Epilepsia, 48(8):1551–1560, 2007 Blackwell Publishing, Inc. C 2007 International League Against

Deep Stimulation in Patients with Refractory

∗ ∗ ∗ ∗ ∗ ∗ Paul Boon, Kristl Vonck, Veerle De Herdt, Annelies Van Dycke, Maarten Goethals, Lut ∗ ∗ ∗ Goossens, Michel Van Zandijcke, TimDeSmedt, Isabelle Dewaele, †Rik Achten, ‡Wytse Wadman, §Frank Dewaele, §Jacques Caemaert, and §Dirk Van Roost

∗ Reference Center for Refractory Epilepsy (RCRE) and Laboratory for Clinical and Experimental Neurophysiology (LCEN), and †Department of ; Department of Radiology and Medical Imaging, Ghent University Hospital, Ghent, Belgium; ‡Swammerdam Institute for Life , Amsterdam University, Amsterdam, The ; and §Department of , Ghent University Hospital, Ghent, Belgium

Summary: Purpose: This pilot study prospectively evaluated patients had a seizure-frequency reduction of ≥50%; two of 10 the efficacy of long-term deep brain stimulation (DBS) in medial patients had a seizure-frequency reduction of 30–49%; and one temporal lobe (MTL) structures in patients with MTL epilepsy. of 10 patients was a nonresponder. None of the patients reported Methods: Twelve consecutive patients with refractory MTL side effects. In one patient, MRI showed asymptomatic intracra- epilepsy were included in this study. The protocol included in- nial hemorrhages along the trajectory of the DBS electrodes. vasive video-EEG monitoring for ictal-onset localization and None of the patients showed changes in clinical neurological evaluation for subsequent stimulation of the ictal-onset zone. testing. Patients who underwent selective amygdalohippocam- Side effects and changes in seizure frequency were carefully pectomy are seizure-free (>1 year), AEDs are unchanged, and monitored. no side effects have occurred. Results: Tenof12patients underwent long-term MTL DBS. Conclusions: This open pilot study demonstrates the poten- Twoof12patients underwent selective amygdalohippocampec- tial efficacy of long-term DBS in MTL structures that should tomy. After mean follow-up of 31 months (range, 12–52 months), now be further confirmed by multicenter randomized controlled one of 10 stimulated patients are seizure free (>1 year), one of 10 trials. KeyWords: Refractory epilepsy—— patients had a >90% reduction in seizure frequency; five of 10 Deep brain stimulation—Temporal lobe.

Epilepsy is the second most common chronic neuro- is another option that leads to long-term seizure freedom logic disease after cerebrovascular disorders, affecting in an average of 58% of the patients, depending on the 0.5–1% of the population (Hauser et al., 1993). More than localization of the seizure focus (Engel et al., 2003; Lee 30% of all epilepsy patients have uncontrolled seizures or et al., 2005). For the remainder of patients, few options are unacceptable medication-related side effects despite ade- left. Neurostimulation, defined as direct administration of quate pharmacologic treatment (Kwan and Brodie, 2000). electrical pulses to nervous tissue to modulate a patho- Refractory epilepsy increases the risk of cognitive deterio- logic substrate and to achieve a therapeutic effect may be ration and psychosocial dysfunction and is associated with such an alternative. Which part of the is excess injury and mortality (Brodie and Dichter, 1996). being targeted and how the stimulation is being admin- Therapeutic options that can be offered to patients with istered may be variable. (VNS) refractory epilepsy include trials with newly developed is an extracranial form of stimulation that was developed antiepileptic drugs (AEDs), resulting in seizure freedom in the 1980s and is now routinely available in epilepsy in ∼7% of these patients (Fisher, 1993). Epilepsy surgery centers worldwide (Ben Menachem, 2002). Deep brain stimulation (DBS) has previously been used for move- Accepted December 3, 2006. ment disorders and (Nguyen et al., 2000; Pollak Address correspondence and reprint requests to Dr. P. Boon at Ref- et al., 2002; Volkmann et al., 2004). Moreover, several erence Center for Refractory Epilepsy (RCRE), Laboratory for Clinical new indications such as obsessive–compulsive behavior and Experimental Neurophysiology (LCEN), Department of Neurology, Ghent University Hospital, De Pintelaan 185, B-9000 Gent, Belgium. and different headache syndromes are being investigated E-mail: [email protected] with promising results (Nuttin et al., 1990; Leone et al., doi: 10.1111/j.1528-1167.2007.01005.x 2003, 2005). In the past, DBS of various targets such as

