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Clinical Neurology and Neurosurgery 115 (2013) 2318– 2323

Contents lists available at ScienceDirect

Clinical Neurology and Neurosurgery

j o ur nal hom epage: www.elsev ier .com/ locate /c l ineuro

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eep brain stimulation of the subthalamic nucleus in Parkinson’sisease: Surgical technique, tips, tricks and complications

rsoy Kocabicaka,b,∗, Yasin Temelb,∗

Department of Neurosurgery, Ondokuz Mayis University, Samsun, TurkeyDepartments of Neurosurgery and Neuroscience, Maastricht University Medical Centre, Maastricht, The Netherlands

r t i c l e i n f o

rticle history:eceived 28 March 2013eceived in revised form 13 August 2013ccepted 20 August 2013vailable online 29 August 2013

a b s t r a c t

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has become a frequently performed sur-gery in patients with advanced Parkinson’s disease. The technique has been further refined throughoutthe years by improved imaging techniques, advanced neurophysiological recording possibilities, andadvances in hardware and software technology. In addition, the complications, which can be divided intosurgery-related, target-related, and hardware-related complications, were better recognised and mana-

eywords:eep brain stimulationarkinson’s diseaseubthalamic nucleusurgical technique

ged. In this review, we describe our experience specifically with the surgery of STN DBS in the light ofthe existing literature. Tips and tricks, complications and their management are the main elements ofthis article. In addition, we provide scientific information from our research and other groups in specificsections.

© 2013 Elsevier B.V. All rights reserved.

omplication

ontents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23182. Preoperative period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23193. Operative period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23194. Inpatient postoperative period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23215. Outpatient period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23216. Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2322

6.1. Surgery-related complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23226.2. Hardware-related complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23226.3. Target-related complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2322

7. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2322Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2323References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2323

. Introduction

In 1993, Pollak et al. published their first case of deep brain

was considered to counteract this abnormal activity and as resultproduce therapeutic benefit. In 1995, the same group published

timulation (DBS) of the subthalamic nucleus (STN) in a patientith advanced Parkinson’s disease (PD) [1]. This clinical activityas based on motivating scientific evidence from animal studies

uggesting a dysfunctional neuronal activity in the STN [2,3]. DBS

∗ Corresponding authors at: Department of Neurosurgery, University Hospitalaastricht, P. Debyelaan 25, 6202 AZ Maastricht, The Netherlands.

el.: +31 43 3876149; fax: +31 43 3876038.E-mail addresses: ersoykocabicak@gmail.com (E. Kocabicak),

.temel@maastrichtuniversity.nl (Y. Temel).

303-8467/$ – see front matter © 2013 Elsevier B.V. All rights reserved.ttp://dx.doi.org/10.1016/j.clineuro.2013.08.020

their results in three patients, establishing the safety and thera-peutic potency of DBS of the STN [4]. Since then, many groupsstarted to perform this procedure, obtained their results and sha-red their experience [5–7]. Nowadays, DBS of the STN has becomea frequently performed surgery in patients with advanced PD. Thetechnique has been further refined throughout the years by impro-ved imaging techniques, advanced neurophysiological recording

possibilities, and advances in hardware and software technology.In addition, the complications, which can be divided into surgery-related, target-related, and hardware-related complications, werebetter recognised and managed.

E. Kocabicak, Y. Temel / Clinical Neurology and

Fig. 1. Representative axial SWI MR image at 7 T (Siemens, Germany) showing bila-terally the subthalamic nucleus (STN) and the medially located nucleus ruber (NR).Ultrahigh field MR technology seems to be able to show the structural and regionala

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natomy in great detail and is currently subject of ongoing research.

ourtesy of Y. Temel.

The procedure of DBS of the STN starts with a careful patientelection, continues with the inpatient period involving surgerynd then the activation of DBS [7,8]. The next period is the out-atient period involving (further) programming of the therapy andurther adjusting the drug therapy. The outpatient period does inrinciple never end, unless the therapy is stopped, since the patient

s followed-up with regular intervals by the multidisciplinary team.n this article, we will mainly deal with the surgical procedure ofBS of the STN. Some centers perform DBS of the globus pallidus

nternus to treat advanced PD, and data show that it’s effectivenessight approach DBS of the STN [9,10]. However, a detailed discus-

ion of target selection is beyond the scope of this article and cane found elsewhere [10,11].

