Clinical Study Received: July 14, 2014 Accepted: September 18, 2014 Published online: February 18, 2015
Stereotact Funct Neurosurg 2015;93:114–121 DOI: 10.1159/000368443
Constant Current versus Constant Voltage Subthalamic Nucleus Deep Brain Stimulation in Parkinson’s Disease Fernando Ramirez de Noriega a Renana Eitan b Odeya Marmor d Adi Lavi b Eduard Linetzky c Hagai Bergman d Zvi Israel a
a
Centre for Functional and Restorative Neurosurgery, Department of Neurosurgery, and Departments of Psychiatry and c Neurology, Hadassah Hebrew University Hospital, and d Department of Medical Neurobiology (Physiology), Canada-Israel Institute for Medical Research, Hebrew University Hadassah Medical School, Jerusalem, Israel
Key Words Current · Voltage · Parkinson’s disease · Subthalamic stimulation
Abstract Background: Subthalamic nucleus (STN) deep brain stimulation (DBS) is an established therapy for advanced Parkinson’s disease (PD). Motor efficacy and safety have been established for constant voltage (CV) devices and more recently for constant current (CC) devices. CC devices adjust output voltage to provide CC stimulation irrespective of impedance fluctuation, while the current applied by CV stimulation depends on the impedance that may change over time. No study has directly compared the clinical effects of these two stimulation modalities. Objective: To compare the safety and clinical impact of CC STN DBS to CV STN DBS in patients with advanced PD 2 years after surgery. Methods: Patients were eligible for inclusion if they had undergone STN DBS surgery for idiopathic PD, had been implanted with a Medtronic Activa PC and if their stimulation program and medication had been stable for at least 1 year. This singlecenter trial was designed as a double-blind, randomized, prospective study with crossover after 2 weeks. Motor equiv-
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alence of the 2 modalities was confirmed utilizing part III of the Unified Parkinson’s Disease Rating Scale (UPDRS). PD diaries and multiple subjective and objective evaluations of quality of life, depression, cognition and emotional processing were evaluated on both CV and on CC stimulation. Analysis using the paired t test with Bonferroni correction for multiple comparisons was performed to identify any significant difference between the stimulation modalities. Results: 8 patients were recruited (6 men, 2 women); 1 patient did not complete the study. The average age at surgery was 56.7 years (range 47–63). Disease duration at the time of surgery was 7.5 years (range 3–12). Patients were recruited 23.8 months (range 22.5–24) after surgery. At the postoperative study baseline, this patient group showed an average motor improvement of 69% (range 51–97) as measured by the change in UPDRS part III with stimulation alone. Levodopa equivalent medication was reduced on average by 67% (range 15–88). Patients were poorly compliant with PD diaries, and these did not yield useful information. The minor deterioration in quality-of-life scores (Parkinson’s Disease Questionnaire-39, Quality of Life Enjoyment and Satisfaction Questionnaire) with CC stimulation were not statistically significant. Two measures of depression (Hamilton Rating Scale D17, Quick Inventory of Depressive Symptomatology – Self-
Zvi Israel, BSc, MBBS Department of Neurosurgery Hadassah Hebrew University Hospital Jerusalem 91120 (Israel) E-Mail israelz @ hadassah.org.il
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b
Introduction
Deep brain stimulation (DBS) is an established therapy for certain neurological and psychiatric disorders. Class I evidence shows that subthalamic nucleus (STN) DBS is more effective than best medical therapy for Parkinson’s disease (PD) [1, 2] and can now be recommended at an earlier stage of the disease, thus possibly even changing the natural course of the disease [3] and significantly improving survival [4]. Globus pallidus internus stimulation for primary dystonia results in an improvement rate of up to 70% [5] and is considered the main surgical treatment for this pathology. Symptom improvement in essential tremor is well documented. There are many other promising neurological and psychiatric applications of DBS. The clinical effects of DBS result from the delivery of electrical charge to brain tissue. Implantable pulse generators (IPGs) may differ in the way this electrical charge is delivered depending on whether voltage or electrical current is controlled [6]. IPGs apply asymmetrical biphasic charge-balanced pulses of electrical stimulation in which voltage or current increases from zero to a maximum value for a period of time (order of tens of microseconds), drops below zero and then returns to zero. Constant voltage (CV) IPGs control the maximum voltage associated with each pulse. The maximum current will vary, depending on the impedance which can be understood as the opposition to the flow of electrical current in a nonlinear circuit. A specific voltage is programmed, and the amount of electrical current delivered will depend on the impedance. Thus, the voltage will not indicate how much electrical charge reaches the tissue, as this parameter will be determined by the impedance. In contrast, constant current (CC) IPGs provide a specific electrical current and will automatically adjust the voltage depending on the impedance. The amount of electrical charge reaching the tissue will thus remain uniform during the Electrical Mode of Deep Brain Stimulation
pulse regardless of differences or changes in the impedance. Impedance is determined by the intrinsic properties of the electrode and the electrode-brain tissue interface. Impedance is further influenced by many variables including the frequency and waveform of the stimulation [6], the time from implantation [7], from onset of stimulation and even the implanted target [8]. Collectively, the factors contributing to the impedance of the DBS system play an important role in the shape of the stimulation waveform and in the amount of electrical charge reaching the tissue. In vivo [9] and modeling experiments [10] have shown that the waveform generated in the brain tissue by CC stimulation closely resembles the output of the IPG, reaching the peak amplitude almost immediately and remaining approximately constant until the end of the pulse. In contrast, the waveform generated by CV stimulation may also reach the peak amplitude at onset, but then quickly declines toward the end of the pulse [11] (fig. 1a, b). Until recently, only CV IPGs were available for DBS. Newer generations of IPGs are now available that can provide either CV or CC. The safety and efficacy of CC DBS in newly operated PD patients has been established [12]. The main benefit of CC stimulation is thought to be in the initial phase after surgery (weeks to months) when impedances change most rapidly, primarily as the result of changes at the electrode-brain tissue interface [7, 8]. This may shorten the time needed to reach optimal programming [13]. Our study was designed to address the unresolved question of whether the modality of delivery of electrical charge in any way alters the clinical benefit or side effects of stimulation. To control for impedance changes, this study was conducted 2 years after surgery, when the chronic impedance values are thought to be established [14, 15]. Thus, the clinical effects of differing stimulus waveform could be studied in isolation.
