Adverse events associated with deep brain stimulation for movement disorders: analysis of 510 consecutive cases.

COMPLICATION

Adverse Events Associated With Deep Brain Stimulation for Movement Disorders: Analysis of 510 Consecutive Cases Daxa M. Patel, MD*‡ Harrison C. Walker, MD*§¶ Rebekah Brooks‡ Nidal Omar, BSk Benjamin Ditty, MD‡ Barton L. Guthrie, MD‡ ‡Division of Neurosurgery, The University of Alabama at Birmingham, Birmingham, Alabama; §Division of Neurology, The University of Alabama at Birmingham, Birmingham, Alabama; ¶Department of Biomedical Engineering, The University of Alabama at Birmingham, Birmingham, Alabama; kSchool of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama *These authors contributed equally to the manuscript. Correspondence: Daxa M. Patel, MD, 1720 2nd Ave S, FOT 1060, Birmingham, AL 35294, E-mail: [email protected] Received, July 24, 2014. Accepted, December 6, 2014. Published Online, January 16, 2015. Copyright © 2015 by the Congress of Neurological Surgeons.

BACKGROUND: Although numerous studies have focused on the efficacy of deep brain stimulation (DBS) for movement disorders, less is known about surgical adverse events, especially over longer time intervals. OBJECTIVE: Here, we analyze adverse events in 510 consecutive cases from a tertiary movement disorders center at up to 10 years postoperatively. METHODS: We conducted a retrospective review of adverse events from craniotomies between January 2003 and March 2013. The adverse events were categorized into 2 broad categories—immediate perioperative and time-dependent postoperative events. RESULTS: Across all targets, perioperative mental status change occurred in 18 (3.5%) cases, and symptomatic intracranial hemorrhage occurred in 4 (0.78%) cases. The most common hardware-related event was skin erosion in 13 (2.5%) cases. The most frequent stimulation-related event was speech disturbance in 16 (3.1%) cases. There were no significant differences among surgical targets with respect to the incidence of these events. Time-dependent postoperative events leading to the revision of a given DBS electrode for any reason occurred in 4.7% 6 1.0%, 9.3% 6 1.4%, and 12.4% 6 1.5% of electrodes at 1, 4, and 7 years postoperatively, respectively. Staged bilateral DBS was associated with approximately twice the risk of repeat surgery for electrode replacement vs unilateral surgery (P = .020). CONCLUSION: These data provide low incidences for adverse events in a large series of DBS surgeries for movement disorders at up to 10 years follow-up. Accurate estimates of adverse events will better inform patients and caregivers about the potential risks and benefits of surgery and provide normative data for process improvement. KEY WORDS: Adverse events, Deep brain stimulation, Globus pallidus interna, Safety, Subthalamic nucleus, Ventral intermediate thalamus Operative Neurosurgery 11:190–199, 2015

D

eep brain stimulation (DBS) has become a routine therapy for patients with disabling symptoms of movement disorders. Because DBS is proposed both for earlier stages of Parkinson disease and for new indications in neurology and psychiatry,1-6 it is increasingly important to understand the risk for adverse events associated with the surgical intervention. Although considerable work has documented ABBREVIATIONS: DBS, deep brain stimulation; GPI, globus pallidus interna; ICH, intracranial hemorrhage; IPG, implanted pulse generator; MER, microelectrode recording; PD, Parkinson disease; STN, subthalamic nucleus; VIM, ventral intermediate thalamus

190 | VOLUME 11 | NUMBER 1 | MARCH 2015

DOI: 10.1227/NEU.0000000000000659

DBS efficacy across a variety of movement disorders, relatively less is known about adverse events, because clinical trials are typically conducted over a short duration and serious adverse events are relatively infrequent.1,7-13 Previous studies have shown that serious adverse events are more common with simultaneous bilateral DBS for Parkinson disease (PD) vs best medical therapy alone at up to 12 months follow-up.14,15 We and others have argued that unilateral DBS surgery followed by staged bilateral surgery (if or when needed) provides significant clinical benefit for most PD patients and may spare risk; however, there are few published data comparing adverse events associated with unilateral vs bilateral surgery.16-18

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ADVERSE EVENTS IN DBS SURGERY

Beyond evaluating different surgical approaches, better characterizing adverse events in a large sample of DBS patients over longer time intervals can clarify the preoperative risk/benefit assessment and provide normative data for process improvement. Here, we describe surgical adverse events from DBS in a consecutive series of 510 unilateral and staged bilateral craniotomies for PD, essential tremor, and dystonia over 10 years of routine care at a tertiary movement disorders center.