In the past years, two main schools have appeared in the surgi-al technique of DBS of the STN. One school advocating the use ofnatomical information to target the STN, and the other one pro-osing the use of intraoperative microelectrode recordings (MER)

n combination with anatomical information [12,13]. Although theroups using MER acknowledge it’s usefulness, strong evidence fort’s superiority is lacking [7,14,15]. Other developments have beenhe progress from indirect anterior commissure (AC) – posteriorommissure (PC) based targeting to the direct targeting of the STNased on high-field and recently ultra-high-field magnetic reso-ance imaging (MRI) (Fig. 1), and the possibility of doing the surgerynder general anesthesia if indicated [16]. In this article, we docu-ent our experience specifically with the surgery of STN DBS in

he light of the existing literature. Tips and tricks, complicationsnd their management are important elements of this article. Inddition, we provide scientific information from our research andther groups in specific sections.

. Preoperative period

The patients with PD who are potentially eligible for DBS ofTN are usually referred by neurologists in peripheral hospitals

nd occassionally by family doctors who treat patients with PDhemselves to movement disorders neurologists. The neurologisterforms the first evaluation and determines for instance whetherhere are still reasonable drug-based therapy options. If not, than

Neurosurgery 115 (2013) 2318– 2323 2319

the patient is considered for DBS. If yes, than a period of optimiseddrug therapy is introduced and usually after this period the patientis again considered for DBS.

The patients who are considered for DBS are hospitalised for aperiod of few days. During this inpatient stay, the patients are eva-luated by a multidisciplinary team consisting of anesthesiologist(s),ergotherapist(s), neuropyschologist(s), neurosurgeon(s), psychia-trist(s), physiotherapist(s), and specialised nurses. The compositionof the team can vary from center to center. In addition, a structuralMRI scan of the brain and routine hematological examination is per-formed. The patient is then discharged. This multidisciplinary teammeets regularly and the findings of the screening of the patients arediscussed and decisions are made whether a patient will be inclu-ded or excluded from surgery. For a detailed list of inclusion andexclusion criteria please see other papers [6,7,10].

3. Operative period

The patient is after inclusion hospitalised for surgery on theNeurology ward. The team will speak to the patient and familyagain on the nature of the procedure, expected outcome at both theshort-term and long-term period, and potential complications. Apreoperative MRI scan is performed and 1 mm T1 axial images withdouble-dose gadolinium and 2 mm T2 axial images are obtained.The first target and trajectory planning can be done already beforethe surgery (Framelink 5, Medtronic, Minneapolis, USA). On theevening before surgery, the patient stops taking antiparkinsonianmedication (12 h before surgery), which is already gradually redu-ced one week before surgery. In the first years of DBS, we stoppedantiparkinsonian medication 24 h before surgery. We experiencedthat this caused substantial discomfort and changed this policy.There are groups which use short-lasting drugs such as apomor-phine to overcome this period. In the same evening, the hair isshaved and washed with povidone–iodine shampoo.

On the day of surgery, in the morning, the patient receives a uri-nary catheter and an intravenous line on the ward. Subsequently,the patient is transferred to the surgery unit. The patient is seatedon a chair and after the application of local anesthesia (combina-tion of short-acting and long-acting ones), the stereotactic frame isplaced parallel to the line between the nose wing and the tragus.We have initially used the CRW frame and (1999–2008) and laterthe Leksell G frame (2008–present). In our experience both framesare suitable and the choice depends on the preference of the surgi-cal team. We feel that it is important to check the accuracy of thestereotactic frame regularly using a phantom or a localiser module.The next step is the stereotactic CT. This is usually a 1 mm-axialscan starting from the infraorbital level and stops at the level of thevertex. The patient is positioned on the CT table with the stereo-tactic frame in a CT adapter to position the head symmetrically andto well fix the head during scanning. We are not using contrast-enhancement for the CT scan. However, there are groups which dothis to visualise vessels which are not detected by double-contrastenhanced MRI [17,18]. This choice is based on the preference of thecenter.

The patient is taken to the operating theater to start prepa-rations for the surgery and the CT images are transferred to theplanning station. A fusion is performed between the previous plan-ning and the stereotactic CT. For targeting the STN, the methodof atlas-based coordinates and adjustments of these based on theT2 MRI images is used. The atlas-based (anterior commissure andposterior commissure based) coordinates are 11–13 mm lateral

to the midcommissural point, 2–4 mm posterior this point, and4 mm inferior this point. The aim to target the dorsolateral partof the STN with the central electrode, which is defined on theT2 MRI image, and subsequenly final stereotactic coordinates are

