Towards unambiguous reporting of complications related to deep brain stimulation surgery: A retrospective single-center analysis and systematic review of the literature

Abstract

Background and objective

To determine rates of adverse events (AEs) related to deep brain stimulation (DBS) surgery or implanted devices from a large series from a single institution. Sound comparisons with the literature require the definition of unambiguous categories, since there is no consensus on the reporting of such AEs.

Patients and methods

123 consecutive patients (median age 63 yrs; female 45.5%) treated with DBS in the subthalamic nucleus (78 patients), ventrolateral thalamus (24), internal pallidum (20), and centre médian-parafascicular nucleus (1) were analyzed retrospectively. Both mean and median follow-up time was 4.7 years (578 patient-years). AEs were assessed according to three unambiguous categories: (i) hemorrhages including other intracranial complications because these might lead to neurological deficits or death, (ii) infections and similar AEs necessitating the explantation of hardware components as this results in the interruption of DBS therapy, and (iii) lead revisions for various reasons since this involves an additional intracranial procedure. For a systematic review of the literature AE rates were calculated based on primary data presented in 103 publications. Heterogeneity between studies was assessed with the I2 statistic and analyzed further by a random effects meta-regression. Publication bias was analyzed with funnel plots.

Results

Surgery- or hardware-related AEs (23) affected 18 of 123 patients (14.6%) and resolved without permanent sequelae in all instances. In 2 patients (1.6%), small hemorrhages in the striatum were associated with transient neurological deficits. In 4 patients (3.3%; 0.7% per patient-year) impulse generators were removed due to infection. In 2 patients electrodes were revised (1.6%; 0.3% per patient-year). There was no lead migration or surgical revision because of lead misplacement. Age was not statistically significant different (p>0.05) between patients affected by AEs or not. AE rates did not decline over time and similar incidences were found among all patients (423) implanted with DBS systems at our institution until December 2016. A systematic literature review revealed that exact AE rates could not be determined from many studies, which could not be attributed to study designs. Average rates for intracranial complications were 3.8% among studies (per-study analysis) and 3.4% for pooled analysis of patients from different studies (per-patient analysis). Annual hardware removal rates were 3.6 and 2.4% for per-study and per-patient analysis, respectively, and lead revision rates were 4.1 and 2.6%, respectively. There was significant heterogeneity between studies (I2 ranged between 77% and 91% for the three categories; p< 0.0001). For hardware removal heterogeneity (I2 = 87.4%) was reduced by taking study size (p< 0.0001) and publication year (p< 0.01) into account, although a significant degree of heterogeneity remained (I2 = 80.0%; p< 0.0001). Based on comparisons with health care-related databases there appears to be publication bias with lower rates for hardware-related AEs in published patient cohorts.

Conclusions

The proposed categories are suited for an unequivocal assessment of AEs even in a retrospective manner and useful for benchmarking. AE rates in the present cohorts from our institution compare favorable with the literature.

About the Authors:

Katja Engel

Contributed equally to this work with: Katja Engel, Torge Huckhagel

Roles Data curation, Formal analysis, Investigation, Methodology, Validation

Affiliation: Klinik für Neurochirurgie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany

Torge Huckhagel

Contributed equally to this work with: Katja Engel, Torge Huckhagel

Roles Data curation, Formal analysis, Investigation, Validation

Affiliation: Klinik für Neurochirurgie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany

Alessandro Gulberti

Roles Investigation, Validation, Writing – review & editing

Affiliation: Institut für Neurophysiologie & Pathophysiologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany

Monika Pötter-Nerger

Roles Investigation, Validation, Writing – review & editing

Affiliation: Klinik für Neurologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany

Eik Vettorazzi

Roles Formal analysis, Methodology, Software, Validation, Visualization, Writing – review & editing

Affiliation: Institut für Medizinische Biometrie und Epidemiologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany

Ute Hidding

Roles Investigation, Validation, Writing – review & editing

Affiliation: Klinik für Neurologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany

Chi-un Choe

Roles Investigation, Validation, Writing – review & editing

Affiliation: Klinik für Neurologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany

Simone Zittel

Roles Investigation, Validation, Writing – review & editing

Affiliation: Klinik für Neurologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany

Hanna Braaß

Roles Investigation, Validation, Writing – review & editing

Affiliation: Klinik für Neurologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany

Peter Ludewig

Roles Investigation, Validation, Writing – review & editing

Affiliation: Klinik für Neurologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany

Miriam Schaper

Roles Investigation, Validation, Writing – review & editing

Affiliation: Klinik für Neurochirurgie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany

Kara Krajewski

Roles Investigation, Validation, Writing – review & editing

Affiliation: Klinik für Neurochirurgie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany

Christian Oehlwein

Roles Investigation, Validation, Writing – review & editing

Affiliation: Praxis für Neurologie, Gera, Germany

Katrin Mittmann

Roles Investigation, Validation, Writing – review & editing

Affiliation: Praxis für Neurologie, Gera, Germany

Andreas K. Engel

Roles Resources, Validation, Writing – review & editing

Affiliation: Institut für Neurophysiologie & Pathophysiologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany

Christian Gerloff

Roles Resources, Validation, Writing – review & editing

Affiliation: Klinik für Neurologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany

Manfred Westphal

Roles Resources, Validation, Writing – review & editing

Affiliation: Klinik für Neurochirurgie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany

Christian K. E. Moll

Roles Investigation, Resources, Validation, Writing – review & editing

Affiliation: Institut für Neurophysiologie & Pathophysiologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany

Carsten Buhmann

Roles Investigation, Resources, Validation, Writing – review & editing

Affiliation: Klinik für Neurologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany

Johannes A. Köppen

Roles Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Software, Supervision, Validation, Visualization, Writing – review & editing

¶‡ These authors also contributed equally to this work.

Affiliation: Klinik für Neurochirurgie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany

Wolfgang Hamel

Roles Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing

* E-mail: [email protected]

¶‡ These authors also contributed equally to this work.

Affiliation: Klinik für Neurochirurgie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany

ORCID logo http://orcid.org/0000-0002-3890-502X

Introduction

Deep brain stimulation (DBS) is one of the most effective treatment modalities for patients suffering from movement disorders [1–7]. It is interesting to note that despite many technical advances and refinements, the overall efficacy of DBS has remained constant over the last few decades. Taking this into consideration, for properly selected patients the actual margin of the overall clinical benefit from DBS therapy will be related to AEs.

DBS surgery- and hardware-related AEs are more obvious than many neurological and psychiatric AEs facilitating the collection and rating (i.e., severity, reversibility and relatedness to DBS surgery or implanted hardware) of such AEs. However, despite the utilization of common categories, such as infections or hemorrhages, inconsistent reporting has hampered straightforward comparisons between studies. Whereas broad categories (e.g., infection of all kinds) may cover non-severe AEs (e.g., superficial wound healing abnormalities), narrowly defined categories (e.g., erosion) result in the dispersal of AE rates. A multitude of categories will be unsuited for benchmarking purposes. It is unlikely that the required information could be extracted from all publications. In addition, too detailed rates may confuse patients.

From a patient’s perspective, the risk of AEs should be based on subjects but not implanted hardware. For example, calculations based on electrodes result in the dilution of AEs rates as most patients become implanted with a bilateral DBS system. AE rates based on electrodes rather serve to evaluate the performance of hardware components. In addition, follow-up time is crucial to assess the cumulative risk for hardware-related AEs, which may occur even years after surgery. Aggregate follow-up of patient cohorts in patient-years can be deducted with ease from most studies (number of patients * mean follow-up) and used for comparison.

In the present study we provide a detailed retrospective analysis of surgery- and hardware-related AEs in a consecutive (‘real world’) patient cohort involving the most common diseases treated by DBS in the most common surgical targets. In a corresponding report the same cohort has already been evaluated for DBS treatment-inherent AEs as well as AEs related to disease progression or comorbidities [8]. Data for this cohort were contrasted with retrospective data on all DBS patients operated at our institution to address possible bias that may stem from the evaluated period. To put these institutional data into a meaningful context we performed a systematic review of 103 publications. AEs were extracted from publications and re-evaluated according to a triad of clearly defined and patient-relevant categories.

Patients and methods

Patient demographics, indications for DBS, surgical targets, and specifics of data acquisition, grading, monitoring, evaluation and statistical analysis have been detailed in a corresponding report providing a detailed workup of AEs related to ongoing DBS therapy [8]. In addition, intra- and postoperative images of all patients were reviewed. The present analysis was performed for the purpose of internal quality control as well as proper patient counseling which should be based on actual AE rates from the treating center and not from the literature. This work is part of a doctoral thesis by one of the authors (K.E.) and was approved by the Medical Faculty of the University of Hamburg. Data entered into the database were analyzed anonymously.