1551 1552 P. BOON ET AL. the cerebellum, the locus coeruleus, and the was fluorodeoxyglucose-positron emission tomography, and performed in patients with or psychiatric dis- comprehensive neuropsychological assessment, accord- orders who also had epilepsy, but the technique was not ing to international standards (EFNS task force, 2000). fully explored or developed into an efficacious treatment Twelve patients with medically refractory epilepsy were option for patients with epilepsy (Cooper, 1978; Wright et included in the study (Fig. 1). Inclusion criteria consisted al., 1984; Upton et al., 1985; Feinstein et al., 1989). The of (a) suspicion of temporal lobe epilepsy on the basis of vast progress in biotechnology along with the experience video-EEG monitoring; (b) seizure frequency of at least in other neurologic diseases in the past decade, has led to a one complex partial seizure (CPS) per month, confirmed renewed interest in DBS for epilepsy. A few epilepsy cen- during a prospective preintervention baseline period of ters worldwide have recently initiated trials with DBS in 6 months; and (c) requirement for invasive video-EEG different intracerebral structures such as the thalamus, the monitoring in the bilateral MTL area and other subdural , the caudate nucleus, and the cerebel- brain areas because of incongruent findings during nonin- lum (Fisher et al., 1992; Velasco et al., 1995; Chkhenkeli vasive presurgical evaluations to localize the seizure onset. and Chkhenkeli, 1992; Chabardes et al., 2002; Hodaie et During the preintervention baseline period, all patients al., 2002; Velasco et al., 2005). Two major stimulation were receiving a stable combination of two or strategies can be pursued. more AEDs. One approach is to target crucial central nervous sys- Surgical procedure tem structures that are considered to have a “pacemaker,” During an MRI-guided stereotactic procedure un- “triggering,” or “gating” role in the epileptogenic net- der general anesthesia, two quadripolar DBS electrodes work, such as the thalamus or the subthalamic nucleus (model 3387; Medtronic, Fridley, MN, U.S.A.) were im- (Iadarole and Gale, 1982). At Ghent University Hospital, planted in each hemisphere through two parietooccipital the approach chosen was to evaluate potential interfer- burrholes. Details of this procedure in our center were ence with the ictal-onset zone. In medial temporal lobe published previously (Vonck et al., 2002). The most an- (MTL) epilepsy, the epileptogenic region is believed to be terior electrode on each side was placed in the amyg- in the medial temporal lobe, as documented by the gold- dala. The second electrode was placed in the anterior standard investigation using intracranial electrodes (King part of the on each side. The trajectory and Spencer, 1995). It is also supported by the high num- of the second electrode had a small angle with the first ber of seizure-free patients after resection of this region one. Each electrode has four cylindrical electrode con- (Engel, 1993). On the one hand, investigating the potential tacts of 1-mm diameter, 1.5-mm length, and an intercon- efficacy of DBS in patients with MTL epilepsy is inspired tact distance of 1.5 mm. On each electrode, the four elec- by the search for less-invasive procedures compared with trode contacts cover a total length of 10.5 mm. In all tissue resection. On the other hand, it fits in the search for patients, additional subdural grids and/or strips in var- alternative treatments for unsuitable candidates for resec- ious combinations were placed on the temporal and/or tive surgery, such as patients with bilateral MTL epilepsy. frontal neocortex, depending on the results of the presur- Patients scheduled for invasive recordings because of gical evaluation during a procedure under general anes- discrepant findings on noninvasive presurgical evaluation thesia. Patients were allowed to recover in the neuro- must undergo an implantation procedure and were con- surgical unit for a period of 48 h. Subsequently all in- sidered to represent ideal candidates for the evaluation of tracranial electrode contacts and 27 scalp-EEG electrodes MTL DBS that can be performed by using the electrodes were connected with the video-EEG monitoring system implanted for diagnostic reasons. (128-channel digital video-EEG, Beehive; Astromed- Preliminary findings in three patients studied in our Grass-Telefactor, West Warwick, RI, U.S.A.). The precise group were reported previously (Vonck et al., 2002). location of the intracranial electrode contacts was assessed by performing MRI by using an MPRAGE sequence. PATIENTS AND METHODS Recording and stimulation paradigm Patient selection After 48 h of video-EEG monitoring, during which The study protocol and the informed-consent docu- AEDs remained unchanged, AEDs were gradually tapered ments were approved by the Ethics Committee of Ghent until habitual seizures were recorded (AED tapering con- University Hospital. Patients with refractory epilepsy dition). The finding of a unilateral or bilateral focal or were enrolled in a presurgical evaluation protocol at regional MTL ictal onset was the criterion for offering the Reference Center for Refractory Epilepsy at Ghent patients the choice to undergo continuous MTL DBS. Pa- University Hospital, a tertiary neurological referral cen- tients with unilateral MTL seizure onset were stimulated ter in Belgium. The presurgical protocol was published by using the ipsilateral amygdalar and hippocampal DBS previously and includes video-EEG monitoring, opti- electrodes. In patients with bilateral MTL onset, bilateral mum 1.5- or 3-T magnetic resonance imaging (MRI), hippocampal stimulation was performed.