2320 E. Kocabicak, Y. Temel / Clinical Neurology and Neurosurgery 115 (2013) 2318– 2323

Fig. 2. Representative T2 weighed images at 3 T (Siemens, Germany) showing the targeting of the dorsolateral part of the subthalamic nucleus (STN) in a patient withadvanced Parkinson’s disease. Please note the red point in the right STN in the images A–E. This illustrates the central trajectory. Image A is an axial image at the level of thetarget showing also the surrounding structures such as the red nucleus (RN), the globus pallidus internus (GPi) and, respectively, its border with the retrochiasmatic part ofthe optic tract (OT). The images B till E show the probe’s eye view of the central trajectory at the level of the target (B), 1.7 mm inferior or target (C), 2.7 mm inferior to target( rmedc

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D) and 4.0 mm inferior to target (E). Trajectory planning toward the target is perfoolor in this figure legend, the reader is referred to the web version of this article.)

etermined (Fig. 2). The width of the third ventricle and the pre-ence of anatomical asymmetry might influence the degree ofdjustment of the atlas-based coordinates. A trajectory throughhe lateral ventricles is avoided. However, this is possible if nee-ed, when a special guide canule is used for the implantation ofhe final electrode. In our clinics, we prefer using 5 microelec-rodes for neurophysiological mapping of the area, if the trajectorylanning allows this. In the case of the presence of vessels inne or more of these trajectories, we discard the respective elec-rode(s).

The patient is positioned in the supine position, with the headlevated slightly. We have experienced that providing neck sup-ort, not for stability reasons, but for patients’ comfort, is helpful. Toeparate the sterile and non-sterile area around the patient to allowdequate simultaneous surgery and patient testing, we use metalurgical stands and a large sterile transparent drape (Molnlyckeealthcare, Gothenburg, Sweden). Since the procedure is generallynder local anesthesia, the presence of a psychologist or a speciali-ed nurse during the surgery to guide the patient is recommendeds well as the presence of two neurosurgeons to double-check theoordinates and the stereotactic frame. After application of localnesthesia, the frontal skin is incised and a precoronary burrhole isade by a handdrill. The position of the burrhole is determined by

tereotactic guidance. We do not prefer an automatic drill becausef the noise. A conical hole is made, by undercutting the tabulanterna, for a good attachment and anchoring effect of the cement.ubsequently, a duratomy and corticotomy is performed. Specialttention is paid to penetrate the brain through a gyrus and not aulcus, when the trajectory is planned. A potential problem can be

false route of the macroelectrode when a (deep) sulcus is used forntering the brain for electrodes. In addition, the dura is openedn cross-form, and corticotomy is performed selectively in the area

here the individual microelectrodes penetrate the brain tissue.Before the electrodes for MER will be placed, a normal blood

ressure level or slightly lower is realised. Descendence of elec-

rodes into the brain should be avoided if the blood pressure is high.he anesthesiological team uses a selected group drugs to lower thelood pressure or to achieve a temporary sedation. Important fac-or is that these drugs should not have a large effect on the MER

on contrast-enhanced T1 weighed images. (For interpretation of the references to

signal. Examples of such drugs are dexmedetomidine, remiphenta-nyl, clonidine and propophol.

Before descending the MER electrodes, the patient is examinedby the neurologist and baseline values for the cardinal symptoms(rigidity, hypokinesia, and tremor if present) are obtained. This isfollowed by the descendence of the MER electrodes to 10 mm abovetarget. The burrhole is covered by cottonoids to prevent substantialCSF leackage. MER is performed in 1-mm steps from 10 mm abovethe target for the first 5 mm, then in 0.25–0.5 mm steps until theend of STN activity and the start of substantia nigra pars reticulata(SNr) activity. The length of these steps and the duration of MER ateach step might differ from center to center. Some authors foundeven 1 s MER per step sufficient to define the electrophysiologicalborders of the STN [19]. The STN has a typical electrophysiologicalactivity consisting of high-voltage spikes, cells firing in the burstmode and an obvious widening of the background (Fig. 3). MERends when STN activity disappears and SNr activity appears. Oneof the possible explanations for burst activity in the STN is the lossof dopamineric input to the STN [20]. The dopaminergic neurons inthe substantia nigra have an inhibitory effect on STN cells [21].

The next step is the intraoperative test stimulation performed bythe neurologist, which can be performed with the same electrodesas used for MER. The stimulation site is often on a short distancefrom the recording site. The trajectory with the largest STN elec-trophysiological activity should be in principle chosen. An effectis considered satisfactory when a therapeutic effect is obtainedwith low amplitude (such as 1 mA) on the cardinal symptoms andlong-lasting or irreversible side-effects appear at higher amplitudes(preferably above 4 mA). This gives a wide therapeutic windowpostoperatively. Evidence and also our experience shows that agood intraoperative effect on hypokinesia and rigidity predicts agood effect postoperatively in patients with the akineto-rigid formof PD [7,22]. If a satisfactory effect is not obtained then the nexttrajectory with the longest STN electrophysiological is used for teststimulation. Hereafter, the final electrode is implanted. First the

stimulation tip of the microelectrode is positioned at the deepestanatomical level where a satisfactory effect is obtained and a fluo-roscopy is performed. The contours and the tip of this electrode onthe fluoroscopy screen are marked, the microelectrode is removed,