Mean and median follow-up for the patients assessed (123) was 4.7 years (standard deviation 1.5 years; range 0.7 to 7.3 years). The follow-up period was <12 months for 1 patient and <24 months for 4 patients. This represents an aggregate period of 578 patient-years (4.7 years x 123 patients). We did not consider electrode-years but only patient-years as explained above.

Surgery was performed by two of the authors (WH and JAK). The procedure was performed using the same surgical technique throughout the investigated period complying with standard of care at our institution. In brief, this involved mounting a Zamorano-Dujovny stereotactic frame under general anaesthesia, MR imaging and intraoperative computed tomography (sliding gantry system; Siemens, Erlangen, Germany) followed by co-registration of the acquired images (iPlan software; Brainlab, Feldkirchen, Germany) as previously described [9]. Following extubation and placement of the burr hole, implantation of quadrupolar electrodes (model 3389; Medtronic, Minneapolis, Minnesota, USA) was guided by microelectrode recordings and microstimulation using a Ben’s gun system (AlphaOmega, Nazareth, Israel). In some instances, GPI electrode implantation and rarely STN stimulation was performed under general anaesthesia [10–12].

Intraoperative CT scanning was used to document the stereotactic electrode position and to assess for complications such as hemorrhage. The pulse generator (Kinetra, Soletra, Activa PC, or Activa RC; Medtronic, Minneapolis, Minnesota, USA) and extensions were implanted on the same or following day. All patients received an antimicrobial prophylaxis during surgery that was continued for an additional three days. Dexamethasone or other steroids were not administered.

AEs related to surgery or the implanted devices may vary over time depending on experience, modification of the procedure or availability of novel implants. Thus, the investigated cohort was contrasted with all patients (423) who underwent implantation of a DBS system at our institution from 2002 until December 2016. With a mean follow-up of 3.6 years this represented a cumulative follow-up of 1523 patient-years. Relevant data on AEs in our DBS patients as a whole were obtained from a complete set of surgical reports, postoperative imaging and from a prospectively acquired patient list maintained for the collection of surgery- and hardware-related complications. The last patient visit at our institution was used to determine follow-up and to calculate patient-years.

In order to compare these data with the literature a systematic review was performed. Since there is no consensus on the reporting of DBS surgery- and hardware-related AEs, an unambiguous reporting system has been created based on the following three categories: (1) intracranial AEs including hemorrhages and other intracranial complications, (2) infections, erosions and related AEs requiring partial or complete hardware removal and (3) lead revisions for various reasons including the indication for lead revision. These categories are relevant from a patient’s perspective and these offer several advantages with only few limitations as summarized in Table 1.

[Figure omitted. See PDF.]

Table 1. Categories for the assessment of adverse events related to DBS surgery and implanted hardware.

https://doi.org/10.1371/journal.pone.0198529.t001

The systematic review adheres to the ‘preferred reporting items for systematic reviews and meta-analyses’ (PRISMA statement [13]; S1 Table). The ‘PubMed’ database (http://www.ncbi.nlm.nih.gov/pubmed) was searched (last search on January 7, 2017) using the following search term: ((deep brain stimulation[Title]) AND ((complication*[Title]) OR (adverse event*[Title]) OR (hemorrh*[Title]) OR (infect*[Title]) OR (hardware[Title]) OR (explant[Title]))). Additional studies were retrieved by searching the reference lists of papers by hand. The pivotal prospective and monitored DBS trials for Parkinson’s disease, tremor, or dystonia, were also included.

According to PICOS criteria the following studies were eligible: (1) Participants (P): Adult patients (age ≥18 years) having undergone implantation of a DBS system for movement disorders; (2) Intervention (I): AEs from DBS surgery or the implanted hardware within the stated follow-up period; Comparator (C): not applicable; control group not required; (3) Outcomes (O): AE rates according to three categories as defined in Table 1; (4) Study Design (S): all study designs except for case reports.

The retrieved articles were screened, and the following studies were excluded: case reports (32); reviews (9); articles not written in English (5); pediatric patient cohorts (2); IPG replacement studies (2; although both studies are discussed in this paper); reports presenting data that are included in later studies (2); studies with a different and non-applicable acceptation of a search term (early motor complications) (4); letter to author (1); non surgical AEs (3), e.g., about psychiatric AEs; studies related to technical defects of hardware and those dealing with MR imaging with DBS systems (2); studies about the diagnosis and management of specific AEs in selected patients cohorts, e.g. Twiddler syndrome, pneumocephalus, abscess, scalp erosion, electrode removal (9).

All studies that have remained after the first selection process were systematically reviewed (cf. flow chart). There was no additional step for the exclusion of studies based on other reasons (e.g. retrospective studies; less informative reporting).

Different approaches have been proposed for the assessement of study quality, but there is no consensus on a particular tool yet. Most tools have been tailored to the needs of intervention-related studies, and in particular recommendations for the assessment of the quality of studies evaluating surgery- and hardware-related complications are not available. Martin et al. have addressed this topic for urological surgery [14]. On the other hand, most of the proposed tools cover similar items. Hence analysis of study quality for the present systematic review will follow core questions included in most questionnaires [15–19]. As explained in Table 2, several issues are irrelevant for the present systematic review as it does not rely on results and statistics provided in the evaluated papers. In addition, a control-group and randomization are not required, and double blinded assessments are impossible for the assessment of AEs that are definitely related to DBS surgery or the implanted hardware. The most relevant issue determining study quality for the purpose of the current review has been the possibility to collect complete and accurate data from the assessed papers. On the other hand study design may have an influence on AE reporting, e.g., underreporting of AEs in studies without external data monitoring. To this end the subgroup of prospective trials involving external data monitoring was compared with other studies. To assess possible differences in AE rates that may be related to study size (number of patients) or duration (follow-up period) additional subgroup comparisons were performed.

[Figure omitted. See PDF.]

Table 2. Evaluation of study quality based on questions from common check lists.

https://doi.org/10.1371/journal.pone.0198529.t002

Data extraction from eligible publications involved: (1) identifying the number of patiens having received DBS implants and calculation of cumulative patient-years based on mean follow-up; (2) extraction and classification of AEs according to the proposed categories (cf. Table 1), followed by calculation of incidences based on patients and patient-years. Eligible papers were reviewed independently by two members of our group of authors and all numbers were compared. In case the numbers extracted from papers differed between two raters, papers were reassessed until consent was reached. Studies were not excluded if exact numbers could not be calculated. For example, several papers only presented the number of symptomatic hemorrhages. In this case the total number of hemorrhages was assumed to be equal or larger than the published number. Another example would be papers stating the incidence of infections but not the number of patients requiring removal of (parts of) their DBS system. In this case the number of patients with hardware removal was assumed to be less or equal to the number of reported infections.

Average AE rates, standard deviations and medians among different studies were calculated in two different ways: (i) AE rates from applicable studies were averaged, thus equal weight was given to each study irrespective of cohort size (per-study analysis); this rate indicates the average risk for a patient who would be randomly assigned to one of the treating centers that had been included into the systematic review; (ii) AE rates were also determined by pooling the incidences of a given AE among all applicable studies and by dividing this number by the total number of patients included in these studies (per-patient analysis); this rate assigns equal weight to each patient and it indicates the average risk for a patient based on all patients who had been reported on in the investigated studies.

Heterogeneity of AE rates between studies was analyzed in a random effects meta-analysis and possible effects of study size and publication year were assessed in a mixed-effects meta-regression by using the meta and the metafor packages in R version 3.4.1 [20–22]. Factors that may contribute to publication bias have been summarized in Table 3. Publication bias (cf. Table 3) was analyzed by funnel plot analysis [23] and comparisons with reported figures from large health-care related databases from the USA containing real-world data from non-academic and academic hospitals. In addition, we compared studies based on the quality of data presentation, i.e. studies for which exact rates could be calculated as opposed to studies permitting us to determine extreme (lowest or highest possible) rates only. Statistical analysis was performed with Sigmastat (Sigmastat 2.03; Systat Software Inc., Chicago, USA).

[Figure omitted. See PDF.]

Table 3. Evaluation of publication bias.

https://doi.org/10.1371/journal.pone.0198529.t003

Results

Among a total of 433 AEs, 23 AEs (5.3%) were related to surgery or the implanted hardware and affected 18 patients (14.6% of 123 patients). All AEs related to the surgical procedure or implanted hardware are presented in detail in S2 Table. The age of patients affected or non-affected by surgery- and hardware-related AEs did not differ (p> 0.05; Mann-Whitney U Test).

