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1.  MRI reveals brain abnormalities in drug-naïve Parkinson’s disease 
Exercise and sport sciences reviews  2014;42(1):10.1249/JES.0000000000000003.
Most brain studies of Parkinson’s disease (PD) focus on patients who are already taking anti-parkinsonian medication. This makes it difficult to isolate the effects of disease from those of treatment. We review MRI evidence supporting the hypothesis that early-stage, untreated PD patients have structural and functional abnormalities in the brain, some of which are related to motor symptoms.
PMCID: PMC3885158  PMID: 24188978
diffusion tensor imaging (DTI); functional magnetic resonance imaging (fMRI); parkinsonism; grip force; subtype; de novo; movement
2.  Surgical Treatment of Parkinson’s Disease: Patients, Targets, Devices, and Approaches 
Neurotherapeutics  2013;11(1):47-59.
Surgical treatment for Parkinson’s disease (PD) has evolved from ablative procedures, within a variety of brain regions, to implantation of electrodes into specific targets of the basal ganglia. Electrode implantation surgery, referred to as deep brain stimulation (DBS), is preferred to ablative procedures by many experts owing to its reversibility, programmability, and the ability to be safely performed bilaterally. Several randomized clinical studies have demonstrated the effectiveness of DBS surgery for control of PD symptoms. Many brain targets, including the subthalamic nucleus and the globus pallidus internus, have emerged as potentially effective, with each target being closely associated with important pros and cons. Selection of appropriate PD candidates through a methodical interdisciplinary screening is considered a prerequisite for a successful surgical outcome. Despite recent growth in DBS knowledge, there is currently no consensus on the ideal surgical technique, the best surgical approach, and the most appropriate surgical target. DBS is now targeted towards treating specific PD-related symptoms in a given individual, and not simply addressing the disease with one pre-defined approach. In this review we will discuss the historical aspects of surgical treatments, the selection of an appropriate DBS candidate, the current surgical techniques, and recently introduced DBS-related technologies. We will address important pre- and postoperative issues related to DBS. We will also discuss the lessons learned from the randomized clinical studies for DBS and the shifting paradigm to tailor to a more patient-centered and symptom-specific approach.
Electronic supplementary material
The online version of this article (doi:10.1007/s13311-013-0235-0) contains supplementary material, which is available to authorized users.
PMCID: PMC3899492  PMID: 24198187
Parkinson’s disease; Deep brain stimulation; subthalamic nucleus DBS; Globus pallidus DBS
3.  Comparable Botulinum Toxin Outcomes between Primary and Secondary Blepharospasm: A Retrospective Analysis 
Blepharospasm is a focal cranial dystonia, which could be idiopathic in origin or secondary to an underlying disorder that commonly impairs quality of life. Botulinum toxin (BoNT) injections have become the treatment of choice; however, a less favorable response to BoNT is expected in secondary blepharospasm. No studies have been conducted comparing outcomes between blepharospasm cohorts. We therefore aim to compare BoNT outcomes in primary and secondary blepharospasm subjects.
A retrospective review of 64 blepharospasm subjects receiving BoNT therapy was conducted. Demographics, BoNT treatment schedules, duration of BoNT therapy, and side effects were recorded. Outcome measures were duration of benefit, peak-dose benefit recorded with the Clinical Global Impressions Scale (CGIS), and related side effects.
No difference was found between the two cohorts regarding duration of benefit from treatment (primary 9.47 weeks vs. secondary 9.63 weeks, p = 0.88). Perceived peak-dose benefit was more commonly reported as “very much improved” in secondary patients, but this was not significant (p = 0.13). Higher BoNT dosages were required in both groups over time, with a mean increase of 20.5% in primary and 26.5% in secondary blepharospasm. Ptosis (8%) and diplopia (6%) were the most common reported side effects. Mean follow-up in years was similar between groups, 3.6 years for primary vs. 2.4 years for secondary blepharospasm (p = 0.17).
BoNT injections were effective with comparable benefits seen in both primary and secondary blepharospasm populations. Clinicians should be aware of the similar benefit from BoNT reported in secondary blepharospasm patients. The average duration of benefit in this cohort was comparable with previous reports.
