tonic, absence and complex partial) seizures, averaging a very high seizure rate of 2,489 per month.35 Generalized seizures decreased by over 90% across the group. All patients benefited from the treatment, and one became seizure-free for 30 months.35 A single-blind, crossover study conducted by another research group found CM stimulation to be effective for generalized seizures (all six patients with such seizures responded to the treatment), but not for frontal seizures: only one of five patients with frontal seizures responded.36 These results are also supported by published case reports and series: status epilepticus was terminated immediately by CM stimulation in a patient recovering from cardiac arrest,36 and epileptiform EEG activity was attenuated by CM stimulation in a patient with cortical dysplasia.37 Published experience in 11 patients with refractory generalized or frontal lobe epilepsy also confirmed previous observations that CM stimulation is beneficial for generalized seizures but not for partial frontal seizures.38

Hippocampus The hippocampi and surrounding tissues are the most seizure-prone structures in the brain, and these areas comprise the substrate for most complex partial seizures. Inhibition of the hippocampi by DBS might, therefore, be expected to benefit patients with complex partial seiz­ ures. Epileptiform bursting activity can be attenuated in rat hippocampal slices by 1 Hz or 100 Hz stimulation of the Shaffer collateral fibres.39 In rats, EEG spiking produced by intracortical administration of penicillin was suppressed by 1 min of continuous hippocampal stimulation with 5.35 ms pulses of 1–5 V at 185 Hz.40 Electrical stimulation of the perforant path (a major input to the hippocampus) that was strong enough to generate afterdischarges reduced seizure frequency in rats with recurrent seizures induced by intrahippocampal administration of kainic acid.41 By contrast, subthreshold stimulation of the hippocampus at 200 Hz did not affect interictal spiking or seizures.42 In 1976, researchers observed reductions in seizure frequency in four patients with either grand mal (that is, tonic–clonic) or partial seizures after stimulating the hippocampus, suggesting that this approach was safe and beneficial.43 All patients had refractory complex partial seizures, some with secondary generalization. The effects of DBS of the hippocampus were studied in 10 patients scheduled to undergo temporal lobectomy to treat refractory (complex, partial and secondarily generalized) seizures.44 Bilateral depth electrodes delivered continuous low-amplitude, high-frequency stimulation to the hippocampus, as biphasic 450 μs pulses at 200–400 μA and 130 Hz, for 23 h daily for 2–3 weeks. From the sixth day

of stimulation onwards, until the end of recording on day 16, seizures were abolished in seven of the 10 patients, and the number of interictal spikes was reduced. The best responses were seen in patients whose electrodes were positioned either in the anterior pes hippocampus or at the anterior parahippocampal gyrus close to the ento­rhinal cortex. In a subsequent study with follow-up periods of 18 months to 7 years, all nine patients showed some seizure reduction with long-term hippocampal stimulation. Five of these patients had normal MRI findings and seizure-frequency reductions of more than 95%, whereas the other four, who had hippocampal sclerosis on baseline MRI, had seizure reductions of 50–70%.45 No patient had neuropsychological deterioration, and no adverse effects of DBS were observed. Other research groups have demonstrated efficacy of hippocampal DBS. One study of eight patients showed an overall seizure reduction of about two-thirds,46 and another study of nine patients documented reductions in seizure frequencies of 66–100% after a mean followup of 30 months.47 Another study 48 evaluated continuous hippo­campal stimulation in nine patients with temporal lobe seizures, followed for 67–120 months. Electrodes were inserted along the long axis of the hippocampus from an occipital approach, bilaterally in seven patients, and uni­ laterally in two patients. Stimulation was set to 300 μs pulses at 1–3.5 V, 130 Hz. Four patients were more than 90% seizure-free for at least 3 years, three experienced 40–70% fewer seizures, and two had seizure-frequency reductions of less than 30%. Bilateral DBS seemed to be more effective than unilateral stimulation. Another strategy has been to stimulate hippocampal fibre tracts, such as the fornix or hippocampal commissure. In seven patients with seizures of hippocampal origin, bipolar stimulation with 200 μs, 8 mA pulses at 5 Hz reduced interictal spiking and lowered the chances of a seizure during the subsequent 48 h by 92%.49

