Parkinson Disease - Top 25

September 2010, Volume 113, Issue 3

Parkinson Disease: Top 25 Cited Articles

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John T. Slevin, Greg A. Gerhardt, Charles D. Smith, Don M. Gash, Richard Kryscio and Byron Young

Object. Glial cell line-derived neurotrophic factor (GDNF) has demonstrated significant antiparkinsonian actions in several animal models and in a recent pilot study in England in which four of five patients received bilateral putaminal delivery. In the present study the authors report on a 6-month unilateral intraputaminal GDNF infusion in 10 patients with advanced Parkinson disease (PD).

Methods. Patients with PD in a functionally defined on and off state were evaluated 1 week before and 1 and 4 weeks after intraputaminal catheter implantation in the side contralateral to the most affected side. Each patient was placed on a dose-escalation regimen of GDNF: 3, 10, and 30 µg/day at successive 8-week intervals, followed by a 1-month wash-out period.

The Unified Parkinson's Disease Rating Scale (UPDRS) total scores in the on and off states significantly improved 34 and 33%, respectively, at 24 weeks compared with baseline scores (95% confidence interval [CI] 18–47% for off scores and 16–51% for on scores). In addition, UPDRS motor scores in both the on and off states significantly improved by 30% at 24 weeks compared with baseline scores (95% CI 15–48% for off scores and 5–61% for on scores). Improvements occurred bilaterally, as measured by balance and gait and increased speed of hand movements. All significant improvements of motor function continued through the wash-out period. The only observed side effects were transient Lhermitte symptoms in two patients.

Conclusions. Analysis of the data in this open-label study demonstrates the safety and potential efficacy of unilateral intraputaminal GDNF infusion. Unilateral administration of the protein resulted in significant, sustained bilateral effects.

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Galit Kleiner-Fisman, David N. Fisman, Elspeth Sime, Jean A. Saint-Cyr, Andres M. Lozano and Anthony E. Lang

Object. The use of deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been associated with a marked initial improvement in individuals with advanced Parkinson disease (PD). Few data are available on the long-term outcomes of this procedure, however, or whether the initial benefits are sustained over time. The authors present the long-term results of a cohort of 25 individuals who underwent bilateral DBS of the STN between 1996 and 2001 and were followed up for 1 year or longer after implantation of the stimulator.

Methods. Patients were evaluated at baseline and repeatedly after surgery by using the Unified Parkinson's Disease Rating Scale (UPDRS); the scale was applied to patients during periods in which antiparkinsonian medications were effective and periods when their effects had worn off. Postoperative UPDRS total scores and subscores, dyskinesia scores, and drug dosages were compared with baseline values, and changes in the patients' postoperative scores were evaluated to assess the possibility that the effect of DBS diminished over time.

In this cohort the median duration of follow-up review was 24 months (range 12–52 months). The combined (ADL and motor) total UPDRS score during the medication-off period improved after 1 year, decreasing by 42% relative to baseline (95% confidence interval [CI 35–50%], p < 0.001) and the motor score decreased by 48% (95% CI 42–55%, p < 0.001). These gains did diminish over time, although a sustained clinical benefit remained at the time of the last evaluation (41% improvement over baseline, 95% CI 31–50%; p < 0.001). Axial subscores at the time of the last evaluation showed only a trend toward improvement (p = 0.08), in contrast to scores for total tremor (p < 0.001), rigidity (p < 0.001), and bradykinesia (p = 0.003), for which highly significant differences from baseline were still present at the time of the last evaluation. Medication requirements diminished substantially, with total medication doses reduced by 38% (95% CI 27–48%, p < 0.001) at 1 year and 36% (95% CI 25–48%, p < 0.001) at the time of the last evaluation; this decrease may have accounted, at least in part, for the significant decrease of 46.4% (95% CI 20.2–72.5%, p = 0.007) in dyskinesia scores obtained by patients during the medication-on period. No preoperative demographic variable, such as the patient's age at the time of disease onset, age at surgery, sex, duration of disease before surgery, preoperative drug dosage, or preoperative severity of dyskinesia, was predictive of long-term outcome. The only predictor of a better outcome was the patient's preoperative response to levodopa.

