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.

Thalamic Deep Brain Stimulation for tremor: The critical role of intraoperative testing.

INTRODUCTION: Optimal placement of Deep Brain Stimulation (DBS) lead is critical to ensure an adequate therapeutic benefit and minimize stimulation-induced side effects. METHODS: We reviewed data from 2004 to 2018 of all cases of essential tremor treated with thalamic DBS at the University of Cincinnati. All procedures were performed with the patient awake. Change in parallel trajectory was classified as major repositioning, whereas a change in depth of electrode classified as minor repositioning. The following data were compared between groups (no vs. minor vs. major repositioning): age at surgery, sex, AC-PC length, third ventricle width, cerebral atrophy, small vessel disease burden, and intraoperative tremor control. Univariate and multivariate analyses were conducted to identify factors associated with intraoperative repositioning. RESULTS: Of the 127 encounters with essential tremor, 71 required repositioning (33 major and 38 minor). Comparing procedures with major, minor, and no repositioning, mean number of changes per procedure (4 vs. 1.2 vs 0; p < 0.001) and AC-PC length (26 vs. 27 vs. 27.2 mm; p = 0.021) differed between the three groups. Older age at surgery (OR 1.04, p = 0.042), left side (OR 2.56, p = 0.04) and decrease in AC-PC length (OR 1.33, p = 0.026) were associated with greater odds of any (minor or major) repositioning. A decrease in AC-PC length was associated with greater odds of major repositioning (OR 1.37, p = 0.009). CONCLUSION: Intraoperative functional testing may be critical to ensure the accuracy of thalamic DBS targeting based on neuroimaging data, particularly in patients with reduced AC-PC length.

Spinal cord stimulation failure: evaluation of factors underlying hardware explantation.

OBJECTIVE: Spinal cord stimulation has been shown to improve pain relief and reduce narcotic analgesic use in cases of complex refractory pain syndromes. However, a subset of patients ultimately undergoes removal of the spinal cord stimulator (SCS) system, presumably because of surgical complications or poor efficacy. This retrospective study addresses the paucity of evidence regarding risk factors and underlying causes of spinal cord stimulation failures that necessitate this explantation. METHODS: In this retrospective single-center review, 129 patients underwent explantation of SCS hardware during a 9-year period (2005-2013) following initial placement at the authors' institution or elsewhere. Medical history, including indication of implantation, device characteristics, revision history, and reported reasons for removal of hardware, were reviewed. RESULTS: The 74 (57%) women and 55 (43%) men were a median of 49 years old (IQR 41-61 years) at explantation; the median time to explantation was 20 months (IQR 7.5-45.5 months). Thoracic or upper lumbar leads were placed in 89.9% of patients primarily for the diagnosis of postsurgical failed-back surgery syndrome (70.5%), chronic regional pain syndrome (14.7%), and neuropathic pain (8.5%). More than half of patients were legally disabled. Initial postoperative reduction in pain was reported in 81% of patients, and 37.8% returned to work. Among 15 patients with acute postsurgical complications (12 infections, 2 hemorrhages, 1 immediate paraplegia), the median time to removal was 2 months. Primary reasons for hardware removal were lack of stimulation efficacy (81%), electrode failure due to migration (14%), and allergic reactions to implanted hardware in 2 patients. The 72 patients who underwent formal psychiatric evaluation before implantation were affected by high rates of major depression (64%), anxiety (34%), posttraumatic stress disorder (PTSD) (12%), drug or alcohol abuse (12%), and physical or sexual abuse (22%). CONCLUSIONS: The authors' findings provide insight regarding the mechanisms of spinal cord stimulation failure that resulted in total removal of the implanted system. The relationship between spinal cord stimulation failure and certain psychiatric disorders, such as PTSD, depression, and anxiety, is highlighted. Ultimately, this work may shed light on potential avenues to reduce morbidity and improve patient outcomes.

Deep brain stimulation in uncommon tremor disorders: indications, targets, and programming.