PMCID: PMC4266684  PMID: 25562037
Cranial dystonia; botulinum toxin; Parkinson's; tardive syndromes; Clinical Global Impressions Scale
4.  Pedunculopontine Nucleus Stimulation: Where are We Now and What Needs to be Done to Move the Field Forward? 
Falls and gait impairment in Parkinson’s Disease (PD) is a leading cause of morbidity and mortality, significantly impacting quality of life and contributing heavily to disability. Thus far axial symptoms, such as postural instability and gait freezing, have been refractory to current treatment approaches and remain a critical unmet need. There has been increased excitement surrounding the surgical targeting of the pedunculopontine nucleus (PPN) for addressing axial symptoms in PD. The PPN and cuneate nucleus comprise the mesencephalic locomotor region, and electrophysiologic studies in animal models and human imaging studies have revealed a key role for the PPN in gait and postural control, underscoring a potential role for DBS surgery. Previous limited studies of PPN deep brain stimulation (DBS) in treating gait symptoms have had mixed clinical outcomes, likely reflect targeting variability and the inherent challenges of targeting a small brainstem structure that is both anatomically and neurochemically heterogeneous. Diffusion tractography shows promise for more accurate targeting and standardization of results. Due to the limited experience with PPN DBS, several unresolved questions remain about targeting and programing. At present, it is unclear if there is incremental benefit with bilateral versus unilateral targeting of PPN or whether PPN targeting should be performed as an adjunct to one of the more traditional targets. The PPN also modulates non-motor functions including REM sleep, cognition, mood, attention, arousal, and these observations will require long-term monitoring to fully characterize potential side effects and benefits. Surgical targeting of the PPN is feasible and shows promise for addressing axial symptoms in PD but may require further refinements in targeting, improved imaging, and better lead design to fully realize benefits. This review summarizes the current knowledge of PPN as a DBS target and areas that need to be addressed to advance the field.
PMCID: PMC4255598  PMID: 25538673
pedunculopontine nucleus; deep brain stimulation; Parkinson’s disease; microelectrode recording; postural instability; gait freezing; diffusion tractography
5.  Acute and Chronic Mood and Apathy Outcomes from a Randomized Study of Unilateral STN and GPi DBS 
PLoS ONE  2014;9(12):e114140.
To study mood and behavioral effects of unilateral and staged bilateral subthalamic nucleus (STN) and globus pallidus internus (GPi) deep brain stimulation (DBS) for Parkinson's disease (PD).
There are numerous reports of mood changes following DBS, however, most have focused on bilateral simultaneous STN implants with rapid and aggressive post-operative medication reduction.
A standardized evaluation was applied to a subset of patients undergoing STN and GPi DBS and who were also enrolled in the NIH COMPARE study. The Unified Parkinson Disease Rating Scale (UPDRS III), the Hamilton depression (HAM-D) and anxiety rating scales (HAM-A), the Yale-Brown obsessive-compulsive rating scale (YBOCS), the Apathy Scale (AS), and the Young mania rating scale (YMRS) were used. The scales were repeated at acute and chronic intervals. A post-operative strategy of non-aggressive medication reduction was employed.
Thirty patients were randomized and underwent unilateral DBS (16 STN, 14 GPi). There were no baseline differences. The GPi group had a higher mean dopaminergic dosage at 1-year, however the between group difference in changes from baseline to 1-year was not significant. There were no differences between groups in mood and motor outcomes. When combining STN and GPi groups, the HAM-A scores worsened at 2-months, 4-months, 6-months and 1-year when compared with baseline; the HAM-D and YMRS scores worsened at 4-months, 6-months and 1-year; and the UPDRS Motor scores improved at 4-months and 1-year. Psychiatric diagnoses (DSM-IV) did not change. No between group differences were observed in the cohort of bilateral cases.
There were few changes in mood and behavior with STN or GPi DBS. The approach of staging STN or GPi DBS without aggressive medication reduction could be a viable option for managing PD surgical candidates. A study of bilateral DBS and of medication reduction will be required to better understand risks and benefits of a bilateral approach.
PMCID: PMC4254912  PMID: 25469706
7.  The Evolving Role of Diffusion Magnetic Resonance Imaging in Movement Disorders 
Current neurology and neuroscience reports  2013;13(11):10.1007/s11910-013-0400-1.
