Ramon L. Rodriguez

Genome-wide genotyping in Parkinson's disease and neurologically normal controls: first stage analysis and public release of data

BACKGROUND Several genes underlying rare monogenic forms of Parkinsons disease have been identified over the past decade. Despite evidence for a role for genetics in sporadic Parkinsons disease, few common genetic variants have been unequivocally linked to this disorder. We sought to identify any common genetic variability exerting a large effect in risk for Parkinsons disease in a population cohort and to produce publicly available genome-wide genotype data that can be openly mined by interested researchers and readily augmented by genotyping of additional repository subjects. METHODS We did genome-wide, single-nucleotide-polymorphism (SNP) genotyping of publicly available samples from a cohort of Parkinsons disease patients (n=267) and neurologically normal controls (n=270). More than 408,000 unique SNPs were used from the Illumina Infinium I and HumanHap300 assays. FINDINGS We have produced around 220 million genotypes in 537 participants. This raw genotype data has been and as such is the first publicly accessible high-density SNP data outside of the International HapMap Project. We also provide here the results of genotype and allele association tests. INTERPRETATION We generated publicly available genotype data for Parkinsons disease patients and controls so that these data can be mined and augmented by other researchers to identify common genetic variability that results in minor and moderate risk for disease.

Cognition and Mood in Parkinson's Disease in Subthalamic Nucleus versus Globus Pallidus Interna Deep Brain Stimulation: The COMPARE Trial

Our aim was to compare in a prospective blinded study the cognitive and mood effects of subthalamic nucleus (STN) vs. globus pallidus interna (GPi) deep brain stimulation (DBS) in Parkinson disease.

SNCA Variants Are Associated with Increased Risk for Multiple System Atrophy

To test whether the synucleinopathies Parkinsons disease and multiple system atrophy (MSA) share a common genetic etiology, we performed a candidate single nucleotide polymorphism (SNP) association study of the 384 most associated SNPs in a genome‐wide association study of Parkinsons disease in 413 MSA cases and 3,974 control subjects. The 10 most significant SNPs were then replicated in additional 108 MSA cases and 537 controls. SNPs at the SNCA locus were significantly associated with risk for increased risk for the development of MSA (combined p = 5.5 × 1012; odds ratio 6.2). Ann Neurol 2009;65:610–614

Aspiration and swallowing in Parkinson disease and rehabilitation with EMST: A randomized trial

Objective: Dysphagia is the main cause of aspiration pneumonia and death in Parkinson disease (PD) with no established restorative behavioral treatment to date. Reduced swallow safety may be related to decreased elevation and excursion of the hyolaryngeal complex. Increased submental muscle force generation has been associated with expiratory muscle strength training (EMST) and subsequent increases in hyolaryngeal complex movement provide a strong rationale for its use as a dysphagia treatment. The current studys objective was to test the treatment outcome of a 4-week device-driven EMST program on swallow safety and define the physiologic mechanisms through measures of swallow timing and hyoid displacement. Methods: This was a randomized, blinded, sham-controlled EMST trial performed at an academic center. Sixty participants with PD completed EMST, 4 weeks, 5 days per week, for 20 minutes per day, using a calibrated or sham, handheld device. Measures of swallow function including judgments of swallow safety (penetration–aspiration [PA] scale scores), swallow timing, and hyoid movement were made from videofluoroscopic images. Results: No pretreatment group differences existed. The active treatment (EMST) group demonstrated improved swallow safety compared to the sham group as evidenced by improved PA scores. The EMST group demonstrated improvement of hyolaryngeal function during swallowing, findings not evident for the sham group. Conclusions: EMST may be a restorative treatment for dysphagia in those with PD. The mechanism may be explained by improved hyolaryngeal complex movement. Classification of evidence: This intervention study provides Class I evidence that swallow safety as defined by PA score improved post EMST.