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Initial DBS was performed by using a temporary exter- were reconnected with the video-EEG monitoring equip- nal pulse generator (DualScreen 3628; Medtronic) during ment for recording of EEG activity in the stimulated area a trial period (acute stimulation condition) before implant- during the remaining 23 h of the day. Epileptiform dis- ing patients with an internalized pulse generator. At any charges were visually identified and manually counted time during the study, patients could make the choice of during four consecutive intervals of 15 min/day. The pe- interrupting the ongoing stimulation treatment and under- riod of spike counting was ≥6 hours remote from the oc- going resective surgery, when indicated. Immediately be- currence of seizures. To assess acute side effects, clinical fore the acute stimulation condition, subdural grids and neurologic examination and bedside neuropsychological strips were removed. The aim was to keep patients on testing (including reading, naming, and memory testing) the tapered AED regimen. In case of an acute increase in were performed daily during the acute stimulation condi- seizure frequency, reinstallation of AEDs at the baseline tion. Formal neuropsychological assessment was planned dosage and/or administration of escape medication was after 12 months in all patients. A detailed account of neu- planned. To determine the output voltage level for initiat- ropsychological outcome data is the object of a separate ing DBS, we connected the hippocampal electrode to the study. EEG recording system, whereas the amygdalar electrode When a >50% reduction of interictal spikes was not was connected to an external generator. We then gradually achieved within 21 days, the study protocol allowed a increased output voltage until a stimulation artifact was prolonged acute-stimulation condition. This consisted of observed on the hippocampal electrode. We performed a trial with an adjusted stimulation frequency of 200 Hz. this action to confirm that stimulation was actually per- When, after a prolonged acute-stimulation phase of an- formed when the electrodes were connected to the gener- other 3 weeks, a >50% reduction of interictal spikes was ator. When a stimulation artifact occurred on the adjacent not achieved during 7 consecutive days, patients were of- electrode, the output voltage was decreased with 0.1 to fered resective surgery when indicated or a continuation 0.2 V, which eliminated the stimulation artifact and was of best medical therapy. determined to be subthreshold. Once amygdalar stimu- When patients entered the prolonged-stimulation con- lation output was determined, the hippocampal electrode dition, the implantable pulse generator was placed in contacts were stimulated by using the same output. The an abdominal subcutaneous pouch. The Kinetra device frequency for both the amygdalar and hippocampal elec- was connected to two DBS electrodes through two ex- trodes was set to 130 Hz, and pulse width, to 450 µs, based tension wires. This required a short surgical proce- on earlier experience with DBS in the medial temporal dure under general anesthesia. After this surgical pro- lobe by Velasco et al. (2001). Pairs of adjacent electrode cedure, patients were followed up in the epilepsy clinic contacts on both DBS electrodes were continuously stim- at regular 2-week intervals. Similar to the short-term ulated in a bipolar way with the most anterior electrode stimulation condition, the aim was to keep patients on contact and the third electrode contact serving as cathodes. the tapered-AED regimen throughout the prolonged- Individual pulses consisted of biphasic square-wave Lilly stimulation condition. In case of an acute increase in pulses. seizure frequency, reinstallation of AEDs at the baseline For patients with unilateral MTL seizure onset, this ac- dosage and/or administration of escape medication was tion was performed ipsilateral to the side of seizure onset. allowed. In patients with bilateral MTL seizure onset, this action After 12 months of long-term DBS, the AED regi- was performed bilaterally only for the hippocampal DBS men could be changed according to best medical practice. electrodes. Gradual increase of stimulation output current in patients To obtain an objective and comparable efficacy param- who were not seizure free was allowed. eter during the acute stimulation condition, interictal spike activity in the stimulated area was evaluated. The criterion Data analysis for implantation of a pulse generator (Kinetra, Medtronic) The present study is a comparative pre–post test, and entering the chronic stimulation condition was the prospective, open pilot trial of efficacy and safety of unilat- finding of a reduction of interictal spikes in the stimulated eral DBS in the MTL. During the entire study period from area of >50% during 7 consecutive days in the acute stim- the prospective 6 month preintervention baseline period ulation condition compared with the AED-tapering condi- over the prospective AED tapering condition and short- tion. The rationale for comparing spike counts during the term stimulation condition to the prolonged-stimulation AED-tapering condition and the acute stimulation con- condition, seizure frequency, adverse events, and con- dition was that the initiation of stimulation was the only comitant AED use were carefully monitored by using a intervention that differentiated these two conditions from seizure diary. Mean spike counts per hour during the short- each other. DBS was interrupted every morning at about term stimulation condition were compared with mean the same time for a 1-h period during quiet wakefulness, spike counts per hour during the entire AED-tapering typically from 10 am to 11 am. The DBS electrodes condition. Frequency of CPS ± secondary generalization

