Kathryn L. Holloway

Pallidal versus subthalamic deep-brain stimulation for Parkinson's disease

BACKGROUND Deep-brain stimulation is the surgical procedure of choice for patients with advanced Parkinsons disease. The globus pallidus interna and the subthalamic nucleus are accepted targets for this procedure. We compared 24-month outcomes for patients who had undergone bilateral stimulation of the globus pallidus interna (pallidal stimulation) or subthalamic nucleus (subthalamic stimulation). METHODS At seven Veterans Affairs and six university hospitals, we randomly assigned 299 patients with idiopathic Parkinsons disease to undergo either pallidal stimulation (152 patients) or subthalamic stimulation (147 patients). The primary outcome was the change in motor function, as blindly assessed on the Unified Parkinsons Disease Rating Scale, part III (UPDRS-III), while patients were receiving stimulation but not receiving antiparkinsonian medication. Secondary outcomes included self-reported function, quality of life, neurocognitive function, and adverse events. RESULTS Mean changes in the primary outcome did not differ significantly between the two study groups (P=0.50). There was also no significant difference in self-reported function. Patients undergoing subthalamic stimulation required a lower dose of dopaminergic agents than did those undergoing pallidal stimulation (P=0.02). One component of processing speed (visuomotor) declined more after subthalamic stimulation than after pallidal stimulation (P=0.03). The level of depression worsened after subthalamic stimulation and improved after pallidal stimulation (P=0.02). Serious adverse events occurred in 51% of patients undergoing pallidal stimulation and in 56% of those undergoing subthalamic stimulation, with no significant between-group differences at 24 months. CONCLUSIONS Patients with Parkinsons disease had similar improvement in motor function after either pallidal or subthalamic stimulation. Nonmotor factors may reasonably be included in the selection of surgical target for deep-brain stimulation. (ClinicalTrials.gov numbers, NCT00056563 and NCT01076452.)

Randomized trial of deep brain stimulation for Parkinson disease: Thirty-six-month outcomes

Objectives: Our objective was to compare long-term outcomes of deep brain stimulation (DBS) of the globus pallidus interna (GPi) and subthalamic nucleus (STN) for patients with Parkinson disease (PD) in a multicenter randomized controlled trial. Methods: Patients randomly assigned to GPi (n = 89) or STN DBS (n = 70) were followed for 36 months. The primary outcome was motor function on stimulation/off medication using the Unified Parkinsons Disease Rating Scale motor subscale. Secondary outcomes included quality of life and neurocognitive function. Results: Motor function improved between baseline and 36 months for GPi (41.1 to 27.1; 95% confidence interval [CI] −16.4 to −10.8; p < 0.001) and STN (42.5 to 29.7; 95% CI −15.8 to −9.4; p < 0.001); improvements were similar between targets and stable over time (p = 0.59). Health-related quality of life improved at 6 months on all subscales (all p values significant), but improvement diminished over time. Mattis Dementia Rating Scale scores declined faster for STN than GPi patients (p = 0.01); other neurocognitive measures showed gradual decline overall. Conclusions: The beneficial effect of DBS on motor function was stable and comparable by target over 36 months. Slight declines in quality of life following initial gains and gradual decline in neurocognitive function likely reflect underlying disease progression and highlight the importance of nonmotor symptoms in determining quality of life. Classification of Evidence: This study provides Class III evidence that improvement of motor symptoms of PD by DBS remains stable over 3 years and does not differ by surgical target. Neurology® 2012;79:55–65

Grafts of adult subependymal zone neuronal progenitor cells rescue hemiparkinsonian behavioral decline

Neuronal progenitor cells (NPCs) residing in the adult subependymal zone (SEZ) are a potential source of expandable cells for autologous transplantation to treat Parkinsons Disease and other types of brain injury. We have previously demonstrated the capacity of transplanted adult SEZ NPCs for heterotypic differentiation in the hippocampus. To further characterize the therapeutic potential of these cells, NPCs expanded from the adult rat SEZ were grafted to the striatum of normal and 6-OHDA lesioned adult rats. Grafted cells were assessed for neuronal differentiation, and lesioned animals were tested for amphetamine-induced rotational asymmetry. In addition, the effect of inducing differentiation in vitro prior to transplantation was assessed. Although grafted cells survived after 2 weeks in all animals, neither striatal deafferentation nor in vitro induction of differentiation resulted in significant neuronal differentiation of transplanted cells. Grafts, however, did produce a behavioral effect. While sham animals exhibited increased rotational behavior (+67%) from 2 to 4 weeks post-lesioning, grafted animals did not (-21%). Grafted cells continued to express nestin at the survival time point, and dopamine transporter (DAT) immunoreactivity was restored in the graft body. These results suggest that although neither the normal nor the deafferented striatum alone support the neuronal differentiation of transplanted adult SEZ NPCs, grafts maintaining a progenitor phenotype may produce a therapeutic benefit.

