Subthalamic nucleus deep brain stimulation with a multiple independent constant current-controlled device in Parkinson's disease (INTREPID): a multicentre, double-blind, randomised, sham-controlled study.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus is an established therapeutic option for managing motor symptoms of Parkinson's disease. We conducted a double-blind, sham-controlled, randomised controlled trial to assess subthalamic nucleus DBS, with a novel multiple independent contact current-controlled (MICC) device, in patients with Parkinson's disease. METHODS: This trial took place at 23 implanting centres in the USA. Key inclusion criteria were age between 22 and 75 years, a diagnosis of idiopathic Parkinson's disease with over 5 years of motor symptoms, and stable use of anti-parkinsonian medications for 28 days before consent. Patients who passed screening criteria were implanted with the DBS device bilaterally in the subthalamic nucleus. Patients were randomly assigned in a 3:1 ratio to receive either active therapeutic stimulation settings (active group) or subtherapeutic stimulation settings (control group) for the 3-month blinded period. Randomisation took place with a computer-generated data capture system using a pre-generated randomisation table, stratified by site with random permuted blocks. During the 3-month blinded period, both patients and the assessors were masked to the treatment group while the unmasked programmer was responsible for programming and optimisation of device settings. The primary outcome was the difference in mean change from baseline visit to 3 months post-randomisation between the active and control groups in the mean number of waking hours per day with good symptom control and no troublesome dyskinesias, with no increase in anti-parkinsonian medications. Upon completion of the blinded phase, all patients received active treatment in the open-label period for up to 5 years. Primary and secondary outcomes were analysed by intention to treat. All patients who provided informed consent were included in the safety analysis. The open-label phase is ongoing with no new enrolment, and current findings are based on the prespecified interim analysis of the first 160 randomly assigned patients. The study is registered with ClinicalTrials.gov, NCT01839396. FINDINGS: Between May 17, 2013, and Nov 30, 2017, 313 patients were enrolled across 23 sites. Of these 313 patients, 196 (63%) received the DBS implant and 191 (61%) were randomly assigned. Of the 160 patients included in the interim analysis, 121 (76%) were randomly assigned to the active group and 39 (24%) to the control group. The difference in mean change from the baseline visit (post-implant) to 3 months post-randomisation in increased ON time without troublesome dyskinesias between the active and control groups was 3·03 h (SD 4·52, 95% CI 1·3-4·7; p<0·0001). 26 serious adverse events in 20 (13%) patients occurred during the 3-month blinded period. Of these, 18 events were reported in the active group and 8 in the control group. One death was reported among the 196 patients before randomisation, which was unrelated to the procedure, device, or stimulation. INTERPRETATION: This double-blind, sham-controlled, randomised controlled trial provides class I evidence of the safety and clinical efficacy of subthalamic nucleus DBS with a novel MICC device for the treatment of motor symptoms of Parkinson's disease. Future trials are needed to investigate potential benefits of producing a more defined current field using MICC technology, and its effect on clinical outcomes. FUNDING: Boston Scientific.

Long-Term Task- and Dopamine-Dependent Dynamics of Subthalamic Local Field Potentials in Parkinson's Disease.

Subthalamic nucleus (STN) local field potentials (LFP) are neural signals that have been shown to reveal motor and language behavior, as well as pathological parkinsonian states. We use a research-grade implantable neurostimulator (INS) with data collection capabilities to record STN-LFP outside the operating room to determine the reliability of the signals over time and assess their dynamics with respect to behavior and dopaminergic medication. Seven subjects were implanted with the recording augmented deep brain stimulation (DBS) system, and bilateral STN-LFP recordings were collected in the clinic over twelve months. Subjects were cued to perform voluntary motor and language behaviors in on and off medication states. The STN-LFP recorded with the INS demonstrated behavior-modulated desynchronization of beta frequency (13-30 Hz) and synchronization of low gamma frequency (35-70 Hz) oscillations. Dopaminergic medication did not diminish the relative beta frequency oscillatory desynchronization with movement. However, movement-related gamma frequency oscillatory synchronization was only observed in the medication on state. We observed significant inter-subject variability, but observed consistent STN-LFP activity across recording systems and over a one-year period for each subject. These findings demonstrate that an INS system can provide robust STN-LFP recordings in ambulatory patients, allowing for these signals to be recorded in settings that better represent natural environments in which patients are in a variety of medication states.

