Accuracy of Intraoperative Computed Tomography during Deep Brain Stimulation Procedures: Comparison with Postoperative Magnetic Resonance Imaging.

OBJECTIVE: To determine the accuracy of intraoperative computed tomography (iCT) in localizing deep brain stimulation (DBS) electrodes by comparing this modality with postoperative magnetic resonance imaging (MRI). BACKGROUND: Optimal lead placement is a critical factor for the outcome of DBS procedures and preferably confirmed during surgery. iCT offers 3-dimensional verification of both microelectrode and lead location during DBS surgery. However, accurate electrode representation on iCT has not been extensively studied. METHODS: DBS surgery was performed using the Leksell stereotactic G frame. Stereotactic coordinates of 52 DBS leads were determined on both iCT and postoperative MRI and compared with intended final target coordinates. The resulting absolute differences in X (medial-lateral), Y (anterior-posterior), and Z (dorsal-ventral) coordinates (ΔX, ΔY, and ΔZ) for both modalities were then used to calculate the euclidean distance. RESULTS: Euclidean distances were 2.7 ± 1.1 and 2.5 ± 1.2 mm for MRI and iCT, respectively (p = 0.2). CONCLUSION: Postoperative MRI and iCT show equivalent DBS lead representation. Intraoperative localization of both microelectrode and DBS lead in stereotactic space enables direct adjustments. Verification of lead placement with postoperative MRI, considered to be the gold standard, is unnecessary.

Revision Surgery of Deep Brain Stimulation Leads.

INTRODUCTION: Deep brain stimulation (DBS) is widely used for various movement disorders. DBS lead revisions are becoming more common as the indications and number of cases increases. METHODS: Patients undergoing DBS lead revisions at a single institution were retrospectively analyzed based on diagnosis, reason for revision, where the lead was relocated, and surgical technique. RESULTS: We reviewed 497 consecutive DBS lead placements and found that there was need for 25 DBS lead revisions with at least six months of follow-up. Loss of efficacy and development of adverse effects over time were the most common reasons for lead revision across all diagnosis. Lead malfunction was the least common. Ten patients requiring 19 DBS lead revisions that underwent their original surgery at another institution were also analyzed. Surgical technique dictated replacing with a new lead while maintaining brain position and tract with the old lead until final placement. Methods to seal exposed wire were developed. CONCLUSION: Surgical technique, as well as variable options are important in lead revision and can be dictated based on reason for revision. Over time patients who have had adequate relief with DBS placement may experience loss of efficacy and development of adverse effects requiring revision of the DBS lead to maintain its effects.

Long-Term Evaluation of Changes in Operative Technique and Hardware-Related Complications With Deep Brain Stimulation.

BACKGROUND: Deep brain stimulation is the most frequent neurosurgical procedure for movement disorders. OBJECTIVE: While this elective procedure carries a low-risk profile, it is not free of complications. As a new procedure, the pattern of complications changed with experience and modification of surgical technique and equipment. METHODS: This review analyzes the most common hardware-related complications that may occur and techniques to avoid them. It is a retrospective review of 432 patients undergoing 1077 procedures over a 14-year period by one surgeon with emphasis on the analysis of surgical technique and the changes over time. Comparisons were made pre and postimplementation of different surgical techniques over different time periods. The epochs relate to the learning curve, new equipment, and new techniques. RESULTS: Overall lead revision was observed at 5.7%, extension revision at 3.2%, infection rate at 1.2%, infarct without intracerebral hemorrhage at 0.8%, and intracerebral hemorrhage at 2.5% with a permanent deficit of 0.2%. An analysis and change in surgical technique which involved isolating the lead from the skin surface at both the cranial and retro-auricular incision also demonstrated a substantial decrease in lead fracture rate and infection rate. There was no mortality. CONCLUSION: This large series of patients and long-term follow-up demonstrates that risks are very low in comparison with other neurosurgical procedures, but DBS is still an elective procedure that necessitates extensive care and precision. In a rapidly evolving field, attention to surgical technique is imperative and will keep rates of complications at a minimum.