Methods Participants Patients included in the study had undergone bilateral STN DBS for advanced idiopathic PD in the Functional Neurosurgery Center at Hadassah Hebrew University Hospital. Patients fulfilled standard preoperative criteria for DBS surgery. Surgery was performed as previously described [16]. Patients were implanted with a Medtronic Activa PCTM device (FDA, CE, 2009). This IPG allows the delivery of electrical energy either by way of CC or CV, thus patients could act as their own controls. Postoperatively, the patients’ stimulation program and medication had to have been stable for at least 1 year to be eligible for inclusion.
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Report) showed a nonsignificant lower score (less depression) with CC stimulation, but a third (Beck Depression Inventory) showed equivalence. Cognitive testing (Mini Mental State Examination) and emotional processing (Montreal Affective Voices) were equivalent for CC and CV. Conclusion: CC STN DBS is safe. For equivalent motor efficacy, no significant difference could be identified between CC and CV stimulation for nonmotor evaluations in PD patients 2 years after surgery. © 2015 S. Karger AG, Basel
b
Fig. 1. The in vitro (saline) current waveform generated (dark gray; red in the online version) by CV stimulation (a) and CC stimulation (b) using a relatively wide pulse width. In vivo, with a higher
impedance and narrower pulse width, the current decay in a CVgenerated pulse might be less. Courtesy of Medtronic, Neuro Division, Minneapolis, Minn., USA.
Study Design The study was designed as a double-blind, randomized, prospective single-center clinical trial with crossover at the end of the second week of the 4-week follow-up (fig. 2). The study protocol was approved by the institutional review board of Hadassah University Hospital (No. 0379-11-HMO) in compliance with the Helsinki regulations and registered with the NIH database (ClinicalTrials.gov identifier: NCT01423565). Written informed consent was obtained from all patients before any study procedures were started. Patients were initially evaluated using the Unified Parkinson’s Disease Rating Scale (UPDRS) in a 4-condition sequence: • off anti-PD medication condition (after 12-hour medication withdrawal) and on stimulation (with the patient’s original electronic modality and stimulation parameters); • off anti-PD medication condition and off stimulation (60 min after turning off stimulation); • off stimulation and on anti-PD medication, after an acute levodopa challenge when the patient reached a self-declared ‘on’; • Finally, the stimulation was restarted using the original parameters (on anti-PD medication and on stimulation condition).
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Statistical Analysis Analysis of data was performed using a 2-tailed paired t test with a custom-designed program on a MATLAB platform. The Bonferroni correction for multiple comparisons was applied to the p values to reduce the chance of a type 1 error. Significance was defined as a p value ≤0.05. The null hypothesis to be tested was that there was no difference between the outcomes for CC and CV stimulation.
Results
Eight patients, 6 men and 2 women, were recruited. One patient was admitted for pneumonia after randomization and opted not to complete the trial. Six patients had had simultaneous bilateral implantation, and 2 patients had been operated in staged procedures. There were no perioperative complications. The patient average Ramirez de Noriega et al.
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a
On the same visit, in the on-on state, the patient underwent cognitive and psychiatric evaluation which included assessment of depressive state: Hamilton Rating Scale (HAM-D17) [17, 18], Beck Depression Inventory (BDI) [19] and Quick Inventory of Depressive Symptomatology – Self-Report (QIDS-SR) [20]. The Parkinson’s Disease Questionnaire (PDQ-39) [21] and the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) [22] were used to assess quality of life. Cognitive state was evaluated using the Mini Mental State Examination (MMSE) [23]. Emotional processing was assessed using a Hebrew version of the Montreal Affective Voices paradigm [24, 25], a validated set of nonlinguistic emotional vocal expressions for research on auditory affective processing. The patient was then blindly randomized to one of two groups: • Group A: the patient’s original electronic modality was changed from CV to CC or from CC to CV. The amplitude of current or voltage to apply was titrated for the best clinical effect and fewest related side effects. No changes in frequency, pulse width, electrode combination or polarity were made. The purpose in this was to insure that the impedance of the two programs would remain as similar as possible (different contacts and contact combinations may have different impedances; impedance is also frequency dependent). • Group B: the patients remained on their original electronic modality with the same stimulation parameters. Patients in this group had their IPG interrogated in order to maintain the patient blinding; a new program was defined and prepared for the crossover phase, but not activated. The patients were instructed on how to fill out PD diaries [26] for the self-assessment of tremor, bradykinesia and dyskinesia. After a 2-week period, the patients were re-evaluated in the outpatient department by the same blinded clinicians and using the same test routine as at baseline. Prior to discharge from this visit, the subjects underwent crossover between the previously described randomized groups by the same unblinded clinician. After a second 2-week period, the patients were evaluated again in an identical fashion. At this point the patients were unblinded and allowed to choose between modalities.
