Irene A. Malaty

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.

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.

Quetiapine improves visual hallucinations in Parkinson disease but not through normalization of sleep architecture: results from a double-blind clinical-polysomnography study.

Polysomnographic studies of Parkinsons disease (PD) patients with visual hallucinations (VH) usually reveal short, fragmented rapid eye movement (REM) sleep, with lower sleep efficiency and reduced total REM sleep. Quetiapine has been demonstrated in open-label trials to be effective for the treatment of insomnia and VH in PD. To confirm quetiapines efficacy in improving VH, and to determine whether the mechanism was due to its effect on REM sleep architecture, we performed a pilot, double-blind, placebo-controlled study. Sixteen PD patients experiencing VH were recruited. Eight patients were randomized to quetiapine and eight patients to placebo. Patients underwent pre- and post-treatment polysomnography. The Clinical Global Impression Scale (CGIS), Brief Psychiatric Rating Scale (BPRS), and Unified Parkinson Disease Rating Scale (UPDRS) motor subscale were obtained. There were no differences in baseline characteristics between the treatment arms except that the placebo group had more sleep in stage REM (74.7 min vs. 40.1 min; p < .001). Data were imputed for all patients who prematurely discontinued (four quetiapine and one placebo) in an intention-to-treat analysis. The average quetiapine dose was 58.3 mg/day. While there was no significant difference in the change in REM duration pre- vs. post-treatment in either arm, patients randomized to quetiapine improved on the CGIS (p = .03) and the hallucination item of the BPRS (p = .02). No difference was noted in the UPDRS motor scores. Despite the small sample, this is the first double-blind trial to show quetiapines efficacy over placebo in controlling VH in the PD population. However, normalization of sleep architecture was not supported as the mechanism.

Binge Eating in Parkinson's Disease: Prevalence, Correlates and the Contribution of Deep Brain Stimulation

Of 96 Parkinsons disease patients surveyed at the University of Florida Movement Disorders Center, one (1%) met diagnostic criteria for binge-eating disorder. Eight (8.3%) exhibited subthreshold binge eating. Psychometric criteria classified problem gambling in 17.8%, hoarding in 8.3%, compulsive buying in 11.5%, hypersexuality in 1.0%, and mania in 1.0% of patients. More overeaters met psychometric criteria for at least one additional impulse-control disorder (67% versus 29%). No more overeaters than non-overeaters were taking a dopamine agonist (44% versus 41%). More overeaters had a history of subthalamic deep brain stimulation (DBS; 44% versus 14%). History of DBS was the only independent predictor of overeating.

Management of the hospitalized patient with Parkinson's disease: current state of the field and need for guidelines.

OBJECTIVE To review the literature and to identify practice gaps in the management of the hospitalized Parkinsons disease (PD) patient. BACKGROUND Patients with PD are admitted to hospitals at higher rates, and frequently have longer hospital stays than the general population. Little is known about outpatient interventions that might reduce the need for hospitalization and also reduce hospital-related complications. METHODS A literature review was performed on PubMed about hospitalization and PD between 1970 and 2010. In addition, in press peer-reviewed papers or published abstracts known to the authors were included. Information was reviewed by a National Parkinson Foundation workgroup and a narrative review article was generated. RESULTS Motor disturbances in PD are believed to be a causal factor in the higher rates of admissions and complications. However, other conditions are commonly recorded as the primary reason for hospitalization including motor complications, reduced mobility, lack of compliance, inappropriate use of neuroleptics, falls, fractures, pneumonia, and other important medical problems. There are many relevant issues related to hospitalization in PD. Medications, dosages and specific dosage schedules are critical. Staff training regarding medications and medication management may help to avoid complications, particularly those related to reduced mobility, and aspiration pneumonia. Treatment of infections and a return to early mobility is also critical to management. CONCLUSIONS Educational programs, recommendations, and guidelines are needed to better train interdisciplinary teams in the management of the PD patient. These initiatives have the potential for both cost savings and improved outcomes from a preventative and a hospital management standpoint.

Using the Timed Up & Go Test in a Clinical Setting to Predict Falling in Parkinson's Disease

OBJECTIVE To investigate the ability of the Timed Up & Go test to identify patients with Parkinsons disease at risk for a fall. DESIGN Cross-sectional cohort study. SETTING Sixteen participating National Parkinsons Foundation Centers of Excellence. PARTICIPANTS A query yielded a total of 2985 records (1828 men and 1157 women). From these, 884 were excluded because of a lack of crucial information (age, diagnosis, presence of deep brain stimulation, disease duration, inability of performing the Timed Up & Go test without assistance) at the time of testing, leaving 2097 patients included in the analysis. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES The primary outcome measure for this study was falls. The chief independent variable was the Timed Up & Go test. RESULTS The initial model examined the prediction of falls from the Timed Up & Go test, adjusting for all study covariates. The estimated models in the imputed data sets represented a significant improvement above chance (χ(2) range [df=17], 531.29-542.39, P<.001), suggesting that 74% of participants were accurately classified as a faller or nonfaller. The secondary model in which the question of whether the effect of Timed Up & Go test was invariant across disease severity demonstrated 75% of participants were accurately classified as a faller or nonfaller. Additional analysis revealed a proposed cut score of 11.5 seconds for discrimination of those who did or did not fall. CONCLUSIONS The findings suggest that the Timed Up & Go test may be an accurate assessment tool to identify those at risk for falls.