Rapid assessment of gait and speech after subthalamic deep brain stimulation.

BACKGROUND: Describe a rapid assessment for patients with idiopathic Parkinson's disease (PD) and deep brain stimulation of the subthalamic nucleus reporting worsening speech and/or gait problems. METHODS: We retrospectively reviewed 29 patients that had improvement in gait and/or speech within 30 min after turning stimulation off. Clinical data analyzed include unified PD rating scale motor scores and stimulation parameters before and after adjusting stimulation. All patients received electrode efficacy and side effect threshold testing. Stimulation parameters were adjusted to maximize efficacy, avoid side effects, and maximize battery longevity. RESULTS: Turning stimulation off revealed reversible speech and/or gait stimulation side effects within 30 min. Focusing on six factors revealed stimulation modifications that improved motor symptoms, eliminated stimulation side effects, and reduced battery drain. Primary stimulation parameters modified were cathode selection and pulse width reduction. CONCLUSIONS: Stimulation-induced side effects impacting gait and speech can be identified within 30 min. A systematic evaluation can distinguish disease progression from reversible stimulation side effects and improve motor outcomes over the long term.

Model-Based Deep Brain Stimulation Programming for Parkinson's Disease: The GUIDE Pilot Study.

BACKGROUND: Achieving optimal results following deep brain stimulation (DBS) typically involves several months of programming sessions. The Graphical User Interface for DBS Evaluation (GUIDE) study explored whether a visual programming system could help clinicians accurately predetermine ideal stimulation settings in DBS patients with Parkinson's disease. METHODS: A multicenter prospective, observational study was designed that utilized a blinded Unified Parkinson's Disease Rating Scale (UPDRS)-III examination to prospectively assess whether DBS settings derived using a neuroanatomically based computer model (Model) could provide comparable efficacy to those determined through traditional, monopolar review-based programming (Clinical). We retrospectively compared the neuroanatomical regions of stimulation, power consumption and time spent on programming using both methods. RESULTS: The average improvement in UPDRS-III scores was 10.4 ± 7.8 for the Model settings and 11.7 ± 8.7 for the Clinical settings. The difference between the mean UPDRS-III scores with the Model versus the Clinical settings was 0.26 and not statistically significant (p = 0.9866). Power consumption for the Model settings was 48.7 ± 22 µW versus 76.1 ± 46.5 µW for the Clinical settings. The mean time spent programming using the Model approach was 31 ± 16 s versus 41.4 ± 29.1 min using the Clinical approach. CONCLUSION: The Model-based DBS settings provided similar benefit to the Clinical settings based on UPDRS-III scores and were often arrived at in less time and required less power than the Clinical settings.

Retrospective review of factors leading to dissatisfaction with subthalamic nucleus deep brain stimulation during long-term management.

BACKGROUND: Subthalamic nucleus deep brain stimulation is effective in reducing motor symptoms in appropriately selected patients with Parkinson's disease. We identified factors that contribute to poor outcomes during early, middle and late stages of stimulation management in a series of patients that were referred for troubleshooting poor outcomes. METHODS: We performed a retrospective review of 50 patients with bilateral STN DBS seen in our movement disorders clinic with unsatisfactory clinical response and/or patient dissatisfaction with deep brain stimulation outcome. All patients underwent a systematic evaluation to assess the primary cause of suboptimal outcome including lead position, hardware integrity, patient selection, patient expectations, effective use of stimulation settings, and pre- and postoperative levodopa responsive symptoms. The data was also analyzed by duration of stimulation to determine if these factors varied by stage of DBS management. RESULTS: Our series included patients implanted 4-68 months. We identified the following primary factors impacting outcome: Suboptimal stimulation settings (52%), disease progression (16%), inappropriate patient selection (10%), hardware damage (8%), lead malposition (8%), met expected motor outcomes (6%). Lead revision surgery occurred in 14%. Reversible factors accounted for dissatisfaction in 74%. Suboptimal stimulation was the dominant factor affecting outcomes in early and long-term management phases. CONCLUSION: STN DBS outcomes can be improved even years after implantation. Stimulation parameters warrant investigation throughout the continuum of DBS management as a reversible cause of poor outcomes.