METHODS We performed a query of our Institutional Review Board-approved outcomes database to evaluate every DBS electrode placement at the University of Alabama at Birmingham Hospital between January 1, 2003 and March 1, 2013, yielding 510 craniotomies and 1020 total procedures. Informed consent was not obtained individually from patients because this was a deidentified, retrospective review of an outcomes database designed for quality improvement. The surgical procedures analyzed in this study included the insertion of the DBS electrode followed by placement of the pulse generator beneath the clavicle and its connection to the DBS wire on approximately the seventh postoperative day. We reviewed patient demographics and identified both perioperative adverse events (including visual inspection of all postoperative brain magnetic resonance images [MRIs]) and time-dependent complications (infection and electrode repositioning). Procedure-related adverse events included intracranial hemorrhage (ICH) and subdural hematoma (either symptomatic or asymptomatic), air embolus, intraoperative or postoperative seizure, cerebrospinal fluid leak, mental status change, and pneumonia. ICH and subdural hematoma were identified from a review of postoperative imaging by an independent radiologist and a neurosurgery resident. Hardware-related adverse events were subdivided into subgroups including hematoma and seroma, lead fracture, skin erosion, and infection. The stimulation-related adverse events were categorized from follow-up clinic visits and include speech disturbance (dysarthria or hypophonia), ballism (abnormal swerving or jerking movements), eyelid apraxia (difficulty with eye opening and visual problems), and corticospinal effects (problems with voluntary movement of 1 side of the body or extremities). All procedures were performed by the same neurosurgeon using previously published methods.16 The placement of the DBS electrode was guided by MRI frame-based stereotaxy with the use of the CRW frame system in conjunction with localization software. The vast majority of patients were awake and responsive throughout the procedure, and microelectrode recordings (MERs) were used to refine targeting in virtually all subthalamic and pallidal cases, and in a minority of ventral intermediate thalamic surgeries for essential tremor. In a few instances, pallidal electrodes were placed under general anesthesia without MERs in children or adolescents with generalized dystonia. We passed 1 MER electrode per recording trajectory and typically performed between 1 and 3 passes per case (mean number of passes, 2.1 6 1.2; median, 2). Postoperative volumetric MRI was obtained within 24 hours of the procedure on a per protocol basis. The pulse generator was placed beneath the clavicle and connected in a separate procedure 1 week later, with the use of either general anesthesia or conscious sedation. We exclusively performed unilateral placement of the DBS electrode followed by contralateral surgery, if and when it was clinically indicated, as described previously.16 All patients underwent a single-channel implanted pulse generator (IPG) placement with each electrode, and possible contralateral electrode

OPERATIVE NEUROSURGERY

followed by contralateral single-channel IPG. Neurologists who are involved in patients’ care programmed the devices. The decision and performance of the staged bilateral implantation is based on individual patient and the type of movement disorder. Our surgical approach is tailored to the individual patient, based on their personal preference in the context of a risk/benefit assessment provided by the treating clinicians. In our experience, patients with essential tremor generally remain unilateral, especially if the stimulator is placed contralateral to their dominant arm. Some patients with severe essential tremor elect to proceed with staged surgery if their tremor is especially prominent or bothersome in the unstimulated arm or if they have significant midline tremor (head, neck, voice). In patients with generalized and cervical dystonia, bilateral stimulators are usually needed for optimal motor improvement, so we typically advise the staged procedure within the first few months of the initial surgery after optimization of their unilateral stimulator during postoperative programming. Our view is that this simplifies postoperative programming in dystonia patients and may give a more nuanced understanding of the effects of 1 stimulator on a given patient’s motor symptoms. Patients with PD vary considerably. Many PD patients with asymmetric motor symptoms have marked motor improvement for greater than 5 years with only unilateral stimulation, but because of the more progressive nature of the disease, many or most patients eventually elect to proceed with the staged contralateral procedure. Despite this, our previous work demonstrated that only 32% of unilateral PD patients underwent the staged bilateral procedure within 2 years of their initial surgery, and, importantly, the subgroup of patients who remained unilateral retained significant improvements in the Unified Parkinson’s Disease Rating Scale parts 2, 3, and 4 vs their preoperative baseline.16 For all patients, the most important motivation for staged placement of a second DBS electrode is to improve residual or progressive motor disability that is severe enough to significantly impair the activities of daily living despite optimal medical management. We performed descriptive statistics evaluating age, sex, and adverse events across the 3 surgical targets (subthalamic nucleus, globus pallidus interna, and ventral intermediate thalamus). The incidence of perioperative events was evaluated as a mean probability 6 standard error, and Fisher exact test was performed to compare the frequency of adverse events by target, regardless of the underlying diagnosis. For time-dependent postoperative adverse events (infection and electrode repositioning/replacement), we used Kaplan-Meier survival analyses regardless of surgical target or diagnosis with the log-rank mean test. The significance threshold for all statistical tests was P = .05.