Nerve Growth Factor Gene Therapy: Activation of Neuronal Responses in Alzheimer Disease.

IMPORTANCE: Alzheimer disease (AD) is the most common neurodegenerative disorder and lacks effective disease-modifying therapies. In 2001, we initiated a clinical trial of nerve growth factor (NGF) gene therapy in AD, the first effort at gene delivery in an adult neurodegenerative disorder. This program aimed to determine whether a nervous system growth factor prevents or reduces cholinergic neuronal degeneration in patients with AD. We present postmortem findings in 10 patients with survival times ranging from 1 to 10 years after treatment. OBJECTIVE: To determine whether degenerating neurons in AD retain an ability to respond to a nervous system growth factor delivered after disease onset. DESIGN, SETTING, AND PARTICIPANTS: Patients in this anatomicopathological study were enrolled in clinical trials from March 2001 to October 2012 at the University of California, San Diego, Medical Center in La Jolla. Ten patients with early AD underwent NGF gene therapy using ex vivo or in vivo gene transfer. The brains of all 8 patients in the first phase 1 ex vivo trial and of 2 patients in a subsequent phase 1 in vivo trial were examined. MAIN OUTCOMES AND MEASURES: Brains were immunolabeled to evaluate in vivo gene expression, cholinergic neuronal responses to NGF, and activation of NGF-related cell signaling. In 2 patients, NGF protein levels were measured by enzyme-linked immunosorbent assay. RESULTS: Among 10 patients, degenerating neurons in the AD brain responded to NGF. All patients exhibited a trophic response to NGF in the form of axonal sprouting toward the NGF source. Comparing treated and nontreated sides of the brain in 3 patients who underwent unilateral gene transfer, cholinergic neuronal hypertrophy occurred on the NGF-treated side (P < .05). Activation of cellular signaling and functional markers was present in 2 patients who underwent adeno-associated viral vectors (serotype 2)-mediated NGF gene transfer. Neurons exhibiting tau pathology and neurons free of tau expressed NGF, indicating that degenerating cells can be infected with therapeutic genes, with resultant activation of cell signaling. No adverse pathological effects related to NGF were observed. CONCLUSIONS AND RELEVANCE: These findings indicate that neurons of the degenerating brain retain the ability to respond to growth factors with axonal sprouting, cell hypertrophy, and activation of functional markers. Sprouting induced by NGF persists for 10 years after gene transfer. Growth factor therapy appears safe over extended periods and merits continued testing as a means of treating neurodegenerative disorders.

Analysis of Stereotactic Accuracy in Patients Undergoing Deep Brain Stimulation Using Nexframe and the Leksell Frame.

OBJECTIVE: To determine and compare the accuracy of Nexframe and the Leksell stereotactic frame in deep brain stimulation (DBS) procedures. BACKGROUND: The 'frameless' Nexframe uses bone fiducials rather than a head-mounted frame, which offers potential benefits for both the patient and the surgical team. Accuracy of lead implantation and factors affecting this accuracy are of crucial importance but have not been extensively studied for the frameless system. DESIGN/METHODS: The location of 194 (Leksell frame, n = 116; Nexframe, n = 78) DBS leads was determined on postoperative MRI. Obtained stereotactic coordinates were compared with expected intraoperative target coordinates. Resulting absolute errors in the X (medial-lateral), Y (anterior-posterior), and Z (dorsal-ventral) coordinates (x0394;X, x0394;Y, and x0394;Z) were then used to calculate the vector error (VE). The vector error describes the total error in 3-D space and represents our main outcome measure. RESULTS: The vector error (mean ± SD) was 2.8 ± 1.3 for Nexframe and 2.5 ± 1.2 for the Leksell frame (p = 0.43). For Nexframe, absolute X, Y, and Z errors were 1.4 ± 1.3, 1.7 ± 1.2, and 1.0 ± 0.9 mm. For the Leksell frame, the absolute X, Y, and Z errors were 1.4 ± 1.0, 1.2 ± 1.0, and 1.3 ± 0.9 mm. On the anterior-posterior plane (Y coordinate), the Leksell frame was more accurate than Nexframe (p = 0.04). In contrast, Nexframe was more accurate on the dorsal-ventral plane (Z coordinate) (p = 0.04). There was no difference in accuracy between the two methods on the medial-lateral plane (X coordinate). CONCLUSION: This comparison of Nexframe and the Leksell frame shows that both techniques have equivalent overall 3-D accuracy.