Anterior nucleus of the thalamus The anterior nucleus of the thalamus (ANT) was one of the targets used in the original human neurostimulation studies.4 ANT sits at a key junction point in the Papez circuit,50 which is believed to be involved in emotional responses, and also in the propagation of seizures. The Papez circuit encompasses the hippocampus and its outflow via the fornix, mammillary bodies of the hypothalamus, mammillothalamic tract, ANT, cingulate cortex, cingulum bundle and entorhinal cortex, and then back to the hippocampus. Since most partial seizures involve mesial temporal or mesial frontal regions, this circuit comprises epileptologically interesting anatomy. Systemic administration of the γ‑aminobutyric acid (GABA) antagonist pentylenetetrazol produces seiz­ ures in guinea pigs.51 Metabolic imaging during seizures revealed high activity in the mammillary bodies, mammillothalamic tract and anterior thalamus,51 and sectioning of the mammillothalamic tract raised the threshold for seizure induction.52 High-frequency stimulation of the mammillary bodies inhibited pentylenetetrazol-induced seizures in rats,53 presumably functioning as a reversible

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Figure 2 | Seizure frequency in active-treatment and control groups of patients undergoing bilateral stimulation of the anterior nucleus of the thalamus. The doubleblind phase of the trial (n = 108) took place in months 1–4, during which time the stimulator was either turned on (5 V, active) or off (0 V, control). For the open-label phase of the study, all devices were set to 5 V stimulation. Permission obtained from John Wiley & Sons, Inc. © Fisher, R. S. et al. Epilepsia 51, 899–908 (2010).

lesion. Although neurostimulation of the hypothalamus can be used clinically to treat seizures,54,55 this site is potentially problematic owing to the risk of electrodeinduced haemorrhage in close proximity to the Circle of Willis at the base of the brain. The anterior thalamus is a possible alternative stimulation target. Bilateral ANT stimulation at 100 Hz and one-third of the current required to produce behavioural arousal doubled the amount of intravenous pentylene­tetrazol needed to induce a seizure.56 Several investigators have shown that inhibiting the ANT (via stimulation, lesions or chemical infusion) reduces seiz­ ures in animal models.57,58 ANT stimulation is usually bilateral, but unilateral (left) ANT stimulation in rats can inhibit pilocarpine-­i nduced seizures. 59 By contrast, ANT stimulation increases the frequency of kainic-acid-induced seizures.60 On the basis of the initial clinical experience4,6,61,62 and the preponderance of results in animal models of epilepsy, several noncontrolled pilot trials of ANT stimulation were performed in people with refractory partial and secondarily generalized seizures. ANT stimulation at 5 V and 100 Hz reduced seizure frequency in three of five such patients.64 Five small nonblinded trials of ANT stimulation64,65 showed an overall improvement in seizure frequency of 53% compared with baseline.66 In another study, the benefits of ANT stimulation with 90–150 μs pulses of 1.5–3.1 V and 100–185 Hz persisted throughout follow-up (mean 27 months), and mean seizure frequency decreased by 70%.67 These favourable pilot results led to implementation of a multicentre randomized controlled trial of bilateral stimulation of the anterior nucleus of the thalamus for 264  |  MAY 2014  |  VOLUME 10