Intracranial complications

In two cases, a small hemorrhage in the striatum along one of the implanted electrodes was detected (Fig 1 and S2 Table). The maximum extent of these hemorrhages was observed in repeated CT scans obtained on postoperative day three (patient#1; diameter 1.2 cm) or day one (patient#2; diameter < 1 cm; Fig 1).

[Figure omitted. See PDF.]

Fig 1. Intracerebral hemorrhages in the striatum along implanted electrodes (arrows) as detected in CT scans obtained on postoperative day three (A and B, patient#1; STN stimulation; diameter 1.2 cm) and day one (C and D, patient#2; GPI stimulation; diameter < 1 cm).

https://doi.org/10.1371/journal.pone.0198529.g001

Both hemorrhages went along with transient impairments that resolved completely. A 65-year-old male suffering from Parkinson’s disease developed moderate deficits in cognition and word fluency. These had improved significantly until discharge and had resolved completely within the following three months. A 75-year-old female suffering from segmental dystonia revealed postoperative dysphasia, gait disturbances with delayed mobilization and problems with movement initiation (but normal strength after full innervation) contralateral to the hematoma. Symptoms improved during the hospital stay and fully resolved within three months. Both patients were suffering from hypertension and coronary artery disease involving prior (in one case repeated) coronary artery stenting. Both patients had discontinued aspirin one week prior to surgery.

The rate of intracranial complications in this cohort (1.6%; n = 123 patients) is slightly lower than among all patients implanted with DBS electrodes at our institution until 2016 (2.1%; n = 423).

Hardware removal and other infection-related AEs without hardware removal

In four patients (3.3%) IPG removal was required because of infection (three patients were reimplanted). The pertinent information is summarized in S2 Table. In only one case, a 60-year-old patient suffering from insulin-dependent diabetes mellitus, infection (Staphylococcus aureus) occurred within the first 3 months. One 69-year-old patient suffered from repeated infections at (different) IPG sites that required an additional course of explantation and replantation. The ages of the other affected patients were 70 (non-purulent chronic inflammation with erosion) and 64 years (purulent infection).

Other wound complications or circumscribed secondary wound healing (four patients; 3.3%) were treated by local revisions (S2 Table). Until preparation of this manuscript these four patients have had between 67 and 119 months follow-up without the recurrence of infections or erosions in the re-operated areas. The ages in these patients (17 to 75 years) had a broader range.

All AEs involving hardware infections were reversible. In the present cohort (and all other patients implanted with DBS systems at our center) we never observed infections at the burr hole or intracranially.

The rates for hardware removal in this cohort of 123 patients (3.3% and 0.7% per patient-year) were similar to all patients implanted with DBS electrodes at our institution until 2016 (n = 423; 2.6% and 0.7% per patient-year).

Lead revisions and other device-related AEs

One defective electrode (low impedance for several contacts) was replaced one week after implantation (S2 Table). There was no lead migration or surgical revision because of lead misplacement. The rates for electrode revisions in this cohort of 123 patients (1.6% and 0.3% per patient-year) were similar to all patients implanted with DBS electrodes at our institution until 2016 (n = 423; 1.4% and 0.4% per patient-year).

Systematic review of literature

For a meaningful comparison of the present cohort with other studies we systematically reviewed 103 studies. Eligible studies were identified as described above and this process is shown in the flow diagram (S1 Fig). In many instances exact numbers could not be derived (Table 4). This was due to missing information. Typical examples for this are: (1) the reporting of symptomatic hemorrhages only; (2) the reporting of a number of SAEs without specifying these; (3) the reporting of infections without giving further details about consequences (e.g. explantation of hardware); (4) the reporting of surgical revisions without indicating electrode revisions.

[Figure omitted. See PDF.]

Table 4. Systematic review of the literature based on a triad of categories.

https://doi.org/10.1371/journal.pone.0198529.t004

The average rate of intracranial complications was 3.8% and 3.4% for per-study and per-patient analysis, respectively (Table 5 and Fig 2). For intracranial complications there was a significant degree of heterogeneity between studies (random effects logistic meta-analysis; I2 = 77.4%; p< 0.0001; S2 Fig). In a mixed-effects meta-regression the degree of heterogeneity was not reduced significantly by taking the number of patients included in respective studies (p> 0.05; S3 Fig) or publication year (p> 0.05) into account (residual heterogeneity I2 = 76.2%; p< 0.001). Significant funnel plot asymmetry was found (p< 0.001, linear regression test of funnel plot asymmetry; S4 Fig).

[Figure omitted. See PDF.]

Table 5. Summary of literature-based rates for adverse events related to DBS surgery and implanted hardware.

https://doi.org/10.1371/journal.pone.0198529.t005

[Figure omitted. See PDF.]

Fig 2. Percent intracranial AEs per patient.

The rate of AEs is color-coded. The number of patients that have been included in respective studies are indicated by the height of the wedges (cutoff value 500 patients).

https://doi.org/10.1371/journal.pone.0198529.g002

The rates for hardware removal were 4.3% and 3.8% for per-study analysis and per-patient analysis, respectively (Table 5; Figs 3 and 4). Similarly, evaluations based on patient-years (i.e., the reported follow-up is taken into account) revealed lower annual rates for per-patient analysis than for per-study analysis (Table 5). Lower rates obtained for per-patient analysis suggest that hardware removal rates may be lower in larger studies. For hardware removal there was a significant degree of heterogeneity between studies (random effects logistic meta-analysis based on per patient-year rates; I2 = 87.4%; p< 0.0001; S5 Fig). In a mixed-effects meta-regression the degree of heterogeneitiy was slightly reduced by taking study size (p< 0.0001; S6 Fig) and publication year (p = 0.006) into account, although a significant amount of residual heterogeneity remained (I2 = 80.0%; p< 0.0001). The meta-regression indicated that rates were lower in studies with higher cumulative patient-years or published more recently (estimates of –0.32 and 0.09, respectively). Significant funnel plot asymmetry (p< 0.001) was detected (S7 Fig).

[Figure omitted. See PDF.]

Fig 3. Percent hardware removal per patient.

The rate of AEs is color-coded. The number of patients that have been included in respective studies are indicated by the height of the wedges (cutoff value 500 patients).

https://doi.org/10.1371/journal.pone.0198529.g003

[Figure omitted. See PDF.]

Fig 4. Percent hardware removal per patient-year.

The rate of AEs is color-coded. The number of patient-years calculated for individual studies is indicated by the height of the wedges (cutoff value 1000 patient-years).

https://doi.org/10.1371/journal.pone.0198529.g004

For lead revisions the incidences were 5.8% and 4.5% for per-study and per-patient analyis, respectively (Table 5; Figs 5 and 6). Similar to hardware removal, this suggested that rates might be lower in larger studies. For lead revisions there was a significant degree of heterogeneity between studies (random effects logistic meta-analysis based on per patient-year rates; I2 = 91.2%; p< 0.0001; S8 Fig). In a mixed-effects meta-regression the degree of heterogeneity was slightly reduced by taking study size (p< 0.02; S9 Fig) but not publication year; p> 0.5) into account, although the degree of remaining heterogeneity was significant (I2 = 88.6%; p< 0.0001). A negative meta-regression estimate of –0.23 indicated that rates were lower in studies with higher cumulative patient-years. Significant funnel plot asymmetry (p< 0.015) was observed (S10 Fig).

[Figure omitted. See PDF.]

Fig 5. Percent lead revision per patient.

The rate of AEs is color-coded. The number of patients that have been included in respective studies are indicated by the height of the wedges (cutoff value 500 patients).

https://doi.org/10.1371/journal.pone.0198529.g005

[Figure omitted. See PDF.]

Fig 6. Percent lead revision per patient-year.

The rate of AEs is color-coded. The number of patient-years calculated for individual studies is indicated by the height of the wedges (cutoff value 1000 patient-years).

https://doi.org/10.1371/journal.pone.0198529.g006

To investigate whether AE rates were associated with the quality of data presentation we compared studies from which exact AE rates could be determined with studies permitting to calculate extreme (lowest or highest possible) rates only (cf. Table 4). For hardware removal and lead revision average rates were lower in studies from which exact rates could be determined (Table 6). Although none of the differences were of statistical significance (p> 0.05; ANOVA), a systematic review that had been limited to studies with exactly calculable rates had resulted in lower mean rates for hardware removal and lead revision.

[Figure omitted. See PDF.]

