oxford textbook of epilepsy and epileptic seizures 320 Parallel to VNS, the precise mechanism of action and the ideal can- didates for this treatm ent option are currently unidentified. Moreover it is unknown which intracerebral structure s should be targeted to achieve optimal clinical ef \201 cacy. Two major strategies for ta rgeting have been followed. One approach is to target crucial central nervous systems struc tures that are assumed to have a \200\230pacemaker \200\231, \200\230triggering \200\231 or \200\230gating \200\231 role in the epileptogenic net- works such as the thalamus or th e subthalamic nucleus (100). Another approach is to interfere with the ictal onset zone its elf. This implies the identi \201 cation of the ictal onset zone, a process that sometimes requires implantation with intracranial electrodes. Initial studies on small patient groups treated for 6 months with VNS showed no negative ef fect on cognitive motor performance and balance (79 \200\22381). These \201 ndings were c on \201 rmed in larger patient groups with a follow-up of 2 years (82, 83). Hoppe et al. s howed no changes in extensive neuropsychological testing in 36 patients treated for 6 month s with VNS (84). Vagus nerve stimulation electrodes can be safely revised and removed, when necessary (85). Cardiac side effects Despite the fact that the initial studies showed no clinical effect on heart rate, occurrence of bradycardia and ventricular asystole during intraoperative testi ng of the device (stimulation parameters: 1 mA, 20 Hz, 500 s, \210 17 s) have been repor ted in a small number of patients. None of the reported patients had a history of cardiac d ysfunction, nor did they show abnormal cardiac testing after surgery. Tatum et al. reported on four patients who experienced ventricular asystole intraoperatively during device testi ng (86). In three patients, the implantation procedure was aborted. Asconape et al. reporte d on a single patient who developed asystole during intraoperative device testing. After re moval of the device, the patient recovered completely (87). Ali et al. described three simi lar cases (88). Andriola et al. reported on three patients who experi- enced an asystole du ring intraoperative lead testing and who were subsequently chronically stimulated (89). Ard esch et al. reported on three patients with intraoperative bradycardia and subsequent uneve ntful stimulation (90). Possible hypotheses with regard to the underlying cause are inadver tent placement of the electrode on one of the cervical branches of the vagus nerve or indir ect stimulation of these branches, reversal of the polarities of the electrodes which would lead to primary stimulation of efferents instead of afferents, indirect stimulation of car diac branches, activation of afferent pathways affecting higher autonomic systems or of the parasympa- thetic pathway with an exaggerated effect on the atrioventricular node, technic al malfunctioning of the device, or idiosyncratic reac- tions. The contributing role of spe ci \201 c AEDs should be further investigated. Very recently, one case report described a late-onset bradyarrhythmia after 2 years of vagus nerve stimulation (91). Targets The earliest reports on intracranial neurostimulation involved stimulation of cereb ellar structures. In most instances electrical cur- rent was administered through electrode s bilaterally placed on the superior medial cerebellar cortex (101). Intermittent (1 \200 \2238 min on, 1 \200\2238 min off) high-frequency (150 \200\223200 Hz) cerebellar stimulati on was initially investigated for the treatment of spasticity due to cere- bral palsy or st roke in several hundreds of patients with implanta- tion duration times of up to 20 years. Some of these patients also had refractory seizures that were completely abolished in 60 % of patients. Two controlled studies in small patient groups (n = 5, n = 12) did, however, n ot show signi \201 cant effects (102, 103). In view of this controversy and with the adven t of fully implantable and program- mable pulse generators, Velasco et al. performed a re-e valuation double-blind study in \201 ve patients showing signi \201 cant decreases in to nic \200\223clonic seizures after 1 \200\2232 months of stimulation (104). The selection of other targets for DBS in humans partially resulted from the progress in th e identi \201 cation of epileptogenic networks (100). Although the cortex plays an essenti al role in sei- zure origin, increasing evidence shows that subcortical structures may be i nvolved in the clinical expression, propagation, control and sometimes initiation of seizur es. Consequently, several sub- cortical nuclei have been targeted in pilot trials for diffe rent types of epilepsy. The suppressive effects of pharmacological or electrical inhibition of the subthalamic nucleus (STN) in different animal models for epilepsy and the extensive experience with STN DBS in patients with movement disorders led to a pilot trial with high - frequency (130 Hz) continuous STN DBS in \201 