Deep Brain Stimulation for Dystonia: A Meta‐Analysis

Objective.  To use a meta‐analysis on all reported cases of deep brain stimulation (DBS) for dystonia to determine which factors significantly influence outcome. The Burke‐Fahn‐Marsden (BFM) movement scale, the most reported measure, was chosen as the primary outcome measure for this analysis.

The application accuracy of a skull-mounted trajectory guide system for image-guided functional neurosurgery

Objective: Frameless image guided systems have traditionally been perceived as being less accurate than stereotactic frames, limiting their adoption for trajectory-based procedures such as deep brain stimulator placement which require submillimetric accuracy. However, some studies have suggested that high degrees of accuracy are attainable with optical localization systems. We evaluated the application accuracy of a skull-mounted trajectory guide coupled to an optical image-guided surgery system in a laboratory setting. Materials and Methods: A plastic skull phantom was fitted with five fiducial markers rigidly attached via self-drilling bone screws. Varying MRI and CT imaging protocols were obtained at 25 different centers. A metal disc marked in 1-mm increments was placed at the expected target point. Following registration and alignment of the trajectory guide, radial and depth localization errors were measured. A total of 560 measurements were obtained and detailed statistical analyses were performed. Results: Mean localization error was 1.25 mm with a 95% confidence interval of 2.7 mm and a 99.9% confidence interval of 4.0 mm. These values were significantly lower than those published for the two most widely used frame systems (p<0.001). Conclusions: Accuracy of image-guided localization using a rigid trajectory guide can meet or exceed that achievable with a stereotactic frame.

Isolation of neuronal progenitor cells from the adult human neocortex.

SummaryBackground. The reliability of harvesting neuronal progenitor cells (NPCs) from the adult human neocortex has not been established, with respect to preparing autologous cell cultures for transplantation in stroke and traumatic brain injured patients. Method. Enriched NPC cultures have been generated from nonneurogenic regions of the adult rodent brain by buoyancy-dependent fractionation, but the feasibility of using such a method to isolate NPCs from the adult human cortex has not been reported previously. To determine if a starter population of human adult cortical NPCs could be isolated for in vitro expansion using this method, tissue samples from five patients undergoing cortical resection for either epilepsy or trauma were assayed. Findings. Cultured cells generated from all patients predominately expressed both the NPC marker nestin and neuron-specific β-tubulin III. The presence of NPCs was verified by in vitro BrdU/β-tubulin III co-labeling and increasing β-tubulin expression in differentiating conditions. Despite the formation of aggregates in monolayer culture, cell proliferation as measured by BrdU incorporation was not as prevalent as that reported from rodent cultures generated by this protocol. Conclusions. NPCs isolated from the adult human neocortex using this method expressed β-tubulin III in larger percentages than has been previously reported for NPCs isolated using other methods. As such, these data suggest the possibility of culturing dividing neuroblasts from the adult neocortex for further manipulation as transplantable cells.

Subcallosal cingulate deep brain stimulation for treatment-resistant depression: a multisite, randomised, sham-controlled trial

BACKGROUND Deep brain stimulation (DBS) of the subcallosal cingulate white matter has shown promise as an intervention for patients with chronic, unremitting depression. To test the safety and efficacy of DBS for treatment-resistant depression, a prospective, randomised, sham-controlled trial was conducted. METHODS Participants with treatment-resistant depression were implanted with a DBS system targeting bilateral subcallosal cingulate white matter and randomised to 6 months of active or sham DBS, followed by 6 months of open-label subcallosal cingulate DBS. Randomisation was computer generated with a block size of three at each site before the site started the study. The primary outcome was frequency of response (defined as a 40% or greater reduction in depression severity from baseline) averaged over months 4-6 of the double-blind phase. A futility analysis was performed when approximately half of the proposed sample received DBS implantation and completed the double-blind phase. At the conclusion of the 12-month study, a subset of patients were followed up for up to 24 months. The study is registered at ClinicalTrials.gov, number NCT00617162. FINDINGS Before the futility analysis, 90 participants were randomly assigned to active (n=60) or sham (n=30) stimulation between April 10, 2008, and Nov 21, 2012. Both groups showed improvement, but there was no statistically significant difference in response during the double-blind, sham-controlled phase (12 [20%] patients in the stimulation group vs five [17%] patients in the control group). 28 patients experienced 40 serious adverse events; eight of these (in seven patients) were deemed to be related to the study device or surgery. INTERPRETATION This study confirmed the safety and feasibility of subcallosal cingulate DBS as a treatment for treatment-resistant depression but did not show statistically significant antidepressant efficacy in a 6-month double-blind, sham-controlled trial. Future studies are needed to investigate factors such as clinical features or electrode placement that might improve efficacy. FUNDING Abbott (previously St Jude Medical).