BACKGROUND: In uncommon tremor disorders, clinical efficacy and optimal anatomical targets for deep brain stimulation (DBS) remain inadequately studied and insufficiently quantified. METHODS: We performed a systematic review of PubMed.gov and ClinicalTrials.gov. Relevant articles were identified using the following keywords: "tremor", "Holmes tremor", "orthostatic tremor", "multiple sclerosis", "multiple sclerosis tremor", "neuropathy", "neuropathic tremor", "fragile X-associated tremor/ataxia syndrome", and "fragile X." RESULTS: We identified a total of 263 cases treated with DBS for uncommon tremor disorders. Of these, 44 had Holmes tremor (HT), 18 orthostatic tremor (OT), 177 multiple sclerosis (MS)-associated tremor, 14 neuropathy-associated tremor, and 10 fragile X-associated tremor/ataxia syndrome (FXTAS). DBS resulted in favorable, albeit partial, clinical improvements in HT cases receiving Vim-DBS alone or in combination with additional targets. A sustained improvement was reported in OT cases treated with bilateral Vim-DBS, while the two cases treated with unilateral Vim-DBS demonstrated only a transient effect. MS-associated tremor responded to dual-target Vim-/VO-DBS, but the inability to account for the progression of MS-associated disability impeded the assessment of its long-term clinical efficacy. Neuropathy-associated tremor substantially improved with Vim-DBS. In FXTAS patients, while Vim-DBS was effective in improving tremor, equivocal results were observed in those with ataxia. CONCLUSIONS: DBS of select targets may represent an effective therapeutic strategy for uncommon tremor disorders, although the level of evidence is currently in its incipient form and based on single cases or limited case series. An international registry is, therefore, warranted to clarify selection criteria, long-term results, and optimal surgical targets.

Deconstructing normal pressure hydrocephalus: Ventriculomegaly as early sign of neurodegeneration.

Idiopathic normal pressure hydrocephalus (NPH) remains both oversuspected on clinical grounds and underconfirmed when based on immediate and sustained response to cerebrospinal fluid diversion. Poor long-term postshunt benefits and findings of neurodegenerative pathology in most patients with adequate follow-up suggest that hydrocephalic disorders appearing in late adulthood may often result from initially unapparent parenchymal abnormalities. We critically review the NPH literature, highlighting the near universal lack of blinding and controls, absence of specific clinical, imaging, or pathological features, and ongoing dependence for diagnostic confirmation on variable cutoffs of gait response to bedside fluid-drainage testing. We also summarize our long-term institutional experience, in which postshunt benefits in patients with initial diagnosis of idiopathic NPH persist in only 32% of patients at 36 months, with known revised diagnosis in over 25% (Alzheimer's disease, dementia with Lewy bodies, and progressive supranuclear palsy). We postulate that previously reported NPH cases with "dual" pathology (ie, developing a "second" disorder) more likely represent ventriculomegalic presentations of selected neurodegenerative disorders in which benefits from shunting may be short-lived, with a consequently unfavorable risk-benefit ratio. Ann Neurol 2017;82:503-513.

Thalamic deep brain stimulation for orthostatic tremor: A multicenter international registry.

BACKGROUND: We report the accumulated experience with ventral intermediate nucleus deep brain stimulation for medically refractory orthostatic tremor. METHODS: Data from 17 patients were reviewed, comparing presurgical, short-term (0-48 months), and long-term (≥48 months) follow-up. The primary end point was the composite activities of daily living/instrumental activities of daily living score. Secondary end points included latency of symptoms on standing and treatment-related complications. RESULTS: There was a 21.6% improvement (P = 0.004) in the composite activities of daily living/instrumental activities of daily living score, which gradually attenuated (12.5%) in the subgroup of patients with an additional long-term follow-up (8 of 17). The latency of symptoms on standing significantly improved, both in the short-term (P = 0.001) and in the long-term (P = 0.018). Three patients obtained no/minimal benefit from the procedure. CONCLUSIONS: Deep brain stimulation of the ventral intermediate nucleus was, in general, safe and well tolerated, yielding sustained benefit in selected patients with medically refractory orthostatic tremor. © 2017 International Parkinson and Movement Disorder Society.

