Invasive (intracranial) EEG is the gold standard for the precise identi \201 cation of the ictal onset and irritative zones. Essentially, almost all cases with negative MRI and thos e cases in which the epileptogenic lesion is close to eloquent cortex will need invasive EE G (23 \200\22325). Careful planning of subdural or depth electrodes placement is essential, based on analysis of the information gath- ered from all non-invasive studies. A clear hyp othesis with regard to the localization of the epileptogenic zone should be formulated and appropriate invasive studies capable of con \201 rming the hypoth- esis as well as de \201 ning with precision the location and extent of the epileptogenic zone, should be plann ed. Invasive EEG studies should be carried out in experienced centers that bene \201 t fro m modern neurophysiological and neurosurgical technologies with highly skilled epileptologi sts and neurosurgeons. In more challenging cases, invasive EEG studies may need to be stage d into more than one implantation operation. During the second stage, more elec- trodes may need to be inserted for accurate localization of the epi- leptogenic zone based on informa tion derived from the \201 rst stage. Direct electrical stimulation of the cortex remains the gold stand- ard for brain mapping. Detailed and careful mapping of eloquent cortex can be done extraoperatively in the epilepsy monitoring unit while patients are fully awake an d cooperative. Cortical mapping needs to be performed by a trained and experienced neurophy si- ologist. Intraoperative mapping is more limited because of time constraints in the oper ative room and technical dif \201 culties in per- forming craniotomies under awake conditi ons. However, mapping in the operative room can be done for patients who do not undergo chr onic invasive EEG recordings or in order to con \201 rm the results of extraoperative mapp ing. MRI is the cornerstone of any search for structural neuropathol- ogies and obtaining a high -resolution epilepsy protocol MRI is crucial in all surgical candidates. Focal cortical dys plasia can be very dif \201 cult to detect on routine MRI. High-resolution, 3 Tesla MRIs r ead by experienced neuroradiologists may not reveal a sub- sequently pathologically con \201 rmed abnormality. Functional MRI (fMRI) is becoming more available in major epilepsy c enters and CHAPTER 29 resective surgery of extratemporal epilepsy 311 dysplasia and generalized ictal EEG patterns have been reported to be other predictors of p oorer surgical outcomes in frontal epilepsy resections. Surgical methods and outcomes Lesionectomy is the most common type of surgical resection in extratemporal epilepsy. In most cases, complete resection of the visible MRI lesion is nec essary to achieve seizure freedom. However, in the majority of the patients, additional res ection of the area surrounding the lesion is also necessary for a successful outcome. The e xtent of perilesional resection is determined by the pathology of the lesion and also the r esults of invasive ictal and interictal EEG recordings. Besides, mapping of possible adjace nt eloquent cortex will also in \202 uence the extent of the cortical resection. In cases with no identi \201 able lesion on MRI the extent of the topectomy is de \201 ned primari ly by functional data (ictal and interic- tal EEG,). Modern neurosurgical operating rooms b ene \201 t from neuronavigation and stereotactic systems that can aid surgery with more pr ecise resection. In large retrospective series, the occurrence of complications have been reported as 0.4 % for perisurgical death, 5 % for infec- tion, 6 % for neurological de \201 cits (3 % were t ransient), and 6 % for behavioral and cognitive complications (26, 29). Case studies Case A A 59-year-old woman with a history of epilepsy since age 25. Her seizur es consisted of stereotyped hypermotor movements of the right upper extremity with no alter ation of awareness, occa- sionally followed by secondary generalized tonic \200\223clonic s eizures. Seizures occurred up to 20 times per day mostly during sleep. Her epilepsy remaine d intractable despite treatment with different antiepileptic medications. She had a surgica l evaluation with inva- sive EEG recording more than 30 years ago, prior to availability of MRI as an investigational tool. At that time she underwent bifron- tal depth electrode pla cement through burr holes. This evaluation