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(SG) during the prolonged-stimulation condition was Invasive video-EEG monitoring yielded long-term inter- compared with the mean monthly frequency of such ictal EEG recordings, habitual seizures, and ictal EEG seizures during 6 months before DBS. Postintervention recordings in all patients within a time period of 5 to seizure outcome was assessed during the last 6 months 12 days. of follow-up and categorized into the following groups: Table 1 describes invasive video-EEG monitoring re- seizure-free; >90% seizure reduction; ≥50% seizure re- sults. In all patients, unilateral or bilateral interictal spikes duction; 30–49% seizure reduction; and <30% seizure were recorded from the MTL electrodes. Focal EEG ic- reduction (nonresponder). tal onset, involving one or more electrode contacts on a single DBS electrode, was identified in six of 12 patients, typically consisting of a low-voltage, high-frequency dis- RESULTS charge in the hippocampal electrode contacts on one side, All patients included in this study were candidates for occurring seconds before clinical seizure onset and fol- invasive EEG recording because of the absence of any lowed by spread to ipsilateral neocortical areas and the structural abnormalities and/or incongruent results in the contralateral MTL structures. In five of 12 patients, in- noninvasive presurgical evaluation. Table 1 shows the pa- tracranial ictal EEG onset was “regional,” referring to a tients’ individual neuroimaging results. In eight of 12 pa- more widespread distribution of early changes involving tients, optimal MRI showed no structural abnormalities; more electrode contacts on different electrodes. The re- in two patients, unilateral MTL signal abnormalities and gional ictal onset was unilateral in all patients, but in pa- some degree of atrophy were found; in one patient, MTL tient 4, spreading to the contralateral medial structures atrophy was associated with anterior temporal and neocor- occurred within a few seconds. In one patient, bilateral tical temporal gliosis; and in one patient, bilateral subcor- MTL onset was found, with five seizures originating from tical white matter lesions in the parietal lobe were found. the left temporal lobe and one from the right temporal The stereotactic implantation procedure of DBS elec- lobe. trodes was uneventful in 11 of 12 patients. In pa- Subsequently, 11 of 12 patients entered the acute- tient 11, asymptomatic hemorrhages occurred along the stimulation condition. One patient with unilateral right trajectory of the depth electrodes. This bleeding was focal ictal onset chose to undergo resective surgery imme- discovered when a routine MRI was performed for diately. During the acute stimulation condition, continu- postoperative localization of the invasive electrodes. ous bipolar 130-Hz stimulation ipsilateral to the ictal onset Postoperative MRI imaging for electrode localization was delivered to the amygdalar and hippocampal electrode confirmed localization of one DBS electrode in the contacts in 10 of 11 patients. The patient with bilateral in- amygdala and one DBS electrode in the anterior hip- dependent seizure onset was stimulated bilaterally with the pocampus in each hemisphere in all patients (Fig. 2). same stimulation parameters in the hippocampus. Ten of

TABLE 1. Results of neuroimaging, invasive video-EEG monitoring, and consequent therapeutic intervention