Brain penetration effects of microelectrodes and deep brain stimulation leads in ventral intermediate nucleus stimulation for essential tremor

OBJECT Microelectrode recording (MER) and macrostimulation (test stimulation) are used to refine the optimal deep brain stimulation (DBS) lead placement within the operative setting. It is well known that there can be a microlesion effect with microelectrode trajectories and DBS insertion. The aim of this study was to determine the impact of intraoperative MER and lead placement on tremor severity in a cohort of patients with essential tremor. METHODS Consecutive patients with essential tremor undergoing unilateral DBS (ventral intermediate nucleus stimulation) for medication-refractory tremor were evaluated. Tremor severity was measured at 5 time points utilizing a modified Tremor Rating Scale: 1) immediately before MER; 2) immediately after MER; 3) immediately after lead implantation; 4) 6 months after DBS implantation in the off-DBS condition; and 5) 6 months after implantation in the on-DBS condition. To investigate the impact of the MER and DBS lead placement, Wilcoxon signed-rank tests were applied to test changes in tremor severity scores over the surgical course. In addition, a generalized linear mixed model including factors that potentially influenced the impact of the microlesion was also used for analysis. RESULTS Nineteen patients were evaluated. Improvement was noted in the total modified Tremor Rating Scale, postural, and action tremor scores (p < 0.05) as a result of MER and DBS lead placement. The improvements observed following lead placement were similar in magnitude to what was observed in the chronically programmed clinic setting parameters at 6 months after lead implantation. Improvement in tremor severity was maintained over time even in the off-DBS condition at 6 months, which was supportive of a prolonged microlesion effect. The number of macrostimulation passes, the number of MER passes, and disease duration were not related to the change in tremor severity score over time. CONCLUSIONS Immediate improvement in postural and intention tremors may result from MER and DBS lead placement in patients undergoing DBS for essential tremor. This improvement could be a predictor of successful DBS lead placement at 6 months. Clinicians rating patients in the operating room should be aware of these effects and should consider using rating scales before and after lead placement to take these effects into account when evaluating outcome in and out of the operating room.

Quantitative Normative Gait Data in a Large Cohort of Ambulatory Persons with Parkinson's Disease

Background Gait performance is widely evaluated to assess health status in older adult populations. While several investigators have presented normative values for spatiotemporal gait parameters drawn from older adult populations, the literature has been void of large-scale cohort studies, which are needed in order to provide quantitative, normative gait data in persons with Parkinson’s disease. The aim of this investigation was to provide reference values for clinically important gait characteristics in a large sample of ambulatory persons with Parkinson’s disease to aid both clinicians and researchers in their evaluations and treatments of gait impairment. Methodology/Principal Findings Gait performance was collected in 310 individuals with idiopathic Parkinson’s disease as they walked across a pressure sensitive walkway. Fourteen quantitative gait parameters were measured and evaluated with respect to Hoehn and Yahr disease staging and gender. Disease duration and age were controlled for in all analyses. Individuals with the greatest Parkinson’s disability walked significantly slower with shorter steps and stride lengths than the mild and moderately affected groups. Further, the most affected patients spent more time with both feet on the ground, and walked with a wider base of support than the moderately disabled patients. No differences were detected between the mild and moderate disability groups on any of the gait parameters evaluated. Conclusions/Significance Reference values for 14 gait parameters in a large cohort of ambulatory patients with Parkinson’s disease are provided and these may be highly useful for assessing and interpreting an individual’s gait dysfunction. It is important for clinicians and researchers to appreciate the lack of change in quantitative parameters as PD patients move from mild to moderate gait impairment.

Are selective serotonin reuptake inhibitors associated with greater apathy in Parkinson's disease?

Apathy is a common neuropsychiatric feature of Parkinsons disease (PD), but little is known of relationships between apathy and specific medications in PD. Following a retrospective database and chart review of 181 Parkinsons patients, relationships between Apathy Scale scores and use of psychotropic and antiparkinsonian medications were examined with multiple regression. Controlling for age, sex, education, and depression, the use of selective serotonin reuptake inhibitors (SSRIs), but not other antidepressants, was associated with greater apathy. Use of monoamine oxidase B inhibitors was associated with less apathy. Longitudinal studies are needed to evaluate a potential SSRI-induced apathy syndrome in PD.

Differential Response of Dystonia and Parkinsonism following Globus Pallidus Internus Deep Brain Stimulation in X-Linked Dystonia-Parkinsonism (Lubag)

Background: X-linked dystonia-parkinsonism (XDP; DYT3; Lubag) is an adult-onset hereditary progressive dystonia/parkinsonism which is typically minimally responsive to pharmacological treatment. Case Report: We report a 63- year-old man with a diagnosis of XDP who underwent bilateral globus pallidus internus deep brain stimulator (GPi-DBS) placement. His course initially began with right hand tremor and dystonia at age 57 and progressed to also include bradykinesia and rigidity. The patient tolerated the procedure without significant complications. GPi-DBS improved his right hand dystonia, but did not significantly improve his parkinsonism. Conclusion: DBS may be a therapeutic option for select cases of XDP, but its specificindications must be carefully discussed, as the available cases have had mixed responses. Whether other targets may be more effective is not known.