failed to lateralize the origin of her seizures and no surgical resec- tion was performed. She underwent another surgical evaluation more r ecently. A presurgical MRI showed bifrontal encephaloma- lacia and gliosis under the previo us surgical burr holes. Due to lack of prior MRI for comparison, a differentiation between the possi- bilities of primary lesions versus postsurgical changes from prior depth electro des placements could not be made. Scalp EEG was negative interictally and showed no changes during her habitual seizures. She underwent stereotactic placement of multiple depth elect rodes in both frontal lobes in two stages. Perilesional, anterior cingulate, orbitofrontal, frontal pole, and lateral frontal areas were sampled bilaterally. After recording numerous seizures it was con- cluded that the seizures originated primarily in the right perile- si onal area and rapidly propagated to the contralateral frontal lobe. She underwent a partial right frontal lobectomy which included There has not been a prospective controlled study in extratem- poral resective surgery and outcomes from published retrospective surgical series vary widely. This outcome variability is likely related to the heterogeneity of these cases, selection biases, different inves- tigational approaches, and the variability of surgical methods amongst different epilepsy c enters. Nevertheless, it is clear that in comparison to temporal lobectomies, seizure-free outcomes are lower in extratemporal resections (2). In a systemic review of out- come data in 298 neocortical resections from 24 published studies with more than 1-year follow-up, a seizure-free rate of 50 % and an improvement rate of 79 % were found (26). Another meta-ana lysis of surgical outcomes found long-term (more than 5 years follow- up) seizure-free rate s of 34 % for extratemporal resections (27). Results from a major epilepsy center showed th at the seizure-free rate for frontal lobe resections drops from 56 % at 1-year follow-up to 30 % at 5 years (28). So far, the existence of an identi \201 able struc- tural lesion is the single most important factor for the prediction of a favorable surgical outcome in ext ratemporal resections. Cortical Fig. 29.5 Bifrontal lesions. Note the burr hole defects in the skull from previous surgery overlying the lesions. oxford textbook of epilepsy and epileptic seizures 312 Fig. 29.6 (See also Color plate 18.) Location of depth electrodes can be determined by the fusion of high-resolution computed tomography images (taken after placing the electrodes) w ith preoperative MRI. The red circle shows the area of seizure onset around the right mesio frontal lesion. Fig. 29.7 Ictal EEG from depth electrodes showing seizure onset in the right mesial area (o val) with rapid propagation to the left mesial electrodes (arrow from oval), the boxed area is blown up to the right depicting selected channels from the right mesial area which show ictal onset characterized by appearance of fast frequencies. CHAPTER 29 resective surgery of extratemporal epilepsy 313 Fig. 29.8 Postoperative MRI of the right frontal resection. the MRI lesion. Pathology examination confirmed cortical dysplasia with balloon cells. She was seizure free at the 6-month follow-up but has remained on antiepileptic medications (Fi gs. 29.5 \200\22329.8 ). arm tonic movements with secondary generalization. MRI revealed a large left frontal enceph alomalacia and gliosis. Scalp EEG showed interictal generalized spikes maximally lateralize d to the left. Invasive EEG recordings of the seizures and electrical stimulation of subdur al electrodes were performed to identify the seizure onset zone and the motor strip. She th en had a partial left frontal lobec- tomy which included the lesion but spared the motor st rip. The patient was seizure free at 6-month follow-up and antiepileptic medications were s afely lowered (Figs. 29.9 \200\22329.12). Case B A 20-year-old woman who had a left frontal intracerebral hemorrhage from a ruptured AVM 5 years previously which left her with right-hand weakness. At that time she underwent evacua- tion of the haematoma and resection of the AVM. She developed epilepsy 4 years late r which rapidly became intractable even to high doses of antiepileptic medications. The sei zures consisted of right Fig. 29.9 Axial and coronal images of the left frontal lesion (residual encephalomalacia an d gliosis from a previously