E. Kocabicak, Y. Temel / Clinical Neurology and Neurosurgery 115 (2013) 2318– 2323 2321

Fig. 3. (A) shows a representative picture of electrophysiological activity measured by a single semi-microelectrode during the STN DBS surgery. The upper trace is 4 mmabove target (thalamic activity), the middle trace is 1 mm under target (typical STN activity), and the lower trace is 7 mm below target (substantia nigra pars reticulata [SNr]activity). (B and C) show a representative picture of electrophysiological activity measured by simultaneously implanted 5 microelectrodes. (B) is the central electrode and(C) the posterior electrode. STN activity has been shown by the black line in both trajectories. Activity of the STN was typically characterized by a neuronal firing patternc s, whi

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onsisting of increased baseline activity and a strong increase of high-voltage spike

dopted from Temel et al. [7].

nd the final electrode is positioned. Before doing this, the distanceetween the stimulation point and the middle of contact of interestusually contact 0 or 1) of the final electrode is measured using auler. There is usually a few mm difference which should be takennto account when placing the final electrode.

The final electrode is fixed in place, without yet removing thenternal guide, with polymethyl methacrylate containing antibio-ics, after placing two layers of Spongostan®. Hereafter, the internaluide is removed, a second layer of acrylic is used to fix the elec-rode. One could argue that the heating of the acrylic or bendingf the electrode could harm the electrode itself. In more than 600lectrode implantations, we have not observed such a problem. Werefer antibiotic-containing acrylic fixation (Antibiotic Simplex;owmedica, Ireland), since it can be preventive for intracranialardware infections. The electrodes are externalised, DBS therapy

s activated, and the patient is observed at the medium care unit. Onhe next day, a MRI scan is performed and the position of the elec-rode is verified and the presence of contusions or (asymptomatic)emorrhages is evaluated. The next step is the internalisation ses-ion. In the past years, many centers have started to implant thenternal pulse generator (IPG) immediately after the stereotacticrocedure. In a small series of patients, we also performed this, andbserved more confusion postoperatively, lasting for a few days.e think that this related to a combination of long awake surgery,

opaminergic medication withdrawal and a relative amount of CSFeackage during the stereotactic surgery which is then followed bynternalisation session under general anesthesia. We perform thenternalization typically 1–2 days after the electrode implantation.he IPG can be implanted subcutaneaously typically in the abdomi-al region or infraclavicularly. We experienced that it is importanto fix the IPG in the pocket by two non-resorbable sutures to preventislocation or rotation of the IPG. A dual stimulator is preferred

n the case of bilateral procedures to have one wound. There areenters who implant two single stimulators on both sides of theody.

. Inpatient postoperative period

The early postoperative evaluations of patients with STN DBS

an be summarised as the evaluation of three domains. The firsts the target-related effects. The degree of therapeutic effects andide-effects of DBS should be assessed. This can be typically doney activating the different contacts with a monopolar setting. For

ch were usually present over a length of 3–6 mm.

the therapeutic effects, concentrating mainly on the cardinal symp-toms of PD is sufficient. Usually a satisfactory effect can be obtainedon the cardinal symptoms. For a detailed review of therapeuticeffects, please see the article of Benabid et al. [23]. The dopami-nergic medication is reduced in a course of few days. Regardingthe side-effects, clinically the most relevant ones are the behavio-ral side-effects [24]. If present, this is managed by changing thestimulation parameters. The psychiatrist and neuropsychologistare closely involved in monitoring and treating these behavioralchanges.

The second domain is the surgery-related issues. Although DBSis not an extensive neurosurgical procedure, wound care is cri-tical because of potential hardware-related infections [25]. Thewound healing is closely monitored during the inpatients stayand the sutures are usually removed at postoperative day 9 or10. After this, the patient is discharged from the hospital. Thisinpatient period can be shorter in other centers. We prefer tokeep the patients 9–10 days in the hospital for the following rea-sons: allowing an adequate and controlled wound healing period,allowing the patients and partners an adequate time to unders-tand and practice the patient programmer, and allowing initialprogramming and observing therapeutic and possible behavioraleffects.