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Study design
2 weeks
Surgery
2 weeks
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Crossover
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side, and 2 patients were on bilateral ‘bimonopolar’ stimulation programs. The average stimulation parameters were 2.56 V (range 1.3–3.5 V) or 3.85 mA (range 3.2–4.5 mA), with an average pulse width of 60 μs and an average frequency of 135 Hz (range 125–170 Hz). The average therapeutic impedance (at the active contact or contacts) was 1,058 Ω (range 851–1,295 Ω) as measured by the EnvisionTM handheld programming computer (Medtronic). At baseline (recruitment), the motor UPDRS evaluation showed an average net response to stimulation
preop OFF meds postop OFF meds, ON stim
preop OFF meds
age was 56.7 years (range 47–63). Disease duration at surgery was 7.5 years (range 3–12). Patients were recruited to the study 23.8 months on average after surgery. At baseline, 6 patients had been programmed to CV stimulation and 1 patient to CC stimulation. Four patients were on simple monopolar programs (i.e. case anode, single contact cathode) bilaterally. The 1 patient on CC stimulation received ‘bimonopolar’ (i.e. case anode with 2 electrode contacts activated as cathodes) on one
of 69% (range 51–97%; fig. 3). This is the percentage improvement compared to the preoperative score and represents the net improvement from STN DBS alone [27]. The average levodopa equivalent dose reduction was 67% (range 15–88%; fig. 3). The average overall motor UPDRS improvement on CV stimulation was 70.5% (range 46–97%) and 66.7% (range 28–88%) on CC stimulation (fig. 4a). The UPDRS III improvement as a result of surgery was highly significant, irrespective of whether this was analyzed for CV or CC. The small difference in UPDRS improvement between CC and CV was not statistically significant and essentially means that the unblinded clinician had titrated the alternate electronic modality efficiently. The nonmotor UPDRS scores on CC and CV are shown in figure 4b. These small differences were not statistically significant. Most patients were noncompliant in filling out and returning complete diaries. Few diaries were complete enough to collect data.
Electrical Mode of Deep Brain Stimulation
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Fig. 3. On the left the average percent improvement in the motor UPDRS score (mean and SEM) at the baseline assessment. This was calculated as and represents the net improvement from STN DBS alone. On the right is the average percent reduction of the levodopa equivalent medication as the result of surgery (error bars show SEM).
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Fig. 2. Chronology and design of the study.
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ments at baseline, on CV and CC stimulation. All assessments were performed while on stimulation and on medication. The yaxis represents the mean score for each test. Error bars show the SEM.
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HAM-D17
When analyzing quality of life, total PDQ-39 scores showed a mean of 54.3 on CV stimulation (range 2–87) and 57.6 on CC stimulation (range 2–90). The mean PDQ-39 change between modalities was 13.9 (range 0–45). The Q-LES-Q showed a mean of 53.9 on CV stimulation (range 51–64) and 52.4 on CC stimulation (range 44–64). The mean Q-LES-Q change between modalities was 2 (range 0–7). None of these differences were statistically significant (fig. 5). On the Hamilton Rating Scale, the mean score for the CC stimulation group was 8.9 (range 1–18) compared to 9.4 (range 0–18) for the CV stimulation group. The mean change between modalities was 1.7 (range 0–4; fig. 5). The QIDS-SR score was 6.7 on CC stimulation (range 2–11) and 7.4 on CV stimulation (range 2–16). The mean change between modalities was 2.1 (range 0–8). The BDI showed a mean score of 30.3 on CC stimulation (range 118
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PDQ-39
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21–38) and 30.3 on CV stimulation (range 22–43). The mean change between modalities was 3.1 (range 0–10; fig. 5). No cognitive difference was shown in the MMSE between CV and CC stimulation. With both modalities, the scores were greater than 25. The CC group showed a mean of 27 (range 22–30) and the CV group a mean of 28 (range 25–30). The mean change between modalities was 1.1 (range 0–4; fig. 5). Emotional processing as assessed with the Montreal Affective Voices paradigm [24] showed that the modality of stimulation had no impact on the accuracy of emotional voice recognition. Five of 7 patients who completed the study elected to stay on the prestudy stimulation modality. The 1 patient who had started on CC stimulation chose to continue with CV stimulation, but has since returned to CC. The Ramirez de Noriega et al.
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Mean score
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Fig. 4. a The mean overall motor UPDRS improvement on CV stimulation was 70.5% (range 46–97%) and 66.7% (range 28–88%) on CC stimulation. This difference was not statistically significant. Error bars show the SEM. b Mean nonmotor UPDRS scores. Error bars show SEM.