REOPERATION FOR SUBOPTIMAL OUTCOMES AFTER DEEP BRAIN STIMULATION SURGERY

OBJECTIVETo examine a case series of reoperations for deep brain stimulation (DBS) leads in which clinical scenarios revealed suboptimal outcome from a previous operation. Suboptimally placed DBS leads are one potential reason for unsatisfactory results after surgery for Parkinsons disease (PD), essential tremor (ET), or dystonia. In a previous study of patients who experienced suboptimal results, 19 of 41 patients had misplaced leads. Similarly, another report commented that lead placement beyond a 2- to 3-mm window resulted in inadequate clinical benefit, and, in 1 patient, revision improved outcome. The goal of the current study was to perform an unblinded retrospective chart review of DBS patients with unsatisfactory outcomes who presented for reoperation. METHODSPatients who had DBS lead replacements after reoperation were assessed with the use of a retrospective review of an institutional review board-approved movement disorders database. Cases of reoperation for suboptimal clinical benefit were included, and cases of replacement of DBS leads caused by infection or hardware malfunction were excluded. Data points studied included age, disease duration, diagnosis, motor outcomes (the Unified Parkinson Disease Rating Scale III in PD, the Tremor Rating Scale in ET, and the Unified Dystonia Rating Scale in dystonia), quality of life (Parkinsons Disease Questionnaire-39 in PD), and the Clinician Global Impression scale. The data from before and after reoperation were examined to determine the estimated impact of repeat surgery. RESULTSThere were 11 patients with PD, 7 with ET, and 4 with dystonia. The average age of the PD group was 52 years, the disease duration was 10 years, and the average vector distance of the location of the active DBS contact was adjusted 5.5 mm. Six patients (54%) with PD had preoperative off medication on DBS Unified Parkinson Disease Rating Scale scores that could be compared with postoperative off medication on DBS scores. The average improvement across this group of patients was 24.4%. The Parkinsons Disease Questionnaire-39 improved in the areas of mobility (28.18), activities of daily living (14.77), emotion (14.72), stigma (17.61), and discomfort (17.42). The average age of the ET group was 66 years, the disease duration was 29 years, and the average adjusted distance was 6.1 mm. Five ET patients (83.3%) in the cohort had a prereplacement on DBS Tremor Rating Scale and a postreplacement on DBS Tremor Rating Scale with the average improvement of 60.4%. The average age of the dystonia group was 39 years, the average disease duration was 7 years, and the average adjusted lead distance was 6.7 mm. Three patients (75%) with dystonia had prereplacement on DBS Unified Dystonia Rating Scale and postreplacement on DBS Unified Dystonia Rating Scale scores. Across these 3 dystonia patients, the improvement was 12.8%. Clinician Global Impression scale scores (1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; 7, very much worse) after replacement revealed the following results in patients with PD: 1, 7 patients; 2, 3 patients; 3, 1 patient); with ET (1, 4 patients; 2, 3 patients); and with dystonia (1, 1 patient; 2, 2 patients; 3, 1 patient). The latency from original lead placement to reoperation (repositioning/revision) overall was 28.9 months (range, 2–104 mo); however, in leads referred from outside institutions (n = 11 patients), this latency was 48 months (range, 12–104 mo) compared with leads implanted by surgeons from the University of Florida (n = 11 patients), which was 9.7 months (range, 2–19 mo). The most common clinical history was failure to achieve a perceived outcome; however, history of an asymmetric benefit was present in 4 (18.2%) of 22 patients, and lead migration was present in 3 (13.6%) of 22 patients. CONCLUSIONThere are many potential causes of suboptimal benefit after DBS. Timely identification of suboptimal lead placements followed by reoperation and repositioning/replacement in a subset of patients may improve outcomes.