Conclusions. In this group of patients with advanced PD who underwent bilateral DBS of the STN, sustained improvement in motor function was present a mean of 2 years after the procedure, and sustained reductions in drug requirements were also achieved. Improvements in tremor, rigidity, and bradykinesia were more marked and better sustained over time than improvements in axial symptoms. A good preoperative response to levodopa predicted a good response to surgery.

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Jérôme Yelnik, Philippe Damier, Sophie Demeret, David Gervais, Eric Bardinet, Boulos-Paul Bejjani, Chantal François, Jean-Luc Houeto, Isabelle Arnulf, Didier Dormont, Damien Galanaud, Bernard Pidoux, Philippe Cornu and Yves Agid

Object. The aim of this study was to correlate the clinical improvement in patients with Parkinson disease (PD) treated using deep brain stimulation (DBS) of the subthalamic nucleus (STN) with the precise anatomical localization of stimulating electrodes.

Methods. Localization was determined by superimposing figures from an anatomical atlas with postoperative magnetic resonance (MR) images obtained in each patient. This approach was validated by an analysis of experimental and clinical MR images of the electrode, and the development of a three-dimensional (3D) atlas—MR imaging coregistration method. The PD motor score was assessed through two contacts for each of two electrodes implanted in 10 patients: the “therapeutic contact” and the “distant contact” (that is, the next but one to the therapeutic contact). Seventeen therapeutic contacts were located within or on the border of the STN, most of which were associated with significant improvement of the four PD symptoms tested. Therapeutic contacts located in other structures (zona incerta, lenticular fasciculus, or midbrain reticular formation) were also linked to a significant positive effect. Stimulation applied through distant contacts located in the STN improved symptoms of PD, whereas that delivered through distant contacts in the remaining structures had variable effects ranging from worsening of symptoms to their improvement.

Conclusions. The authors have demonstrated that 3D atlas—MR imaging coregistration is a reliable method for the precise localization of DBS electrodes on postoperative MR images. In addition, they have confirmed that although the STN is the main target during DBS treatment for PD, stimulation of surrounding regions, particularly the zona incerta or the lenticular fasciculus, can also improve symptoms of PD.

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Joachim K. Krauss, Thomas J. Loher, Ralf Weigel, H. Holger Capelle, Sabine Weber and Jean-Marc Burgunder

Object. The authors studied the long-term efficacy of deep brain stimulation (DBS) of the posteroventral lateral globus pallidus internus up to 2 years postoperatively in patients with primary non-DYT1 generalized dystonia or choreoathetosis. The results are briefly compared with those reported for DBS in DYT1 dystonia (Oppenheim dystonia), which is caused by the DYT1 gene.

Methods. Enrollment in this prospective expanded pilot study was limited to adult patients with severely disabling, medically refractory non-DYT1 generalized dystonia or choreoathetosis. Six consecutive patients underwent follow-up examinations at defined intervals of 3 months, 1 year, and 2 years postsurgery. There were five women and one man, and their mean age at surgery was 45.5 years. Formal assessments included both the Burke-Fahn-Marsden dystonia scale and the recently developed Unified Dystonia Rating Scale. Two patients had primary generalized non-DYT1 dystonia, and four suffered from choreoathetosis secondary to infantile cerebral palsy. Bilateral quadripolar DBS electrodes were implanted in all instances, except in one patient with markedly asymmetrical symptoms. There were no adverse events related to surgery.