Significant advances have allowed diffusion MRI (dMRI) to evolve into a powerful tool in the field of movement disorders that can be used to study disease states and connectivity between brain regions. dMRI represents a promising potential biomarker for Parkinson’s disease and other forms of parkinsonism, and may allow for the distinction of different forms of parkinsonism. Techniques such as tractography have contributed to our current thinking regarding the pathophysiology of dystonia and possible mechanisms of penetrance. dMRI measures could potentially assist in monitoring disease progression in Huntington’s disease, and in uncovering the nature of the processes and structures involved the development of essential tremor. The ability to represent structural connectivity in vivo also makes dMRI an ideal adjunctive tool for the surgical treatment of movement disorders. We will review recent studies utilizing dMRI in movement disorders research and present the current state of the science as well as future directions.
PMCID: PMC3824956  PMID: 24046183
diffusion magnetic resonance imaging; diffusion tensor imaging; movement disorders; Parkinson’s disease; parkinsonism; dystonia; Huntington’s disease; essential tremor
8.  Atrophy and Other Potential Factors Affecting Long Term Deep Brain Stimulation Response: A Case Series 
PLoS ONE  2014;9(10):e111561.
To describe three DBS cases which presented with new side effects or loss of benefit from stimulation after long-term follow-up and to discuss the potential contributing factors.
A University of Florida (UF) database (INFORM) search was performed, identifying three patients, two Parkinson's disease (PD) and one Essential Tremor (ET), with an unexpected change in long-term programming thresholds as compared to initial evaluation. Clinical follow-up, programming, imaging studies, and lead measurements were reviewed. The UF Institutional Review Board (IRB) approved this study.
A substantial increase in the 3rd ventricular width (120%), Evans index (6%), ventricular index (5%), and cella media index (17%) was uncovered. A change in thresholds across lead contacts with a decrease in current densities as well as a relative lateral change of lead location was also observed. Hardware-related complications, lead migration, and impedance variability were not identified.
Potential factors contributing to long-term side effects should be examined during a DBS troubleshooting assessment. Clinicians should be aware that in DBS therapy there is delivery of electricity to a changing brain, and atrophy may possibly affect DBS programming settings as part of long-term follow-up.
PMCID: PMC4216112  PMID: 25360599
9.  Gait variability magnitude but not structure is altered in essential tremor 
Journal of biomechanics  2013;46(15):10.1016/j.jbiomech.2013.07.039.
Essential tremor (ET) is a common tremor disorder affecting postural/action tremor of the upper extremities and midline. Recent research revealed a cerebellar-like deficit during tandem gait in persons with ET, though spatiotemporal variability during normal gait in ET has been relatively ignored. The first purpose of this study was to investigate gait variability magnitude and structure in ET as compared to healthy older adults (HOA). To address this issue, 11 ET and 11 age-matched HOAs walked on a treadmill for five minutes at preferred walking speeds. HOAs walked for an additional minute while speed-matched to an ET participant. The second purpose was to describe the clinical correlates of gait variability in this population. To address this aim, 31 persons with ET walked on a treadmill for five minutes and completed the Fahn-Tolosa-Marin Tremor Rating Scale. Gait variability magnitude was derived by calculating coefficients of variation in stride length, stride time, step length, step time, and step width. Gait variability structure was derived using a detrended fluctuation analysis technique. At preferred walking speeds, ET participants walked significantly slower with significantly increased variability magnitude in all five spatiotemporal gait parameters. At speed-matched walking, ET participants exhibited significantly higher step width variability. Gait variability structure was not different between groups. We also observed that gait variability magnitude was predicted by severity of upper extremity and midline tremors. This study revealed that self-selected gait in ET is characterized by high variability that is associated with tremor severity in the upper extremity and midline.
PMCID: PMC3832140  PMID: 24011360
gait; variability; essential tremor; motor control; cerebellum
10.  Gait initiation impairments in both Essential Tremor and Parkinson’s Disease 
Gait & posture  2013;38(4):956-961.