The clinical effects of DBS are thought to be charge or current dependent. However, until quite recently, the electronic mode used for DBS IPGs has been based on CV stimulation. When DBS implants were developed in the 1980s, IPGs evolved with technology available at that time for implanted cardiac pacemakers which were intentionally designed as CV devices, with the purpose of greater efficiency, smaller size and improved longevity. Indeed, CV DBS was found to be safe and effective for a number of neurological and psychiatric conditions. Ongoing debate suggested that CC stimulation might offer significant advantages over CV stimulation. Clinical experience with DBS programming shows that patients are often exquisitely sensitive to even small changes in the parameters of stimulation both for desired benefit and undesired side effects. Electrical charge delivery to brain tissue is a function of impedance, and impedance varies with multiple factors related to the electrode, electrodebrain interface and stimulation parameters. Thus, changes of impedance may contribute to nonuniform charge delivery and result in fluctuations of clinical effect, stimulation-induced side effects or even tissue damage. CC stimulation compensates for changes of impedance by automatically adjusting the voltage. It was therefore proposed that CC stimulation, by preventing fluctuations of charge delivery caused by impedance variations, would be relatively safe and advantageous. Indeed, it has been shown in nonhuman primates that compared to CV stimulation, CC stimulation can minimize fluctuations in the voltage distribution generated in the brain even with large changes in electrode impedance [28]. The chronology of impedance fluctuations after DBS electrode implantation has been investigated by several groups in different experimental and clinical situations [7, 8, 14, 28–30]. Clinically relevant impedance increases occur in the first few weeks after implantation, possibly as a result of changes at the electrode-brain interface [31]. Initiating stimulation is accompanied by an acute decrease in impedance over minutes to hours. The clinical
corollary is that frequent programming adjustments are required in the first few weeks after implantation, certainly when using CV mode. It is generally agreed that after several months of chronic continuous stimulation on stable stimulation parameters, there are no further clinically relevant impedance changes. For these reasons, inclusion in this study was restricted to patients who had been stable on their stimulation program and medication for at least 12 months. Impedance will also vary with stimulation parameters and between electrode contacts. It was thus important to replicate as closely as possible the exact program between the two arms of the study. This was achieved by recruiting patients who had been implanted with an IPG capable of delivering electrical charge either by way of CC or CV and using them as their own controls. By controlling for all relevant factors that have an effect on impedance, and using patients as their own controls, this study could assess, in isolation, any potential clinical changes that might arise from different stimulation waveforms. STN DBS is a very powerful therapeutic intervention for the motor features and drug-induced complications of advanced PD. As individuals and as a group, the PD patients included in this study had a very good motor outcome, as demonstrated in the very significant UPDRS improvement and reduction in the levodopa equivalent dose. Motor function as evaluated by part III of the UPDRS could easily be titrated to equivalence for both electronic modalities. Okun et al. [12] have shown that CC stimulation is safe and effective for patients with idiopathic PD after STN DBS with a significant increase in good-quality on time, improvement of the motor UPDRS, depression scales and quality of life scales, together with reduction of levodopa equivalent dose compared to patients after surgery but with no stimulation. Emerging evidence also supports the initial use of CC DBS to reduce the time to clinical stability [13]. Some investigators have implicated STN DBS with a worsening of neurocognitive and psychiatric features of the disease. This may be associated with stimulation reaching nonmotor elements of the STN or with changes of medication or both. Thus, we felt it important to compare the safety and clinical impact of CC STN DBS to CV STN DBS for selected nonmotor features often associated with advanced PD. Across multiple objective and subjective evaluations of cognition, depression, quality of life and activities of daily living, no significant difference was found when changing the electronic modality of stimulation. The Montreal
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Discussion
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other patient who chose to change from CV to CC has remained on CC stimulation, but freely admits that there is no subjective difference. In the absence of any statistical difference for any of the tests administered, the null hypothesis of no significant difference in nonmotor symptoms could not be rejected at a significance level of 5%.
tool [24] can be used to evaluate emotion recognition accuracy before, during and after surgery [25]. PD patients can identify ‘negative’ emotive voices as well as healthy controls, but are significantly less accurate at identifying ‘positive’ emotive voices. Here too, electronic modality had no impact on emotion recognition accuracy. Limitations of the Study The inability to obtain full PD diaries from the patients restricted the possibility to assess the patients’ motor function more globally over a period of time. It is interesting to speculate as to why our patients were noncompliant with the diaries whereas other studies have achieved compliance in a much larger patient cohort [12]. Completing diaries was not a precondition to any other therapy, so lack of incentive may be one explanation. Furthermore, all the patients in this study had a high level of motor functioning and may have viewed continually completing the diaries with zeroes as somewhat futile. Sample size is small. When this study was conceived, it had been intended to recruit approximately 20 patients. Interim results were analyzed after 7 patients by one of the unblinded investigators. As presented here, there appeared to be no significant difference in any of the variables studied. It was appreciated that in order to now hope to show significance in any variable, the study would have to recruit a number of patients that was larger by at least 1 order of magnitude. The protocol had not been easy on some of the participants recruited, having to come off antiparkinsonian medication 3 times in 1 month. It was therefore felt that there was no justification to continue recruitment. In conclusion, this study provides evidence that CC STN DBS is as safe as CV STN DBS for patients 2 years after surgery. For equivalent motor efficacy, no significant difference could be identified between CC and CV stimulation for multiple nonmotor domains in PD patients 2 years after surgery. It would be of great interest to perform a similar study with a larger number of patients from initiation of stimu-
lation and, in addition, to compare parameters including time to clinical stability/plateau, number of outpatient clinic visits and also to determine whether IPG longevity is a function of stimulation modality. Such a study was proposed in 2012 in Princeton at a meeting of the Parkinson Alliance with representatives of the DBS industry. It was concluded that the scope and cost of a large-scale study would not be justified [32]. The findings of this study imply that the clinical effects of DBS in PD may be independent of impulse waveform. However, the differences between CC and CV waveform as observed in vitro may be attenuated in the clinical DBS setting where impedances and frequencies are higher. It has been suggested that more sophisticated pulse waveforms might decrease energy consumption [33, 34]. It is interesting to speculate whether such waveforms might impact differently on diverse neural elements for different clinical effects. Such manipulations may also lend themselves to a more complete understanding of the mechanisms of DBS with important implications for tailored therapy and closed loop DBS.
Acknowledgment This work was supported in part by a research grant from the Bloom Foundation (UK) to Z.I.
Disclosure Statement Z.I. has received educational honoraria from Medtronic. H.B. receives support from the Simone and Bernard Guttman Chair of Brain Research, the European Research Council and the Rosetrees Foundations. H.B. and Z.I. share a research grant from the Adelis Foundation. H.B., R.E. and Z.I. receive research grants from the Israel Science Foundation and US-Israel Binational Scientific Foundation. None of the authors have any conflict of interest related to the research in this paper.