Ictal onset Short-term Long-term Patient MRI (invasive video- stimulation stimulation Resective number results EEG recording) phase phase surgery

1 Normal L focal T L AH L AH — 2 Normal R regional T R AH R AH — 3 Normal R regional T RAH R AH — 4 Normal L regional T with LAH LAH — early right-sided involvement 5LHippocampal and Lregional T L AH L AH — anterior and neocortical T gliosis 6 Normal L focal T L AH L AH — 7 Normal L focal T L AH — L SAH 8LHS L focal T L AH L AH — 9 Normal B T B H B H — 10 Normal R regional T R AH R AH — 11 B P WML L focal T L AH L AH — 12 R HS R focal T — — R SAH

MRI, magnetic resonance imaging; L, left; T, temporal; AH, amygdalohippocampal; R, right; SAH, selective amygdaohippocampectomy; TL, temporal lobectomy; HS, hippocampal sclerosis; B, bilateral; P, parietal; WML, white matter lesions.

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FIG. 1. Overview of different phases of the study and the inclusion criteria at different stages of the study.

11 patients showed a >50% reduction in interictal spikes of follow-up was compared with a preintervention base- in 1-h recording sessions on 7 consecutive days. In patient line period, one of 10 patients was seizure free (for ≥12 7, interictal spike frequency remained unchanged after a months); one in 10 patients had >90% reduction of seizure short-term stimulation condition of 6 weeks and despite an frequency; five of 10 patients had a reduction of seizure increase of stimulation frequency from 130 to 200 Hz af- frequency of ≥50%; two of 10 patients had a reduction of ter 3 weeks. This patient underwent temporal lobectomy. seizure frequency of 30–49%; and one of 10 patients had Table 1 provides an overview of therapeutic interventions a <30% seizure frequency reduction and was considered in each patient. a nonresponder. Both patients who underwent resective The other 10 patients entered the long-term stimula- surgery have been seizure free for ≥12 months. Table 2 tion condition and had a generator implanted. At maxi- provides an overview of seizure-frequency reduction per mal follow-up, mean stimulation output current was 2.3 patient. V (range, 2–3 V); stimulation frequency was 130 Hz in Changes in AEDs and increase in output current were all but one patient, who was stimulated at 200 Hz. Pulse allowed after 12 months of DBS. In none of the patients width remained unchanged to 450 µsinall patients. Mean did this further affect seizure frequency. Table 3 shows follow-up was 31 months (range, 12–52 months). When seizure frequency at maximal follow-up and a summary mean monthly seizure frequency during the last 6 months of changes in AEDs and output current.

TABLE 2. Follow-up duration, results of changes in seizure frequency, and side effects per patient

Patient Mean monthly Mean monthly Seizure- number seizure frequency seizure frequency frequency (type of FU before DBS or RS after DBS or RS reduction Side therapy) (mo) CPSs/GTCs/SPSs CPSs/GTCs/SPSs (%) effects

1 (DBS) 52 30/4/20 1 per yr/0/0.5 >90 None 2 (DBS) 47 20/0/0 15/0/0 30–49 None 3 (DBS) 44 4/0/0 4/0/0 <30 None 4 (DBS) 40 8/2/30 4/1/15 ≥50 None 5 (DBS) 37 12/0/0 5/0/0 ≥50 None 6 (DBS) 33 30/0/0 5 (only nightly)/0/0 ≥50 None 7 (RS) 26 4/0/0 0/0/0 100 None 8 (DBS) 26 8/0/0 0/0/0 100 None 9 (DBS) 20 10/0/0 7/0/0 30–49 None 10 (DBS) 19 2/0/0 0.5/0/0 ≥50 None 11 (DBS) 15 2/2/0 0.5/0.5/0 ≥50 Asymptomatic hemorrhages along trajectory of depth electrodes 12 (RS) 12 6/0/0 0/0/0 100 None

FU, follow-up; DBS, deep-brain stimulation; RS, resective surgery; CPSs, complex partial seizures; GTCs, generalized tonic–clonic seizures; SPSs, simple partial seizures.