Dual Electrode Thalamic Deep Brain Stimulation For The Treatment Of Posttraumatic And Multiple Sclerosis Tremor

OBJECTIVE: To report the results of ventralis intermedius nucleus/ventralis oralis posterior nucleus (VIM) plus ventralis oralis anterior (VOA)/ventralis oralis posterior (VOP) thalamic deep brain stimulation (DBS) for the treatment of posttraumatic and multiple sclerosis tremor. OBJECTIVE: The treatment of posttraumatic tremor and multiple sclerosis tremor, by either medication or surgery, has proven difficult. Lesions and DBS have had mixed and somewhat disappointing results. Previously, we reported the use of two DBS electrodes (one at the VIM/VOP border and one at the VOA/VOP border) as effective for the treatment of posttraumatic tremor in a single patient. In this study, we report the results of this technique on four patients. METHODS: Four patients with either posttraumatic tremor (n = 3) or multiple sclerosis tremor (n = 1) underwent placement of two DBS electrodes (one at the VIM/VOP border and one at the VOA/VOP border). Patients underwent preoperative testing and testing at a minimum of 6 months after implantation in four conditions: On VIM DBS/On VOA/VOP DBS; On VIM DBS/Off VOA VOP DBS (5 h DBS washout); Off VIM DBS/Off VOA/VOP DBS (12 h overnight washout); and Off VIM DBS/On VOA/VOP DBS (5 h DBS washout). RESULTS: Each of the patients showed improvements in all four conditions when compared with the baseline. All of the improvements were maintained with chronic DBS, without tremor rebound. An analysis was performed to determine whether each condition was associated with symptom reduction (percentage change). The percentage reduction was significant for each condition and measure, despite the small number of participants. For the total tremor rating scale score, the Off VIM/Off VOA/VOP condition yielded less symptom reduction than the On VIM condition or the On VOA/VOP condition. The On VIM and On VOA/VOP conditions did not differ significantly from each other in terms of contralateral upper extremity symptoms or total clinical score. Activation of both the VIM and VOA/VOP electrodes was associated with the greatest symptom reduction. CONCLUSION: Tremors, such as those examined in this study, that are refractory to medications and have a poor response to VIM DBS monotherapy, may respond favorably to VIM plus VOA/VOP DBS. Two electrodes may be better than one for the treatment of certain disorders; however, more study will be required to confirm this hypothesis.

Depression symptoms in movement disorders: Comparing Parkinson's disease, dystonia, and essential tremor

Depression is common in Parkinsons disease (PD) and affects 30 to 50% of all patients. In contrast to the wealth of research on depression in PD, little is known about the occurrence of depression in other movement disorders. The primary objective of the current study was to determine whether the high prevalence of depression symptoms seen in PD is also found in other movement disorders, by directly comparing rates of specific depression symptoms and depression severity across PD, dystonia, and essential tremor (ET). Three hundred and fifty‐four patients with PD, 83 patients with dystonia, and 53 patients with ET completed the Beck Depression Inventory (BDI). We found no significant between‐groups differences for depression severity, frequency, or endorsement of specific depression symptoms. Forty‐eight percent of PD patients, 37.3% of dystonia patients, and 34% of ET patients were found to be at least mildly depressed (BDI score of 10 or higher). The most commonly endorsed symptoms were fatigability, difficulty with work, anhedonia, and sleep disturbance. Clinicians should be aware that depression is a frequent problem in dystonia and ET, in addition to PD, and inquire about depression symptoms in these patients so that they can be appropriately treated

Brain penetration effects of microelectrodes and DBS leads in STN or GPi

Objective: To determine how intraoperative microelectrode recordings (MER) and intraoperative lead placement acutely influence tremor, rigidity, and bradykinesia. Secondarily, to evaluate whether the longevity of the MER and lead placement effects were influenced by target location (subthalamic nucleus (STN) or globus pallidus interna (GPi)). Background: Currently most groups who perform deep brain stimulation (DBS) for Parkinson disease (PD) use MER, as well as macrostimulation (test stimulation), to refine DBS lead position. Following MER and/or test stimulation, however, there may be a resultant “collision/implantation” or “microlesion” effect, thought to result from disruption of cells and/or fibres within the penetrated region. These effects have not been carefully quantified. Methods: 47 consecutive patients with PD undergoing unilateral DBS for PD (STN or GPi DBS) were evaluated. Motor function was measured at six time points with a modified motor Unified Parkinson Disease Rating Scale (UPDRS): (1) preoperatively, (2) immediately after MER, (3) immediately after lead implantation/collision, (4) 4 months following surgery—off medications, on DBS (12 h medication washout), (5) 6 months postoperatively—off medication and off DBS (12 h washout) and (6) 6 months—on medication and off DBS (12 h washout). Results: Significant improvements in motor scores (p<0.05) (tremor, rigidity, bradykinesia) were observed as a result of MER and lead placement. The improvements were similar in magnitude to what was observed at 4 and 6 months post-DBS following programming and medication optimisation. When washed out (medications and DBS) for 12 h, UPDRS motor scores were still improved compared with preoperative testing. There was a larger improvement in STN compared with GPi following MER (p<0.05) and a trend for significance following lead placement (p<0.08) but long term outcome was similar. Conclusion: This study demonstrated significant acute intraoperative penetration effects resulting from MER and lead placement/collision in PD. Clinicians rating patients in the operating suite should be aware of these effects, and should consider pre- and post-lead placement rating scales prior to activating DBS. The collision/implantation effects were greater intraoperatively with STN compared with GPi, and with greater disease duration there was a larger effect.