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Stereotact Funct Neurosurg 2015;93:114–121 DOI: 10.1159/000368443
Constant Current versus Constant Voltage Subthalamic Nucleus Deep Brain Stimulation in Parkinson’s Disease Fernando Ramirez de Noriega a Renana Eitan b Odeya Marmor d Adi Lavi b Eduard Linetzky c Hagai Bergman d Zvi Israel a
a
Centre for Functional and Restorative Neurosurgery, Department of Neurosurgery, and Departments of Psychiatry and c Neurology, Hadassah Hebrew University Hospital, and d Department of Medical Neurobiology (Physiology), Canada-Israel Institute for Medical Research, Hebrew University Hadassah Medical School, Jerusalem, Israel
Key Words Current · Voltage · Parkinson’s disease · Subthalamic stimulation
Abstract Background: Subthalamic nucleus (STN) deep brain stimulation (DBS) is an established therapy for advanced Parkinson’s disease (PD). Motor efficacy and safety have been established for constant voltage (CV) devices and more recently for constant current (CC) devices. CC devices adjust output voltage to provide CC stimulation irrespective of impedance fluctuation, while the current applied by CV stimulation depends on the impedance that may change over time. No study has directly compared the clinical effects of these two stimulation modalities. Objective: To compare the safety and clinical impact of CC STN DBS to CV STN DBS in patients with advanced PD 2 years after surgery. Methods: Patients were eligible for inclusion if they had undergone STN DBS surgery for idiopathic PD, had been implanted with a Medtronic Activa PC and if their stimulation program and medication had been stable for at least 1 year. This singlecenter trial was designed as a double-blind, randomized, prospective study with crossover after 2 weeks. Motor equiv-
© 2015 S. Karger AG, Basel 1011–6125/15/0932–0114$39.50/0 E-Mail [email protected] www.karger.com/sfn
alence of the 2 modalities was confirmed utilizing part III of the Unified Parkinson’s Disease Rating Scale (UPDRS). PD diaries and multiple subjective and objective evaluations of quality of life, depression, cognition and emotional processing were evaluated on both CV and on CC stimulation. Analysis using the paired t test with Bonferroni correction for multiple comparisons was performed to identify any significant difference between the stimulation modalities. Results: 8 patients were recruited (6 men, 2 women); 1 patient did not complete the study. The average age at surgery was 56.7 years (range 47–63). Disease duration at the time of surgery was 7.5 years (range 3–12). Patients were recruited 23.8 months (range 22.5–24) after surgery. At the postoperative study baseline, this patient group showed an average motor improvement of 69% (range 51–97) as measured by the change in UPDRS part III with stimulation alone. Levodopa equivalent medication was reduced on average by 67% (range 15–88). Patients were poorly compliant with PD diaries, and these did not yield useful information. The minor deterioration in quality-of-life scores (Parkinson’s Disease Questionnaire-39, Quality of Life Enjoyment and Satisfaction Questionnaire) with CC stimulation were not statistically significant. Two measures of depression (Hamilton Rating Scale D17, Quick Inventory of Depressive Symptomatology – Self-
Zvi Israel, BSc, MBBS Department of Neurosurgery Hadassah Hebrew University Hospital Jerusalem 91120 (Israel) E-Mail israelz @ hadassah.org.il
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Introduction
Deep brain stimulation (DBS) is an established therapy for certain neurological and psychiatric disorders. Class I evidence shows that subthalamic nucleus (STN) DBS is more effective than best medical therapy for Parkinson’s disease (PD) [1, 2] and can now be recommended at an earlier stage of the disease, thus possibly even changing the natural course of the disease [3] and significantly improving survival [4]. Globus pallidus internus stimulation for primary dystonia results in an improvement rate of up to 70% [5] and is considered the main surgical treatment for this pathology. Symptom improvement in essential tremor is well documented. There are many other promising neurological and psychiatric applications of DBS. The clinical effects of DBS result from the delivery of electrical charge to brain tissue. Implantable pulse generators (IPGs) may differ in the way this electrical charge is delivered depending on whether voltage or electrical current is controlled [6]. IPGs apply asymmetrical biphasic charge-balanced pulses of electrical stimulation in which voltage or current increases from zero to a maximum value for a period of time (order of tens of microseconds), drops below zero and then returns to zero. Constant voltage (CV) IPGs control the maximum voltage associated with each pulse. The maximum current will vary, depending on the impedance which can be understood as the opposition to the flow of electrical current in a nonlinear circuit. A specific voltage is programmed, and the amount of electrical current delivered will depend on the impedance. Thus, the voltage will not indicate how much electrical charge reaches the tissue, as this parameter will be determined by the impedance. In contrast, constant current (CC) IPGs provide a specific electrical current and will automatically adjust the voltage depending on the impedance. The amount of electrical charge reaching the tissue will thus remain uniform during the Electrical Mode of Deep Brain Stimulation
pulse regardless of differences or changes in the impedance. Impedance is determined by the intrinsic properties of the electrode and the electrode-brain tissue interface. Impedance is further influenced by many variables including the frequency and waveform of the stimulation [6], the time from implantation [7], from onset of stimulation and even the implanted target [8]. Collectively, the factors contributing to the impedance of the DBS system play an important role in the shape of the stimulation waveform and in the amount of electrical charge reaching the tissue. In vivo [9] and modeling experiments [10] have shown that the waveform generated in the brain tissue by CC stimulation closely resembles the output of the IPG, reaching the peak amplitude almost immediately and remaining approximately constant until the end of the pulse. In contrast, the waveform generated by CV stimulation may also reach the peak amplitude at onset, but then quickly declines toward the end of the pulse [11] (fig. 1a, b). Until recently, only CV IPGs were available for DBS. Newer generations of IPGs are now available that can provide either CV or CC. The safety and efficacy of CC DBS in newly operated PD patients has been established [12]. The main benefit of CC stimulation is thought to be in the initial phase after surgery (weeks to months) when impedances change most rapidly, primarily as the result of changes at the electrode-brain tissue interface [7, 8]. This may shorten the time needed to reach optimal programming [13]. Our study was designed to address the unresolved question of whether the modality of delivery of electrical charge in any way alters the clinical benefit or side effects of stimulation. To control for impedance changes, this study was conducted 2 years after surgery, when the chronic impedance values are thought to be established [14, 15]. Thus, the clinical effects of differing stimulus waveform could be studied in isolation.