The Burke-Fahn-Marsden scores in the two patients with generalized dystonia improved by 78 and 71% at 3 months, by 82 and 69% at 1 year, and by 78 and 70% at 2 years postoperatively. This was paralleled by marked amelioration of disability scores. The mean improvement in Burke-Fahn-Marsden scores in patients with choreoathetosis was 12% at 3 months, 29% at 1 year, and 23% at 2 years postoperatively, which was not significant. Two of these patients thought that they had achieved marked improvement at 2 years postoperatively, although results of objective evaluations were less impressive. In these two patients there was a minor but stable improvement in disability scores. All patients had an improvement in pain scores at the 2-year follow-up review. Medication was tapered off in both patients with generalized dystonia and reduced in two of the patients with choreoathetosis. All stimulation-induced side effects were reversible on adjustment of the DBS settings. Energy consumption of the batteries was considerably higher than in patients with Parkinson disease.

Conclusions. Chronic pallidal DBS is a safe and effective procedure in generalized non-DYT1 dystonia, and it may become the procedure of choice in patients with medically refractory dystonia. Postoperative improvement of choreoathetosis is more modest and varied, and subjective ratings of outcome may exceed objective evaluations.

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Jean A. Saint-Cyr, Tasnuva Hoque, Luiz C. M. Pereira, Jonathan O. Dostrovsky, William D. Hutchison, David J. Mikulis, Aviva Abosch, Elspeth Sime, Anthony E. Lang and Andres M. Lozano

Object. The authors sought to determine the location of deep brain stimulation (DBS) electrodes that were most effective in treating Parkinson disease (PD).

Methods. Fifty-four DBS electrodes were localized in and adjacent to the subthalamic nucleus (STN) postoperatively by using magnetic resonance (MR) imaging in a series of 29 patients in whom electrodes were implanted for the treatment of medically refractory PD, and for whom quantitative clinical assessments were available both pre- and postoperatively. A novel MR imaging sequence was developed that optimized visualization of the STN. The coordinates of the tips of these electrodes were calculated three dimensionally and the results were normalized and corrected for individual differences by using intraoperative neurophysiological data (mean 5.13 mm caudal to the midcommissural point [MCP], 8.46 mm inferior to the anterior commissure—posterior commissure [AC—PC], and 10.2 mm lateral to the midline).

Despite reported concerns about distortion on the MR image, reconstructions provided consistent data for the localization of electrodes. The neurosurgical procedures used, which were guided by combined neuroimaging and neurophysiological methods, resulted in the consistent placement of DBS electrodes in the subthalamus and mesencephalon such that the electrode contacts passed through the STN and dorsally adjacent fields of Forel (FF) and zona incerta (ZI). The mean location of the clinically effective contacts was in the anterodorsal STN (mean 1.62 mm posterior to the MCP, 2.47 mm inferior to the AC—PC, and 11.72 mm lateral to the midline). Clinically effective stimulation was most commonly directed at the anterodorsal STN, with the current spreading into the dorsally adjacent FF and ZI.

Conclusions. The anatomical localization of clinically effective electrode contacts provided in this study yields useful information for the postoperative programming of DBS electrodes.

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Emmanuel Cuny, Dominique Guehl, Pierre Burbaud, Christian Gross, Vincent Dousset and Alain Rougier

Object. The goal of this study was to determine the most suitable procedure(s) to localize the optimal site for high-frequency stimulation of the subthalamic nucleus (STN) for the treatment of advanced Parkinson disease.

Methods. Stereotactic coordinates of the STN were determined in 14 patients by using three different methods: direct identification of the STN on coronal and axial T2-weighted magnetic resonance (MR) images and indirect targeting in which the STN coordinates are referred to the anterior commissure—posterior commissure (AC—PC) line, which, itself, is determined either by using stereotactic ventriculography or reconstruction from three-dimensional (3D) MR images. During the surgical procedure, electrode implantation was guided by single-unit microrecordings on multiple parallel trajectories and by clinical assessment of stimulations. The site where the optimal functional response was obtained was considered to be the best target. Computerized tomography scanning was performed 3 days later and the scans were combined with preoperative 3D MR images to transfer the position of the best target to the same system of stereotactic coordinates. An algorithm was designed to convert individual stereotactic coordinates into an all-purpose PC-referenced system for comparing the respective accuracy of each method of targeting, according to the position of the best target.