RESULTS We evaluated 510 consecutive unilateral and staged bilateral DBS electrode placements in 313 male (61.4%) and 197 female (38.6%) patients aged 59.1 6 14.3 years over an average followup duration of 49.3 6 1.4 months. The most common DBS target was the subthalamic nucleus (STN) (n = 270, 52.9%), followed by the ventral intermediate thalamus (VIM) (n = 140, 27.5%), and the globus pallidus interna (GPI) (n = 100, 29.6%) (Table 1). Adverse events in the perisurgical period were relatively uncommon. These events are itemized specifically in Table 2. Intraoperative adverse events related to electrode placement including ICH, subdural hemorrhage, air embolus, and seizure occurred in 5.1% 6 1.0% of cases. Intracranial hemorrhage was

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PATEL ET AL

TABLE 1. Demographicsa Target

Number of cases, n (%) Male Female Age at surgery, mean 6 SD

Total

GPI

STN

VIM

510 (100.0) 313 (61.4) 197 (38.6) 59.1 6 14.3

100 (19.6) 42 (42.0) 58 (58.0) 48.2 6 19.4

270 (52.9) 179 (66.3) 91 (33.7) 60.7 6 9.8

140 (27.5) 92 (65.7) 48 (34.3) 63.8 6 13.5

P Value ,.001b ,.001c

a

GPI, globus pallidus interna; STN, subthalamic nucleus; VIM, ventralis intermediate nucleus. P value for sex was determined by using x2 statistic. P value for age was determined by using the F-statistic from Proc GLM (General Linear Model).

b c

associated with permanent neurological symptoms in 4 of 510 electrode placements (0.78% 6 1.83%). Complications in the immediate postoperative period occurred in 6.1% 6 1.0% of electrode placements, including seizure, spinal fluid leak, mental status change, and pneumonia. Acute or subacute mental status change was the most frequent immediate postoperative complication. The mental status change associated with surgery was

present in 18 cases (3.5% 6 0.8%). Hardware-related complications occurred in 4.9% 6 1.0% of cases including hematoma or seroma, lead fracture, skin erosion, and infection. Only 1 subject was concerned with repeated infectious complications. The stimulation-related adverse events occurred in 5.7% 6 1.03% of cases including speech disturbance, ballism, eyelid apraxia, and corticospinal effects.

TABLE 2. Adverse Eventsa Total (n = 510)

Procedure ICH Symptomatic ICH Asymptomatic ICH SDH Air embolus Intraoperative seizure Postoperative seizure CSF leak Mental status change Pneumonia Total Hardware Hematoma/seroma Lead fracture Skin erosion Infection Total Stimulation Speech disturbance Ballism Eyelid apraxia Corticospinal effects Total

GPI (n = 100)

STN (n = 270)

VIM (n = 140)