The third is the software-related domain. The patient is pro-grammed in such a way that, that he/she can leave the hospital inan acceptable condition. Further fine-tuning, also of the medication,is performed during the outpatient visits. The patient and partner,if present, if not then a close relative or friend, is instructed withthe hardware and software, including the patient programmer. Inour experience, most patients can handle the patient programmerand therefore are allowed to increase or decrease their amplitudesif necessary.

5. Outpatient period

In the outpatient period the patient is mainly followed upby the neurologist in close communication with the multidis-ciplinary team. There is one standard outpatient visit to theneurosurgeon usually 6–8 weeks after surgery. Then, the patients

is seen according to our protocol 3 months after surgery andthen each year with routine motor and neurospychological eva-luations. In between, the patient can be seen for any otherreason.

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322 E. Kocabicak, Y. Temel / Clinical Neurolo

. Complications

Although we have mentioned the potential complications brie-y in the sections above, here we will discuss these in more detail.

.1. Surgery-related complications

The surgery related complications of STN DBS are more or lessimilar to other DBS procedures. The most relevant surgery-relatedomplications are intracerebral hemorrhages (ICH). An ICH cane considered as the most feared complication of DBS in general26,27]. While ICH can be small and asymptomatic, it can also beymptomatic and present in a broad spectrum of symptoms varyingrom headache, vomiting to aphasia and extremity hemiparesia28]. There are publications suggesting that age, sex, hypertension,leeding disorders are predisposing factors [29,30]. Some groupsave suggested that the number of microelectrodes used for MERan be a risk-factor for ICH formation while others found no orinimal bleeding with MER. There is no consensus on this matter

7,30]. In a comparative study of single-electrode versus multiplelectrode guided STN DBS, we found no increased risk of ICH due toore MER electrodes [7]. In our patient series, the risk of a symp-

omatic ICH has been calculated as lower as 1% and the mortalityate below 0.4%. In our opinion, to minimize the risk for an ICHhe following measures can be taken: careful evaluation of coagu-ation functions of the patient, adequate control of blood pressure,nd a meticulous trajectory planning to avoid vessels. In the case ofn ICH after DBS, the management is similar to a spontaneous ICH.urgical or conservative management depends on the size, locationf the hematoma and the symptoms it causes.

Although extremely rare, late phase venous infarction can beeen in some cases due to the damage to the venous structures31]. We have not seen this in our series.

Epileptic seizures following STN DBS are rare [32]. If a seizuretarts intraoperatively, immediate anti-convulsive therapy shoulde started and the head of the patient secured to prevent injury dueo the frame [33,34]. When possible, CT imaging should be perfor-

ed since a common cause is an ICH [32,33]. In our routine DBSases, we have observed in one patient intraoperative seizure dueo an intracerebral hemorrhage. However, in a small pilot studyith motor cortex stimulation and DBS, we observed seizures due

o cortical stimulation and these patients were managed with anti-pileptic drugs [35].

.2. Hardware-related complications

Infection of the hardware is a most distressing hardware-relatedomplication of DBS in general. Incidence rate is related to theatients’ general medical condition, method and duration of sur-ery, antibiotic use and ranges from 1.5% to 22.2% [25]. Infections ofhe hardware could result in prolonged hospitalization, long-termntibiotic use or removal of the device. No consensus has been rea-hed about the best treatment. Because removal of the hardwareas considerable consequences for the patient it is still a subjectf debate. In common neurosurgical practice, an infected cerebros-inal fluid shunt should be removed as it is considered a medicalmergency because of its intracerebral location, so the question ishether an infected DBS-device should be removed since it is alsoas an intracerebral location.

In our experience, in the case of localized extracranial infec-ions, immediate antibiotic treatment is started and in case of theailure of treatment, debridement of the wounds and removal of

he hardware is performed preserving the intracerebral electrodess much as possible. We think that antibiotic-containing cementhich is used to fix electrodes can form an active barrier against

acteria spread [25]. In 5 out of 12 cases of hardware-related

d Neurosurgery 115 (2013) 2318– 2323

infections in a series of more than 300 patients with DBS, we wereable to manage the infection with antibiotic therapy. In the othercases, we had to remove the IPG and extensions cables, and reim-plant new hardware. The electrodes were not removed in any ofthe cases.

The average rate of lead migration for each electrode is 4–5%in the literature to date [32]. Many centers use electrode cap’sprovided by the electrode manifacturer to prevent macroelectrodemigration. Although we have not systematically analysed the dataof our series using follow-up CT or MR scans, except for the imme-diate postoperative ones, we have not observed a case of leadmigration. Perhaps the use of bone cement reduces the risk oflead migration. To draw final conclusions, a comparative study bet-ween electrode caps and cement is needed. One drawback of thecementation technique is that a high-speed micro-drill is neededto decompress the cement to be able to reach the lead. The lead canthen be removed but usually cannot be reused. In the case of leadrepositioning, a new one is needed.