Progression of intestinal permeability changes and alpha-synuclein expression in a mouse model of Parkinson's disease.

Parkinson's disease (PD) is a multifocal degenerative disorder for which there is no cure. The majority of cases are sporadic with unknown etiology. Recent data indicate that untreated patients with de novo PD have increased colonic permeability and that both de novo and premotor patients have pathological expression of α-synuclein (α-syn) in their colon. Both endpoints potentially can serve as disease biomarkers and even may initiate PD events through gut-derived, lipopolysaccharide (LPS)-induced neuronal injury. Animal models could be ideal for interrogating the potential role of the intestines in the pathogenesis of PD; however, few current animal models of PD encompass these nonmotor features. We sought to establish a progressive model of PD that includes the gastrointestinal (GI) dysfunction present in human patients. C57/BL6 mice were systemically administered one dose of either LPS (2.5 mg/kg) or saline and were sacrificed in monthly intervals (n = 5 mice for 5 months) to create a time-course. Small and large intestinal permeability was assessed by analyzing the urinary output of orally ingested sugar probes through capillary column gas chromatography. α-Syn expression was assessed by counting the number of mildly, moderately, and severely affected myenteric ganglia neurons throughout the GI tract, and the counts were validated by quantitative optical density measurements. Nigrostriatal integrity was assessed by tyrosine hydroxylase immunohistochemistry stereology and densitometry. LPS caused an immediate and progressive increase in α-syn expression in the large intestine but not in the small intestine. Intestinal permeability of the whole gut (large and small intestines) progressively increased between months 2 and 4 after LPS administration but returned to baseline levels at month 5. Selective measurements demonstrated that intestinal permeability in the small intestine remained largely intact, suggesting that gut leakiness was predominately in the large intestine. Phosphorylated serine 129-α-syn was identified in a subset of colonic myenteric neurons at months 4 and 5. Although these changes were observed in the absence of nigrostriatal degeneration, an abrupt but insignificant increase in brainstem α-syn was observed that paralleled the restoration of permeability. No changes were observed over time in controls. LPS, an endotoxin used to model PD, causes sequential increases in α-syn immunoreactivity, intestinal permeability, and pathological α-syn accumulation in the colon in a manner similar to that observed in patients with PD. These features are observed without nigrostriatal degeneration and incorporate PD features before the motor syndrome. This allows for the potential use of this model in testing neuroprotective and disease-modifying therapies, including intestinal-directed therapies to fortify intestinal barrier integrity.

A phase1 study of stereotactic gene delivery of AAV2-NGF for Alzheimer's disease.

BACKGROUND: Nerve growth factor (NGF) is an endogenous neurotrophic-factor protein with the potential to restore function and to protect degenerating cholinergic neurons in Alzheimer's disease (AD), but safe and effective delivery has proved unsuccessful. METHODS: Gene transfer, combined with stereotactic surgery, offers a potential means to solve the long-standing delivery obstacles. An open-label clinical trial evaluated the safety and tolerability, and initial efficacy of three ascending doses of the genetically engineered gene-therapy vector adeno-associated virus serotype 2 delivering NGF (AAV2-NGF [CERE-110]). Ten subjects with AD received bilateral AAV2-NGF stereotactically into the nucleus basalis of Meynert. RESULTS: AAV2-NGF was safe and well-tolerated for 2 years. Positron emission tomographic imaging and neuropsychological testing showed no evidence of accelerated decline. Brain autopsy tissue confirmed long-term, targeted, gene-mediated NGF expression and bioactivity. CONCLUSIONS: This trial provides important evidence that bilateral stereotactic administration of AAV2-NGF to the nucleus basalis of Meynert is feasible, well-tolerated, and able to produce long-term, biologically active NGF expression, supporting the initiation of an ongoing multicenter, double-blind, sham-surgery-controlled trial.