Analysis of Stereotactic Accuracy of the Cosman-Robert-Wells Frame and Nexframe Frameless Systems in Deep Brain Stimulation Surgery

Introduction: The primary goal of stereotactic systems in deep brain stimulation (DBS) surgery is accurate delivery of a DBS lead to a target identified on imaging. Thus, it is critical to understand the accuracy of the stereotactic systems and the factors which may be associated with a decrease in accuracy. Methods: Ninety patients underwent microelectrode recording-guided placement of 139 DBS leads by a single surgeon using the Cosman-Roberts-Wells (CRW) frame (n = 70) or a frameless skull-mounted trajectory guide (Nexframe; n = 69). The final DBS location was identified on a postoperative CT fused to the preoperative CT and MRI scans. The difference between this final location and the expected location was calculated. Results: The vector error was 2.65 mm (standard error, 0.22) for the frame and 2.78 mm (standard error, 0.25) for the frameless methods (p = 0.69). There was a gradual decline in error for both systems over time, as the vector error of the last 20 implants was 1.99 for the CRW frame and 2.04 for the Nexframe (p = 0.86). Conclusions: This study shows that the CRW frame and Nexframe frameless systems have equivalent accuracy. Furthermore, the accuracy of both techniques improved over time, from 3 mm initially to 2 mm with current techniques.

Antibiotic prophylaxis during clean neurosurgery: a large, multicenter study using cefuroxime

Cefuroxime is a second-generation cephalosporin with in vitro activity against the organisms that are commonly associated with neurosurgical wound infections. Other properties of cefuroxime are an elimination half-life of 1.3 hours, which yields prolonged serum concentrations, and its ability to penetrate the blood-brain barrier in proportion to the degree of inflammation. A prospective, multicenter, open-label study was conducted to evaluate the efficacy and safety of cefuroxime for antibiotic prophylaxis in patients undergoing clean neurosurgery. Cefuroxime 1.5 g was given intravenously 25 to 60 minutes before surgery; for procedures lasting more than 3 hours, cefuroxime 750 mg was given intravenously 8 hours after the initial dose. Patients were examined before surgery, daily during hospitalization, and at 8 weeks after surgery. A total of 956 adults were enrolled in the study. The most common procedures in study patients were laminectomy (41.8% of patients) or craniotomy (24.3%), and the mean duration of surgery was 3.2 hours. Infection occurred in 2 (0.3%) of 592 assessable patients by the time of discharge and in 1 additional patient by the 8-week follow-up evaluation for a total of 3 (0.5%) of 560 assessable patients. Drug-related adverse events occurred in 5 (0.5%) of 956 patients. These results indicate that antibiotic prophylaxis with cefuroxime is associated with a low incidence of postoperative wound infection and is well tolerated in patients undergoing clean neurosurgery.

Heterotypic neuronal differentiation of adult subependymal zone neuronal progenitor cells transplanted to the adult hippocampus

Neuronal progenitor cells (NPCs) residing in the adult subependymal zone (SEZ) are a potential source of expandable cells for autologous transplantation to replace neurons lost in multiple types of brain injury. To characterize the capacity of these cells for neuronal differentiation in a mature ectopic environment, NPCs expanded from the SEZ of adult rats were transplanted to the adult dentate gyrus. Cultures comprised a heterogeneous population of proliferating cells, which expressed nestin (47%) and GFAP (37%), with many cells expressing both progenitor cell markers (31%). In grafts of undifferentiated cells, as well as in grafts of cells that were induced to differentiate in vitro with retinoic acid, 35% of the transplanted SEZ-derived cells exhibited immunohistochemical and morphological features characteristic of hippocampal granule cell neurons. These novel results indicate that in vitro expanded adult SEZ NPCs are capable of heterotypic neuronal differentiation in a neurogenic region of the adult brain.