No. of Electrodes

%

No. of Electrodes

%

No. of Electrodes

%

No. of Electrodes

%

15 4 11 9 1 1 7 4 18 2 72

2.94 0.78 2.16 1.76 0.20 0.20 1.37 0.78 3.53 0.39 11.2 6 2.03

4 1 3 1 1 0 0 2 2 0

4.00 1.00 3.00 1.00 1.00 0 0 2.00 2.00 0.00

6 3 3 5 0 1 5 2 13 1

2.22 1.11 1.11 1.85 0 0.37 1.85 0.74 4.81 0.37

5 0 5 3 0 0 2 0 3 1

3.57 0 3.57 2.14 0 0 1.43 0 2.14 0.71

4 2 13 6 25

0.78 0.39 2.54 1.18 4.9 6 0.96

0 1 2 3

0 1.00 2.00 3.00

4 0 3 0

1.48 0 1.11 0

0 1 8 3

0 0.71 5.71 2.14

16 6 2 5 29

3.14 1.18 0.39 0.98 5.7 6 1.03

2 0 1 1

2.00 0 1.00 1.00

8 6 1 3

2.96 2.22 0.37 1.11

6 0 0 1

4.29 0 0 0.71

P Valueb .57 .53 .19 .91 .20 1.00 .52 .17 .36 1.00

.32 .22 .02c .008c

.62 .08 .43 1.00

a

CSF, cerebrospinal fluid; GPI, globus pallidus interna; ICH, intracranial hemorrhage; SDH, subdural hematoma; STN, subthalamic nucleus; VIM, ventralis intermediate nucleus. Unless otherwise noted, statistical significance was determined using the Fisher exact test. c Statistically significant at P , .05 indicated in bold. b





Among surgical targets, skin erosion and infection were statistically significant at P , .05 (Table 2), with the VIM target most likely to result in skin erosion (n = 8, 5.71%, P = .02) and GPI site most likely to result in infection (n = 3, 3%, P = .008). At our level of statistical power, there were no significant differences among surgical targets with respect to the incidence of any other adverse events. Overall, electrode revision (infection, repositioning, device mechanical failure) occurred in 4.7% 6 1.0%, 9.3% 6 1.4%, and 12.4% 6 1.5% of cases at 1, 4, and 7 years postoperatively (Figure 1). Electrode revision for both infection and repositioning (complete replacement) occurred at the highest rate during the first postoperative year (1.6% 6 0.6% and 1.7% 6 0.7%, respectively) but continued to accumulate at a slower rate thereafter (4.5% 6 0.6% and 4.7% 6 1.5% at 7 years). Adjustment of the DBS electrode position within the same trajectory (without complete electrode replacement) occurred less frequently and usually slightly later vs complete replacements of migrated or frankly malpositioned electrodes (0.7% 6 0.3% at 1 year). The electrode replacement was typically performed to raise it dorsally to avoid capsular side effects, providing a larger number of DBS electrode contacts with a wider therapeutic window. At our level of statistical power, there was no significant difference among surgical targets (P = .19) or between brain hemispheres (P = .14) with respect to the probability of revision for location, nor were there differences in the probability of postoperative infection (P = .09 and P = .42, respectively). We were typically unable to salvage the intracranial lead when the

IPG or the connector wire became infected. The infection of either the connector wire or IPG in most cases would track up and cause problems of the main intracranial lead and increase the risk of intracranial infection. Therefore, the intracranial lead was difficult to recover. Furthermore, staged bilateral DBS is associated with electrode revision (infection, repositioning, and device mechanical failure) in 7.5% 6 2.7%, 16.3% 6 3.8%, and 25.5% 6 5.7% of cases at 1, 4, and 7 years postoperatively (Figure 2). At our level of statistical power, there was a statistically significant difference in the probability of surgery for DBS electrode revision between staged bilateral and unilateral DBS surgery (P = .020).

FIGURE 1. Probability of DBS electrode revision over time. We separately characterize overall revision, device infection, complete reposition, and repositioning the same DBS electrode without complete electrode replacement. Revision for both infection and repositioning occurred at the highest rate during the first postoperative year but continued to accumulate at a slower rate over the subsequent years. DBS, deep brain stimulation.

FIGURE 2. Probability of DBS electrode revision over time for staged bilateral and unilateral DBS surgery. We characterize overall revision between these 2 techniques and show that bilateral DBS is associated with more long-term surgical adverse events than unilateral DBS and that the difference between the unilateral and bilateral DBS electrode repositioning is statistically significant. DBS, deep brain stimulation.