Table 6. AE rates dependent on quality of AE reporting.

https://doi.org/10.1371/journal.pone.0198529.t006

Discussion

This study provides comprehensive short- and long-term data on complications related to DBS surgery or the implanted devices. In the present cohort all AEs related to surgery and the implanted hardware were reversible and resolved without permanent sequelae. To obtain comparable data about the frequency of such AEs in the literature a systematic review was performed on 103 studies involving a reassessment of AE rates based on a triad of clearly defined categories.

Intracranial complications

The incidence of intracranial AEs at our institution compares favorable with rates determined from a systematic literature review. It is disputed whether age and hypertension represent true risk factors for intracranial hemorrhages as, for example, age may only serve as a surrogate for medical comorbidity (e.g. [54, 94, 122]). In our cohort, hemorrhages occurred at the ages of 65 and 75, and both patients were suffering from hypertension and coronary artery disease treated with coronary artery stenting. Both patients had discontinued aspirin one week prior to surgery. As a consequence from these two cases, we now require patients to discontinue aspirin for two weeks prior to surgery.

Microelectrode recordings (MER) have been related to an increased risk of intracerebral hemorrhages [54, 89, 101, 123]. Nevertheless, it has been demonstrated that MER can also be performed with a very low risk of hemorrhagic complications (e.g. [36]). In consideration of the potential risks, we limit the number of microelectrode passes to a minimum, but continue to regard MER very highly as these generate patterns that provide a high level of confidence for proper electrode implantation. Since 2002 the position of only one electrode has been revised. In this case a properly placed GPI lead was repositioned within the GPI 14 months after primary implantation, which, however, did not result in increased efficacy. In another patient we recommended revision of a suboptimally placed VIM electrode, but surgery was declined. We attribute our low rates of lead revisions to the information gathered from MER.

Hardware removal

Hardware removal rates in the investigated cohorts appear to be relatively low when compared to the literature. This might be due to the fact that a tried and tested implantation procedure has been adopted from the beginning. In 6 of 11 (2.6%) cases non-purulent chronic inflammation had resulted in erosion of the skin and occured late. This number also includes three non-purulent infections that occurred between 17 and 32 months after IPG replacement (see below). In rare instances, chronic inflammation might be due to an abnormal foreign body reaction [124–126], but it is unclear whether this played a role in the patients affected. It would be desirable to obtain a histological workup in future cases. One patient suffered from mechanical erosion at the IPG site caused by backpacking.

In contrast to other reports [37, 43, 127–129], we found that the risk for device infection after IPG replacements is lower than after primary implantation. We have performed >330 IPG replacement procedures since 2002 without purulent infections. In three patients there were long-term complications in the form of chronic inflammation or erosion that had occurred between 17 and 32 months after IPG replacement.

Lead revisions

Lead revison rates in the investigated cohorts were lower than those from a systematic literature review. One patient required a lead replacement after low impedances were detected for one of the electrodes during monopolar review. Since we could not rule out that the miniplate used for lead fixation had caused a short circuit, we now use a piece of silicon to pad the miniplate. This problem has not been observed in the cases operated thereafter. We did not observe any electrode dislocations. It is now common knowledge that the connector should not be placed into the neck region as this had represented one of the most crucial risk factors for lead dislocation or fracture [130, 131].

Systematic review of literature

When we attempted to relate the surgery- and hardware-related AEs of our cohort with the literature we realized fundamental, yet largely unrecognized problems related to inconsistent reporting, which required the recalculation of AE rates according to unambiguous categories (cf. Table 1). In their entirety the three proposed categories cover most surgery- and hardware-related complications that would require a rating as severe and serious. Nonetheless, exact numbers could not be derived from many publications including monitored prospective trials. Thus it had not been possible to collect more precise data by restricting the present systematic review to monitored prospective trials only. On the other hand, the exclusion of less informative studies had resulted in lower mean AE rates (cf. Table 6). Hence it represented a more conservative approach to refrain from a second selection step elimating such studies.

A significant degree of heterogeneity between studies was observed for all three categories. With regard to hardware removal and lead revision, by meta-regression analysis a significant, but only minor degree of heterogeneity was explained by study size, with lower rates in studies with higher cumulative patient-years. Funnel plot asymmetry was found for all three categories and may be explained by publication bias with a relative lack of studies reporting higher rates of AEs. This gains support from recent analyses of health care-related databases reporting rates for lead revision and hardware removal that were markedly higher than the figures derived from the present systematic literature review [26, 31, 35, 132].

Strengths and limitations of the study

A consecutive (’real world’) patient cohort was investigated reflecting the most common diseases treated by DBS and the most common surgical targets. This study has the advantage of exclusion from the unavoidable selection bias of prospective studies that recruit patients according to defined inclusion criteria. Thus, our cohort is likely to represent patient populations similar to those of other DBS centers. Follow-up was relatively homogeneous and comparably long (cf. Table 4). Complication rates did not decline over time, which may be explained by the fact that a tried and tested procedure has been used from the beginning.

Possible limitations of the present study might be its retrospective design and lack of independent data monitoring. Prospective reporting has been demonstrated to lead to higher AE rates [69]. However, precisely for that reason we have created categories that are based on AEs involving readily accessible and archived source documents (i.e., postoperative imaging, surgical reports), which minimizes the risk of underreporting.

Conclusions

The incidence of adverse events related to surgery or DBS implants in the present cohorts compare favorable with rates derived from a systematic review of the literature. Benchmarking was based on three categories that are clearly defined and relevant from a patient’s perspective. The categories require no more than selected and readily accessible source documents, and they are applicable to retrospective assessments. Although the categories cover mostly severe and serious AEs, a systematic re-evaluation of 103 publications revealed that exact AE rates could not be determined from many studies. This could not be attributed to study designs. There was significant heterogenity between studies for all three categories. For hardware removal and lead revision a significant, but only minor degree of heterogeneity between studies was explained by study size. Due to possible publication bias literature-based assessments may underrate actual complication rates.

Supporting information

[Figure omitted. See PDF.]

S1 Table. PRISMA_checklist.

https://doi.org/10.1371/journal.pone.0198529.s001

(DOC)

S2 Table. Cohort analysis of adverse events related to DBS surgery or implanted hardware.

https://doi.org/10.1371/journal.pone.0198529.s002

(DOCX)

S1 Fig. PRISMA flowchart.

https://doi.org/10.1371/journal.pone.0198529.s003

(TIF)

S2 Fig. Forest plots indicating rates and 95% confidence intervals for intracranial AEs.

Data from our institution (UKE Hamburg) have not been included into the meta-analysis.

https://doi.org/10.1371/journal.pone.0198529.s004

(TIF)

S3 Fig. Plotting of study size (no. of pats) vs. rates for intracranial AEs (y axis).

The blue line indicates a local polinomial regression fitting (loess estimator), and the grey shaded area indicates the 95% confidence interval.

https://doi.org/10.1371/journal.pone.0198529.s005

(TIF)

S4 Fig. Funnel plot analysis of intracranial AEs.

The diagonal lines (dashed) indicate the expected 95% confidence intervals around the summary estimate. According to the trim-and-fill method 29 studies were added (open circles) to adjust for funnel plot asymmetry.

https://doi.org/10.1371/journal.pone.0198529.s006

(TIF)

S5 Fig. Forest plots indicating rates and 95% confidence intervals for hardware removal.

Data from our institution (UKE Hamburg) have not been included into the meta-analysis.

https://doi.org/10.1371/journal.pone.0198529.s007

(TIF)

S6 Fig. Plotting of study size (total pt.yrs) vs. rates for hardware removal (y axis).

The blue line indicates a local polinomial regression fitting (loess estimator), and the grey shaded area indicates the 95% confidence interval.

https://doi.org/10.1371/journal.pone.0198529.s008

(TIF)

S7 Fig. Funnel plot analysis of hardware removal.

The diagonal lines (dashed) indicate the expected 95% confidence intervals around the summary estimate. According to the trim-and-fill method 34 studies were added (open circles) to adjust for funnel plot asymmetry.

https://doi.org/10.1371/journal.pone.0198529.s009

(TIF)

S8 Fig. Forest plots indicating rates and 95% confidence intervals for lead revision.

Data from our institution (UKE Hamburg) have not been included into the meta-analysis.

https://doi.org/10.1371/journal.pone.0198529.s010

(TIF)

S9 Fig. Plotting of study size (total pt.yrs) vs. rates for lead revision (y axis).

The blue line indicates a local polinomial regression fitting (loess estimator), and the grey shaded area indicates the 95% confidence interval.

https://doi.org/10.1371/journal.pone.0198529.s011

(TIF)

S10 Fig. Funnel plot analysis of lead revision.