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TABLE 3. Overview of changes in AED treatment and changes in output current after 1 year of DBS Output Output current current Patient AED treatment AED during first 12 mo during at number before DBS or RS of DBS or RS first max (type of Changes after 12 mo 12 mo follow- therapy) Number AED Number AED of DBS or RS of DBS up

1 (DBS) 4 PHT, 300; CBZ, 1,000; 2 PHT, 300; CZP, 3 +LEV, 4,000, no effect 1.5 3 LTG, 100; CZP, 3 2 (DBS) 3 VPA, 1,000; LEV, 2VPA, 500; LEV,2,000 None 1 2 2,000; CLB, 10 3 (DBS) 3 PHT, 300; CBZ, 1,600; 2 PHT, 300; CBZ, 1,600 PB, 100, no effect 1 2 PRM, 375 4 (DBS) 3 CBZ, 1,200; GBP, 900; 2 CBZ, 1,200; PHT, 300 +PGB, 450, no effect 1.5 3 PHT, 300 5 (DBS) 3 CBZ, 1,000; LTG, 200; 1LTG, 450 +LEV, 2,000, no effect 1 2 VGB, 2,000 6 (DBS) 3 VPA, 1,600; GBP, 1VPA, 1,000 +LEV, 2,000, + PB, 50, 1.5 2 2,800; TGB, 10 no effect 7 (RS) 2 TPM, 600; OXC, 1,200 2 TPM, 350; OXC, ——— 1,200 8 (DBS) 3 VPA, 1,500; LTG, 400; 2LTG, 400; LEV,3,000 — 2.5 3 LEV, 3,000 9 (DBS) 3 CBZ, 800; VPA, 1,000; 1 CBZ, 800 +LTG, 150, no effect 1 2 CZP, 1 10 (DBS) 2 LTG, 400; TPM, 400 1 LTG, 300 +LEV, 2,000 +CZP, 1, 1.5 3 no effect 11 (DBS) 4 CBZ, 900; GBP, 1,200; 3 CBZ, 600; PHT, 450 CZP, 2, no effect 2 3 PHT, 300; LEV, 1,000 12 (RS) 2 CBZ, 800; CZP, 1.5 2 CBZ, 800; CZP, 1.5 — — —

AED, antiepileptic drug; DBS, deep-brain stimulation; RS, resective surgery; PHT, phenytoin; CBZ, carbamazepine; LTG, lamotrigine; CZP, clonazepam; LEV, levetiracetam; VPA, valproic acid; CLB, clobazam; PRM, primidone; PB, phenobarbital; GBP, gabapentin; PGB, pregabalin; VGB, vigabatrin; TGB, tiagabine; TPM, topiramate; OXC, oxcarbazepine.

During the short- and long-term stimulation condition, et al., 2003; Gleissner et al., 2004). Studies have shown none of the patients reported side effects. Surgical im- that TLE patients without hippocampal sclerosis have a plantation of the generator and perioperative course were greater risk for postoperative neuropsychological deficit. uneventful in all patients. None of the patients showed The removal of nonatrophic hippocampus is associated changes in bedside neurologic and neuropsychological with verbal memory decline in patients with left TLE. In testing. right temporal lobe patients, a decline in visual-spatial learning was observed postoperatively (Trenerry et al., DISCUSSION 1993; Stroup et al., 2003). Patients with bilateral ictal onset are unsuitable candi- The development of neurostimulation for neurological dates for epilepsy surgery. Patients showing widespread indications is driven by two major concerns related to stan- ictal onset have a less successful outcome after tempo- dard available treatments. First, a general tendency is to ral lobectomy. The recurrence rate of seizures after long- find treatments that are minimally invasive and minimally term seizure freedom after temporal lobectomy is ∼15% harmful to the patient. Second, the refractoriness of some (Keleman et al., 2006). Hence, epilepsy surgery is not an neurologic diseases and the inability to treat them with the option for all patients with refractory epilepsy; it may not currently available means provides an impetus to search cure patients in the long term; it is an irreversible proce- for novel treatments. dure, less successful for patients who have regional ictal MTL epilepsy is the most prevalent type of refractory onset or in patients with normal MRI; and a risk of post- partial epilepsy. In patients with MTL epilepsy, amyg- operative neurologic and/or neuropsychological deficits dalohippocampectomy or modified temporal lobectomy exists. This provides an impetus for further developing al- and hippocampectomy are standard procedures of choice, ternative treatment modalities such as neurostimulation. with postoperative long-term seizure-freedom rates of 60– 75%. However, several postoperative neuropsychological Strategy for a medial temporal lobe DBS pilot trial studies have shown verbal memory decline after resec- The choice of targeting the MTL region for a pilot trial tion, mainly in left-sided operation patients, despite suffi- in humans at Ghent University Hospital was based on sev- cient memory scores during the Wada test (Helmstaedter eral considerations. The MTL is a region that often shows