ruptured arteriovenous malformation which was resected 5 years ago). oxford textbook of epilepsy and epileptic seizures 314 Fig. 29.10 Intraoperative photograph of subdural grid covering the lesion and surrounding n ormal cortex. Frontal SF MF LF Central Sulcus Seizure Onset Zone R R Fig. 29.11 Three-dimensional reconstruction of fused preoperative MRI and postoperative CT shows exact location of three subdural grids; lateral frontal (LF), superior frontal (SF), and mesiofrontal (MF). Subdural grids cover the left frontal lesion and surrounding normal cortex. Maps of the ictal onset zone (circle), and central sulcus (black line) are shown. Fig. 29.12 Left frontal partial lobectomy anterior to the central sulcus (arrow shows the m otor strip) and intraoperative MRI to con \201 rm an adequate resection. CHAPTER 29 resective surgery of extratemporal epilepsy 315 References lobectomies and functional hemispherectomies . Acta Neuropathol (Berlin) 1993 ; 86 : 466 \200\223 72 . 1. Mohanraj R , Brodie MJ . Outcomes in newly diagnosed localization- 17. Vital A , Rivel J , Loiseau H , Marchal C , Rougier A , Vital C . The related epilepsies . 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B autista JF , L ders HO . Semiological seizure classi \201 cation: relevance to pediatric epilepsy . Epileptic Disord 2000 ; 2 ( 1 ): 65 \200\223 72; discussion 73 . 6. L ders HO , Amina S , Baumgartner C , Benbadis S , Bermeo-Ovalle A , 20. Kutsy RL. Focal extratemporal epilepsy: clinical features, EEG patterns, and surgical approach . J Neurol Sci 1999 ; 166 : 1 \200\223 15 . 21. O \200\231Brien TJ , So EL , Mullan BP , Cascino GD , Hauser MF , Brinkmann BH , et al . Subtraction peri-ictal SPECT is predictive of extratemporal epilepsy surgery outcome . Ne urology 2000 ; 55 : 1668 \200\223 77 . Devereaux M , et al . Modern technology calls for a modern approach to classi \201 cation of epileptic seizures and the epilepsies . Epilepsia 2012 : 53 ( 3 ): 405 \200\223 11 . 22. O \200\231Brien TJ , So EL , Cascino GD , Hauser MF , Marsh WR , Meyer FB , et al . Subtraction SPECT coregistered to MRI in focal malformations of cortical developmen t: localization of the epileptogenic zone in epilepsy surgery candidates . Epilepsia 2004 ; 45 : 367 \200\223 76 . 7. L ders HO , Najm I , Nair D , Widdess-Walsh P , Bingman W . The epileptogenic zone: general principles . Epileptic Disord 2006 ; 8( Suppl 2) : S1 \200\223 9 . 23. Wetjen NM , Marsh WR , Meyer FB , Cascino GD , So E , Britton JW , et al . Intracranial electroencephalography seizure onset patterns and surgical outcomes in nonlesional extratemporal epilepsy . J Neurosurg 2009 ; 110 : 1147 \200\223 52 . 8. L ders , HO , Noachtar S . Atlas of Epileptic Seizures and Syndromes . Philadelphia, PA : W.B. Saunders Company , 2001 . 9. VanGompel J , Worrel GA . Semiology of extratemporal lobe epilepsy (overview) . In: Koub eissi MZ, Maciunas RJ (eds) Extratemporal Lobe Epilepsy Surgery . Paris : John Libbey Eurot ext , in press . 10. Duncan JS . Imaging and epilepsy . Brain 1997 ; 120 : 339 \200\223 77 . 11. Duncan JS . Imaging in the surgical treatment of epilepsy . Nat Rev 24. Munari C , Hoffmann D , Francione S , Kahane P , Tassi L , Lo Russo G , et al . Stereo- electroencephalography methodology: advantages and limits . Acta Neurol Scand Suppl 1994 ; 152 : 56 \200\223 67, discussion 68 \200\22359 . 25. Cossu M , Cardinale F , Colombo N , M ai R , Nobili L , Sartori I , et al . Stereoelectroencephalography in the presurgical evaluation of children with drug-resistant focal epilepsy . J Neurosurg 2005 ; 103 : 333 \200\223 43 . 26. Engel J Jr , Wiebe S , Fre nch J , Sperling M , Williamson P , Spencer D , et al. Practice parameter: temporal lobe an d localized neocortical resections for epilepsy . Epilepsia 2003 ; 44 : 741 \200\223 51 . Neurol 2010 ; 6 ( 10 ): 537 \200\223 50 . 12. Talairach J , Bancaud J , Bonis A , Szikla G , Trottier S , Vignal JP , et al . Surgical therapy for frontal epilepsies . In: Chauvel P , Delgado-Escueta AV , Halgren E , Bancaud J (eds) Frontal lobe seizures and epilepsies , pp. 707 \200\223 32 . New York : Ra ven Press , 1992 . 27. Tellez-Zenteno JF , Dhar R , Wiebe S. Long-term seizure outcomes following epilepsy sur gery: a systematic review and meta-analysis . Brain 2005 ; 128 : 1188 \200\223 98 . 13. Van Ness PC . Surgical outcome for neocortical (extrahippocampal) focal epilepsy . In: L ders H (ed) Epilepsy surgery , pp. 337 \200\223 47 . New York : Raven Press , 1992 . 