Methods Participants Patients included in the study had undergone bilateral STN DBS for advanced idiopathic PD in the Functional Neurosurgery Center at Hadassah Hebrew University Hospital. Patients fulfilled standard preoperative criteria for DBS surgery. Surgery was performed as previously described [16]. Patients were implanted with a Medtronic Activa PCTM device (FDA, CE, 2009). This IPG allows the delivery of electrical energy either by way of CC or CV, thus patients could act as their own controls. Postoperatively, the patients’ stimulation program and medication had to have been stable for at least 1 year to be eligible for inclusion.
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Report) showed a nonsignificant lower score (less depression) with CC stimulation, but a third (Beck Depression Inventory) showed equivalence. Cognitive testing (Mini Mental State Examination) and emotional processing (Montreal Affective Voices) were equivalent for CC and CV. Conclusion: CC STN DBS is safe. For equivalent motor efficacy, no significant difference could be identified between CC and CV stimulation for nonmotor evaluations in PD patients 2 years after surgery. © 2015 S. Karger AG, Basel
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Fig. 1. The in vitro (saline) current waveform generated (dark gray; red in the online version) by CV stimulation (a) and CC stimulation (b) using a relatively wide pulse width. In vivo, with a higher
impedance and narrower pulse width, the current decay in a CVgenerated pulse might be less. Courtesy of Medtronic, Neuro Division, Minneapolis, Minn., USA.
Study Design The study was designed as a double-blind, randomized, prospective single-center clinical trial with crossover at the end of the second week of the 4-week follow-up (fig. 2). The study protocol was approved by the institutional review board of Hadassah University Hospital (No. 0379-11-HMO) in compliance with the Helsinki regulations and registered with the NIH database (ClinicalTrials.gov identifier: NCT01423565). Written informed consent was obtained from all patients before any study procedures were started. Patients were initially evaluated using the Unified Parkinson’s Disease Rating Scale (UPDRS) in a 4-condition sequence: • off anti-PD medication condition (after 12-hour medication withdrawal) and on stimulation (with the patient’s original electronic modality and stimulation parameters); • off anti-PD medication condition and off stimulation (60 min after turning off stimulation); • off stimulation and on anti-PD medication, after an acute levodopa challenge when the patient reached a self-declared ‘on’; • Finally, the stimulation was restarted using the original parameters (on anti-PD medication and on stimulation condition).
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Statistical Analysis Analysis of data was performed using a 2-tailed paired t test with a custom-designed program on a MATLAB platform. The Bonferroni correction for multiple comparisons was applied to the p values to reduce the chance of a type 1 error. Significance was defined as a p value ≤0.05. The null hypothesis to be tested was that there was no difference between the outcomes for CC and CV stimulation.
Results
Eight patients, 6 men and 2 women, were recruited. One patient was admitted for pneumonia after randomization and opted not to complete the trial. Six patients had had simultaneous bilateral implantation, and 2 patients had been operated in staged procedures. There were no perioperative complications. The patient average Ramirez de Noriega et al.
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a
On the same visit, in the on-on state, the patient underwent cognitive and psychiatric evaluation which included assessment of depressive state: Hamilton Rating Scale (HAM-D17) [17, 18], Beck Depression Inventory (BDI) [19] and Quick Inventory of Depressive Symptomatology – Self-Report (QIDS-SR) [20]. The Parkinson’s Disease Questionnaire (PDQ-39) [21] and the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) [22] were used to assess quality of life. Cognitive state was evaluated using the Mini Mental State Examination (MMSE) [23]. Emotional processing was assessed using a Hebrew version of the Montreal Affective Voices paradigm [24, 25], a validated set of nonlinguistic emotional vocal expressions for research on auditory affective processing. The patient was then blindly randomized to one of two groups: • Group A: the patient’s original electronic modality was changed from CV to CC or from CC to CV. The amplitude of current or voltage to apply was titrated for the best clinical effect and fewest related side effects. No changes in frequency, pulse width, electrode combination or polarity were made. The purpose in this was to insure that the impedance of the two programs would remain as similar as possible (different contacts and contact combinations may have different impedances; impedance is also frequency dependent). • Group B: the patients remained on their original electronic modality with the same stimulation parameters. Patients in this group had their IPG interrogated in order to maintain the patient blinding; a new program was defined and prepared for the crossover phase, but not activated. The patients were instructed on how to fill out PD diaries [26] for the self-assessment of tremor, bradykinesia and dyskinesia. After a 2-week period, the patients were re-evaluated in the outpatient department by the same blinded clinicians and using the same test routine as at baseline. Prior to discharge from this visit, the subjects underwent crossover between the previously described randomized groups by the same unblinded clinician. After a second 2-week period, the patients were evaluated again in an identical fashion. At this point the patients were unblinded and allowed to choose between modalities.