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Very limited data are available on the results of stim- ulating the ictal-onset zone itself, which is believed to consist of hyperexcitable cortex. To date, several studies have shown that DBS in MTL epilepsy has positive effects on interictal epileptiform discharges and seizures (Velasco et al., 2000; Wiebe et al., 2006). Our previously published preliminary study in three patients showed that MTL DBS in nonlesional patients leads to a significant decrease of the number of seizures and interictal epileptiform abnor- malities and is a safe treatment (Vonck et al., 2002). The present study describes a larger patient series, also including patients with structural abnormalities, who were selected for invasive video-EEG monitoring because of incongruent findings in the course of noninvasive presur- gical evaluation. Stimulation parameters The stimulation parameters that were used in the present study were based on the early experience reported by Ve- lasco et al. and by our group. The rationale for using high- frequency stimulation was that low-frequency stimulation induces EEG synchronization, whereas high frequency is associated with desynchronization, the latter condition be- ing more likely to have a therapeutic effect in epilepsy. The rationale for increasing the stimulation frequency from 130 Hz to 200 Hz was that Osorio and colleagues sug- gested better seizure control in some patients when stimu- lation frequency was increased (Osorio et al., 2001). Care- fully increasing the output current was thought to affect a larger volume of epileptic tissue, which could be useful in patients who were still having seizures after 1 year of FIG. 2. MRI image showing susceptibility artifacts of (A) left amyg- dalar electrode in a sagittal plane and (B) left amygdalar and hip- continuous DBS. Also because of safety concerns, out- pocampal electrode and right amygdalar electrode in a coronal put currents were kept below the values used in Parkin- plane in patient 2. son’s disease. Pulse width was set at 450 µs and kept unchanged throughout the study. A decrease to lower val- ues could be feasible and based on particular stimulation paradigms used by Osorio and colleagues and lower pulse- specific initial EEG epileptiform discharges as a reflec- width values applied in Parkinson’s disease. In the present tion of seizure onset in human MTL epilepsy (Spencer trial, continuous stimulation was used. Intermittent or on- et al., 1992). Basic research involving evoked potential demand stimulation may become an option when DBS can excitability studies in humans and anatomic studies with be linked to seizure anticipation and detection algorithms tracer injections and single-unit recordings with histologic in a closed-loop system (Le Van Quyen et al., 2001). It studies in animals have also confirmed the involvement of must be stressed that our basic assumptions with regard to the amygdala and the hippocampus in the epileptogenic stimulation parameters remain speculative, as only limited network (Wilson and Engel, 1993; Bragin et al., 2000; animal or human data are available on the effect of differ- Kemppainen et al., 2002). Some studies have applied elec- ent stimulation parameters applied to temporal lobe tissue. trical fields to in vitro hippocampal slices with positive ef- Systematic evaluation of different stimulation parameters fects on epileptic activity (Lian et al., 2003). Bragin et al. in experimental animal studies is urgently needed. When (2002) described repeated stimulation of the hippocampal more information becomes available on effective stimu- perforant path in rats showing spontaneous seizures 4–8 lation parameters, the implanted pulse generator in our months after kainate injection in the hippocampus. Dur- patients allows further adjustments in the future. ing perforant-path stimulation, spontaneous seizures were significantly reduced. In humans, preliminary studies on Efficacy of DBS in MTL region stimulation of hippocampal structures showed promising The efficacy results of the present study further cor- results on interictal epileptiform activity and seizure fre- roborate our previous findings that long-term DBS in the quency (Velasco et al., 2000). ictal-onset zone, as defined by invasive EEG recording,