Gait initiation is a transitional task involving a voluntary shift from a static, stable position to a relatively less-stable state of locomotion. During gait initiation, anticipatory postural adjustments precede stepping in order to generate forward momentum while balance is maintained. While deficits in gait initiation are frequently reported for persons with Parkinson’s disease, there is a paucity of information regarding gait initiation performance in persons with Essential Tremor. We investigated anticipatory postural adjustments and spatiotemporal characteristics of gait initiation in persons with Essential Tremor and compared them to persons with Parkinson’s disease as well as age-matched neurologically-healthy adults. Twenty-four persons with Essential Tremor, 31 persons with Parkinson’s disease, and 38 age-matched controls participated. We compared anterior-posterior and mediolateral center of pressure movements and spatiotemporal stepping characteristics during gait initiation among the three groups using Mann-Whitney U-tests with Bonferroni corrections for multiple comparisons and one-way ANOVAs. Persons with Parkinson’s disease demonstrated significantly reduced displacement and velocity of the center of pressure during early phases of anticipatory postural adjustments relative to controls. Displacement of the center of pressure was also reduced in persons with Essential Tremor, although at a later stage of the gait initiation process. Persons with Parkinson’s disease and Essential Tremor demonstrated similar reductions in step length during gait initiation when compared to controls. Persons with Parkinson’s disease and Essential Tremor exhibit different deficits in gait initiation when compared to healthy older adults. Therefore, this study provides further evidence differentiating motor control features in these movement disorders.
PMCID: PMC3778167  PMID: 23726428
gait initiation; Parkinson’s disease; Essential Tremor; anticipatory postural adjustments; motor control
11.  Cerebral Venous Infarction: A Potentially Avoidable Complication of Deep Brain Stimulation Surgery 
Despite numerous reports on the morbidity and mortality of deep brain stimulation (DBS), cerebral venous infarction has rarely been reported. We present four cases of venous infarct secondary to DBS surgery.
The diagnosis of venous infarction was based on: 1) delayed onset of new neurologic deficits on post-operative day 1 or 2, and 2) significant edema surrounding the superficial aspect of the implanted lead, with or without subcortical hemorrhage on CT scan.
Four cases (0.8%/lead, 1.3%/patient) of symptomatic cerebral venous infarction were identified out of 500 DBS lead implantation procedures between July 2002 and August 2009. All four patients had Parkinson’s disease (PD). Their DBS leads were implanted in the subthalamic nucleus (STN) (n=2), and the internal globus pallidus (GPi) (n=2). Retrospective review of the targeting confirmed that the planned trajectory passed within 3mm of a cortical vein in two cases for which contrast-enhanced pre-operative MRI was available. In the other two cases, contrasted targeting images were not obtained preoperatively.
Cerebral venous infarction is a potentially avoidable, but serious complication. To minimize its incidence, we propose the use of high resolution, contrast-enhanced, T1 weighted MR images to delineate cerebral venous anatomy, along with careful stereotactic planning of the lead trajectory to avoid injury to venous structures.
PMCID: PMC3772976  PMID: 23738501
Deep Brain Stimulation; Venous Infarction; Complication; Adverse Event; Hemorrhage
12.  Using the Timed Up & Go Test in a Clinical Setting to Predict Falling in Parkinson's Disease 
To investigate the ability of the Timed Up & Go test to identify patients with Parkinson's disease at risk for a fall.
Cross-sectional cohort study.
Sixteen participating National Parkinson's Foundation Centers of Excellence.
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.
Not applicable.
Main Outcome Measures
The primary outcome measure for this study was falls. The chief independent variable was the Timed Up & Go test.
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 (χ2 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.
The findings suggest that the Timed Up & Go test may be an accurate assessment tool to identify those at risk for falls.
PMCID: PMC4144326  PMID: 23473700
Accidental falls; Gait; Nervous system diseases; Rehabilitation
13.  Reliability of Three Benton Judgment of Line Orientation Short Forms in Idiopathic Parkinson’s Disease 
The Clinical neuropsychologist  2013;27(7):10.1080/13854046.2013.827744.
Individuals with Parkinson’s disease (PD) often exhibit deficits in visuospatial functioning throughout the course of their disease. These deficits should be carefully assessed as they may have implications for patient safety and disease severity. One of the most commonly administered tests of visuospatial ability, the Benton Judgment of Line Orientation (JLO), consists of 30 pairs of lines requiring the patient to match the orientation of two lines to an array of 11 lines on a separate page. Reliable short forms have been constructed out of the full JLO form, but the reliability of these forms in PD has yet to be examined. Recent functional MRI studies examining the JLO demonstrate right parietal and occipital activation, as well as bilateral frontal activation and PD is known to adversely affect these pathways. We compared the reliability of the original full form to three unique short forms in a sample of 141 non-demented, idiopathic PD patients and 56 age and education matched controls. Results indicated that a two-thirds length short form can be used with high reliability and classification accuracy in patients with idiopathic PD. The other short forms performed in a similar, though slightly less reliable manner.