Conclusions. The target that is directly identified by MR imaging is more remote (mainly in the lateral axis) from the site of the optimal functional response than targets obtained using other procedures, and the variability of this method in the lateral and superoinferior axes is greater. In contrast, the target defined by 3D MR imaging is closest to the target of optimal functional response and the variability of this method is the least great. Thus, 3D reconstruction adjusted to the AC—PC line is the most accurate technique for STN targeting, whereas direct visualization of the STN on MR images is the least effective. Electrophysiological guidance makes it possible to correct the inherent inaccuracy of the imaging and surgical techniques and is not designed to modify the initial targeting.

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Philip A. Starr, Chadwick W. Christine, Philip V. Theodosopoulos, Nadja Lindsey, Deborah Byrd, Anthony Mosley and William J. Marks Jr.

Object. Chronic deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a procedure that is rapidly gaining acceptance for the treatment of symptoms in patients with Parkinson disease (PD), but there are few detailed descriptions of the surgical procedure itself. The authors present the technical approach used to implant 76 stimulators into the STNs of patients with PD and the lead locations, which were verified on postoperative magnetic resonance (MR) images.

Methods. Implantation procedures were performed with the aid of stereotactic MR imaging, microelectrode recording (MER) in the region of the stereotactic target to define the motor area of the STN, and intraoperative test stimulation to assess the thresholds for stimulation-induced adverse effects. All patients underwent postoperative MR imaging, which was performed using volumetric gradient-echo and T2-weighted fast—spin echo techniques, computational reformatting of the MR image into standard anatomical planes, and quantitative measurements of lead location with respect to the midcommissural point and the red nucleus. Lead locations were statistically correlated with physiological data obtained during MER and intraoperative test stimulation.

Conclusions. The authors' approach to implantation of DBS leads into the STN was associated with consistent lead placement in the dorsolateral STN, a low rate of morbidity, efficient use of operating room time, and robust improvement in motor function. The mean coordinates of the middle of the electrode array, measured on postoperative MR images, were 11.6 mm lateral, 2.9 mm posterior, and 4.7 mm inferior to the midcommissural point, and 6.5 mm lateral and 3.5 mm anterior to the center of the red nucleus. Voltage thresholds for several types of stimulation-induced adverse effects were predictive of lead location. Technical nuances of the surgery are described in detail.

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Tanya Simuni, Jurg L. Jaggi, Heather Mulholland, Howard I. Hurtig, Amy Colcher, Andrew D. Siderowf, Bernard Ravina, Brett E. Skolnick, Reid Goldstein, Matthew B. Stern and Gordon H. Baltuch

Object. Palliative neurosurgery has reemerged as a valid therapy for patients with advanced Parkinson disease (PD) that is complicated by severe motor fluctuations. Despite great enthusiasm for long-term deep brain stimulation (DBS) of the subthalamic nucleus (STN), existing reports on this treatment are limited. The present study was designed to investigate the safety and efficacy of bilateral stimulation of the STN for the treatment of PD.

Methods. In 12 patients with severe PD, electrodes were stereotactically implanted into the STN with the assistance of electrophysiological conformation of the target location. All patients were evaluated preoperatively during both medication-off and -on conditions, as well as postoperatively at 3, 6, and 12 months during medication-on and -off states and stimulation-on and -off conditions. Tests included assessments based on the Unified Parkinson's Disease Rating Scale (UPDRS) and timed motor tests.

The stimulation effect was significant in patients who were in the medication-off state, resulting in a 47% improvement in the UPDRS Part III (Motor Examination) score at 12 months, compared with preoperative status. The benefit was stable for the duration of the follow-up period. Stimulation produced no additional benefit during the medication-on state, however, when compared with patient preoperative status. Significant improvements were made in reducing dyskinesias, fluctuations, and duration of off periods.