ve patients by the group from Grenoble (4 , 105). Three patients with symptomatic partial seizures had a > 60 % reduction in seizure frequency. Four other centers have reported STN DBS results. In one patient with LGS, gener alized seizures were fully suppressed and myoclonic and absence seizures reduced by more th an 75 % (106). Loddenkemper et al. reported seizure frequency reductions of more than 60 % in two out of \201 ve patients treated with STN DBS (107). Handforth et al. reported on o ne patient with bitemporal seizures in whom half of the seizures were suppressed and on one patient with frontal lobe epilepsy who experienced a one-third reduction of seizures (108) . Vesper et al. described a 50 % reduction in myoclonic sei- zures in a patient with progre ssive myoclonic epilepsy in whom generalized seizures had been successfully treated with pr evious VNS (109). Magnetic resonance imaging Based on laboratory testing using a phantom to simulate a human body, the VNS TherapyTM system device is labeled magnetic reso- nance imaging (MRI) compati ble when used with a send and receive head coil (92). In addition to the safety issues, the re was no signi \201 - cant image distortion (93). A retrospective analysis of 27 MRI scan s performed in 25 patients at 12 different centers using a 1.5 Tesla machine reported one p atient with a mild voice change for several minutes; one child reported chest pain and clau strophobia. Twenty- three patients reported no discomfort around the lead or the gen- erato r. It was concluded that MRI is safe as long as guidelines stated in the physician \200\231 s manual of the implanted device are followed (94). In these guidelines it is suggested to program the pulse generator output current to 0 mA. There have been several studies in pati ents treated with VNS for epilepsy as well as for depression showing that functional MRI is safe and feasible (95 \200\22399). Thalamocortical interactions are known to play an important role in several types of seizur es. Since 1984, Velasco et al. have investigated a large patient series (n = 57) with diffe rent seizure types who underwent DBS of the centromedian (CM) nucleus, a Deep brain stimulation DBS is a relatively more recently explored treatment modality in epi lepsy. Compared to VNS it is a more invasive treatment option. CHAPTER 30 vagal nerve stimulation and deep brain stimulation in epilepsy 321 structure that can be stereotactically targeted fairly easily due to its relatively large s ize, its spherical shape and location on each side of the third ventricle (110, 111). Inter mittent (1 min on, 4 min off) high-frequency (60 \200\223130 Hz) stimulation that alternate d between the left and right CM thalamic nucleus was most effective in chil- dren (n = 5) w ith epilepsia partialis continua in whom full seizure control was reached between 3 \200 \2234 months after stimulation. Secondary generalized seizures in these children were the e arliest to respond after 1 month of treatment. Atypical absences and gener- alized seizures responded signi \201 cantly. Three out of 22 patients with LGS became seizure-free. Compl ex partial seizures responded less although after long-term stimulation over 1 year partial improvements were found and patients tended to be satis \201 ed with the treatment that s igni \201 cantly decreased or abolished secondary generalized convulsions. In a separate r eport Velasco et al. report on 11 patients with LGS with an overall seizure reduction of 80 % and two patients rendered seizure free (112). stimulated group were more likely to report depression or memory problems as adverse events . The medial temporal lobe region, more speci \201 cally the hippoc- ampus is a rational tar get for DBS. This region often shows speci \201 c initial electroencephalographic epilepti form discharges that can be recorded with invasive EEG electrodes and represent the ictal o nset zone. Temporal lobectomy and more speci \201 cally selective amy- gdalohippocampectom y are effective in reducing seizures with a well-de \201 ned mesiobasal limbic ictal onset (118). Basic research involving evoked potential excitability studies in humans and ana- t omical studies with tracer injections and single-unit recordings with histological studies in animals have also confirmed the involvement of the amygdala and the hippocampus in the e pilep- togenic network (119 \200\223121). Some studies have applied electrical \201 elds to in vitro hippocampal slices with positive effects on epilep- tic activity (122, 123). Al so our own in vivo studies in rats have shown that high-frequency stimulation affects seizu res in the kin- dling model (Fig. 30.3 ) (124). In a double-blind cross-over protocol performed by Fisher et al., CM thalamic stimulation d id not signi \201 cantly improve generalized seizures in seven patients (113). Bilateral i ntermittent (1 min on, 5 min off during 2 h/day) high-frequency (60 Hz) stimulation was per formed in blocks of 3 months alternating between on and off stimulation in a double-blinded