28. Jeha LE , Najm I , Bingaman W , Dinner D , Widdess-Walsh P , Luders H. Surgical outcome and prognostic factors of frontal lobe epilepsy surgery . Brain 2007 ; 130 : 574 \200\223 84 . 14. Zentner J , Hufnagel A , Ostertun B , Wolf HK , Behrens E , Campos MG , et al . Surgica l treatment of extratemporal epilepsy: clinical, radiologic, and histopathologic \201 ndi ngs in 60 patients . Epilepsia 1996 ; 37 : 1072 \200\223 80 . 29. Behrens E , Schramm J , Zentner J , Konig R. Surgical and neurological 15. Pasquier B , Bost F , Peoc \200\231h M , Barnoud R , Pasquier D . Neuro- complications in a series of 708 epilepsy surgery procedures . Neurosurgery 1997 ; 41 : 1 \200\223 9 . pathologic data in drug-resistant partial epilepsy. Report of a series of 195 cases . Ann P athol 1996 ; 16 : 174 \200\223 81 . 30. Chassoux F , Rodrigo S , Semah F , Beuvon F , Landre E , Devaux B , et al. FDG-PET impr oves surgical outcome in MRI negative Taylor-type focal cortical dysplasia . Neurology 2010 ; 75 ( 24 ): 2168 \200\223 75 . 16. Wolf HK , Zentner J , Hufnagel A , Campos MG , Schramm J , Elger CE , et al . Surgical pathology of chronic epileptic seizure disorders: experience with 63 speci mens from extratemporal corticectomies, This page intentionally left blank CHAPTER 30 Vagal Nerve Stimulation and Deep Brain Stimulation in Epilepsy Paul A. J. M. Boon and Krist l E. Vonck Introduction Although neurostimulation is not a new treatment modality, it is emerging for medical treatment-resistant neuropsychiatric disor- ders. Currently about 30 % of patients with epilepsy are not seizure- free with the available pharmacological and surgical treatme nts (1). Electrical stimulation of the 10th cranial nerve or vagus nerve stimulation (VNS) is an extracranial type of stimulation that is cur- rently routinely available. Through an implanted device and elec- trode, electrical pulses are administered to the afferent \201 bres of the left vagus nerve in the neck. VNS is indicated in patients with refrac- tory e pilepsy who are unsuitable candidates for epilepsy surgery or who have had insuf \201 cien t bene \201 t from such a treatment (2). and gastrointestinal tract and of approximately 20 % efferent \201 bres that provide para sympathetic innervation of these structures and also innervate the voluntary striated muscl es of the larynx and the pharynx (8 \200\22310). Afferent \201 bres that are targeted for therapeutic VNS, have their origin in the nodose ganglion and primarily project to the nuc leus of the solitary tract. At the cervical level the vagus nerve mainly consists of small diameter unmyelinated C- \201 bres (65 \200\22380 % ) and of a smaller portion of intermed iate-diameter mye- linated B-fibers and large-diameter myelinated A-fibers. The nucleus of the solitary tract connects to other brainstem nuclei and has widespread projections to num erous areas in the forebrain including important areas for epilepsy such as the amygdala an d the thalamus. Fig. 30.1 shows the main anatomical and functional connections of the vagus nerve in the central nervous system. The diffuse pathways of the vagus nerve mediate impor tant visceral re \202 exes such as coughing, vomiting, swallowing, control of blood pressu re, and heart rate (which is mostly in \202 uenced by the right vagus nerve) (11). Intracerebral neurostimulation requires access to the intracra- nial nervous system for the insertion of stimulation electrodes into speci \201 c targets for \200\230deep brain sti mulation \200\231 (DBS) or placement over the cortical convexity for \200\230cortical stim ulation \200\231 (CS). Recently trials with DBS in various intracerebral structures such as the tha- lamus, the subthalamic nucleus, the caudate nucleus, and medial temporal lobe str uctures have been performed (3 \200\2236). CS in a closed loop system (responsive neurostim ulator system, RNS) has recently been investigated in a multicentre trial (7). It seems lik ely that neu- rostimulation for epilepsy will become a more practical and more frequently u sed treatment modality for patients with refractory epilepsy. Following a limited number of animal experiments in dogs and monkeys, investigating safety and ef \201 cacy, the \201 rst human trial was performed (12). To date, the precise mech anism of action of VNS and how it suppresses seizures remains to be elucidated. Research directed towards