Displacement of a deep brain stimulator lead during placement of an additional ipsilateral lead.

OBJECTIVE: The use of Deep Brain Stimulation (DBS) has been increasing. It follows the premise of neuromodulation in that it is reversible, as compared to previous lesioning procedures. MATERIALS AND METHODS: Complications with DBS are inherently low and range from short-term complications during surgery such as hemorrhage to long-term complications that include lead fractures and infection. Over time, the authors have experienced indications for additional lead placements or change in position of the lead on the ipsilateral side. There is the inherent possibility of direct contact between leads or the microelectrode. This can lead to malpositioning, displacement of a lead placed previously, and malfunctioning. RESULT: We report a case in which a lead placed previously becomes displaced during microelectrode recording on the ipsilateral side. CONCLUSION: This scenario was corrected and had no clinical or functional complication. Placement of an additional ipsilateral DBS lead can be a safe and effective treatment option.

An evaluation of hardware and surgical complications with deep brain stimulation based on diagnosis and lead location.

INTRODUCTION: Deep brain stimulation is the most frequently performed neurosurgical procedure for movement disorders. This procedure is well tolerated, but not free of complications. Analysis of hardware complications based on patient diagnosis and lead location could prove valuable in recognizing potential pitfalls and patients at higher risk. METHODS: This review analyzes the most common surgery-related complications that may occur based on diagnosis and lead location. Patients were categorized based on diagnosis - Parkinson's disease (PD), dystonia, and essential tremor (ET) - as well as by lead location - subthalamic nucleus (STN), globus pallidus interna (GPi), and ventral intermediate nucleus of the thalamus (Vim). It is a retrospective review of 326 patients undergoing 949 procedures over a 10-year period by one surgeon. Fisher's exact test and χ(2) test were employed and multivariate logistic regression analysis was performed to identify the significant variables of correlation. RESULTS: Overall lead revision was observed at 5.7%, but was observed at 11.9% of GPi lead placements, and 10.7% of dystonia patients with only 4.6% of STN lead placements. Total extension revision was at 2.5%, but observed at 5.3% for dystonia patients and at only 1.4% for ET patients. Overall infection rate was at 1.9% with the highest rate observed in dystonia and ET patients. Postoperative complications with hardware, erosion, infection, and delayed stimulation failure were observed more often with ET and dystonia than with PD. This difference was statistically significant between dystonia and PD (p < 0.03) but not between the other disease entities (p > 0.05). On multivariate analysis, age and gender had no correlation with these complications. PD had significantly fewer complications on forward selection regression analysis (p = 0.004). Asymptomatic intracerebral hemorrhage was at 2.5% with the majority in Vim and none observed in GPi placements. There was only one symptomatic hemorrhage with a permanent deficit. Infarcts were observed at 0.8%. There were no mortalities. CONCLUSION: This large series of patients and long-term follow-up demonstrate that risks of complications are not universal among movement disorder patients. Diagnosis and lead location are important risk stratification factors in determining complications.

Intraoperative x-ray to measure distance between DBS leads: A reliability study.

BACKGROUND: Many factors can jeopardize the accuracy of deep brain stimulation (DBS) lead placement. Confirmation of lead placement while the patient is still in the operating room would be advantageous. Intraoperative MRI or CT can identify placement errors, but these modalities can be cost- or time prohibitive. Intraoperative fluoroscopy may give information on the accuracy of the Y coordinate, but the accuracy of the X coordinate usually cannot be confirmed. When an object of known dimensions is present in the brain, such as a unilateral DBS lead, its dimensions can be used to calculate unknown distances. The objective of this study was to determine if intraoperative AP skull x-ray accurately predicts the distance between DBS electrodes using postoperative MRI as the gold standard. METHODS: The distance between 32 pairs of DBS leads was measured by 2 independent raters under blinded conditions on intraoperative AP x-ray and postoperative axial and coronal MRI. Variable x-ray magnification was accounted for using the formula: actual distance between 2 leads = (measured distance between DBS leads)/(average measured length of electrodes) × 7.5 mm. RESULTS: The mean (± SD) distance on x-ray was 22.62 ± 2.23 mm, on axial MRI 22.78 ± 1.90 mm, and on coronal MRI 22.79 ± 2.00 mm. ANOVA revealed no difference based on method (P = .887) or raters (P = .940). The intraclass correlation coefficient showed excellent interrater reliability, CONCLUSIONS: Intraoperative AP x-ray accurately predicts the distance between DBS leads. The technique is especially useful when the location of the first DBS lead relative to the midline is known, such as during staged bilateral procedures or lead replacement procedures.