Conclusions. This study demonstrates that DBS of the STN is an effective treatment for patients with advanced, medication-refractory PD. Deep brain stimulation of the STN produced robust improvements in motor performance in these severely disabled patients while they were in the medication-off state. Serious adverse events were common in this cohort; however, only two patients suffered permanent sequelae.

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Ivar Mendez, Alain Dagher, Murray Hong, Paula Gaudet, Swarna Weerasinghe, Vivian McAlister, David King, Jacques Desrosiers, Sultan Darvesh, Tanya Acorn and Harold Robertson

✓ The main neural transplantation strategy in Parkinson disease (PD) has been focused on reinnervating the striatum. The clinical results reported in patients who receive transplants have been limited and do not justify the use of neural transplantation as a routine therapeutic procedure for PD. Identifying the optimal target for transplantation may be one of the critical factors for optimizing clinical outcomes. Evidence from preclinical studies indicates that simultaneous intrastriatal and intranigral grafts (double grafts) may produce a more complete functional recovery. The authors report the clinical and positron emission tomography (PET) scanning results in three patients enrolled in a safety and feasibility pilot study who received double grafts and who have been followed for up to 13 months posttransplantation.

Patients included in the study had idiopathic PD. All patients underwent detailed assessments before and after surgery, in accordance with the Core Assessment Program for Intracerebral Transplantation. The patients received implants of fetal mesencephalic cell suspensions in the putamen and substantia nigra (SN) bilaterally. There were no intraoperative or perioperative complications. Follow-up PET scans demonstrated an increase in the mean fluorodopa uptake constant values in the putamen and SN 12 months postsurgery. Improvements were also noted in the total Unified Parkinson′s Disease Rating Scale, Hoehn and Yahr, Schwab and England, and pronation/supination scores after transplantation. The authors demonstrate the feasibility of reinnervating the SN and striatum by using a double transplant strategy in humans.

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Jürgen Voges, Jens Volkmann, Niels Allert, Ralph Lehrke, Athanasios Koulousakis, Hans-Joachim Freund and Volker Sturm

Object. The goal of this study was to relate the degree of clinical improvement and that of energy consumption to the anatomical position of electrode poles used for long-term stimulation.

Methods. The authors conducted a retrospective analysis of 15 consecutive patients in whom targeting of the subthalamic nucleus (STN) had been performed using ventriculography, three-dimensional (3D) magnetic resonance (MR) imaging, and 3D computerized tomography, together with macrostimulation and teleradiographic control of the electrode position. In these patients the follow-up period ranged from 6 to 12 months. Postoperative improvement in contralateral motor symptoms, which was assessed by assigning a lateralized motor subscore of the Unified Parkinson's Disease Rating Scale (UPDRS), and stimulus intensity required for optimal treatment results were correlated with the intracerebral position of the active electrode pole.

Bilateral high-frequency stimulation of the STN improved the UPDRS motor score during the medication-off period by an average of 60.5% compared with that at baseline. Repeated transfer of stereotactic coordinates from postoperative teleradiography to treatment-planning MR images documented the proper localization of the most distal electrode pole (pole 0) in the targeted STN. Nevertheless, in most cases the best clinical improvement was achieved using electrode poles that were located several millimeters above the electrode tip. If the relative improvement in motor symptoms was correlated with the required electrical energy for chronic stimulation, the best coefficient was observed for active electrode poles projecting onto white matter dorsal to the STN.

Conclusions. This observation makes blocking or activation of large fiber connections arising in the STN or running nearby more likely than electrical interference with cell bodies inside the STN. Anatomical correlates may be the pallidothalamic bundle (including Field H of Forel and the thalamic fascicle), the pallidosubthalamic tract, and/or the zona incerta.