DISCUSSION Serious adverse events from DBS surgery are uncommon, but their occurrence underscores the specific risks associated with this elective procedure. In this large, comprehensive sample from a single tertiary center, we provide several new findings regarding adverse events associated with DBS surgery. First, we provide evidence that staged bilateral DBS is associated with more surgical adverse events than unilateral DBS alone. Additionally, we characterize adverse events across stimulation targets and diagnoses over a longer follow-up interval than previous studies, allowing estimates for additional adverse events that occur years after the initial electrode placement. Clinical trials focus on DBS efficacy over relatively short time intervals (6-12 months postoperatively), potentially leading to underestimates of the frequency of surgical adverse events over time3,19-21 (Table 3). Furthermore, we



PATEL ET AL

characterize the 3 main categories of complications, including the procedure-, hardware-, and stimulation-related adverse events. The previous studies on adverse events often comment on selected subgroups of adverse events or focus more narrowly on 1 or 2 DBS targets in a single disease state (Table 3). More recently, Hamani and Lozano evaluated hardware-related problems through a systematic review, but did not mention other surgical adverse events like many previous authors who focused on hardware adverse events.22-26 Also, Kleiner-Fisman et al, Videnovic and Metman, and Pollack et al performed a metaanalysis and commented on the prevalence of adverse events following DBS for PD, but they lacked sufficient investigation into several of the complications and the 3 main movement disorders12,27,28 (Table 3). Procedure-Related Adverse Events Among procedure-related adverse events, changes in mental status or behavior occurred in 18 cases (3.5% 6 0.8%). Although this tended to occur most commonly in STN cases, the STN target exclusively was used in patients with advanced PD, whereas a sizeable number of GPI and VIM cases involved patients with essential tremor and dystonia. These results are much lower than several studies in the previous literature that quote the prevalence of altered mental status from 4.7% to 27.7% in unilateral DBS12,20,27-29 (Table 3). Furthermore, our study’s findings demonstrate a lower rate of mental status changes compared with the 10.7% to 14.6% and 8.0% to 22.0% published rate of encephalopathy after surgery with the simultaneous bilateral procedure15,30 and staged or simultaneous bilateral DBS,21,31 respectively. One possibility for this difference might be the difficulty in capturing all the symptoms of encephalopathy such as anxiety, apathy, mood disturbances, or memory or cognition decline from the chart review. Another likely explanation is that our analysis includes unilateral or staged bilateral DBS procedures, instead of simultaneous bilateral procedure as discussed in the previous study. In the comparison of intraoperative events, ICH occurred in 15 (2.9%) cases; however, in only 4 (0.8%) of these cases, patients experienced long-term neurological symptoms. These findings are within the ICH incidence range of 1.1% to 6.3% published in retrospective reviews consisting of sample sizes between approximately 30 and 200 patients19,29,30,32-35 and similar to the 3.1% ICH rate of a prospective randomized controlled trial.31 The symptomatic ICH rate of 0.8% is also similar to the 0.6% results of Binder et al35 and 0.8% from a multicenter surveillance by Voges et al19 (Table 3). DBS target and underlying diagnosis were not associated with differential risk for ICH at our level of statistical power; however, even with our relatively large sample of more than 500 electrode placements, there were very few hemorrhages. Hardware-Related Adverse Events Systematic studies on hardware-related adverse events for all 3 DBS targets are rare. Although our rate of overall hardware-related problems of 4.9% is less than those in previous studies