Electrophysiologic monitoring for placement of laminectomy leads for spinal cord stimulation under general anesthesia.

OBJECTIVES: Spinal cord stimulation (SCS) is a valid option for intractable neuropathic pain syndromes, yet some patients cannot undergo the standard awake procedure. Our retrospective study chronicles laminectomy-electrode placement for SCS under general anesthesia and use of compound muscle action potentials (CMAPs) to guide placement in the absence of patient verbal feedback. METHODS: After nonsurgical measures proved ineffective for relief of neuropathic pain, 8 men and 11 women underwent SCS lead placement under general rather than local anesthesia because of deafness, language barriers, lidocaine allergy, or extensive scar tissue. A midline thoracic laminectomy was performed, and paddle SCS leads were placed. CMAPs of the rectus abdominis, quadriceps, gastrocnemius, anterior tibialis, abductor hallicus, and intercostal muscles were analyzed. Final lead placement was determined by the right-to-left symmetry of the CMAPs in conjunction with fluoroscopic imaging. Stimulation coverage was evaluated postoperatively. RESULTS: Inconsistencies were found in lower-extremity CMAPs in the first two procedures. Thereafter, intercostal and rectus abdominis muscle CMAPs obtained in the remaining 17 procedures were consistent, more predictive of final results. Immediately postoperatively, 16 (84.2%) of 19 patients had adequate stimulation coverage and good pain relief with appropriate programming. Of three (15.8%) patients with minimal or no short-term pain relief, lack of response was not attributable to inadequate distribution of stimulation. CONCLUSIONS: With electrophysiologic monitoring and fluoroscopy guidance, placement of SCS laminectomy leads in select patients under general anesthesia may result in appropriate stimulation coverage and pain relief in most.

Deep brain stimulation of the ventral intermediate nucleus of the thalamus in medically refractory orthostatic tremor: preliminary observations.

Orthostatic tremor (OT) is a disabling movement disorder associated with postural and gait impairment in the elderly. Medical therapy often yields insufficient benefit. We report the clinical and electrophysiological data on two patients with medication-refractory OT treated with deep brain stimulation of the ventral intermediate thalamic nucleus (Vim DBS). Patient 1 underwent bilateral deep brain stimulation (DBS) and Patient 2 unilateral Vim DBS following 28 and 30 years of disease duration, respectively. Both patients showed increased latency to symptom onset after rising from a seated position, improved tolerance for prolonged standing, and slower crescendo of tremor severity when remaining upright. Postoperative evaluation demonstrated decreased amplitude of electromyographic activity with persistence of well-defined oscillatory behavior showing strong coherence at 15 Hz between all muscles tested in the upper and lower limbs. Postural sway was unchanged. Clinical benefits have been sustained for over 18 months in Patient 1, and receded after 3 months in Patient 2. These findings support the consideration of bilateral Vim DBS implantation as a therapeutic option in patients with medically refractory OT. Further efficacy studies on chronic stimulation to disrupt the abnormal oscillatory activity in this disorder are warranted.

Surgical treatment of movement disorders.

A substantial body of evidence has accumulated regarding the efficacy and safety of neurosurgery for Parkinson's disease, essential tremor, and dystonia. Surgery for movement disorders (thalamotomy, pallidotomy, and subthalamic nucleotomy or subthalamotomy) was largely ablative (lesion-based). Given the safety and anatomy-preservation advantage, long-term electrical stimulation of these same targets (thalamus, globus pallidus, and subthalamic nucleus) is discussed as the treatment of choice. High-frequency deep brain stimulation procedures replicate the effects of ablative interventions, but do not require making a destructive brain lesion. This article outlines patient eligibility for surgery, targeting techniques, intraoperative findings, and potential complications and discusses the outcomes expected for each of the major interventions for which clinical trial data are available.