epilepsy (SANTE) in 110 adult patients who had partial seizures with or without secondary generalization at least six times per month, but not more than 10 times per day.68 Baseline seizure frequency was recorded for 3 months, followed by DBS lead implantation, 1 month of recovery, and then a 3 month blinded period of either active stimulation or no stimulation (placebo). On-stimulation parameters were 1 min of 90 μs pulses of 5 V at 145 Hz followed by 5 min without stimulation.68 Seizure frequency decreased from baseline by a median of 20% during the 1 month recovery period.68 Thereafter, seizure frequencies in the two treatment groups significantly diverged, with a median improvement of 40.4% in the active group and 14.5% in the placebo group (Figure 2). The active group experienced significantly fewer com­ plex partial seizures, and also significantly fewer seizures of the type prospectively designated as “most severe” by the patients. Injuries from seizures were also reduced in the active versus the placebo group. When the control group’s stimulators were activated for the open-label phase of the trial, 4 months after implantation, their seizure frequency also declined. Long-term follow-up of the patients receiving open-label stimulation showed that the benefits were sustained: in the intent-to-treat analysis (for patients with at least 70 days of recorded seizure diary), the median seizure frequency improved by 69% from baseline by 5 years after implantation.69 The responder rates—that is, the number of patients showing 50% or greater improvements in seizure frequency and quality-of-life scores—did not differ in the two groups during the blinded phase, but both outcome measures improved during long-term follow-up. A detailed animal study of ANT stimulation was performed in sheep.70 Penicillin, a GABAA receptor antagonist, produces ictal EEG activity in the sheep hippocampus, with reflected EEG ictal activity in the ipsilateral ANT. Stimulation of the ANT (using frequencies of 5, 10, 20, 40, 80, 120 and 160 Hz, applied consecutively) inhibited hippocampal epileptiform activity only at frequencies at or above 80 Hz. After cessation of stimulation, seizure activity returned to at least half that of prestimulation levels after about 5 min. These findings provided retrospective justification for the neurostimulation parameters used in the SANTE clinical trial. At time of writing, DBS of the ANT has been approved for the treatment of refractory partial seizures in several countries, but not yet in the USA.

Motor cortex open-loop neurostimulation One of the greatest challenges in epilepsy is the elimination of an epileptic focus that overlaps with an eloquent area such as the primary or supplementary motor cortex. In 2006, successful direct stimulation of a frontal lobe focus was reported.71 Refractory motor seizures were treated by cortical stimulation in six patients (Figure 3).72,73 The epileptic focus was localized using cortical grid electrodes, which were then exchanged for permanent strip DBS electrodes placed directly over the epileptic focus, which was found to be in the primary motor cortex in three patients and in the supplementary motor cortex in three other patients. Bipolar stimulation was delivered as 450 ms pulses at 350 μA and 130 Hz, in cycles of



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FOCUS ON EPILEPSY b

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Figure 3 | Four stages of neurostimulation planning in one patient. a | Presurgical functional MRI scan obtained during right hand activity, which activated the right hand motor area (red shading). b | EEG recording of a spontaneous partial seizure, showing localized onset. c | MRI scan illustrating the location of diagnostic grid electrodes placed over the involved motor cortex. d | A red circle depicts the position selected for the permanent stimulating electrode.

1 min on and 4 min off. Stimulation for 1 year resulted in more than 90% reductions in seizure frequency across the group. Neuropsychological test results showed no difference during stimulation compared with baseline, and no adverse effects were observed.

Responsive neurostimulation Most regimens of DBS for movement disorders employ continuous stimulation. The SANTE trial used intermittent stimulation, applied according to a programmed clock schedule, which helps to preserve battery life. A third strategy is to deliver stimulation only when seizure onset is detected, a paradigm called responsive neurostimulation.74 In 2004, a proof-of-principle study of responsive neurostimulation in three patients with epilepsy was published, in which two patients were treated via cortical grid or strip electrodes, and one via hippocampal depth electrodes. 75 Individual seizures could be truncated at the onset of stimulation, and overall seizure frequency was reduced by 50–75%. The procedure was well-tolerated. Technical aspects of the device and implantation procedure76 have been described in conjunction with a nonblinded study that documented at least a 45% improvement in seizure frequency in seven of eight patients undergoing responsive neurostimulation.77 Other researchers demonstrated that detection and neurostimulation of a seizure focus in the ANT could be automated; this approach reduced seizure f­ requency by 41%.78 A randomized multicentre trial of responsive neurostimulation involved 191 patients with refractory partial seizures with or without secondary generalization.79 Mean daily seizure frequency at entry was 1.2 ± 2.2 (range 0.1–12.1), 32% of the patients had prior epilepsy surgery,