(5.4%-22.8%),3,6,12,22-25,36 this may be because we did not include IPG malfunction, lack of benefit, premature loss of battery power, or abnormal healing among our hardware-related problems. Skin erosion or breakdown of the skin over the lead or the battery was most commonly seen with the VIM surgical target, and skin infection was mostly present in GPI site in terms of percentage. In analyzing the actual number of cases, however, it is important to note that the absolute number of infections were equal between VIM and GPI. The cause of the relationship between skin erosion and each target is difficult to pinpoint. It is most likely secondary to multiple factors, including the underlying medical condition, age, and the type of the movement disorder. One potential explanation for this is that the VIM patients primarily have essential tremor and are significantly older than the patients in the STN target. The older patients are more likely to have numerous comorbidities, compromised skin integrity,37 increased skin fragility, and rheological abnormalities,38 possibly making them more prone to skin erosion and infection, especially in the background of tremor activity. Furthermore, GPI patients have dystonia and are in poorer condition. Nevertheless, our results lack confidence because of the presence of too few events. Stimulation-Related Adverse Events The most common stimulation-associated effect is speech disturbance. It occurred in 16 cases (3.14%). Eyelid apraxia was present in 2 cases (0.39%). Owing to the wide variations in the report of these events, it is difficult to compare these prevalences with the previous studies. Nevertheless, our findings are much lower than the majority of the previously published rates of 10% to 45% ocular and speech disturbance.6,10,20,28 This could be attributed to the fact that stimulation-related adverse events are confounded by natural disease progression and medical therapy. One other limitation of our stimulation-related adverse events is the lack of report on weight gain. This adverse effect is well established in the literature.39,40 However, it is difficult to obtain data on weight gain from retrospective chart review because it is not measured or reported systematically. Time-Dependent Postoperative Adverse Events Overall, electrode replacement or adjustment occurred in 4.7% 6 1.0%, 9.3% 6 1.4%, and 12.4% 6 1.5% of cases at 1, 4, and 7 years postoperatively. Although lead revisions for device infection and repositioning occurred at the highest rate during the first postoperative year, these events continued to accumulate at a slower rate at up to 10 years after the original surgery. This suggests that the previous literature underestimates the probability for these adverse events in real-world clinical care. Although symptomatic ICH occurred less frequently than infection or electrode repositioning, it can be associated with permanent neurological disability, underscoring perhaps the most important risk associated with DBS. Our infection rate of 1.2% at 6 months and 1.6% at 1 year is largely consistent with the published literature.24,41,42 The risk for




TABLE 3. Literature Review of Complications of DBS in Series With More Than 30 Patientsa,b Study’s Information

Authors, year

Surgical Approach (Unilateral, Sim. Bilateral, staged Bilateral)

Patients, Electrodes (n, n)

0, 121, 0 0, 48, 0 0, 121 0, 66

121, 121 48, 48 NR, 121 66, 66

3, 56 89, 92, 99 282, 0, 110

62, 62 280, 481 392, 510 993, 1183

Weaver et al15 Herzog et al30 Follett et al31 Kondziolka et al23 Carlson et al21 Binder et al35 Present study Voges et al19

Mortality

Target/ Diagnoses

Follow-up (mo)

Mortality %; Cause

Prospective RCT Retrospective Prospective RCT Retrospective multicenter Retrospective Retrospective Retrospective Retrospective multicenter Systematic review

STN, GPI; PD STN; PD STN, GPI; PD VIM; Tremor

24 24 29

2.1, MI 8.3, ICH, PNA, sepsis, MI

STN, GPI; PD All All All

1 24 49.3 1

STN; PD

Design

Videnovic and Metman12 Kleiner-Fisman et al28

928, 1154

Hamani and Lozano24 Sillay et al42 Pollack et al27 Pepper et al26 Burdick et al20 Constantoyannis et al25 Limousin-Dowsey et al32 Umemura et al34 Beric et al29 Lyons et al36 Oh et al22 Hariz et al10

856, 1491 420, 1374 300, 515 273, 519 198, 270 144, 203

Systematic review & meta-analysis Systematic review Retrospective Literature review Retrospective Retrospective Prospective RCT

110, 135

Retrospective

109, 179 86, 149 81, 160 79, 124 69, 69

Retrospective Retrospective Retrospective Retrospective Retrospective multicenter Retrospective Prospective RCT Retrospective Prospective RCT

921, NR

Starr et al33 Kupsch et al3 Joint et al11 Schuurman et al, 20006

44, 40, 39, 34,

76 40 79 34

0.2, ICH 0.4, PNA, PE, MS

STN, GPI; PD

All All All; PD All All

14.8

6 0.4, PE, ICH 6

0.7, NR

STN, VIM; PD

12

0.0

All All All; PD All STN, GPI; PD

20

1.1, PE, PNA

17 12 48

All; PD GPI; dystonia All All

20 3 12.4 6

0.0

2.9, ICH

Procedure-Related Adverse Eventsc ICH Total

Symptomatic ICH

2.1 3.1

SDH

Air Embolus

Seizure

CSF Leak

2.1

Mental Status Change

PNA

10.7 14.6 8.0

8.0

DVT/PE

22 3.3 2.94 2.2 6.3 3.9

0.6 0.78 0.8 3.8

1.76

0.20

1.57

0.78

3.53

1.6 1.5

0.2

27.7 15.6

0.39 0.6

0.00 2 0.3

(Continues)