Epilepsia, Vol. 48, No. 8, 2007 1558 P. BOON ET AL. significantly reduces seizures. Because of the open de- 1979). In 1969, Stevens et al. described a variety of both sign of our study, additional antiseizure effects of simply negative and positive emotional changes after stimulation implanting invasive electrodes cannot completely be ruled of the amygdala and, to a lesser degree, the hippocam- out (Boon and Vandekerckhove, 1996; Katariwala et al., pus in three patients who were bilaterally implanted with 2001). Some reports in the literature support the hypoth- amygdalar and hippocampal depth electrodes for a pe- esis that actual stimulation is not necessary to achieve riod of ≤7 months (Stevens et al., 1969). In our study, efficacy and claim that efficacy is based on the lesion in none of the patients were stimulation-related objective provoked by the insertion of the electrode (Hodaie et al., or subjective side effects found. Besides MRI, our safety 2002). This observation was described for electrode inser- data rely mainly on self-reported side effects and bedside tion in the anterior nucleus of the thalamus and referred neurologic and neuropsychological testing. Formal neu- to as “microthalamotomy.” Because in some epilepsy ropsychological testing to assess cognitive function after centers, an interval occurs between the invasive record- long-term stimulation has been performed, and results are ings and consequent resective procedures or because after the topic of a separate study (Vonck et al., 2004). The lack the results of invasive recordings, a resective procedure of side effects in MTL DBS patients is most likely due was not feasible, seizure frequency after the removal of to the use of different stimulation parameters. In previous the implanted electrodes was evaluated without immedi- studies, stimulation was often performed with the purpose ate further interventions (Katariwala et al., 2001). When of eliciting observable effects, performing functional map- the anterior nucleus is targeted, provoked lesions may be ping of human brain, or eliciting afterdischarges or seizure more easily effective in such a confined area compared onset in the course of a presurgical evaluation. In the latter with targets such as the MTL region. It is not impossible cases, stimulation frequencies usually ranged between 1 that in an individual patient, essential pathways could be and 60 Hz, and pulse width was often 1 ms, with relatively accidentally or coincidently lesioned during MTL target- high output currents. In our study, relatively low output ing. However, this seems an unlikely hypothesis in a series currents with high frequency (130–200 Hz) and medium of treated patients. pulse widths of 0.45 ms were used. In none of the patients In a SPECT study by Velascoet al. (2001) in six patients were increased seizure frequency or afterdischarges ob- that underwent 3 weeks of hippocampal stimulation with served. This is in agreement with the preliminary findings subdural strips, the postimplantation SPECT (before stim- in the short-term study from Velasco et al. (2001). Uni- ulation) shows similar findings to the preimplantation im- lateral MTL DBS using similar stimulation parameters ages, whereas the images after 3 weeks of DBS show clear during 2–3 weeks in patients with MTL epilepsy did not hippocampal hypoperfusion comparable to images taken produce any subjective or objective behavioral responses. after anterior temporal lobectomy. Implantation causing a One occurrence of intracranial bleeding in the area sur- lesion might be expected to provoke earlier signs of hy- rounding the trajectory of the depth electrode was reported poperfusion in the lesioned region. Moreover, in contrast as a result of our systematic MRI screening of the correct to the findings by Hodaie et al., seizures did not decrease positioning of the intracranial electrodes. Large groups of until several days after initiation of stimulation. patients have been investigated with regard to the safety It may be that the lesioning hypothesis holds true for of conventional depth electrodes implanted for diagnostic some targets but is not applicable for others. Blinded purposes (Espinosa et al., 1994; Fernandez et al., 1997). randomization of patients to “on” and “off” stimulation Reported morbidity rates are no higher than 4% and most paradigms after implantation for substantial periods (e.g., often include surgical complications such as infection and, 6 months) might clarify this and might also simultane- less frequently, neurologic complications secondary to ously clarify the potential effect of sham stimulation of small infarcts or bleeding. Permanent sequelae occur in an implanted device. That patients are unaware of stimu- <1% of cases. Especially because of their size, conven- lation in MTL structures represents a favorable factor for tional electrodes are not suitable for long-term implanta- designing blinded controlled studies in the future. tion for the purpose of prolonged stimulation. From the extensive experience of DBS for movement disorders, it Side effects of DBS in the MTL region is known that specifically designed DBS electrodes are Numerous reports in the literature describe the ef- suitable for long-term implantation and stimulation (Rise, fects induced by stimulation of central nervous system 2000). structures by using implanted electrodes for diagnos- Although postoperative MRI could be safely performed tic and/or therapeutic purposes in animals as well as in before the implantation of the generator, no MRIs were humans. From these studies, it has become clear that performed when the generator was implanted. The pres- stimulation of the hippocampus predominantly affects ence of an implanted generator limits further diagnos- memory functions, whereas amygdalar stimulation pre- tic workup in these patients, which has to be weighed dominantly provokes emotional or affective–autonomic against the potential therapeutic benefit of such a device. changes (Bancaud et al., 1966; Shandurina and Kalyagina, Future safety studies should address optimal conditions

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