Pearls in patient selection for deep brain stimulation.

Background:Deep brain stimulation (DBS) has emerged as an important treatment for medication refractory movement and neuropsychiatric disorders. General neurologists and even general practitioners may be called upon to screen potential candidates for DBS. The patient selection process plays an important role in this procedure. Review Summary:In this article, we discuss “pearls” for the clinician who may be called upon to identify appropriate candidates for DBS. Additionally, we will discuss the important points that should be considered when referring patients for surgical intervention. Conclusion:Diagnosis, response to levodopa, cognitive status, psychiatric status, access to care, and patient expectations are all essential elements of the patient selection process for DBS. These areas must be adequately addressed prior to any surgical procedure.

A Trial of Scheduled Deep Brain Stimulation for Tourette Syndrome Moving Away From Continuous Deep Brain Stimulation Paradigms

OBJECTIVE To collect the information necessary to design the methods and outcome variables for a larger trial of scheduled deep brain stimulation (DBS) for Tourette syndrome. DESIGN We performed a small National Institutes of Health-sponsored clinical trials planning study of the safety and preliminary efficacy of implanted DBS in the bilateral centromedian thalamic region. The study used a cranially contained constant-current device and a scheduled, rather than the classic continuous, DBS paradigm. Baseline vs 6-month outcomes were collected and analyzed. In addition, we compared acute scheduled vs acute continuous vs off DBS. SETTING A university movement disorders center. PATIENTS Five patients with implanted DBS. MAIN OUTCOME MEASURE A 50% improvement in the Yale Global Tic Severity Scale (YGTSS) total score. RESULTS Participating subjects had a mean age of 34.4 (range, 28-39) years and a mean disease duration of 28.8 years. No significant adverse events or hardware-related issues occurred. Baseline vs 6-month data revealed that reductions in the YGTSS total score did not achieve the prestudy criterion of a 50% improvement in the YGTSS total score on scheduled stimulation settings. However, statistically significant improvements were observed in the YGTSS total score (mean [SD] change, -17.8 [9.4]; P=.01), impairment score (-11.3 [5.0]; P=.007), and motor score (-2.8 [2.2]; P=.045); the Modified Rush Tic Rating Scale Score total score (-5.8 [2.9]; P=.01); and the phonic tic severity score (-2.2 [2.6]; P=.04). Continuous, off, and scheduled stimulation conditions were assessed blindly in an acute experiment at 6 months after implantation. The scores in all 3 conditions showed a trend for improvement. Trends for improvement also occurred with continuous and scheduled conditions performing better than the off condition. Tic suppression was commonly seen at ventral (deep) contacts, and programming settings resulting in tic suppression were commonly associated with a subjective feeling of calmness. CONCLUSIONS This study provides safety and proof of concept that a scheduled DBS approach could improve motor and vocal tics in Tourette syndrome. Refinements in neurostimulator battery life, outcome measure selection, and flexibility in programming settings can be used to enhance outcomes in a future larger study. Scheduled stimulation holds promise as a potential first step for shifting movement and neuropsychiatric disorders toward more responsive neuromodulation approaches. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01329198.