PMCID: PMC3832287  PMID: 23957375
Visuospatial function; Parkinson’s disease; Benton Judgment of Line Orientation (JLO); short form; Neuropsychological assessment
14.  Hedonic and Behavioral Deficits Associated with Apathy in Parkinson’s Disease: Potential Treatment Implications 
Many individuals with Parkinson’s disease (PD) experience apathy independent of depression. In this study we examined hedonic and behavioral deficits related to apathy in 50 PD patients and 42 healthy older adults who completed standardized measures. Regression analyses revealed that apathy was associated with anticipatory, but not consummatory, anhedonia and reduced goal-directed behavior, independent of PD diagnosis, age, education and depressive symptoms. These findings suggest that apathy is characterized by deficits in anticipatory pleasure and behavioral drive rather than consummatory pleasure or reward responsiveness. Therefore, PD patients with apathy would likely benefit from psychotherapeutic treatment that encourages structured, goal-directed plans for pleasurable events and stimulation which provide adaptive hedonic effects. In addition, given the proposed shared mechanism of dopamine depletion within the ventral striatum in apathy and anticipatory anhedonia, future trials of dopamine-eliciting activities (e.g. exercise and other non-pharmacologic methods) appear warranted to improve these symptoms in PD.
PMCID: PMC3760996  PMID: 23712560
Parkinson’s disease; anhedonia; apathy
15.  Deep Brain Stimulation for Tremor Associated with Underlying Ataxia Syndromes: A Case Series and Discussion of Issues 
Deep brain stimulation (DBS) has been utilized to treat various symptoms in patients suffering from movement disorders such as Parkinson's disease, dystonia, and essential tremor. Though ataxia syndromes have not been formally or frequently addressed with DBS, there are patients with ataxia and associated medication refractory tremor or dystonia who may potentially benefit from therapy.
A retrospective database review was performed, searching for cases of ataxia where tremor and/or dystonia were addressed by utilizing DBS at the University of Florida Center for Movement Disorders and Neurorestoration between 2008 and 2011. Five patients were found who had DBS implantation to address either medication refractory tremor or dystonia. The patient's underlying diagnoses included spinocerebellar ataxia type 2 (SCA2), fragile X associated tremor ataxia syndrome (FXTAS), a case of idiopathic ataxia (ataxia not otherwise specified [NOS]), spinocerebellar ataxia type 17 (SCA17), and a senataxin mutation (SETX).
DBS improved medication refractory tremor in the SCA2 and the ataxia NOS patients. The outcome for the FXTAS patient was poor. DBS improved dystonia in the SCA17 and SETX patients, although dystonia did not improve in the lower extremities of the SCA17 patient. All patients reported a transient gait dysfunction postoperatively, and there were no reports of improvement in ataxia-related symptoms.
DBS may be an option to treat tremor, inclusive of dystonic tremor in patients with underlying ataxia; however, gait and other symptoms may possibly be worsened.
PMCID: PMC4101398  PMID: 25120941
Tremor; SCA2; SCA17; fragile X syndrome; myoclonic dystonia; deep brain stimulation; unilateral
16.  Brittle Dyskinesia Following STN but not GPi Deep Brain Stimulation 
The aim was to describe the prevalence and characteristics of difficult to manage dyskinesia associated with subthalamic nucleus (STN) deep brain stimulation (DBS). A small subset of STN DBS patients experience troublesome dyskinesia despite optimal programming and medication adjustments. This group of patients has been referred to by some practitioners as brittle STN DBS-induced dyskinesia, drawing on comparisons with brittle diabetics experiencing severe blood sugar regulation issues and on a single description by McLellan in 1982. We sought to describe, and also to investigate how often the “brittle” phenomenon occurs in a relatively large DBS practice.
An Institutional Review Board-approved patient database was reviewed, and all STN and globus pallidus internus (GPi) DBS patients who had surgery at the University of Florida from July 2002 to July 2012 were extracted for analysis.
There were 179 total STN DBS patients and, of those, four STN DBS (2.2%) cases were identified as having dyskinesia that could not be managed without the induction of an “off state,” or by the precipitation of a severe dyskinesia despite vigorous stimulation and medication adjustments. Of 75 GPi DBS cases reviewed, none (0%) was identified as having brittle dyskinesia. One STN DBS patient was successfully rescued by bilateral GPi DBS.