Effects of intralaminar thalamic stimulation on language functions.

Fifteen neurosurgical subjects, who were undergoing thalamic chronic electrode implants as a treatment for dyskinesia and chronic pain, were evaluated on a series of neurolinguistic functions to determine if the stimulation of the centromedianum nucleus of the thalamus affected language and cognitive processing. Analysis of the data revealed that the stimulation of the left centromedianum nucleus had resulted in a notable facilitatory influence on the processing of language functions; this facilitatory effect was measured in terms of the number of errors produced and the patients' response latency time. The facilitatory effect was also noted to have extended to other language functions. The nature of the facilitation from the stimulation of the left centromedianum nucleus, an extension of the brainstem reticular formation, on language functions is discussed.

Concept of arteriovenous malformation compartments and surgical management.

Cerebral AVMs are known to be a source of intracranial hemorrhages and epileptic seizures. Their natural history indicates approximately 15% mortality and 35% morbidity over a 15-year period. This significant mortality and morbidity mandates a need for satisfactory treatment of this entity, ideally by elimination of AVMs. Microsurgical resection, endovascular embolization and radiosurgery (irradiation) are the three effective modes of treatment currently available. However, no objective criteria have been established for which mode(s) of treatment should be selected for individual patients with AVMs. Considering the complexity of AVMs and variable conditions of individual patients, neurosurgeons, intravascular interventionalists and radiosurgeons must make their own decisions on how to treat each patient based on their experience. In practice, treatment of small AVMs in non-functional areas is favored equally by each of these specialists, while they tend to avoid treatment of large AVMs, particularly those in functional areas of the brain. The authors report the surgical intervention of large AVMs, including those located in functional areas of the hemisphere by special techniques. One can demonstrate AVM compartments by using angiography and with the aid of color Doppler ultrasonography, each compartment can be outlined and dissected individually until all the compartments are isolated without causing any damage to the surrounding brain and the entire AVM is rendered shrunken and then removed. The concept of compartmental treatment of AVMs may be applied in the future to radiosurgery and intravascular embolization of large AVMs.

Cytotoxicity of ventricular cerebrospinal fluid from Parkinson patients: correlation with clinical profiles and neurochemistry.

Other investigators have reported that the cerebrospinal fluid (CSF) from patients with Parkinson's disease (PD) might contain endogenous dystrophic factors. Using CSF samples drawn from individual PD patients during surgery, we investigated the toxic effect of ventricular CSF (vCSF) on the growth of PC12 cells and the correlation between the clinical profiles of the patients and CSF neurochemistry. Ventricular CSF samples from 28 patients with PD or essential tremor (ET) were collected during ventriculography for stereotactic pallidotomy or thalamotomy. PC12 cells were incubated with 20% vCSF from both clinical groups for up to 72 h. Microdialysis was used to analyze four neurochemical parameters (glucose, lactate, pyruvate, and glutamate) in each vCSF sample. We observed that vCSF drawn from PD patients exerted nonspecific growth inhibition on PC12 cells in a time-dependent manner. The growth inhibitory action of PD-vCSF decreased significantly after heat treatment. Microdialysis demonstrated no statistical differences between PD and ET samples among the four parameters studied. In addition, PC12 cell survival after 72 h incubation with PD-vCSF correlated with no neurochemical parameter or individual clinical profile (age, onset age, duration of disease, Hoehn & Yahr stage, disease progression rate), except for a slight correlation between vCSF and disease progression rate in heat treated samples from female patients. One or more endogenous cytotoxic factors in PD-vCSF inhibit PC12 cell growth. This factor or factors are partially sensitive to heat which suggests proteins or peptides as possible agents. The cytotoxic effect of PD-vCSF did not directly correlate with any clinical profiles studied or energy metabolism of PD brain.