and 34% had previously undergone VNS. Strip or depth electrodes were implanted adjacent to either one or two previously identified seizure foci, and connected to an implanted sensor–stimulator device embedded in the skull. Algorithms were individually tuned to recognize the EEG correlates of seizures. After a training phase, the sensor delivered stimulation to the focus (or foci) as soon as onset of a seizure was recognized. A reduction in seizure frequency of about 20%—similar to that seen in the SANTE trial 68—was also observed during the recovery period after device implantation, before initi­ ation of stimulation. Seizure counts began 2 months after implantation (that is, 1 month after onset of stimulation). The patients could not sense the stimulation, so blinding was possible. During the blinded phase, seizure frequency decreased by 37.9% with respect to baseline in the active-­stimulation group and by 17.3% in the control (no stimulation) group, representing a significant benefit of stimulation. Long-term follow-up (median 4.5 years) data were presented in a conference abstract:80 the median seizure frequency reduction compared with baseline was 38.9% at 1 year and 51.1% at 2 years. Seizure freedom for at least 6 months was achieved by 20% of patients. The study met its primary end point, and responsive ­neurostimulation has since been approved by the FDA.

Caudate The basal ganglia have been argued to have a role in inhib­ition of seizures.81 In cats, caudate stimulation inhibits penicillin-­evoked hippocampal seizures82 and cobalt-induced chronic neocortical seizures.83 Stimu­ lation of the caudate head at 4–8 Hz was similarly effective against alumina-gel-induced cortical seizures in monkeys, but a rebound increase in seizure frequency occurred after stimulation ceased.12 Conversely, a few studies have found a lowering of the seizure threshold with caudate stimulation.84 In early clinical trials, seizures were eliminated in two patients, and reduced in frequency in another four, with caudate electrostimulation.43 In 2004, the same researchers reported their accumulated experience with neuro­ stimulation of the caudate head in 57 patients with epilepsy.85,86 Consistent with prior experience in monkeys, 4–8 Hz stimulation reduced seizure frequency in these patients, but 50–100 Hz stimulation increased EEG activity.85,87 However, status epilepticus could be interrupted by caudate stimulation.86 Subthalamic nucleus The subthalamic nucleus (STN) is a popular target for DBS therapy in movement disorders, and genetic absence seizures in rats can be suppressed by STN stimulation.88 Inhibition of the STN by drugs89,90 or stimulation at 130 Hz (but not 260 or 800 Hz)91 suppresses chemically induced generalized seizures. Initial studies of STN stimulation in patients with epilepsy used 60–90 μs pulses at 1.5–5.2 V and 130 Hz, which led to a mean reduction of 62% in seizure frequency, with three of five patients showing a good response.92 However, subsequent studies have shown that only about half of

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REVIEWS patients benefit from STN stimulation.93,94 No large trials of STN stimulation for epilepsy have been conducted.

Other sites Neurostimulation at several other sites has been explored in small numbers of patients. Favourable outcomes have been observed for individual patients, but in the absence of randomized, blinded studies with adequate sample sizes, no definite conclusions can be drawn. Unilateral stimulation of the locus coeruleus inhibited interictal spiking in a woman with generalized absence and tonic–clonic seizures,95 and reduced complex partial and tonic–clonic seizures in two additional patients.96 Stimulation of the substantia nigra pars reticulata was of substantial benefit in five patients with progressive myoclonic epilepsy.97 Corpus callosum stimulation benefited 10 patients with refractory generalized epilepsy, as an alternative to callosotomy.98 Stimulation of the caudal zona incerta alleviated partial motor and secondarily generalized seizures in one patient with refractory nonresectable epilepsy.99 The globus pallidus interna is a common stimulation target for movement disorders, and stimulation of this region also might benefit patients with refractory myoclonus.100

Safety The safety data for DBS are derived primarily from experi­­ ence in patients with movement disorders. In a study of data from the Nationwide Inpatient Sample (which represents around 20% of all discharges from nonfederal hospitals in the USA), 18,313 DBS surgeries were performed for Parkinson disease over an 8‑year period,101 suggesting that well over 100,000 DBS surgeries have been conducted for this indication in the USA alone. In one large study of US centres, the overall complication rate for DBS surgeries in patients with Parkinson disease was 6.5%, which included mechanical complications (3.1%), haemorrhage or infarction (1.2%), lead removal (0.5%), haematoma (0.4%), and infection (0.4%).97 Small hospitals with low procedural volumes did not have higher complication rates than high-volume centres, perhaps because functional neurosurgeons are trained at high-volume centres. Here, space only permits comment on selected individual studies. A series of 119 patients who underwent 139 implantation procedures between 1993 and 2002, during which 161 electrodes were implanted, were followed up for 540 electrode-years (a minimum of 1 year per patient).102 A total of 17 patients (15%) experienced 23 complications, representing a complication rate of 4.3% per electrode-­year. Of these, 16 were equipment malfunctions or migrations, and seven were erosions or infections. In another investigation, 79 patients who received 124 DBS electrode implants were followed up for a mean of 33 months.103 Overall, 25.3% had complications, usually mechanical equipment problems, erosions, infections or foreign body reactions. Death is a rare complication of neurostimulation, but it has been reported.104,105 The most feared complication from DBS is serious haemorrhage. In a study of 567 electrodes placed in 259 266  |  MAY 2014  |  VOLUME 10