PATEL ET AL

TABLE 3. Continued Procedure-Related Adverse Eventsc ICH Total

Symptomatic ICH

1.7

SDH

1.0

0.6

5.3

3.7

2.2 1.1 2.1

Air Embolus

Seizure

2

1.1

0.19

8.3

5.3

17.7

0.5 1.34 0.6

0.6

2.6

0.6

2.6 2.5

Lead Fracture

Skin Erosion

PNA

DVT/PE

0.5

0.5

4.7

2.5

Hardware-Related Eventsc Hematoma/seroma

Mental Status Change

CSF Leak

Stimulation-Related Adverse Eventsc Infection

Totald

Speech Disturbance

Ballism

Eyelid Apraxia

CS Effects

Totale

9.9

15.2

4.5

0.78

0.39

2.54

3.1

0.7

1.2

5.0

1.3 1.4

0.3

0.7 1.4

0.7 1.4 0.6

1.3 5.1 1.3 2.5 5 2.9

0.6 2.5

2.5 2.5

15.4 10.6

1.18 0.4 4.6 3.6 6.1 4.5 1.9 3 4.0 7.6 2.2 2.2 1.1 1.9 15.2 2.6 10.0 2.9

63 30.3

4.89

3.14

1.18

0.39

0.98

5.69

9.6

5.4 9.3

0.2 2.6

0.7 3.6

4.0

6.3 19.5

6.7

16.0

7.4 4.08 5.4 10.4

8.0

1.3

1.34

1.34

26.6

15.6

2.68

3.8 22.8

15.0

15

57.2

12.5 20.6

2.9

23.5

a

CS, corticospinal; DVT, deep venous thrombosis; GPI, globus pallidus interna; IPH, intraparenchymal hemorrhage; MI, myocardial infarction; NR, not reported; PD, Parkinson disease; PE, pulmonary embolism; PNA, pneumonia; Sim., simultaneous; STN, subthalamic nucleus; VIM, ventralis intermediate nucleus; All, all 3 targets (STN, VIM, GPI) and multiple indications including movement disorders (essential tremor, dystonia, Parkinson disease). b Color coding is based on surgical approaches. Light gray is simultaneous bilateral. Medium gray is simultaneous bilateral 1 staged bilateral. Dark gray includes staged bilateral. c All reported as percentages of total number of electrodes. d Total = total number of hardware events summed if more than 3 specific subcategories are present. e Total = total number of stimulation related events summed if more than 2 specific subcategories are present.





device infection diminished over time, in contrast to a previous report suggesting that infection is more common following subsequent IPG replacement.26 Early infections occurred most often around the IPG, whereas later infections were typically erosions of the wire through the surface of the skin. We were typically unable to salvage the intracranial lead when infection of the IPG or connector wire occurred, unlike a previous report by Sillay et al.42 A potential advantage of implanting single-channel IPGs is that the revision of an infected system involves unilateral rather than bilateral craniotomy for the replacement of the system, in contrast to infection of dual-channel devices.43 However, placement of single-channel devices likely results in more frequent IPG replacements for battery expiration in patients with bilateral devices, although there is evidence that Soletra devices typically have slightly longer IPG longevity than the Kinetra dual-channel devices.44 DBS repositioning surgeries within the first 6 months postoperatively were typically complete replacement of malpositioned or migrated DBS electrodes, driven by the lack of efficacy or unacceptable side effects at low stimulation thresholds. The criteria were always clinical need first, followed by radiographic evaluation. If the postoperative brain MRI suggested that the DBS was in the wrong position and was consistent with side effect thresholds or clinical effects in a particular patient, that would provide further confidence that electrode repositioning was warranted. In the rare instances where the DBS was well-tolerated and postoperative MRI demonstrated satisfactory electrode position, we typically considered the patients nonresponders and did recommend electrode repositioning. Reasons for later repositioning surgeries were more heterogeneous, tending to include minor adjustment of the original DBS electrode within the same trajectory to further improve efficacy or tolerability in the contexts of superimposed disease progression, tolerance/habituation, or stimulation side effects upon attempts at DBS programming. The authors readjusted the original electrode within the same trajectory varying the depths of insertion with a micrometric precision. The loss of partial therapeutic effect was based on clinical examination, and variations in depths of the electrode were correlated to ensure there was no symptom rebound.