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Study design
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Surgery
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side, and 2 patients were on bilateral ‘bimonopolar’ stimulation programs. The average stimulation parameters were 2.56 V (range 1.3–3.5 V) or 3.85 mA (range 3.2–4.5 mA), with an average pulse width of 60 μs and an average frequency of 135 Hz (range 125–170 Hz). The average therapeutic impedance (at the active contact or contacts) was 1,058 Ω (range 851–1,295 Ω) as measured by the EnvisionTM handheld programming computer (Medtronic). At baseline (recruitment), the motor UPDRS evaluation showed an average net response to stimulation
preop OFF meds postop OFF meds, ON stim
preop OFF meds
age was 56.7 years (range 47–63). Disease duration at surgery was 7.5 years (range 3–12). Patients were recruited to the study 23.8 months on average after surgery. At baseline, 6 patients had been programmed to CV stimulation and 1 patient to CC stimulation. Four patients were on simple monopolar programs (i.e. case anode, single contact cathode) bilaterally. The 1 patient on CC stimulation received ‘bimonopolar’ (i.e. case anode with 2 electrode contacts activated as cathodes) on one
of 69% (range 51–97%; fig. 3). This is the percentage improvement compared to the preoperative score and represents the net improvement from STN DBS alone [27]. The average levodopa equivalent dose reduction was 67% (range 15–88%; fig. 3). The average overall motor UPDRS improvement on CV stimulation was 70.5% (range 46–97%) and 66.7% (range 28–88%) on CC stimulation (fig. 4a). The UPDRS III improvement as a result of surgery was highly significant, irrespective of whether this was analyzed for CV or CC. The small difference in UPDRS improvement between CC and CV was not statistically significant and essentially means that the unblinded clinician had titrated the alternate electronic modality efficiently. The nonmotor UPDRS scores on CC and CV are shown in figure 4b. These small differences were not statistically significant. Most patients were noncompliant in filling out and returning complete diaries. Few diaries were complete enough to collect data.
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Fig. 3. On the left the average percent improvement in the motor UPDRS score (mean and SEM) at the baseline assessment. This was calculated as and represents the net improvement from STN DBS alone. On the right is the average percent reduction of the levodopa equivalent medication as the result of surgery (error bars show SEM).
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Fig. 2. Chronology and design of the study.
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ments at baseline, on CV and CC stimulation. All assessments were performed while on stimulation and on medication. The yaxis represents the mean score for each test. Error bars show the SEM.
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When analyzing quality of life, total PDQ-39 scores showed a mean of 54.3 on CV stimulation (range 2–87) and 57.6 on CC stimulation (range 2–90). The mean PDQ-39 change between modalities was 13.9 (range 0–45). The Q-LES-Q showed a mean of 53.9 on CV stimulation (range 51–64) and 52.4 on CC stimulation (range 44–64). The mean Q-LES-Q change between modalities was 2 (range 0–7). None of these differences were statistically significant (fig. 5). On the Hamilton Rating Scale, the mean score for the CC stimulation group was 8.9 (range 1–18) compared to 9.4 (range 0–18) for the CV stimulation group. The mean change between modalities was 1.7 (range 0–4; fig. 5). The QIDS-SR score was 6.7 on CC stimulation (range 2–11) and 7.4 on CV stimulation (range 2–16). The mean change between modalities was 2.1 (range 0–8). The BDI showed a mean score of 30.3 on CC stimulation (range 118
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21–38) and 30.3 on CV stimulation (range 22–43). The mean change between modalities was 3.1 (range 0–10; fig. 5). No cognitive difference was shown in the MMSE between CV and CC stimulation. With both modalities, the scores were greater than 25. The CC group showed a mean of 27 (range 22–30) and the CV group a mean of 28 (range 25–30). The mean change between modalities was 1.1 (range 0–4; fig. 5). Emotional processing as assessed with the Montreal Affective Voices paradigm [24] showed that the modality of stimulation had no impact on the accuracy of emotional voice recognition. Five of 7 patients who completed the study elected to stay on the prestudy stimulation modality. The 1 patient who had started on CC stimulation chose to continue with CV stimulation, but has since returned to CC. The Ramirez de Noriega et al.
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Mean score
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Fig. 4. a The mean overall motor UPDRS improvement on CV stimulation was 70.5% (range 46–97%) and 66.7% (range 28–88%) on CC stimulation. This difference was not statistically significant. Error bars show the SEM. b Mean nonmotor UPDRS scores. Error bars show SEM.