Effect of intraoperative subthalamic nucleus DBS on human single-unit activity in the ipsilateral and contralateral subthalamic nucleus.

OBJECT: Insight may be gained into the physiological mechanisms of deep brain stimulation (DBS) by analyzing local and contralateral subthalamic nucleus (STN) single-unit activity during activation of previously placed DBS electrodes. Special techniques are required to perform such analysis due to the presence of a large stimulus artifact. The purpose of this study was to determine the effects of DBS stimulation on single unit activity acquired from patients undergoing new or revised DBS placements. METHODS: Subthalamic nucleus single unit activity was acquired from awake patients during activation of a previously implanted STN DBS electrode. Stimulation was contralateral to the recording site in 4 cases and ipsilateral in 3. Data were acquired at stimulation frequencies of 30, 60, and 130 Hz and with other stimulation parameters at clinically effective settings. Cells were included if they showed kinesthetic activity before and after the stimulation paradigm and if their action potential morphology was maintained throughout the experiment. Analysis of single-unit activity acquired before, during, and after stimulation was performed employing a time-domain algorithm to overcome the stimulus artifact. RESULTS: Both ipsilateral and contralateral acute stimulation resulted in reversible STN firing rate suppression. The degree of suppression became greater as stimulus frequency increased and was significant at 60 Hz (t-test, p < 0.05) and 130 Hz (p < 0.01). Suppression with ipsilateral 130-Hz stimulation ranged between 52.8% and 99.8%, whereas with similar contralateral STN stimulation, the range was lower (1.9%-50.3%). Return to baseline activity levels typically occurred within seconds after stimulation ended. CONCLUSIONS: Stimulation of the STN at clinically effective frequencies has an acute suppressive rather than an excitatory effect on STN single-unit activity. The effect is bilateral, even though the degree of suppression is greater on the ipsilateral than the contralateral STN. The authors' algorithm helps reveal this effect in human patients.

Intrastriatal transplantation of microcarrier-bound human retinal pigment epithelial cells versus sham surgery in patients with advanced Parkinson's disease: a double-blind, randomised, controlled trial.

BACKGROUND: Human retinal pigment epithelial (RPE) cells produce levodopa and their transplantation into the striatum might improve continuity of administration compared with that achieved with oral levodopa. We aimed to assess the safety, tolerability, and efficacy of transplantation of microcarrier-bound human RPE cells versus a sham surgery control in patients with advanced Parkinson's disease. METHODS: In this randomised, double-blind study eligible patients were aged 36-70 years, had been symptomatic for at least 5 years, were in Hoehn and Yahr stage 3-4 and had unified Parkinson's disease rating scale (UPDRS) motor scores of 38-70 when off medication (off state), and had symptoms that responded to oral levodopa but were insufficiently controlled by optimised pharmacotherapy. Randomisation was done in a 1:1 ratio. Only the neurosurgical team was aware of treatment assignments. During stereotactic transplantation around 325,000 cells per side were injected into the postcommissural putamen; sham surgery patients received partial burr holes. The primary efficacy endpoint was change in UPDRS off-state motor score at 12 months. This study is registered with ClinicalTrials.gov, number NCT00206687. FINDINGS: Of 71 enrolled patients, 35 underwent cell transplantation and 36 sham surgery. Change in mean motor scores did not differ significantly between groups (-10.5 [SD 10.26] for transplantation vs -10.1 [SD 12.26] for sham surgery, p=0.9). The overall rate of adverse events was similar in the two study groups, although the number attributable to surgery or RPE cells (mostly neurological or psychiatric) was higher in transplant recipients. Two and seven patients died in the sham surgery and transplantation group, respectively; one death in the latter group was possibly related to surgery or RPE cells. INTERPRETATION: Transplantation of human RPE cells provided no antiparkinsonian benefits compared with sham surgery. FUNDING: Bayer HealthCare AG.