manner. A reduction of 30 % of tonic \200\223clonic seizures had been observed during bloc ks with the stimulation on versus 8 % in blocks with stimulation off. An open extension pha se of the trial using 24-hour stimulation resulted in a 50 % decrease in three out of six o f the patients. It has become clear, especially from the experience with VNS, but also from other stud- ies, that increased ef \201 cacy may be observed after longer duration of sti mulation, possibly on the basis of neuromodulatory changes that take time to develop (111, 114). High-frequency stimulation is more efficacious than low- frequency stimulation and Poisson- distributed stimulation seems more ef \201 cacious compared to regular high-frequency stim ulation (125, 126). Bragin et al. described repeated stimulation of the hippocampal perfora nt path in rats showing spontaneous seizures 4 \200\2238 months after intrahippocampal kain ate injection (127). During perforant path stimulation spontaneous seizures were signi \201 cantly reduced. In humans, preliminary short-term stimulation of hip- pocampal structu res showed promising results on interictal epilep- tiform activity and seizure frequency (1 28). Not all patients with temporal lobe epilepsy who underwent resective epilepsy surgery remain seizure free in the long term. Moreover, temporal lobe resection, especially left-si ded, may be associated with memory decline and temporal lobe resection is contraindicated i n patients with bilateral ictal onset. In a pilot trial, 10 patients scheduled for invasive video-EEG monitoring of the medial temporal lobe were offered high-frequency medial tempor al lobe DBS following ictal onset localization (6). Long-term follow-up in 10 of these pati ents showed that one stimulated patient was seizure-free ( > 1 year), one patient had a mor e than 90 % reduction in seizure frequency; \201 ve patients had a seizure frequency redu ction of 50 % or more; two patients had a seizure frequency reduction of 30 \200\22349 % ; one patients was considered a non-responder. None of the patients reported side effects. In one patient MRI showed an asymptomatic intracra- nial hemorrhage at the occipital cortical entry of one of the DBS electrodes. None of the patients showed changes in clinical neurol ogical testing. Fig. 30.4 shows the electrode positions in the hippocampus. A controlled ra ndomized multicentre study (CoRaStiR \200\224 Controlled Randomized Stimulation versus Res ection) is currently recruiting patients with unilateral hippoc- ampal sclerosis and TLE to be randomized to amygdalohippocam- pal resection or medial temporal lobe DBS. There is suf \201 cient evidence to suggest an equally important role of the anterior nucl eus (AN) of the thalamus in the pathogenesis of seizure generalization. Hodaie et al. perfo rmed bilateral AN tha- lamic DBS (1 min on, 5 min off, 100 Hz, alternating between right an d left AN) in \201 ve patients and showed a seizure frequency reduc- tion between 24 \200 \22389 % (115). Andrade et al. reported on the long- term follow-up of six patients with AN DBS. After 7 years of follow-up \201 ve patients showed a more than 50 % reduction in se i- zure frequency (116). Changes in stimulation parameters over the years did not further i mprove seizure control. Kerrigan et al. reported that four out of \201 ve patients who un derwent high fre- quency AN DBS showed signi \201 cant decreases in seizure severity and i n the frequency of secondarily generalized seizures. Moreover, there was an immediate seizu re recurrence when DBS was stopped (117). These studies all preceded a multicentre double-b lind rand- omized trial of bilateral AN stimulation (SANTE trial) in patients with partial onset seizures with or without secondary generaliza- tion (3). One hundred and ten patients have been included at 17 medical centers in the USA. Half received stimulation and half di d not receive stimulation during a 3-month blinded phase; then all received unblinded stimu lation. In the last month of the blinded phase the stimulated group had a 29 % greater redu ction in seizures compared with the control group. Complex partial and \200\230most severe \200\231 seizures were signi \201 cantly reduced by stimulation. By 2 years, there was a 56 % median percent reduction in seizure fre- quency; 54 % of patients had a seizure reduct ion of at least 50 % , and 14 patients were seizure-free for at least 6 months. Cognition a nd mood showed no group differences, but participants in the In four patients with complex partial seizures based on left-sided hippocampal sclerosis hi gh-frequency stimulation was performed in a randomized, double-blind protocol with periods of 1 month off or on by Tellez-Zenteno et al. (129). During the stimulation on periods seiz ures decreased by 26 % as compared to baseline. During the off periods seizures increased b y 49 % . Neuropsychological test- ing revealed no difference between on or off periods, not even in one patient who was stimulated left-sided following previous right-sided temporal lobectomy. Velasco et al. reported results in oxford textbook of epilepsy and epileptic seizures 322 Fig. 30.3 Increase of afterdischarge latency and decrease of afterdischarge Rproduced from Epilepsia 48, Wyckhuys T, De Smedt T, Claeys P, et al. High frequency deep brain stimulatio n in the hippocampus modi \201 es seizure characteristics in kindled rats, 1543 \200\22350 . Copyright (2007), with permission from Wiley. Conclusion The lack of adequate treatments for all medically refractory epi- lepsy patients , the general search for less invasive treatments, and the progress in biotechnology have l ed to an renewed and increas- ing interest in neurostimulation as a therapeutic option. 