The clinical effects of DBS are thought to be charge or current dependent. However, until quite recently, the electronic mode used for DBS IPGs has been based on CV stimulation. When DBS implants were developed in the 1980s, IPGs evolved with technology available at that time for implanted cardiac pacemakers which were intentionally designed as CV devices, with the purpose of greater efficiency, smaller size and improved longevity. Indeed, CV DBS was found to be safe and effective for a number of neurological and psychiatric conditions. Ongoing debate suggested that CC stimulation might offer significant advantages over CV stimulation. Clinical experience with DBS programming shows that patients are often exquisitely sensitive to even small changes in the parameters of stimulation both for desired benefit and undesired side effects. Electrical charge delivery to brain tissue is a function of impedance, and impedance varies with multiple factors related to the electrode, electrodebrain interface and stimulation parameters. Thus, changes of impedance may contribute to nonuniform charge delivery and result in fluctuations of clinical effect, stimulation-induced side effects or even tissue damage. CC stimulation compensates for changes of impedance by automatically adjusting the voltage. It was therefore proposed that CC stimulation, by preventing fluctuations of charge delivery caused by impedance variations, would be relatively safe and advantageous. Indeed, it has been shown in nonhuman primates that compared to CV stimulation, CC stimulation can minimize fluctuations in the voltage distribution generated in the brain even with large changes in electrode impedance [28]. The chronology of impedance fluctuations after DBS electrode implantation has been investigated by several groups in different experimental and clinical situations [7, 8, 14, 28–30]. Clinically relevant impedance increases occur in the first few weeks after implantation, possibly as a result of changes at the electrode-brain interface [31]. Initiating stimulation is accompanied by an acute decrease in impedance over minutes to hours. The clinical
corollary is that frequent programming adjustments are required in the first few weeks after implantation, certainly when using CV mode. It is generally agreed that after several months of chronic continuous stimulation on stable stimulation parameters, there are no further clinically relevant impedance changes. For these reasons, inclusion in this study was restricted to patients who had been stable on their stimulation program and medication for at least 12 months. Impedance will also vary with stimulation parameters and between electrode contacts. It was thus important to replicate as closely as possible the exact program between the two arms of the study. This was achieved by recruiting patients who had been implanted with an IPG capable of delivering electrical charge either by way of CC or CV and using them as their own controls. By controlling for all relevant factors that have an effect on impedance, and using patients as their own controls, this study could assess, in isolation, any potential clinical changes that might arise from different stimulation waveforms. STN DBS is a very powerful therapeutic intervention for the motor features and drug-induced complications of advanced PD. As individuals and as a group, the PD patients included in this study had a very good motor outcome, as demonstrated in the very significant UPDRS improvement and reduction in the levodopa equivalent dose. Motor function as evaluated by part III of the UPDRS could easily be titrated to equivalence for both electronic modalities. Okun et al. [12] have shown that CC stimulation is safe and effective for patients with idiopathic PD after STN DBS with a significant increase in good-quality on time, improvement of the motor UPDRS, depression scales and quality of life scales, together with reduction of levodopa equivalent dose compared to patients after surgery but with no stimulation. Emerging evidence also supports the initial use of CC DBS to reduce the time to clinical stability [13]. Some investigators have implicated STN DBS with a worsening of neurocognitive and psychiatric features of the disease. This may be associated with stimulation reaching nonmotor elements of the STN or with changes of medication or both. Thus, we felt it important to compare the safety and clinical impact of CC STN DBS to CV STN DBS for selected nonmotor features often associated with advanced PD. Across multiple objective and subjective evaluations of cognition, depression, quality of life and activities of daily living, no significant difference was found when changing the electronic modality of stimulation. The Montreal
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Discussion
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other patient who chose to change from CV to CC has remained on CC stimulation, but freely admits that there is no subjective difference. In the absence of any statistical difference for any of the tests administered, the null hypothesis of no significant difference in nonmotor symptoms could not be rejected at a significance level of 5%.
tool [24] can be used to evaluate emotion recognition accuracy before, during and after surgery [25]. PD patients can identify ‘negative’ emotive voices as well as healthy controls, but are significantly less accurate at identifying ‘positive’ emotive voices. Here too, electronic modality had no impact on emotion recognition accuracy. Limitations of the Study The inability to obtain full PD diaries from the patients restricted the possibility to assess the patients’ motor function more globally over a period of time. It is interesting to speculate as to why our patients were noncompliant with the diaries whereas other studies have achieved compliance in a much larger patient cohort [12]. Completing diaries was not a precondition to any other therapy, so lack of incentive may be one explanation. Furthermore, all the patients in this study had a high level of motor functioning and may have viewed continually completing the diaries with zeroes as somewhat futile. Sample size is small. When this study was conceived, it had been intended to recruit approximately 20 patients. Interim results were analyzed after 7 patients by one of the unblinded investigators. As presented here, there appeared to be no significant difference in any of the variables studied. It was appreciated that in order to now hope to show significance in any variable, the study would have to recruit a number of patients that was larger by at least 1 order of magnitude. The protocol had not been easy on some of the participants recruited, having to come off antiparkinsonian medication 3 times in 1 month. It was therefore felt that there was no justification to continue recruitment. In conclusion, this study provides evidence that CC STN DBS is as safe as CV STN DBS for patients 2 years after surgery. For equivalent motor efficacy, no significant difference could be identified between CC and CV stimulation for multiple nonmotor domains in PD patients 2 years after surgery. It would be of great interest to perform a similar study with a larger number of patients from initiation of stimu-
lation and, in addition, to compare parameters including time to clinical stability/plateau, number of outpatient clinic visits and also to determine whether IPG longevity is a function of stimulation modality. Such a study was proposed in 2012 in Princeton at a meeting of the Parkinson Alliance with representatives of the DBS industry. It was concluded that the scope and cost of a large-scale study would not be justified [32]. The findings of this study imply that the clinical effects of DBS in PD may be independent of impulse waveform. However, the differences between CC and CV waveform as observed in vitro may be attenuated in the clinical DBS setting where impedances and frequencies are higher. It has been suggested that more sophisticated pulse waveforms might decrease energy consumption [33, 34]. It is interesting to speculate whether such waveforms might impact differently on diverse neural elements for different clinical effects. Such manipulations may also lend themselves to a more complete understanding of the mechanisms of DBS with important implications for tailored therapy and closed loop DBS.
Acknowledgment This work was supported in part by a research grant from the Bloom Foundation (UK) to Z.I.
Disclosure Statement Z.I. has received educational honoraria from Medtronic. H.B. receives support from the Simone and Bernard Guttman Chair of Brain Research, the European Research Council and the Rosetrees Foundations. H.B. and Z.I. share a research grant from the Adelis Foundation. H.B., R.E. and Z.I. receive research grants from the Israel Science Foundation and US-Israel Binational Scientific Foundation. None of the authors have any conflict of interest related to the research in this paper.
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