Understanding the potential risk factors for postoperative troublesome and brittle dyskinesia may have an impact on the initial surgical target selection (STN vs. GPI) in DBS therapy. Rescue GPi DBS therapy may be a viable treatment option, though more cases will be required to verify this observation.
PMCID: PMC4050173  PMID: 24932426
Subthalamic; induced; globus pallidus; adverse event; complication; fluctuation
17.  Stimulation region within the globus pallidus does not affect verbal fluency performance 
Brain stimulation  2012;6(3):248-253.
Subthalamic (STN) and globus pallidus (GP) deep brain stimulation (DBS) have been previously shown to be efficacious in the treatment of selected Parkinson patients with medication resistant motor fluctuations and/or tremor. Deep brain stimulation of the STN has been implicated with more cognitive and mood side effects as compared to GP DBS; however, more studies are needed to better understand possible target differences. Previously, Mikos et al. (1) reported worsening of verbal fluency depending on the stimulation location within the STN region.
The current study applied the methods used by Mikos et al. (2011) to a different sample of Parkinson patients who underwent GP DBS. Based on differences in the size and functional somatotopy between structures (GP 412mm3 vs. STN 167mm3), we hypothesized that there would be a less robust relationship between volume of tissue activated, fluency performance, and stimulation contact within the GP compared to what was reported in the STN.
Patient-specific DBS models were created and the volume of tissue activated within the GP was calculated. These data were correlated with patients’ verbal fluency performance at dorsal, optimal, and ventral stimulation contacts.
In contrast to STN findings, there was no significant relationship between stimulation location and fluency performance in patients who received GP DBS.
These results suggest that fluency may be less sensitive to stimulation location in the globus pallidus and thus there may be more flexibility in terms of DBS programming with GP DBS patients.
PMCID: PMC3491090  PMID: 22766102
DBS; Parkinson’s; globus pallidus; verbal fluency; cognition
18.  Surgical Treatment of Dyskinesia in Parkinson’s Disease 
One of the main indications for stereotactic surgery in Parkinson’s disease (PD) is the control of levodopa-induced dyskinesia. This can be achieved by pallidotomy and globus pallidus internus (GPi) deep brain stimulation (DBS) or by subthalamotomy and subthalamic nucleus (STN) DBS, which usually allow for a cut down in the dosage of levodopa. DBS has assumed a pivotal role in stereotactic surgical treatment of PD and, in fact, ablative procedures are currently considered surrogates, particularly when bilateral procedures are required, as DBS does not produce a brain lesion and the stimulator can be programed to induce better therapeutic effects while minimizing adverse effects. Interventions in either the STN and the GPi seem to be similar in controlling most of the other motor aspects of PD, nonetheless, GPi surgery seems to induce a more particular and direct effect on dyskinesia, while the anti-dyskinetic effect of STN interventions is mostly dependent on a reduction of dopaminergic drug dosages. Hence, the si ne qua non-condition for a reduction of dyskinesia when STN interventions are intended is their ability to allow for a reduction of levodopa dosage. Pallidal surgery is indicated when dyskinesia is a dose-limiting factor for maintaining or introducing higher adequate levels of dopaminergic therapy. Also medications used for the treatment of PD may be useful for the improvement of several non-motor aspects of the disease, including sleep, psychiatric, and cognitive domains, therefore, dose reduction of medication withdrawal are not always a fruitful objective.
PMCID: PMC4010755  PMID: 24808889
Parkinson’s disease; dyskinesia; deep brain stimulation; DBS; pallidotomy
19.  Variability in clinical phenotypes of heterozygous and homozygous cases of Parkin-related Parkinson’s disease 
Parkin mutations are a common cause of early-onset Parkinson’s disease. To study the clinical features and treatment responses of patients with homozygous or heterozygous Parkin mutations, we performed a retrospective chart review in six early-onset parkinsonism patients with pathogenic Parkin mutations. The clinical phenotypes observed in this cohort, all drawn from different families, were variable. All patients had a slowly progressive form of parkinsonism that responded well to dopaminergic therapy with the exception of one advanced case. Homozygous patients had an earlier age at disease onset than heterozygous patients. Two of our patients underwent bilateral deep brain stimulation (DBS) of the subthalamic nucleus or globus pallidus leading to a sustained positive response. Our observations support an earlier age of onset for homozygous cases and possible beneficial effects of DBS in Parkin-related parkinsonism.