Frameless deep brain stimulation using intraoperative O-arm technology. Clinical article.

OBJECT: Correct lead location in the desired target has been proven to be a strong influential factor for good clinical outcome in deep brain stimulation (DBS) surgery. Commonly, a surgeon's first reliable assessment of such location is made on postoperative imaging. While intraoperative CT (iCT) and intraoperative MR imaging have been previously described, the authors present a series of frameless DBS procedures using O-arm iCT. METHODS: Twelve consecutive patients with 15 leads underwent frameless DBS placement using electrophysiological testing and O-arm iCT. Initial target coordinates were made using standard indirect and direct assessment. Microelectrode recording (MER) with kinesthetic responses was performed, followed by microstimulation to evaluate the side-effect profile. Intraoperative 3D CT acquisitions obtained between each MER pass and after final lead placement were fused with the preoperative MR image to verify intended MER movements around the target area and to identify the final lead location. Tip coordinates from the initial plan, final intended target, and actual lead location on iCT were later compared with the lead location on postoperative MR imaging, and euclidean distances were calculated. The amount of radiation exposure during each procedure was calculated and compared with the estimated radiation exposure if iCT was not performed. RESULTS: The mean euclidean distances between the coordinates for the initial plan, final intended target, and actual lead on iCT compared with the lead coordinates on postoperative MR imaging were 3.04 ± 1.45 mm (p = 0.0001), 2.62 ± 1.50 mm (p = 0.0001), and 1.52 ± 1.78 mm (p = 0.0052), respectively. The authors obtained good merging error during image fusion, and postoperative brain shift was minimal. The actual radiation exposure from iCT was invariably less than estimates of exposure using standard lateral fluoroscopy and anteroposterior radiographs (p < 0.0001). CONCLUSIONS: O-arm iCT may be useful in frameless DBS surgery to approximate microelectrode or lead locations intraoperatively. Intraoperative CT, however, may not replace fundamental DBS surgical techniques such as electrophysiological testing in movement disorder surgery. Despite the lack of evidence for brain shift from the procedure, iCT-measured coordinates were statistically different from those obtained postoperatively, probably indicating image merging inaccuracy and the difficulties in accurately denoting lead location. Therefore, electrophysiological testing may truly be the only means of precisely knowing the location in 3D space intraoperatively. While iCT may provide clues to electrode or lead location during the procedure, its true utility may be in DBS procedures targeting areas where electrophysiology is less useful. The use of iCT appears to reduce radiation exposure compared with the authors' traditional frameless technique.

Deep brain stimulation for Parkinson disease: an expert consensus and review of key issues.

OBJECTIVE: To provide recommendations to patients, physicians, and other health care providers on several issues involving deep brain stimulation (DBS) for Parkinson disease (PD). DATA SOURCES AND STUDY SELECTION: An international consortium of experts organized, reviewed the literature, and attended the workshop. Topics were introduced at the workshop, followed by group discussion. DATA EXTRACTION AND SYNTHESIS: A draft of a consensus statement was presented and further edited after plenary debate. The final statements were agreed on by all members. CONCLUSIONS: (1) Patients with PD without significant active cognitive or psychiatric problems who have medically intractable motor fluctuations, intractable tremor, or intolerance of medication adverse effects are good candidates for DBS. (2) Deep brain stimulation surgery is best performed by an experienced neurosurgeon with expertise in stereotactic neurosurgery who is working as part of a interprofessional team. (3) Surgical complication rates are extremely variable, with infection being the most commonly reported complication of DBS. (4) Deep brain stimulation programming is best accomplished by a highly trained clinician and can take 3 to 6 months to obtain optimal results. (5) Deep brain stimulation improves levodopa-responsive symptoms, dyskinesia, and tremor; benefits seem to be long-lasting in many motor domains. (6) Subthalamic nuclei DBS may be complicated by increased depression, apathy, impulsivity, worsened verbal fluency, and executive dysfunction in a subset of patients. (7) Both globus pallidus pars interna and subthalamic nuclei DBS have been shown to be effective in addressing the motor symptoms of PD. (8) Ablative therapy is still an effective alternative and should be considered in a select group of appropriate patients.