During DBS procedure, electrode breakage is unlikely but if theconnection is between the lead and the extension behind the earrather than at the calvarium, it can become more likely [32,36,37].Nevertheless, the risk for lead fracture is extremely low and has notoccurred in our series.

6.3. Target-related complications

DBS of the STN can cause specific stimulation-inducedside-effects. The most common non-behavioral side-effects aredyskinesia, worsening of axial symptoms (freezing, balance, andgait disturbance), speech disturbance, involuntary muscle contrac-tions, paresthesia, and diplopia. Stimulation-induced dyskinesiacan be managed with dopaminergic medication dose reduction[28,31]. In some cases temporary hemiballismus has been observed[38].

Major target-related side-effect is at the level of the beha-vior. Mild changes in emotional and cognitive parameters canbe frequently observed [24]. Substantial changes such as mania,depression or psychosis are less frequently seen and are most pro-bably related to current spread to the non-motor parts of the STN.Affective changes can usually be managed by medication targetingthe serotonergic system, such as SSRIs. In a set of preclinical expe-riments, we have found evidence that STN DBS impairs the activityof the serotonergic neurons in the midbrain, resulting in lowerextracellular levels of serotonin in the forebrain and accompanyingdepression-like behavior [39,40]. Using citalopram, a well-knownSSRI, it was possible to reverse the depression-like behavior in rats.

7. Conclusion

DBS of the STN has become a routine surgical therapy forpatients with the advanced stage of PD. The inclusion and exclu-sion criteria for surgery are extensively described. Recent evidencesuggests that patients at an earlier stage of the disease might alsobenefit from DBS of the STN [41]. The surgical part of the therapyhas been refined during the years and this process is still ongoing.Two main approaches are currently being performed: localising theSTN with and without MER. There is no conclusive data to favorone approach. Believers in the MER acknowledge its usefullness,since the radiological STN and electrophysiological STN can differin anatomical configuration. On 1.5 and 3.0 T MR images the three-dimensional borders of the STN with its rich dendritic structure

cannot be well visualised. This might change with ultra-highfieldMR technology, thereby using sequences going beyond the classicalT1 and T2 weighed imaging. Another dichotomy in the field is whe-ther a patient should be tested during surgery (local anesthesia) or

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o perform the procedure under general anesthesia. Under anes-hesia is more comfortable for the patient, but side-effects can note tested adequately. Most important and relevant intra-operativeide-effects are the ones related to the internal capsule. This mighte overcome in the near future when more advanced electrodes willecome available which can steer the electrical fields in differentirections. In addition, different methods have been described tox the final electrode and the timing of the internalision part of theurgery.

DBS of the STN is a relatively safe and effective minimal inva-ive surgery requiring a multidisciplinary team. Changes in theurgical field are ongoing. We expect that the surgery will be modi-ed with advances in hardware and software technology making

t more patient-friendly, more effective (i.e. less side-effects) andore economic (i.e. reduction of surgery time).

cknowledgements

We are greatful to the members of the DBS working group inaastricht University Hospital and Samsun Ondokuz Mayis Uni-

ersity Hospital. The DBS programme in Maastricht has started in999 and has been introduced in Samsun at 2011. The authors arerateful to Dr. Visser-Vandewalle for her contributions to the DBSrogramme in Maastricht University Medical Center.

eferences

[1] Pollak P, Benabid AL, Gross C, Gao DM, Laurent A, Benazzouz A, et al. Effectsof the stimulation of the subthalamic nucleus in Parkinson disease. Rev Neurol1993;149:175–6.

[2] Benazzouz A, Gross C, Féger J, Boraud T, Bioulac B. Reversal of rigidity andimprovement in motor performance by subthalamic high-frequency stimula-tion in MPTP-treated monkeys. Eur J Neurosci 1993;5(4):382–9, 1.

[3] Bergman H, Wichmann T, DeLong MR. Reversal of experimental parkinsonismby lesions of the subthalamic nucleus. Science 1990;249(4975):1436–8, 21.

[4] Limousin P, Pollak P, Benazzouz A, Hoffmann D, Le Bas JF, Broussolle E, et al.Effect of parkinsonian signs and symptoms of bilateral subthalamic nucleusstimulation. Lancet 1995;345:91–5.

[5] Benabid AL, Pollak P, Gervason C, Hoffmann D, Gao DM, Hommel M, et al. Long-term suppression of tremor by chronic stimulation of the ventral intermediatethalamic nucleus. Lancet 1991;337(8738):403–6, 16.