The diagonal lines (dashed) indicate the expected 95% confidence intervals around the summary estimate. According to the trim-and-fill method 18 studies were added (open circles) to adjust for funnel plot asymmetry.

https://doi.org/10.1371/journal.pone.0198529.s012

(TIF)

Citation: Engel K, Huckhagel T, Gulberti A, Pötter-Nerger M, Vettorazzi E, Hidding U, et al. (2018) Towards unambiguous reporting of complications related to deep brain stimulation surgery: A retrospective single-center analysis and systematic review of the literature. PLoS ONE 13(8): e0198529. https://doi.org/10.1371/journal.pone.0198529

References

1. Deuschl G, Schade-Brittinger C, Krack P, Volkmann J, Schafer H, Botzel K, et al. A randomized trial of deep-brain stimulation for Parkinson’s disease. N Engl J Med. 2006;355(9):896–908. pmid:16943402.

2. Weaver FM, Follett K, Stern M, Hur K, Harris C, Marks WJ Jr., et al. Bilateral deep brain stimulation vs best medical therapy for patients with advanced Parkinson disease: a randomized controlled trial. Jama. 2009;301(1):63–73. pmid:19126811.

3. Williams A, Gill S, Varma T, Jenkinson C, Quinn N, Mitchell R, et al. Deep brain stimulation plus best medical therapy versus best medical therapy alone for advanced Parkinson’s disease (PD SURG trial): a randomised, open-label trial. Lancet Neurol. 2010;9(6):581–91. pmid:20434403.

4. Rehncrona S, Johnels B, Widner H, Tornqvist AL, Hariz M, Sydow O. Long-term efficacy of thalamic deep brain stimulation for tremor: double-blind assessments. Mov Disord. 2003;18(2):163–70. pmid:12539209.

5. Schuurman PR, Bosch DA, Bossuyt PM, Bonsel GJ, van Someren EJ, de Bie RM, et al. A comparison of continuous thalamic stimulation and thalamotomy for suppression of severe tremor. N Engl J Med. 2000;342(7):461–8. pmid:10675426.

6. Volkmann J, Wolters A, Kupsch A, Muller J, Kuhn AA, Schneider GH, et al. Pallidal deep brain stimulation in patients with primary generalised or segmental dystonia: 5-year follow-up of a randomised trial. Lancet Neurol. 2012;11(12):1029–38. pmid:23123071.

7. Mueller J, Skogseid IM, Benecke R, Kupsch A, Trottenberg T, Poewe W, et al. Pallidal deep brain stimulation improves quality of life in segmental and generalized dystonia: results from a prospective, randomized sham-controlled trial. Mov Disord. 2008;23(1):131–4. pmid:17973330.

8. Buhmann C, Huckhagel T, Engel K, Gulberti A, Hidding U, Poetter-Nerger M, et al. Adverse events in deep brain stimulation: A retrospective long-term analysis of neurological, psychiatric and other occurrences. PloS one. 2017;12(7):e0178984. pmid:28678830.

9. Hamel W, Fietzek U, Morsnowski A, Schrader B, Herzog J, Weinert D, et al. Deep brain stimulation of the subthalamic nucleus in Parkinson’s disease: evaluation of active electrode contacts. J Neurol Neurosurg Psychiatry. 2003;74(8):1036–46. pmid:12876231.

10. Moll CK, Galindo-Leon E, Sharott A, Gulberti A, Buhmann C, Koeppen JA, et al. Asymmetric pallidal neuronal activity in patients with cervical dystonia. Frontiers in systems neuroscience. 2014;8:15. pmid:24574981.

11. Moll CK, Payer S, Gulberti A, Sharrott A, Zittel S, Boelmans K, et al. STN stimulation in general anaesthesia: evidence beyond ‘evidence-based medicine’. Acta Neurochir Suppl. 2013;117:19–25. pmid:23652652.

12. Moll CK, Sharott A, Hamel W, Munchau A, Buhmann C, Hidding U, et al. Waking up the brain: a case study of stimulation-induced wakeful unawareness during anaesthesia. Prog Brain Res. 2009;177:125–45. pmid:19818899.

13. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med. 2009;6(7):e1000100. pmid:19621070.

14. Martin RC 2nd, Brennan MF, Jaques DP. Quality of complication reporting in the surgical literature. Ann Surg. 2002;235(6):803–13. pmid:12035036.

15. National Heart L, and Blood Institute. Study Quality Assessment Tools: National Institute of Health; [updated April 2014; cited 2017].

16. Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses [cited 2017].

17. Thomas BH, Ciliska D, Dobbins M, Micucci S. A process for systematically reviewing the literature: providing the research evidence for public health nursing interventions. Worldviews Evid Based Nurs. 2004;1(3):176–84. pmid:17163895.

18. Armijo-Olivo S, Stiles CR, Hagen NA, Biondo PD, Cummings GG. Assessment of study quality for systematic reviews: a comparison of the Cochrane Collaboration Risk of Bias Tool and the Effective Public Health Practice Project Quality Assessment Tool: methodological research. J Eval Clin Pract. 2012;18(1):12–8. pmid:20698919.

19. Ryan R, Hill S, Prictor M, McKenzie J. Cochrane Consumers and Communication Review Group. Study Quality Guide [updated May 2013; cited 2017].

20. Schwarzer G. Meta: An R Package for Meta-Analysis. R News 2007;7(3):40–5.

21. RCoreTeam. R: A Language and Environment for Statistical Computing Vienna, Austria2017.

22. Viechtbauer W. Conducting Meta-Analyses in R with the metafor Package. Journal of Statistical Software. 2010;36(3):1–48. http://www.jstatsoft.org/v36/i03/.

23. Sterne JA, Sutton AJ, Ioannidis JP, Terrin N, Jones DR, Lau J, et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ. 2011;343:d4002. pmid:21784880.

24. White-Dzuro GA, Lake W, Eli IM, Neimat JS. Novel Approach to Securing Deep Brain Stimulation Leads: Technique and Analysis of Lead Migration, Breakage, and Surgical Infection. Stereotact Funct Neurosurg. 2016;94(1):18–23. pmid:26882003.

25. Rasouli JJ, Kopell BH. The Adjunctive Use of Vancomycin Powder Appears Safe and May Reduce the Incidence of Surgical-Site Infections After Deep Brain Stimulation Surgery. World Neurosurg. 2016;95:9–13. pmid:27474456.

26. Petraglia FW 3rd, Farber SH, Han JL, Verla T, Gallis J, Lokhnygina Y, et al. Comparison of Bilateral vs. Staged Unilateral Deep Brain Stimulation (DBS) in Parkinson’s Disease in Patients Under 70 Years of Age. Neuromodulation. 2016;19(1):31–7. pmid:26568568.

27. Rosa M, Scelzo E, Locatelli M, Carrabba G, Levi V, Arlotti M, et al. Risk of Infection after Local Field Potential Recording from Externalised Deep Brain Stimulation Leads in Parkinson’s Disease. World Neurosurg. 2016. pmid:27686508.

28. Wang X, Wang J, Zhao H, Li N, Ge S, Chen L, et al. Clinical analysis and treatment of symptomatic intracranial hemorrhage after deep brain stimulation surgery. Br J Neurosurg. 2016:1–6. pmid:27760466.

29. Levi V, Carrabba G, Rampini P, Locatelli M. "Short term surgical complications after subthalamic deep brain stimulation for Parkinson’s disease: does old age matter?". BMC Geriatr. 2015;15:116. pmid:26438346.

30. Falowski SM, Ooi YC, Bakay RA. Long-Term Evaluation of Changes in Operative Technique and Hardware-Related Complications With Deep Brain Stimulation. Neuromodulation. 2015;18(8):670–7. pmid:26245633.

31. Verla T, Marky A, Farber H, Petraglia FW 3rd, Gallis J, Lokhnygina Y, et al. Impact of advancing age on post-operative complications of deep brain stimulation surgery for essential tremor. J Clin Neurosci. 2015;22(5):872–6. pmid:25669119.

32. Patel DM, Walker HC, Brooks R, Omar N, Ditty B, Guthrie BL. Adverse events associated with deep brain stimulation for movement disorders: analysis of 510 consecutive cases. Neurosurgery. 2015;11 Suppl 2:190–9. pmid:25599204.

33. Timmermann L, Jain R, Chen L, Maarouf M, Barbe MT, Allert N, et al. Multiple-source current steering in subthalamic nucleus deep brain stimulation for Parkinson’s disease (the VANTAGE study): a non-randomised, prospective, multicentre, open-label study. Lancet Neurol. 2015;14(7):693–701. pmid:26027940.

34. Gocmen S, Celiker O, Topcu A, Panteli A, Acar G, Acar F. Reuse of internal pulse generator in cases of infection after deep brain stimulation surgery. Stereotact Funct Neurosurg. 2014;92(3):140–4. pmid:24776691.