11 patients after 18 months of hippocampal high frequency stimu- lation (uni- or bilateral, with or without hippocampal sclerosis on MRI) (130). Patients with normal MRIs showed opti mal outcome with four of them seizure-free after 1 \200\2232 months of stimulation. None of the patients showed neuropsychological decline with a trend towards improval. For all types of neurostimulation currently being used and investigated, major issues remai n unresolved. The ideal targets and stimulation parameters for a speci \201 c type of pati ent, seizure, or epilepsy syndrome are unknown. Long-term side effects need to be further i nvestigated. The elucidation of the mechanism(s) of action of different neurostimulation te chniques requires more basic research in order to demonstrate its potential to achieve long -term changes and true neuromodulation. An implanted responsive neurostimulator (the RNS system) has been evaluated for safety and ef \201 cacy in a multicentre trial. The device records cortical EEG signals by means of s ubdural electrodes and delivers responsive stimulation. Morrell reported 19 patients with p artial onset epilepsy who were treated with the RNS system and showed a 37.9% reduction in seizure frequency in the stimu- lated group versus 17.3% in the SHAM group (p= 0.012) (7). VNS is a moderately ef \201 cacious treatment for patients with refractory epilepsy; it is a broad-spectrum treatment; identi \201 cation of speci \201 c responders on the basis o f type of epilepsy or speci \201 c patient characteristics proves dif \201 cult. Large pa tient groups have been examined and identifying predictive factors for response may demand more complex investigations. VNS is a safe treatment and lacks the typical cognitive side e ffects associated with many other antiepileptic treatments. Moreover, many patients experie nce a positive effect of VNS on mood, alertness, and memory. In con- trast to many pharmaco logical compounds, treatment tolerance does not develop in VNS. In contrast, ef \201 cacy tends to increase with longer treatment. However, on the basis of currently available data the responder rate in patients treated with VNS is not substan- tially higher compared to r ecently marketed AEDs. To increase ef \201 cacy, research towards the elucidation of the m echanism of action and optimization of stimulation parameters is crucial. Deep brain stimulation is evolving from an experimental stage towards a reasonable treatmen t option for patients with refractory epilepsy. In addition to several pilot trials in diff erent targets one ran- domized controlled trial of DBS in the anterior nucleus of the thala - mus showed to be a feasible and safe treatment option, responder rate being slightly supe rior to the results of VNS. Results of randomized Fig. 30.4 Electrode positions in the hippocampus and amygdala; R, right-sided; L, left-side d; A, amygdala; H, hippocampus. From Boon et al. (6). CHAPTER 30 vagal nerve stimulation and deep brain stimulation in epilepsy 323 trials in hippocampal DBS are currently pending. The precise role of DBS in the treatment i n refractory epilepsy remains to be determined. 18. Krahl SE , Clark KB , Smith DC, Browning RA . Locus coeruleus lesions suppress the seiz ure-attenuating effects of vagus nerve stimulation . Epilepsia 1998 ; 39 ( 7 ): 709 \200 \223 14 . 19. Osharina V , Bagaev V , Wallois F, Larnicol N . Autonomic response and Fos expression i n the NTS following intermittent vagal stimulation: importance of pulse frequency . Auton N eurosci 2006 ; 126 \200\223127 : 72 \200\223 80 . 20. Ben-Menachem E , Hamberger A , Hedne r T , Hammond EJ , Uthman BM , Slater J , et al . Effects of vagus nerve stimulation on ami no acids and other metabolites in the CSF of patients with partial seizures . Epilepsy Res 1995 ; 20 : 221 \200\223 7 . Acknowledgements Professor Boon and Professor Vonck are supported by grants from the Fund f or Scienti \201 c Research Flanders, the Ghent University Research Fund and the European U nion (6FP Imane). They have received support from Cyberonics and Medtronic in the form of c onsultancy fees, speaker fees and educational grants in favor of the Ghent University Hospi tal Clinical Epilepsy Grant. 21. Raedt R , Clinckers R , Mollet L , Vonck K , El Tahry R , Wyckhuys T , et al . 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