improve significantly with unilateral stimulation, simultaneous or immediate staged placement of a contralateral stimulator adds an incremental risk for potentially avoidable adverse events. Although the present data do not address the relative efficacy of unilateral vs bilateral surgery, our group and others have previously demonstrated that unilateral subthalamic DBS provides significant improvement in the Unified Parkinson’s Disease Rating Scale parts 2, 3, and 4 in patients with advanced PD at up to 2 years follow-up.10,31,45 In patients who undergo unilateral DBS and retain sufficient clinical improvement with a single DBS electrode, it could be argued that not implanting the second contralateral electrode spares patients from the incremental surgical risk associated with having a bilateral system. Additionally, bilateral simultaneous DBS are known to significantly worsen speech and gait in some patients, as well.46,47 One previous retrospective review of 22 patients demonstrates that the rate of adverse events in the staged group (20%) was less than that of the simultaneous group (42%), although the difference was not statistically significant.48 The relative efficacy and tolerability of unilateral, staged bilateral, and simultaneous bilateral surgical approaches would best be addressed by a prospective, randomized study design.

Unilateral vs Staged Bilateral DBS Our standard surgical practice is to place a unilateral DBS electrode on the most affected side of the brain, followed by staged placement of a contralateral electrode if and when it is needed for symptomatic management. The results from this study demonstrate that staged bilateral DBS is associated with more long-term surgical adverse events than unilateral DBS, and our estimates for the risk of adverse events with a single electrode placement compare favorably to the risk associated with bilateral simultaneous electrode placement for PD in clinical trials (Table 3).15,18,45 These findings are not surprising considering that an additional DBS electrode, connector wire, and battery are implanted in patients with bilateral systems. In patients whose motor symptoms and daily activities

Limitations These analyses have several potential limitations, as well. First, the probability estimate of DBS revision/replacement events at later follow-up dates may be less precise, because the average duration of follow-up for a given patient was approximately 4 years. This is mitigated in part by the Kaplan-Meier analyses, because patients without shorter follow-up are censored from the probability estimates at later time points. Second, some patients may have died for any reason during the follow-up period, potentially yielding falsely low probability estimates at longer follow-up intervals. Third, although the sample size is relatively large, our study reflects the practice patterns and surgical techniques of a single center that does not perform simultaneous


Strengths This study has a number of strengths. First, it is a relatively large series from a single center with extensive long-term follow-up, potentially allowing more accurate estimates of the frequency of relatively uncommon serious adverse events. Second, KaplanMeier analyses provide better time resolution for adverse events vs other methods that choose arbitrary end points for statistical comparisons. Third, rather than focusing on a single type of surgical adverse event (infection, hemorrhage, reposition), this study provides a more comprehensive survey of different types of events, providing a more global view of the risk/benefit assessment associated with the intervention. Also, our data provide the first evidence comparing adverse events between unilateral DBS with staged bilateral DBS. Finally, the data for this study are collected from a single institution where all procedures are performed by 1 neurosurgeon, ensuring consistency of data capture.



PATEL ET AL

bilateral electrode implants, potentially limiting the generalizability of the results. Despite being a single surgeon study, no trend or decline in complication rate was identified over time. Fourth, this is a retrospective review, potentially introducing selection bias on different surgical targets based on our local practice patterns or on the population of DBS patients in our region.

CONCLUSION Our findings provide a low estimate for the incidence of serious adverse events over time associated with unilateral and staged bilateral DBS for movement disorders. As DBS is proposed in earlier disease stages and for new indications, these findings provide normative data to clarify the risk-benefit assessment for this therapy that can markedly alter health-related quality of life. Disclosures Dr Walker receives research funding from the National Institutes of Health/ National Institutes of Neurological Disorders and Stroke (K23NS067053) and a Center of Excellence grant from the Bachmann-Strauss Dystonia & Parkinson’s Foundation. The other authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.

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