35. DeLong MR, Huang KT, Gallis J, Lokhnygina Y, Parente B, Hickey P, et al. Effect of advancing age on outcomes of deep brain stimulation for Parkinson disease. JAMA neurology. 2014;71(10):1290–5. pmid:25155481.

36. Zibetti M, Romagnolo A, Crobeddu E, Fornaro R, Merola A, Rizzone MG, et al. Does intraoperative microrecording really increase the risk of hemorrhagic complications in deep brain stimulation? Brain stimulation. 2014;7(6):911–2. pmid:25151542.

37. Bjerknes S, Skogseid IM, Saehle T, Dietrichs E, Toft M. Surgical site infections after deep brain stimulation surgery: frequency, characteristics and management in a 10-year period. PloS one. 2014;9(8):e105288. pmid:25122445.

38. Tolleson C, Stroh J, Ehrenfeld J, Neimat J, Konrad P, Phibbs F. The factors involved in deep brain stimulation infection: a large case series. Stereotact Funct Neurosurg. 2014;92(4):227–33. pmid:25096381.

39. Volkmann J, Mueller J, Deuschl G, Kuhn AA, Krauss JK, Poewe W, et al. Pallidal neurostimulation in patients with medication-refractory cervical dystonia: a randomised, sham-controlled trial. Lancet Neurol. 2014;13(9):875–84. pmid:25127231.

40. Seijo F, Alvarez de Eulate Beramendi S, Santamarta Liebana E, Lozano Aragoneses B, Saiz Ayala A, Fernandez de Leon R, et al. Surgical adverse events of deep brain stimulation in the subthalamic nucleus of patients with Parkinson’s disease. The learning curve and the pitfalls. Acta Neurochir (Wien). 2014;156(8):1505–12; discussion 12. pmid:24752724.

41. Fenoy AJ, Simpson RK Jr. Risks of common complications in deep brain stimulation surgery: management and avoidance. J Neurosurg. 2014;120(1):132–9. pmid:24236657.

42. Piacentino M, Zambon G, Pilleri M, Bartolomei L. Comparison of the incidence of intracranial hemorrhage in two different planning techniques for stereotactic electrode placement in the deep brain stimulation. J Neurosurg Sci. 2013;57(1):63–7. pmid:23584221.

43. Pepper J, Zrinzo L, Mirza B, Foltynie T, Limousin P, Hariz M. The risk of hardware infection in deep brain stimulation surgery is greater at impulse generator replacement than at the primary procedure. Stereotact Funct Neurosurg. 2013;91(1):56–65. pmid:23207787.

44. Schuepbach WM, Rau J, Knudsen K, Volkmann J, Krack P, Timmermann L, et al. Neurostimulation for Parkinson’s disease with early motor complications. N Engl J Med. 2013;368(7):610–22. pmid:23406026.

45. Odekerken VJ, van Laar T, Staal MJ, Mosch A, Hoffmann CF, Nijssen PC, et al. Subthalamic nucleus versus globus pallidus bilateral deep brain stimulation for advanced Parkinson’s disease (NSTAPS study): a randomised controlled trial. Lancet Neurol. 2013;12(1):37–44. pmid:23168021.

46. Rughani AI, Hodaie M, Lozano AM. Acute complications of movement disorders surgery: effects of age and comorbidities. Mov Disord. 2013;28(12):1661–7. pmid:23861366.

47. Halpern CH, Mitchell GW, Paul A, Kramer DR, McGill KR, Buonacuore D, et al. Self-administered preoperative antiseptic wash to prevent postoperative infection after deep brain stimulation. Am J Infect Control. 2012;40(5):431–3.

48. Dlouhy BJ, Reddy A, Dahdaleh NS, Greenlee JD. Antibiotic impregnated catheter coverage of deep brain stimulation leads facilitates lead preservation after hardware infection. J Clin Neurosci. 2012;19(10):1369–75. pmid:22854128.

49. Guridi J, Rodriguez-Oroz MC, Alegre M, Obeso JA. Hardware complications in deep brain stimulation: electrode impedance and loss of clinical benefit. Parkinsonism Relat Disord. 2012;18(6):765–9. pmid:22522071.

50. Kahn E, D’Haese PF, Dawant B, Allen L, Kao C, Charles PD, et al. Deep brain stimulation in early stage Parkinson’s disease: operative experience from a prospective randomised clinical trial. J Neurol Neurosurg Psychiatry. 2012;83(2):164–70. pmid:21890575.

51. Okun MS, Gallo BV, Mandybur G, Jagid J, Foote KD, Revilla FJ, et al. Subthalamic deep brain stimulation with a constant-current device in Parkinson’s disease: an open-label randomised controlled trial. Lancet Neurol. 2012;11(2):140–9. pmid:22239915.

52. Baizabal Carvallo JF, Mostile G, Almaguer M, Davidson A, Simpson R, Jankovic J. Deep brain stimulation hardware complications in patients with movement disorders: risk factors and clinical correlations. Stereotact Funct Neurosurg. 2012;90(5):300–6. pmid:22797749.

53. Falowski S, Ooi YC, Smith A, Verhargen Metman L, Bakay RA. An evaluation of hardware and surgical complications with deep brain stimulation based on diagnosis and lead location. Stereotact Funct Neurosurg. 2012;90(3):173–80. pmid:22678355.

54. Zrinzo L, Foltynie T, Limousin P, Hariz MI. Reducing hemorrhagic complications in functional neurosurgery: a large case series and systematic literature review. J Neurosurg. 2012;116(1):84–94. pmid:21905798.

55. Park JH, Chung SJ, Lee CS, Jeon SR. Analysis of hemorrhagic risk factors during deep brain stimulation surgery for movement disorders: comparison of the circumferential paired and multiple electrode insertion methods. Acta Neurochir (Wien). 2011;153(8):1573–8. pmid:21476122.

56. Piacentino M, Pilleri M, Bartolomei L. Hardware-related infections after deep brain stimulation surgery: review of incidence, severity and management in 212 single-center procedures in the first year after implantation. Acta Neurochir (Wien). 2011;153(12):2337–41. pmid:21874271.

57. Fily F, Haegelen C, Tattevin P, Buffet-Bataillon S, Revest M, Cady A, et al. Deep brain stimulation hardware-related infections: a report of 12 cases and review of the literature. Clin Infect Dis. 2011;52(8):1020–3. pmid:21460317.

58. Servello D, Sassi M, Gaeta M, Ricci C, Porta M. Tourette syndrome (TS) bears a higher rate of inflammatory complications at the implanted hardware in deep brain stimulation (DBS). Acta Neurochir (Wien). 2011;153(3):629–32. pmid:21052744.

59. Doshi PK. Long-term surgical and hardware-related complications of deep brain stimulation. Stereotact Funct Neurosurg. 2011;89(2):89–95. pmid:21293168.

60. Foltynie T, Zrinzo L, Martinez-Torres I, Tripoliti E, Petersen E, Holl E, et al. MRI-guided STN DBS in Parkinson’s disease without microelectrode recording: efficacy and safety. J Neurol Neurosurg Psychiatry. 2011;82(4):358–63.

61. Fisher R, Salanova V, Witt T, Worth R, Henry T, Gross R, et al. Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy. Epilepsia. 2010;51(5):899–908. pmid:20331461.

62. Fytagoridis A, Blomstedt P. Complications and side effects of deep brain stimulation in the posterior subthalamic area. Stereotact Funct Neurosurg. 2010;88(2):88–93. pmid:20068384.

63. Bhatia S, Zhang K, Oh M, Angle C, Whiting D. Infections and hardware salvage after deep brain stimulation surgery: a single-center study and review of the literature. Stereotact Funct Neurosurg. 2010;88(3):147–55. pmid:20357522.

64. Boviatsis EJ, Stavrinou LC, Themistocleous M, Kouyialis AT, Sakas DE. Surgical and hardware complications of deep brain stimulation. A seven-year experience and review of the literature. Acta Neurochir (Wien). 2010;152(12):2053–62. pmid:20658301.

65. Fernandez FS, Alvarez Vega MA, Antuna Ramos A, Fernandez Gonzalez F, Lozano Aragoneses B. Lead Fractures in Deep Brain Stimulation during Long-Term Follow-Up. Parkinsons Dis. 2010;2010:409356. pmid:20975776.

66. Zhang K, Bhatia S, Oh MY, Cohen D, Angle C, Whiting D. Long-term results of thalamic deep brain stimulation for essential tremor. J Neurosurg. 2010;112(6):1271–6. pmid:19911883.