patients, symptomatic haemorrhage occurred in 1.2% of participants, among whom lasting adverse effects occurred in 0.7%.106 Infection is a fairly common complication. In a single-centre study of 484 DBS implants in 270 patients, the overall infection rate was 9.3%.107 Hardware was replaced in about half of these individuals. Cognitive and psychiatric complications of electrode implantation are also seen; one study documented several cases of depression or mania time-linked to DBS for Parkinson disease, which improved with adjustment of stimulation parameters.108 MRI scans heat up DBS electrodes, raising concern that imaging could result in local tissue injury. Safe stimulation parameter limits and local specific absorption rates are, therefore, specified in DBS equipment package inserts. However, when researchers at the University of Kansas analysed 1,092 1.5 T MRI scans performed in 249 patients with DBS implants, no hardware or clinical consequences were identified, despite estimated local specific absorption rates often being higher than those specified in the DBS product labelling.109 Safety of MRI in patients with DBS electrodes in situ has been debated.110 The National DBS Brain Tissue Network studied 21 postmortem brains of patients who had received 1.5–3.0 T MRI with DBS leads in place, and no relevant pathology was identified.111 Comparatively little information is available on the complications of neurostimulation in patients with epilepsy. Adverse events in the pivotal SANTE randomized trial were mainly those expected from implanted electrodes, including stimulation-related paraesthesias and subclinical (but neuroimaging-visible) bleeding around electrodes. 68 Stimulation-induced status epilepticus occurred in one patient, but responded to lowering of the stimulation voltage. The overall population risk of status epilepticus was not, however, increased in this study. At the time of writing, two patients have succumbed to sudden unexpected death in epilepsy after surgery (one during the unblinded phase, and one during the longterm follow-up phase), which is within the usual rate for this population, and one suicide occurred during the unblinded phase.68 In the randomized multicentre trial of responsive neurostimulation, adverse events comprised dysaesthesias, headache and implant-site infections.79 Intracranial haemorrhages were observed in nine patients, and three of these required device explantation.79 An analysis of pooled safety data from the three pivotal trials of VNS, thalamic DBS and responsive neurostimulation concluded that the overall rate of serious adverse events, death or paralysis was less than 1–2%.112 In the SANTE trial, neuropsychological testing did not show a difference between active and control groups; however, significantly more patients in the active group reported subjective depression and memory problems.68 By contrast, a different study of ANT stimulation showed improvement in several cognitive tasks.113 Cognitive function was mostly unchanged after 6 months of amygdalo­ hippocampal stimulation, but overall group scores for emotional well-being increased.114 Mood and cognitive function testing of patients undergoing responsive



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FOCUS ON EPILEPSY neurostimulation showed no mean worsening during the blinded phase.79 One patient committed suicide during the open-label phase, and another during the long-term follow-up of the study participants. 79 Eight of the actively stimulated patients and one of the control patients enrolled in the SANTE trial68 reported new or worsening of symptoms associated with depression. However, more evidence is required before the effects of responsive neurostimulation and thalamic DBS on mood can be c­ onfidently characterized. DBS electrode implantation procedures can provoke acute symptomatic seizures owing to the surgical trauma. In a literature review, 16 papers (describing implantations in 1,555 patients) mentioned seizures as a complication of DBS at an overall rate of 2.7%, whereas 16 other papers, encompassing implantations in 1,254 patients, did not mention seizures.115 About three-quarters of DBS-related seizures occurred at the time of electrode implantation, and were especially prevalent in those with haemorrhage. The estimated seizure risk from DBS was over 2.4% (95% CI 1.7–3.3%). Repeated electrical stimulation of the brain in certain experimental conditions can produce ­kindling,116 which manifests as the new emergence or the increased duration, severity and frequency of seizures. Kindling has been reported (albeit very rarely) in patients treated with DBS,117 but whether kindling could appear in patients receiving very long-term DBS is unknown.