[6] Rodriguez-Oroz MC, Obeso JA, Lang AE, Houeto JL, Pollak P, Rehncrona S, et al.Bilateral deep brain stimulation in Parkinson’s disease: a multicentre studywith 4 years follow-up. Brain 2005;128(Pt 10):2240–9.

[7] Temel Y, Wilbrink P, Duits A, Boon P, Tromp S, Ackermans L, et al. Single elec-trode and multiple electrode guided electrical stimulation of the subthalamicnucleus in advanced Parkinson’s disease. Neurosurgery 2007;61:346–55 [dis-cussion 355–7].

[8] Starr PA, Christine CW, Theodosopoulos PV, Lindsey N, Byrd D, Mosley A, et al.Implantation of deep brain stimulators into the subthalamic nucleus: technicalapproach and magnetic resonance imaging-verified lead locations. J Neurosurg2002;97(2):370–87.

[9] Follett KA, Weaver FM, Stern M, Hur K, Harris CL, Luo P, et al. Pallidal versussubthalamic deep-brain stimulation for Parkinson’s disease. N Engl J Med2010;362(22):2077–91, 3.

10] Odekerken VJ, van Laar T, Staal MJ, Mosch A, Hoffmann CF, Nijssen PC, et al.Subthalamic nucleus versus globus pallidus bilateral deep brain stimulation foradvanced Parkinson’s disease (NSTAPS study): a randomised controlled trial.Lancet Neurol 2012;12(1):37–44.

11] Temel Y, Visser-Vandewalle V. Targets for deep brain stimulation in Parkinson’sdisease. Expert Opin Ther Targets 2006;10(3):355–62.

12] Benabid AL, Pollak P, Gross C, Hoffmann D, Benazzouz A, Gao DM, et al.Acute and long-term effects of subthalamic nucleus stimulation in Parkinson’sdisease. Stereotact Funct Neurosurg 1994;62(1–4):76–84.

13] Nakajima T, Zrinzo L, Foltynie T, Olmos IA, Taylor C, Hariz MI, et al. MRI-guidedsubthalamic nucleus deep brain stimulation without microelectrode recor-ding: can we dispense with surgery under local anaesthesia? Stereotact FunctNeurosurg 2011;89(5):318–25.

14] Benazzouz A, Breit S, Koudsie A, Pollak P, Krack P, Benabid AL. Intraoperative

microrecordings of the subthalamic nucleus in Parkinson’s disease. Mov Disord2002;17(Suppl. 3):145–9.

15] Starr PA, Theodosopoulos PV, Turner R. Surgery of the subthalamic nucleus: useof movement-related neuronal activity for surgical navigation. Neurosurgery2003;53(5):1146–9.

[

Neurosurgery 115 (2013) 2318– 2323 2323

16] Kocabicak E, Aygun D, Alptekin O, Guz H, Kurt M, Sarihasan B, et al. Conversionof local anesthesia guided deep brain stimulation of the subthalamic nucleusto general anesthesia. J Neurol Surg A Cent Eur Neurosurg 2013 [Epub ahead ofprint].

17] Reck C, Maarouf M, Wojtecki L, Groiss SJ, Florin E, Sturm V, et al. Clinicaloutcome of subthalamic stimulation in Parkinson’s disease is improved byintraoperative multiple trajectories microelectrode recording. J Neurol SurgA Cent Eur Neurosurg 2012;73(6):377–86.

18] Tanei T, Kajita Y, Kaneoke Y, Takebayashi S, Nakatsubo D, Wakabayashi T. Stagedbilateral deep brain stimulation of the subthalamic nucleus for the treatmentof Parkinson’s disease. Acta Neurochir 2009;151(6):589–94.

19] Shamir RR, Zaidel A, Joskowicz L, Bergman H, Israel Z. Microelectroderecording duration and spatial density constraints for automatic targe-ting of the subthalamic nucleus. Stereotact Funct Neurosurg 2012;90(5):325–34.

20] Janssen ML, Zwartjes DG, Tan SK, Vlamings R, Jahanshahi A, Heida T, et al.Mild dopaminergic lesions are accompanied by robust changes in subthalamicnucleus activity. Neurosci Lett 2012;508(2):101–5, 6.

21] Ni Z, Bouali-Benazzouz R, Gao D, Benabid AL, Benazzouz A. Intrasubthalamicinjection of 6-hydroxydopamine induces changes in the firing rate and patternof subthalamic nucleus neurons in the rat. Synapse 2001;40(2):145–53.

22] Machado A, Rezai AR, Kopell BH, Gross RE, Sharan AD, Benabid AL. Deepbrain stimulation for Parkinson’s disease: surgical technique and perioperativemanagement. Mov Disord 2006;21(Suppl. 14):S247–58.