67. Follett KA, Weaver FM, Stern M, Hur K, Harris CL, Luo P, et al. Pallidal versus subthalamic deep-brain stimulation for Parkinson’s disease. N Engl J Med. 2010;362(22):2077–91. pmid:20519680.

68. Vergani F, Landi A, Pirillo D, Cilia R, Antonini A, Sganzerla EP. Surgical, medical, and hardware adverse events in a series of 141 patients undergoing subthalamic deep brain stimulation for Parkinson disease. World Neurosurg. 2010;73(4):338–44. pmid:20849789.

69. Burdick AP, Fernandez HH, Okun MS, Chi YY, Jacobson C, Foote KD. Relationship between higher rates of adverse events in deep brain stimulation using standardized prospective recording and patient outcomes. Neurosurg Focus. 2010;29(2):E4. pmid:20672921.

70. Xiaowu H, Xiufeng J, Xiaoping Z, Bin H, Laixing W, Yiqun C, et al. Risks of intracranial hemorrhage in patients with Parkinson’s disease receiving deep brain stimulation and ablation. Parkinsonism Relat Disord. 2010;16(2):96–100. pmid:19682943.

71. Sixel-Doring F, Trenkwalder C, Kappus C, Hellwig D. Skin complications in deep brain stimulation for Parkinson’s disease: frequency, time course, and risk factors. Acta Neurochir (Wien). 2010;152(2):195–200. pmid:19727546.

72. Hu X, Jiang X, Zhou X, Liang J, Wang L, Cao Y, et al. Avoidance and management of surgical and hardware-related complications of deep brain stimulation. Stereotact Funct Neurosurg. 2010;88(5):296–303. pmid:20588081.

73. Okun MS, Fernandez HH, Wu SS, Kirsch-Darrow L, Bowers D, Bova F, et al. Cognition and mood in Parkinson’s disease in subthalamic nucleus versus globus pallidus interna deep brain stimulation: the COMPARE trial. Ann Neurol. 2009;65(5):586–95. pmid:19288469.

74. Elias WJ, Sansur CA, Frysinger RC. Sulcal and ventricular trajectories in stereotactic surgery. J Neurosurg. 2009;110(2):201–7. pmid:18821828.

75. Maldonado IL, Roujeau T, Cif L, Gonzalez V, El-Fertit H, Vasques X, et al. Magnetic resonance-based deep brain stimulation technique: a series of 478 consecutive implanted electrodes with no perioperative intracerebral hemorrhage. Neurosurgery. 2009;65(6 Suppl):196–201; discussion -2. pmid:19934995.

76. Ben-Haim S, Asaad WF, Gale JT, Eskandar EN. Risk factors for hemorrhage during microelectrode-guided deep brain stimulation and the introduction of an improved microelectrode design. Neurosurgery. 2009;64(4):754–62; discussion 62–3. pmid:19349834.

77. Gervais-Bernard H, Xie-Brustolin J, Mertens P, Polo G, Klinger H, Adamec D, et al. Bilateral subthalamic nucleus stimulation in advanced Parkinson’s disease: five year follow-up. J Neurol. 2009;256(2):225–33. pmid:19242649.

78. Chan DT, Zhu XL, Yeung JH, Mok VC, Wong E, Lau C, et al. Complications of deep brain stimulation: a collective review. Asian J Surg. 2009;32(4):258–63. pmid:19892631.

79. Hariz MI, Rehncrona S, Quinn NP, Speelman JD, Wensing C, Multicentre Advanced Parkinson’s Disease Deep Brain Stimulation G. Multicenter study on deep brain stimulation in Parkinson’s disease: an independent assessment of reported adverse events at 4 years. Mov Disord. 2008;23(3):416–21. pmid:18067188.

80. Khatib R, Ebrahim Z, Rezai A, Cata JP, Boulis NM, John Doyle D, et al. Perioperative events during deep brain stimulation: the experience at cleveland clinic. J Neurosurg Anesthesiol. 2008;20(1):36–40. pmid:18157023.

81. Wider C, Pollo C, Bloch J, Burkhard PR, Vingerhoets FJ. Long-term outcome of 50 consecutive Parkinson’s disease patients treated with subthalamic deep brain stimulation. Parkinsonism Relat Disord. 2008;14(2):114–9. pmid:17822940.

82. Schuurman PR, Bosch DA, Merkus MP, Speelman JD. Long-term follow-up of thalamic stimulation versus thalamotomy for tremor suppression. Mov Disord. 2008;23(8):1146–53. pmid:18442104.

83. Bhatia S, Oh M, Whiting T, Quigley M, Whiting D. Surgical complications of deep brain stimulation. A longitudinal single surgeon, single institution study. Stereotact Funct Neurosurg. 2008;86(6):367–72. pmid:19033705.

84. Sillay KA, Larson PS, Starr PA. Deep brain stimulator hardware-related infections: incidence and management in a large series. Neurosurgery. 2008;62(2):360–6; discussion 6–7. pmid:18382313.

85. Derost PP, Ouchchane L, Morand D, Ulla M, Llorca PM, Barget M, et al. Is DBS-STN appropriate to treat severe Parkinson disease in an elderly population? Neurology. 2007;68(17):1345–55. pmid:17452578.

86. Seijo FJ, Alvarez-Vega MA, Gutierrez JC, Fdez-Glez F, Lozano B. Complications in subthalamic nucleus stimulation surgery for treatment of Parkinson’s disease. Review of 272 procedures. Acta Neurochir (Wien). 2007;149(9):867–75; discussion 76. pmid:17690838.

87. Chou YC, Lin SZ, Hsieh WA, Lin SH, Lee CC, Hsin YL, et al. Surgical and hardware complications in subthalamic nucleus deep brain stimulation. J Clin Neurosci. 2007;14(7):643–9. pmid:17532500.

88. Vidailhet M, Vercueil L, Houeto JL, Krystkowiak P, Lagrange C, Yelnik J, et al. Bilateral, pallidal, deep-brain stimulation in primary generalised dystonia: a prospective 3 year follow-up study. Lancet Neurol. 2007;6(3):223–9. pmid:17303528.

89. Sansur CA, Frysinger RC, Pouratian N, Fu KM, Bittl M, Oskouian RJ, et al. Incidence of symptomatic hemorrhage after stereotactic electrode placement. J Neurosurg. 2007;107(5):998–1003. pmid:17977273.

90. Ory-Magne F, Brefel-Courbon C, Simonetta-Moreau M, Fabre N, Lotterie JA, Chaynes P, et al. Does ageing influence deep brain stimulation outcomes in Parkinson’s disease? Mov Disord. 2007;22(10):1457–63. pmid:17516457.

91. Vesper J, Haak S, Ostertag C, Nikkhah G. Subthalamic nucleus deep brain stimulation in elderly patients—analysis of outcome and complications. BMC neurology. 2007;7:7. pmid:17367531.

92. Kenney C, Simpson R, Hunter C, Ondo W, Almaguer M, Davidson A, et al. Short-term and long-term safety of deep brain stimulation in the treatment of movement disorders. J Neurosurg. 2007;106(4):621–5. pmid:17432713.

93. Tir M, Devos D, Blond S, Touzet G, Reyns N, Duhamel A, et al. Exhaustive, one-year follow-up of subthalamic nucleus deep brain stimulation in a large, single-center cohort of parkinsonian patients. Neurosurgery. 2007;61(2):297–304; discussion -5. pmid:17762742.

94. Voges J, Hilker R, Botzel K, Kiening KL, Kloss M, Kupsch A, et al. Thirty days complication rate following surgery performed for deep-brain-stimulation. Mov Disord. 2007;22(10):1486–9. pmid:17516483.

95. Voges J, Waerzeggers Y, Maarouf M, Lehrke R, Koulousakis A, Lenartz D, et al. Deep-brain stimulation: long-term analysis of complications caused by hardware and surgery—experiences from a single centre. J Neurol Neurosurg Psychiatry. 2006;77(7):868–72. pmid:16574733.

96. Paluzzi A, Belli A, Bain P, Liu X, Aziz TM. Operative and hardware complications of deep brain stimulation for movement disorders. Br J Neurosurg. 2006;20(5):290–5. pmid:17129876.

97. Goodman RR, Kim B, McClelland S 3rd, Senatus PB, Winfield LM, Pullman SL, et al. Operative techniques and morbidity with subthalamic nucleus deep brain stimulation in 100 consecutive patients with advanced Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2006;77(1):12–7. pmid:16361585.

98. Kupsch A, Benecke R, Muller J, Trottenberg T, Schneider GH, Poewe W, et al. Pallidal deep-brain stimulation in primary generalized or segmental dystonia. N Engl J Med. 2006;355(19):1978–90. pmid:17093249.