the identi \201 cation of involved \201 bres, intracranial str uctures, and neurotransmitter systems has been performed. Animal experiments and research i n humans treated with VNS have comprised electrophysiological studies (electroen- cephalogr aphy (EEG), electromyography, electrophysiology), functional anatomical brain imaging studi es (positron emission tomography, single-positron emission computed tomography, functional magnetic resonance imaging, c-fos, densitometry), neu- ropsychological, and behavioral stud ies. Also from the extensive clinical experience with VNS interesting clues concerning the mechanism of action of VNS have arisen. More recently the role of the vagus nerve in the im mune system has been investigated. Vagus nerve stimulation Electrical stimulation of the 10th cranial nerve or VNS has become a valuable treatment option for patients with refractory epilepsy and it is currently routi nely available in epilepsy centers worldwide. Through an implanted device and electrode, el ectrical pulses are administered to the afferent \201 bres of the left vagus nerve in the neck. It is indicated in patients with refractory epilepsy who are unsuitable candidates f or epilepsy surgery or who have had insuf- \201 cient bene \201 t from such a treatment (2). From the extensive body of research on the mechanism of action, it has become conceivable t hat effective stimulation in humans is pri- marily mediated by afferent vagal A- and B- \201 bres (13, 14). Unilateral stimulation influences both cerebral hemispheres, as shown i n several functional imaging studies (15, 16). Crucial brainstem and Anatomical basis and mechanism of action The vagus nerve is a mixed cranial nerve that cons ists of approxi- mately 80 % afferent \201 bres originating from the heart, aorta, lungs, oxford textbook of epilepsy and epileptic seizures 318 Brain hemispheres Brainstem Insular cortex Cerebellum Forebrain Amygdala Thalamus Vermis and inferior cerebellum Parabranchial nucleus Locus coeruleus Hypothalamus + \200\223 R a p h e NTS bilateral input n u c l e i Skull basis Reticular formation area posterma DMN, nucleus ambiguus Jugular nad nodose ganglion Fig. 30.1 Anatomical and functional connections in the central nervous system of the vagus nerve. Clinical ef \201 cacy The \201 rst descriptions of the implantable VNS Therapy TM system for electrical stimulation of the vagus nerve for epilepsy in humans appeared in the liter ature in the early 1990s (23, 24). At the same time initial results from two single-blinded pilot clinical trials (phase-1 trials EO1 and EO2) in a small group of patients with refra ctory complex partial seizures who were implanted since November 1988 in three epilepsy cen ters in the US were reported (12, 25 \200\22327). In nine out of 14 patients, treated for 3 \200\22322 months a reduction in seizure frequency of at least 50 % was observed (24). Com plex partial seizures, simple partial seizures, as well as second- ary generalized seizures were affected (25). It was noticed that a reduction in frequency, duration, and intensity of seizures lagged 4 \200\2238 weeks after the initiation of treatment (12). In the meantim e, two prospective multicentre (n = 17) double-blind randomized studies (EO3 and EO5) were started including patients from cen- tres in the US (n = 12), Canada (n = 1), as well as in Europe (n = 4) (28 \200\22332). In these two studies patients over the age of 12 with par- tial seizures were randomized 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 s, 30 s on, 5 min off) were those believed to be ef \201 cacious based on animal data and the initial hu man pilot studies. Because patients can sense stimulation, the LOW stimulation parameters ( output: single increase to point of patient perception, no further increase, 1 Hz, 130 s, 30 s on, 3 hours off) were chosen to provide some sensation to the patient in order to pro tect the blinding of the study. LOW stimulation param- eters were believed to be less ef \201 cacious and the patients in this group represented an active control group. The result s of EO3 in 113 patients showed a decrease in seizures of 24 % in the HIGH stimulation grou p versus 6 % in the LOW stimulation group after 3 months of treatment (29 \200\22331). The number of patients was insuf- \201 cient to achieve Food and Drug Administration (FDA) ap proval leading to the EO5 study in the US including 198 patients. intracranial structures have been identi \201 ed and include the locus coeruleus, the nucl eus of the solitary tract, the thalamus, and limbic structures (17 \200\22319). Neurotransm itters playing a role may involve the major inhibitory neurotransmitter gamma-aminobutyric acid but also serotoninergic and adrenergic systems (20). Recent microdi- alysis experiment s in pilocarpine-induced limbic seizures from our own group suggest that increased hippocam pal noradrenaline may be a biomarker for the ef \201 cacy of VNS (Fig. 30.2 ) (21). An ext en- sive overview on the mechanism of action of vagus nerve stimula- tion can be found in V onck et al. (22). 