23] Benabid AL, Chabardes S, Mitrofanis J, Pollak P. Deep brain stimulation of thesubthalamic nucleus for the treatment of Parkinson’s disease. Lancet Neurol2009;8(1):67–81.

24] Temel Y, Kessels A, Tan S, Topdag A, Boon P, Visser-Vandewalle V. Behaviouralchanges after bilateral subthalamic stimulation in advanced Parkinson disease:a systematic review. Parkinsonism Relat Disord 2006;12(5):265–72.

25] Temel Y, Ackermans L, Celik H, Spincemaille GH, van der Linden C, WalenkampGH, et al. Management of hardware infections following deep brain stimulation.Acta Neurochir 2004;146:355–61 [discussion 361].

26] Binder DK, Rau GM, Starr PA. Risk factors for hemorrhage duringmicroelectrode- guided deep brain stimulator implantation for movementdisorders. Neurosurgery 2005;56(4):722–32 [discussion 722–32].

27] Gorgulho A, De Salles AA, Frighetto L, Behnke E. Incidence of hemorrhage asso-ciated with electrophysiological studies performed using macroelectrodes andmicroelectrodes in functional neurosurgery. J Neurosurg 2005;102(5):888–96.

28] Pilitsis JG, Bakay RA. Deep brain stimulation for treatment of Parkinson’sdisease. Contemp Neurosurg 2007;29(19):1–8.

29] Sansur CA, Frysinger RC, Pouratian N, Fu KM, Bittl M, Oskouian RJ, et al. Inci-dence of symptomatic hemorrhage after stereotactic electrode placement. JNeurosurg 2007;107(5):998–1003.

30] Xiaowu H, Xiufeng J, Xiaoping Z, Bin H, Laixing W, Yiqun C, et al. Risks of intra-cranial hemorrhage in patients with Parkinson’s disease receiving deep brainstimulation and ablation. Parkinsonism Relat Disord 2010;16(2):96–100.

31] Machado AG, Deogaonkar M, Cooper S. Deep brain stimulation for move-ment disorders: patient selection and technical options. Cleve Clin J Med2012;79(Suppl. 2):S19–24.

32] Boviatsis EJ, Stavrinou LC, Themistocleous M, Kouyialis AT, Sakas DE. Sur-gical and hardware complications of deep brain stimulation. A seven-yearexperience and review of the literature. Acta Neurochir 2010;152(12):2053–62.

33] Chou YC, Lin SZ, Hsieh WA, Lin SH, Lee CC, Hsin YL, et al. Surgical and hardwarecomplications in subthalamic nucleus deep brain stimulation. J Clin Neurosci2007;14:643–9.

34] Hariz MI. Safety and risk of microelectrode recording in surgery for movementdisorders. Stereotact Funct Neurosurg 2002;78:146–57.

35] Janssen ML, Zwartjes DG, Temel Y, van Kranen-Mastenbroek V, Duits A, BourLJ, et al. Subthalamic neuronal responses to cortical stimulation. Mov Disord2012;27(3):435–8.

36] Blomstedt P, Hariz MI. Hardware-related complications of deep brain stimu-lation: a ten year experience. Acta Neurochir 2005;147:1061–4 [discussion1064].

37] Schwalb JM, Riina HA, Skolnick B, Jaggi JL, Simuni T, Baltuch GH. Revision of deepbrain stimulator for tremor. Technical note. J Neurosurg 2001;94:1010–2.

38] Spiegel J, Fuss G, Backens M, Reith W, Magnus T, Becker G, et al. Transientdystonia following magnetic resonance imaging in a patient with deep brainstimulation electrodes for the treatment of Parkinson disease. Case report. JNeurosurg 2003;(4):772–4.

39] Tan SK, Hartung H, Visser-Vandewalle V, Steinbusch HW, Temel Y, Sharp T. Acombined in vivo neurochemical and electrophysiological analysis of the effectof high-frequency stimulation of the subthalamic nucleus on 5-HT transmis-sion. Exp Neurol 2012;233(1):145–53.

40] Temel Y, Boothman LJ, Blokland A, Magill PJ, Steinbusch HW, Visser-VandewalleV, et al. Inhibition of 5-HT neuron activity and induction of depressive-like

behavior by high-frequency stimulation of the subthalamic nucleus. Proc NatlAcad Sci U S A 2007;104(43):17087–92, 23.

41] Schuepbach WM, Rau J, Knudsen K, Volkmann J, Krack P, Timmermann L, et al.Neurostimulation for Parkinson’s disease with early motor complications. NEngl J Med 2013;368(7):610–22, 14.