99. Blomstedt P, Hariz MI. Are complications less common in deep brain stimulation than in ablative procedures for movement disorders? Stereotact Funct Neurosurg. 2006;84(2–3):72–81. pmid:16790989.

100. Vidailhet M, Vercueil L, Houeto JL, Krystkowiak P, Benabid AL, Cornu P, et al. Bilateral deep-brain stimulation of the globus pallidus in primary generalized dystonia. N Engl J Med. 2005;352(5):459–67. pmid:15689584.

101. Binder DK, Rau GM, Starr PA. Risk factors for hemorrhage during microelectrode-guided deep brain stimulator implantation for movement disorders. Neurosurgery. 2005;56(4):722–32; discussion -32. pmid:15792511.

102. Constantoyannis C, Berk C, Honey CR, Mendez I, Brownstone RM. Reducing hardware-related complications of deep brain stimulation. Can J Neurol Sci. 2005;32(2):194–200. pmid:16018154.

103. Visser-Vandewalle V, van der Linden C, Temel Y, Celik H, Ackermans L, Spincemaille G, et al. Long-term effects of bilateral subthalamic nucleus stimulation in advanced Parkinson disease: a four year follow-up study. Parkinsonism Relat Disord. 2005;11(3):157–65. pmid:15823480.

104. Schupbach WM, Chastan N, Welter ML, Houeto JL, Mesnage V, Bonnet AM, et al. Stimulation of the subthalamic nucleus in Parkinson’s disease: a 5 year follow up. J Neurol Neurosurg Psychiatry. 2005;76(12):1640–4. pmid:16291886.

105. Blomstedt P, Hariz MI. Hardware-related complications of deep brain stimulation: a ten year experience. Acta Neurochir (Wien). 2005;147(10):1061–4; discussion 4. pmid:16041470.

106. Coubes P, Cif L, El Fertit H, Hemm S, Vayssiere N, Serrat S, et al. Electrical stimulation of the globus pallidus internus in patients with primary generalized dystonia: long-term results. J Neurosurg. 2004;101(2):189–94. pmid:15309907.

107. Temel Y, Ackermans L, Celik H, Spincemaille GH, van der Linden C, Walenkamp GH, et al. Management of hardware infections following deep brain stimulation. Acta Neurochir (Wien). 2004;146(4):355–61; discussion 61. pmid:15057529.

108. Lyons KE, Wilkinson SB, Overman J, Pahwa R. Surgical and hardware complications of subthalamic stimulation: a series of 160 procedures. Neurology. 2004;63(4):612–6. pmid:15326230.

109. Krack P, Batir A, Van Blercom N, Chabardes S, Fraix V, Ardouin C, et al. Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med. 2003;349(20):1925–34. pmid:14614167.

110. Umemura A, Jaggi JL, Hurtig HI, Siderowf AD, Colcher A, Stern MB, et al. Deep brain stimulation for movement disorders: morbidity and mortality in 109 patients. J Neurosurg. 2003;98(4):779–84. pmid:12691402.

111. Herzog J, Volkmann J, Krack P, Kopper F, Potter M, Lorenz D, et al. Two-year follow-up of subthalamic deep brain stimulation in Parkinson’s disease. Mov Disord. 2003;18(11):1332–7. pmid:14639676.

112. Pollak P, Fraix V, Krack P, Moro E, Mendes A, Chabardes S, et al. Treatment results: Parkinson’s disease. Mov Disord. 2002;17 Suppl 3:S75–83. pmid:11948759.

113. Starr PA, Christine CW, Theodosopoulos PV, Lindsey N, Byrd D, Mosley A, et al. Implantation of deep brain stimulators into the subthalamic nucleus: technical approach and magnetic resonance imaging-verified lead locations. J Neurosurg. 2002;97(2):370–87. pmid:12186466.

114. Oh MY, Abosch A, Kim SH, Lang AE, Lozano AM. Long-term hardware-related complications of deep brain stimulation. Neurosurgery. 2002;50(6):1268–74; discussion 74–6. pmid:12015845.

115. Kondziolka D, Whiting D, Germanwala A, Oh M. Hardware-related complications after placement of thalamic deep brain stimulator systems. Stereotact Funct Neurosurg. 2002;79(3–4):228–33. 70836. pmid:12890981.

116. Joint C, Nandi D, Parkin S, Gregory R, Aziz T. Hardware-related problems of deep brain stimulation. Mov Disord. 2002;17 Suppl 3:S175–80. pmid:11948774.

117. Vesper J, Chabardes S, Fraix V, Sunde N, Ostergaard K, Kinetra Study G. Dual channel deep brain stimulation system (Kinetra) for Parkinson’s disease and essential tremor: a prospective multicentre open label clinical study. J Neurol Neurosurg Psychiatry. 2002;73(3):275–80. pmid:12185158.

118. Beric A, Kelly PJ, Rezai A, Sterio D, Mogilner A, Zonenshayn M, et al. Complications of deep brain stimulation surgery. Stereotact Funct Neurosurg. 2001;77(1–4):73–8. 64600. pmid:12378060.

119. Deep-Brain Stimulation for Parkinson’s Disease Study G. Deep-brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in Parkinson’s disease. N Engl J Med. 2001;345(13):956–63. pmid:11575287.

120. Koller WC, Lyons KE, Wilkinson SB, Troster AI, Pahwa R. Long-term safety and efficacy of unilateral deep brain stimulation of the thalamus in essential tremor. Mov Disord. 2001;16(3):464–8. pmid:11391740.

121. Benabid AL, Krack PP, Benazzouz A, Limousin P, Koudsie A, Pollak P. Deep brain stimulation of the subthalamic nucleus for Parkinson’s disease: methodologic aspects and clinical criteria. Neurology. 2000;55(12 Suppl 6):S40–4. pmid:11188974.

122. Rughani AI, Hodaie M, Lozano AM. Acute complications of movement disorders surgery: Effects of age and comorbidities. Mov Disord. 2013. pmid:23861366.

123. Gorgulho A, De Salles AA, Frighetto L, Behnke E. Incidence of hemorrhage associated with electrophysiological studies performed using macroelectrodes and microelectrodes in functional neurosurgery. J Neurosurg. 2005;102(5):888–96. pmid:15926715.

124. Syburra T, Schurr U, Rahn M, Graves K, Genoni M. Gold-coated pacemaker implantation after allergic reactions to pacemaker compounds. Europace: European pacing, arrhythmias, and cardiac electrophysiology: journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. 2010;12(5):749–50. pmid:20022879.

125. Hayes DL, Loesl K. Pacemaker component allergy: case report and review of the literature. Journal of interventional cardiac electrophysiology: an international journal of arrhythmias and pacing. 2002;6(3):277–8. pmid:12154330.

126. Dery JP, Gilbert M, O’Hara G, Champagne J, Desaulniers D, Cartier P, et al. Pacemaker contact sensitivity: case report and review of the literature. Pacing and clinical electrophysiology: PACE. 2002;25(5):863–5. pmid:12049383.

127. Bhatia R, Dalton A, Richards M, Hopkins C, Aziz T, Nandi D. The incidence of deep brain stimulator hardware infection: the effect of change in antibiotic prophylaxis regimen and review of the literature. Br J Neurosurg. 2011;25(5):625–31. pmid:21501065.

128. Thrane JF, Sunde NA, Bergholt B, Rosendal F. Increasing infection rate in multiple implanted pulse generator changes in movement disorder patients treated with deep brain stimulation. Stereotact Funct Neurosurg. 2014;92(6):360–4. pmid:25358956.

129. Fytagoridis A, Heard T, Samuelsson J, Zsigmond P, Jiltsova E, Skyrman S, et al. Surgical Replacement of Implantable Pulse Generators in Deep Brain Stimulation: Adverse Events and Risk Factors in a Multicenter Cohort. Stereotact Funct Neurosurg. 2016;94(4):235–9. pmid:27554079.

130. Schwalb JM, Riina HA, Skolnick B, Jaggi JL, Simuni T, Baltuch GH. Revision of deep brain stimulator for tremor. Technical note. J Neurosurg. 2001;94(6):1010–2. pmid:11409503.

131. Hamel W, Schrader B, Weinert D, Herzog J, Muller D, Deuschl G, et al. Technical complication in deep brain stimulation. Zentralbl Neurochir. 2002;63(3):124–7. pmid:12457339.

132. Rolston JD, Englot DJ, Starr PA, Larson PS. An unexpectedly high rate of revisions and removals in deep brain stimulation surgery: Analysis of multiple databases. Parkinsonism Relat Disord. 2016;33:72–7. pmid:27645504.