PMCID: PMC4001762  PMID: 23767969
20.  The “Brittle Response” to Parkinson’s Disease Medications: Characterization and Response to Deep Brain Stimulation 
PLoS ONE  2014;9(4):e94856.
Formulate a definition and describe the clinical characteristics of PD patients with a “brittle response” (BR) to medications versus a “non-brittle response” (NBR), and characterize the use of DBS for this population.
An UF IRB approved protocol used a retrospective chart review of 400 consecutive PD patients presenting to the UF Center for Movement Disorders and Neurorestoration. Patient records were anonymized and de-identified prior to analysis. SPSS statistics were used to analyze data.
Of 345 included patients, 19 (5.5%) met criteria for BR PD. The BR group was comprised of 58% females, compared to 29% in the NBR group (P = .008). The former had a mean age of 63.4 compared to 68.1 in the latter. BR patients had lower mean weight (63.5 vs. 79.6, P = <.001), longer mean disease duration (12.6 vs. 8.9 years, P = .003), and had been on LD for more years compared to NBR patients (9.8 vs. 5.9, P = .001). UPDRS motor scores were higher (40.4 vs. 30.0, P = .001) in BR patients. No differences were observed regarding the Schwab and England scale, PDQ-39, and BDI-II. Sixty-three percent of the BR group had undergone DBS surgery compared to 18% (P = .001). Dyskinesias were more common, severe, and more often painful (P = <.001) in the BR group. There was an overall positive benefit from DBS.
BR PD occurred more commonly in female patients with a low body weight. Patients with longer disease duration and longer duration of LD therapy were also at risk. The BR group responded well to DBS.
PMCID: PMC3986256  PMID: 24733172
21.  Coordinate-Based Lead Location Does Not Predict Parkinson's Disease Deep Brain Stimulation Outcome 
PLoS ONE  2014;9(4):e93524.
Effective target regions for deep brain stimulation (DBS) in Parkinson's disease (PD) have been well characterized. We sought to study whether the measured Cartesian coordinates of an implanted DBS lead are predictive of motor outcome(s). We tested the hypothesis that the position and trajectory of the DBS lead relative to the mid-commissural point (MCP) are significant predictors of clinical outcomes. We expected that due to neuroanatomical variation among individuals, a simple measure of the position of the DBS lead relative to MCP (commonly used in clinical practice) may not be a reliable predictor of clinical outcomes when utilized alone.
55 PD subjects implanted with subthalamic nucleus (STN) DBS and 41 subjects implanted with globus pallidus internus (GPi) DBS were included. Lead locations in AC-PC space (x, y, z coordinates of the active contact and sagittal and coronal entry angles) measured on high-resolution CT-MRI fused images, and motor outcomes (Unified Parkinson's Disease Rating Scale) were analyzed to confirm or refute a correlation between coordinate-based lead locations and DBS motor outcomes.
Coordinate-based lead locations were not a significant predictor of change in UPDRS III motor scores when comparing pre- versus post-operative values. The only potentially significant individual predictor of change in UPDRS motor scores was the antero-posterior coordinate of the GPi lead (more anterior lead locations resulted in a worse outcome), but this was only a statistical trend (p<.082).
The results of the study showed that a simple measure of the position of the DBS lead relative to the MCP is not significantly correlated with PD motor outcomes, presumably because this method fails to account for individual neuroanatomical variability. However, there is broad agreement that motor outcomes depend strongly on lead location. The results suggest the need for more detailed identification of stimulation location relative to anatomical targets.
PMCID: PMC3972103  PMID: 24691109
22.  An Eight-Year Clinic Experience with Clozapine Use in a Parkinson’s Disease Clinic Setting 
PLoS ONE  2014;9(3):e91545.
To examine our eight year clinic-based experience in a Parkinson’s disease expert clinical care center using clozapine as a treatment for refractory psychosis in Parkinson's disease (PD).
The study was a retrospective chart review which covered eight years of clozapine registry use. Statistical T-tests, chi-square, correlations and regression analysis were used to analyze treatment response for potential associations of age, disease duration, and Hoehn & Yahr (H&Y) score, and degree of response to clozapine therapy.