14 12 ) S S S T ( 10 8 y t i r e v e s R2=0.81; p < 0.01 6 e r u z i e S 4 2 0 \210\22225 \210\22250 25 50 75 100 125 150 175 0 Increase of NAD conc (%) Fig. 30.2 VNS induces increases of noradrenaline in the hippocampus; the increase in noradr enaline is linearly related to the seizure suppressing effect of VNS; TSSS, total seizure s everity score. Reproduced with permission from J Neurochem 117(3). Raedt R, Clinckers R, Mo llet L, et al., Increased hippocampal noradrenaline is a biomarker for ef \201 cacy of vag us nerve stimulation in a limbic seizure model, 461 \200\2239. Copyright (2011), with permi ssion from Wiley. CHAPTER 30 vagal nerve stimulation and deep brain stimulation in epilepsy 319 43 % after a follow-up of at least 12 months (54). Ben-Menachem et al. included nine patien ts with generalized seizures in a prospective long-term follow-up study. Especially the pat ients with absence epilepsy had a signi \201 cant seizure reduction (38). Ninety-four patients in the HIGH stimulation group had a 28 % decrease in seizure frequency versus 15 % in patients in the LOW stimulation group (32). The controlled EO3 and EO5 studies had their primary ef \201 cacy end-point after 12 weeks of VNS. In all published reports on long- term results increased ef \201 cacy with longer treatment was found (33 \200\22337). The mean reduction in seizure frequency increased up to 35 % at 1 year and up to 44 % at 2 years of follow-up. After that improved seizure contr ol reached a plateau (36). A few studies are available speci \201 cally describing the use of VNS in patients diagnos ed with Lennox \200\223Gastaut syndrome (LGS). One prospective study in 16 patients with LG S found that one-fourth of patients had a more than 50 % reduction in seizure frequency aft er 6 months of follow-up which is comparable to the response rates in the controlled studie s, that included few patients with LGS (55). Other prospective studies reported higher resp onder rates with a more than 50 % seizure frequency reduction in half of the patients (n = 13, follow-up = 6 months) (56), in six of seven patients (follow-up = 6 months) (57) and in seven of nine patients (follow-up = 1 \200\22335 months) (58). A retrospective multicentre study in 46 patients with LGS reported responder rates of 43 % (59). In the following years, other large prospective clinical trials were conducted in different epilepsy centers worldwide. In Sweden, long-term follow-up in the largest patient series ( n = 67) in one center not belonging to the sponsored clinical trials at that time, reported similar ef \201 cacy rates with a mean decrease in seizure fre- quency of 44 % in patient s treated up to 5 years (38). A joint study of two epilepsy centers in Belgium and the US i ncluded 118 patients with a minimum follow-up duration of 6 months. They found a mean reduc tion in monthly seizure frequency of 55 % (39). Only in a small minority of patients (7 % ) long-term seizure freedom was achieved. In China, a mean seizure reduction of 40 % was fou nd in 13 patients after 18 months of VNS (40). From a clinical point of view, prospective r andomized trials investigating long-term ef \201 - cacy in comparison to other therapeutic options for patients with refractory epilepsy are still lacking. A multicentre randomized trial called PulSE failed to recruit enough patients and was arrested pre- maturely. On the basis of currently available data the responder rate in patients treated with VNS is not s ubstantially higher com- pared to recently marketed antiepileptic drugs (AEDs). There have been many reports on various other seizure types and syndromes such as seizures in patients with hypothalamic hamar- tomas (60), tuberous sclerosis (61, 62), progressive m yoclonic epi- lepsy (63, 64), Landau \200\223Kleffner