Comparing neurostimulation techniques No trials have directly compared VNS, responsive neuro­ stimulation and thalamic DBS. In terms of safety, VNS probably has the advantage of being inherently lower-risk than brain-penetrating therapies. VNS seems to have the advantage in terms of cost as well, as implantation of brain electrodes costs more than does implantation of VNS neck electrodes. This cost differential is minor compared with long-term costs of uncontrolled epilepsy, however. Efficacy data must be compared with care, as—unlike the trials for DBS and responsive neurostimulation—the trials of VNS could not be fully blinded because of perceptible neck sensations. The percentage improvements from baseline seizure frequency observed in the controlled phases of pivotal trials for these three therapies were higher for both thalamic DBS (40.4% stimulated versus 14.5% control)68 and responsive neurostimulation (37.9% versus 17.3%)79 than for VNS (27.9% versus 15.2%).118 All three trials showed further improvements in seizure control over a period of years during the nonblinded phases.68,79,118 Moreover, patients in the thalamic DBS and responsive neurostimulation trials who had not significantly benefited from previous VNS could still benefit from brain stimulation.68,79 Whether some patients might benefit from VNS after the failure of DBS has yet to be explored. Even less evidence is available to compare the efficacy and safety of thalamic DBS and responsive neurostimulation. With such similar outcomes in their respective trials,68,79 detecting a difference would require a very large sample size. The pragmatic way to choose the stimulation method that is most appropriate for a given patient is based on the location of the seizure focus. Responsive

neurostimulation requires a priori knowledge of the focus or foci, in contrast to thalamic DBS, in which electrodes are always placed in the same anterior thalamic nuclei. In some patients for whom the location of the seizure focus is known, resection might be a more effective approach than neurostimulation. By definition, responsive neurostimulation requires a seizure to begin, which might have certain behavioural consequences. Further investigation might show that responsive neurostimulation actually prevents— as well as ameliorates—seizures, but until such data are available, stimulation administered either continuously or intermittently (that is, according to a clock-determined cycle) may be expected to be more effective than responsive neurostimulation for the prevention of seizures. In general, therefore, responsive neurostimulation and thalamic DBS can be viewed as complementary therapies for different patient populations, with one notable area of overlap being patients with bilateral temporal lobe ­seizures, for whom either approach might be employed.

Conclusions Neurostimulation represents a new modality of therapy for epilepsy that is potentially supplemental to pharmaco­ therapy. Neurostimulation has the advantages of flexi­bility and reversibility, both of which are lacking with conventional epilepsy surgery. Two pivotal trials of neuro­ stimulation, one of ANT stimulation68 and another of DBS at the seizure focus,79 have documented efficacy and general safety for patients with partial seizures, with or without secondary generalization. Many other targets have shown promise in small or noncontrolled studies. Some high-quality animal studies of neurostimulation have been conducted, but basic research pertaining to neurostimulation is surprisingly scarce, given its rapidly growing acceptance in clinical use. The efficacy of neuro­ stimulation therapy might be enhanced by improved understanding of the mechanisms involved, which are poorly understood. Furthermore, as epilepsy is a heterogeneous condition, improvements in identification of the optimal candidates, and the best stimulation targets and methods, could also lead to better treatment outcomes. Guidance on these topics will probably emerge from future laboratory studies. Brain stimulation for epilepsy may now be considered as another option for treatment of people with medication-­resistant epilepsy. Further study and experience will be required to define the optimal role of brain stimulation. In the absence of any single compelling factor, a decision on whether to use neurostimulation— and which form to use—will, as usual, rest on the availability of the therapy, the goals of the patient, and the judgement of the clinician. Review criteria Articles were selected for review by searching PubMed using the term “epilepsy stimulation”. All languages were searched, but those in non-English languages received less coverage. The reference list of each article was used to identify further relevant studies.

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