Psychosis from subthalamic nucleus deep brain stimulator lesion effect.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) in particular is highly effective in relieving symptoms of Parkinson's disease (PD). However, it can also have marked psychiatric side effects, including delirium, mania, and psychosis. The etiologies of those effects are not well-understood, and both surgeons and consulting psychiatrists are in need of treatment strategies. CASE DESCRIPTION: Two patients with young onset of PD and without significant prior psychiatric problems presented for bilateral STN DBS when medications became ineffective. Both had uneventful operative courses but developed florid psychosis 1-2 weeks later, before stimulator activation. Neither showed signs of delirium, but both required hospitalization, and one required treatment with a first-generation antipsychotic drug. Use of that drug did not worsen PD symptoms, contrary to usual expectations. CONCLUSION: These cases describe a previously unreported post-DBS syndrome in which local tissue reaction to lead implantation produces psychosis even without electrical stimulation of subcortical circuits. The lesion effect also appears to have anti-Parkinsonian effects that may allow the safe use of otherwise contraindicated medications. These cases have implications for management of PD DBS patients postoperatively, and may also be relevant as DBS is further used in other brain regions to treat behavioral disorders.

Lead wire fracture associated with normal therapeutic impedance measurements in a patient with a kinetra neurostimulator.

Objectives. We present a case report of a patient with complete lead wire fracture with approximately 3-mm separation of the wire fragments that had three electrode impedance measurements and therapy impedance measurement that would be consistent with an intact wire. Materials and Methods. Retrospective chart review. Results. The patient experienced abrupt worsening of gait freezing while tremor control remained stable. Despite normal therapeutic impedance measurement, clinical suspicion for a hardware problem remained due to her description of brief dystonic hand posturing witnessed during impedance measurements in the clinic. This led to further diagnostic evaluation and eventual surgical replacement of the lead wire. Conclusions. Impedance measurements are not absolutely reliable for the detection of hardware malfunction in a patient with a Kinetra neurostimulator.

Deep brain stimulation and the ethics of protection and caring for the patient with Parkinson's dementia.

Deep brain stimulation (DBS) is an effective neurosurgical treatment for patients with advanced Parkinson's disease (PD) suffering from motor complications that are refractory to further medication management. DBS requires an invasive procedure of implanting brain electrodes while awake, followed by implantation of neurostimulators under general anesthesia. The neurostimulator requires battery monitoring and replacement approximately every 3 to 5 years. These two elements of the technology provide numerous decision points about continuing therapies that can involve ethical choices. Although motor function can be improved with subthalamic nucleus (STN) DBS, the long-term risks of living with implanted hardware should be carefully evaluated for patients with diminishing cognitive capacity. We describe two cases where ethical dilemmas occurred postoperatively as a result of cognitive decline and describe salient ethical dimensions that illustrate the need for a proactive postoperative plan for supervision as a prerequisite for surgery to include neuropsychological testing to predict the likelihood of net benefit to the patient and family beyond just motor improvement.

Gait changes after deep brain stimulation for Parkinson's disease in a patient with cervical myelopathy.

Subthalamic (STN) deep brain stimulation (DBS) is an effective treatment for advanced Parkinson's disease. We present a patient with significant gait problems due to Parkinson's disease (PD) who underwent STN DBS. Gait worsened after surgery despite significant improvement in parkinsonian signs, due to underlying spasticity previously overshadowed by his parkinsonian motor symptoms. This case illustrates an emergence of dysfunction in gait in a patient with otherwise improved function and reinforces the need for an interdisciplinary approach to care of these patients.

Deep brain stimulation hardware complications: the role of electrode impedance and current measurements.

Deep brain stimulation (DBS) is an effective therapy for advanced Parkinson's disease patients. Successful DBS outcomes depend on appropriate patient selection, surgical placement of the lead, intact hardware systems, optimal programming, and medical management. Despite its importance, there is little guidance in reference to hardware monitoring, hardware troubleshooting, and patient management. Technical manuals produced by the hardware manufacturer (Medtronic, Minneapolis, MN) are not presented in an applied clinical format, making impedance and current measurements difficult to interpret when the results are not straightforward. We present four patients with evolving DBS hardware complications that occurred during long-term follow-up, that shaped our clinical protocol for long-term care management and hardware troubleshooting.