syndrome (65), Asperger syndrome (66) , epileptic encephalopathies (76), and syndromes with devel- opmental disability and mental retardation (67 \200\22370) and infantile spasms (71). All these studies reported limited to reasonable ef \201 - cacy with regard to controlling seizures as well as other disease- related symptoms such as cerebellar dysfunction, behavioral and mood disturbances. A recen t report on the ef \201 cacy of VNS in \201 ve children with mitochondrial electron tran sportation chain de \201 ciencies described no signi \201 cant seizure reduction in any o f the children (72). Also a study in patients with previous resective epilepsy surgery show ed a limited seizure suppressing effect of VNS (73) although another report described impro ved seizure control in this speci \201 c patient group (74). Children There are no controlled studies of VNS in children, but many epi- lepsy centers ha ve reported safety and ef \201 cacy results in patients less than 18 years of age in a pro spective way. All these studies report similar ef \201 cacy and safety pro \201 les compa red to \201 ndings in adults (41 \200\22344). Rare adverse events, unique to this age gro up, included drooling and increased hyperactivity (45). In children with epileptic encephal opathies ef \201 cacy may become evident only after more than 12 months of treatment (46). A recent Korean multicentre study evaluated long-term ef \201 cacy in 28 children with in tractable epilepsy. In half of the children there was a greater than 50 % seizure reduction after a follow-up of at least 12 months (47). In our own prospective analysis of 118 patie nts, 13 children with a mean age of 12 years (range: 4 \200\22317 years) were included with similar ef \201 cacy rates and without speci \201 c side effects (39). Safety, side effects, and tolerability The most prominent and consistent sensation in patie nts when the vagus nerve is stimulated for the \201 rst time, even at low output current levels, is a tingling sensation in the throat and hoarseness of the voice due to secondary stimulation of the superior laryngeal nerve (75 \200\22377). With regard to side effects re lated to stimulation of vagal effer- ents, effect on heart rate and gastrointestinal digest ion are of major concern. Stimulation of the efferent \201 bres may induce bradycardia an d hypersecretion of gastric acid. The stimulation electrode is always implanted on the left vagus nerve, which is believed to con- tain fewer sinoatrial \201 bres than the right. I t has been suggested that the electrode is implanted below the superior cardiac branch of t he vagus nerve. No systematic side effects on heart functioning or other internal organ or cerebral functions were found. There was no effect on AED serum levels (12, 78). Elderly A study of Sirven et al. included 45 patients who were 50 years of age and older. T hirty-one of 45 patients had a follow-up of 1 year, with a reported responder rate of 68 % , good tolerance, and improvement of quality of life scores (48). In the long-term extension trials, the most frequent side effects were hoarseness in 19 % o f patients and coughing in 5 % of patients at 2 years follow-up; shortness of breath in 3 % of patients at 3 years (36). There was a clear trend towards diminishing side effects over the 3-year stimulation period. Ninety-eight per cent of the symp- toms were rated mild or moderate by the patients and the investi- gators (78). Side effects can usually be resolved by decreasing stimulation parameters. Central nervous system side effects typi- cally seen with AEDs were not reported. After 3 years of treatment, 72 % of the patients were still o n the treatment (36). The most frequent reason for discontinuation was lack of ef \201 cac y. Seizure types and syndromes The open label, longitudinal, multicentre EO4 study also includ ed patients with generalized epilepsy (n = 24) (49, 50). In these patients overall seizure frequency reduction was 46 % . Quintana et al. (51), Michael et al. (52), and Kostov et al. (53) described in a retrospective way that primary generalized seizures and general- ized epilepsy syndromes responded equally well to VNS compared to partial epilepsy syndromes. A prospective study of Holmes et al. in 16 patients with generalized epilepsy syndromes and s table AED regimens showed an overall mean seizure frequency reduction of 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