Dyskinesias do not develop after chronic intermittent levodopa therapy in clinically hemiparkinsonian rhesus monkeys.

The stable 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced hemiparkinsonian (HP) rhesus monkey model of Parkinson's disease (PD) has been frequently used to test preclinical experimental therapeutics targeted to treat patients with advanced PD who suffer from motor fluctuations and drug-induced dyskinesias. We retrospectively analyzed data from 17 stable HP rhesus monkeys treated long-term with chronic intermittent dosing of levodopa (LD) in an attempt to induce choreoathetoid and dystonic dyskinesias. Rhesus monkeys in stable HP state for greater than 6 months as confirmed by multiple blinded behavioral ratings and (18)F-dopa Positron Emission Tomography (PET) were treated with optimal doses of LD to provide maximal amelioration of unilateral clinical parkinsonism without any adverse effects. Thereafter, each animal was given chronic intermittent daily challenge with doses of LD up to 700 mg/day orally or with 300 mg/kg/day parenteral injections. LD treatments failed to induce choreoathetoid and dystonic dyskinesias in these animals despite chronic intermittent high dose administration. These results suggest that the stable strictly unilateral HP rhesus monkey model of PD may not be a suitable animal model to test experimental therapeutics targeted against dyskinesias, and that bilateral parkinsonian rhesus models that readily demonstrate drug-induced dyskinesias and clinically relevant motor fluctuations are more appropriate for preclinical experimental testing of therapies designed to treat patients with advanced PD.

Gene delivery of AAV2-neurturin for Parkinson's disease: a double-blind, randomised, controlled trial.

BACKGROUND: In an open-label phase 1 trial, gene delivery of the trophic factor neurturin via an adeno-associated type-2 vector (AAV2) was well tolerated and seemed to improve motor function in patients with advanced Parkinson's disease. We aimed to assess the safety and efficacy of AAV2-neurturin in a double-blind, phase 2 randomised trial. METHODS: We did a multicentre, double-blind, sham-surgery controlled trial in patients with advanced Parkinson's disease. Patients were randomly assigned (2:1) by a central, computer generated, randomisation code to receive either AAV2-neurturin (5·4 × 10¹¹ vector genomes) injected bilaterally into the putamen or sham surgery. All patients and study personnel with the exception of the neurosurgical team were masked to treatment assignment. The primary endpoint was change from baseline to 12 months in the motor subscore of the unified Parkinson's disease rating scale in the practically-defined off state. All randomly assigned patients who had at least one assessment after baseline were included in the primary analyses. This trial is registered at ClinicalTrials.gov, NCT00400634. RESULTS: Between December, 2006, and November, 2008, 58 patients from nine sites in the USA participated in the trial. There was no significant difference in the primary endpoint in patients treated with AAV2-neurturin compared with control individuals (difference -0·31 [SE 2·63], 95% CI -5·58 to 4·97; p=0·91). Serious adverse events occurred in 13 of 38 patients treated with AAV2-neurturin and four of 20 control individuals. Three patients in the AAV2-neurturin group and two in the sham surgery group developed tumours. INTERPRETATION: Intraputaminal AAV2-neurturin is not superior to sham surgery when assessed using the UPDRS motor score at 12 months. However, the possibility of a benefit with additional targeting of the substantia nigra and longer term follow-up should be investigated in further studies. FUNDING: Ceregene and Michael J Fox Foundation for Parkinson's Research.