There were 36 participants included in the analysis (32 PD, 4 parkinsonism-plus). The characteristics included 30.6% female, age 45–87 years (mean 68.3±10.15), disease duration of 17–240 months (mean 108.14±51.13) and H&Y score of 2 to 4 (mean 2.51±0.51). The overall retention rate on clozapine was 41% and the most common reasons for discontinuation were frequent blood testing (28%), nursing home (NH) placement (11%) and leucopenia (8%). Responses to clozapine across the cohort were: complete (33%), partial (33%), absent (16%), and unknown (16%). Age (r = −0.36, p<0.01) and H&Y score (r = −0.41, p<0.01) were shown to be related to response to clozapine therapy, but disease duration was not an associated factor (r = 0.21, p>0.05).
This single-center experience highlights the challenges associated with clozapine therapy in PD psychosis. Frequent blood testing remains a significant barrier for clozapine, even in patients with therapeutic benefit. Surprisingly, all patients admitted to a NH discontinued clozapine due to logistical issues of administration and monitoring within that setting. Consideration of the barriers to clozapine therapy will be important to its use and to its continued success in an outpatient setting.
PMCID: PMC3960134  PMID: 24646688
23.  The history of cerebral PET scanning 
Neurology  2013;80(10):952-956.
To review the discoveries underpinning the introduction of cerebral PET scanning and highlight its modern applications.
Important discoveries in neurophysiology, brain metabolism, and radiotracer development in the post–World War II period provided the necessary infrastructure for the first cerebral PET scan.
A complete review of the literature was undertaken to search for primary and secondary sources on the history of PET imaging. Searches were performed in PubMed, Google Scholar, and select individual journal Web sites. Written autobiographies were obtained through the Society for Neuroscience Web site at A reference book on the history of radiology, Naked to the Bone, was reviewed to corroborate facts and to locate references. The references listed in all the articles and books obtained were reviewed.
The neurophysiologic sciences required to build cerebral PET imaging date back to 1878. The last 60 years have produced an evolution of technological advancements in brain metabolism and radiotracer development. These advancements facilitated the development of modern cerebral PET imaging. Several key scientists were involved in critical discoveries and among them were Angelo Mosso, Charles Roy, Charles Sherrington, John Fulton, Seymour Kety, Louis Sokoloff, David E. Kuhl, Gordon L. Brownell, Michael Ter-Pogossian, Michael Phelps, and Edward Hoffman.
Neurophysiology, metabolism, and radiotracer development in the postwar era synergized the development of the technology necessary for cerebral PET scanning. Continued use of PET in clinical trials and current developments in PET-CT/MRI hybrids has led to advancement in diagnosis, management, and treatment of neurologic disorders.
PMCID: PMC3653214  PMID: 23460618
24.  Increased Precursor Cell Proliferation after Deep Brain Stimulation for Parkinson's Disease: A Human Study 
PLoS ONE  2014;9(3):e88770.
Deep brain stimulation (DBS) has been used for more than a decade to treat Parkinson's disease (PD); however, its mechanism of action remains unknown. Given the close proximity of the electrode trajectory to areas of the brain known as the “germinal niches,” we sought to explore the possibility that DBS influences neural stem cell proliferation locally, as well as more distantly.
We studied the brains of a total of 12 idiopathic Parkinson's disease patients that were treated with DBS (the electrode placement occurred 0.5–6 years before death), and who subsequently died of unrelated illnesses. These were compared to the brains of 10 control individuals without CNS disease, and those of 5 PD patients with no DBS.
Immunohistochemical analyses of the subventricular zone (SVZ) of the lateral ventricles, the third ventricle lining, and the tissue surrounding the DBS lead revealed significantly greater numbers of proliferating cells expressing markers of the cell cycle, plasticity, and neural precursor cells in PD-DBS tissue compared with both normal brain tissue and tissue from PD patients not treated with DBS. The level of cell proliferation in the SVZ in PD-DBS brains was 2–6 fold greater than that in normal and untreated PD brains.
Our data suggest that DBS is capable of increasing cellular plasticity in the brain, and we hypothesize that it may have more widespread effects beyond the electrode location. It is unclear whether these effects of DBS have any symptomatic or other beneficial influences on PD.
PMCID: PMC3940428  PMID: 24594681
25.  Rescue GPi-DBS for a Stroke-associated Hemiballism in a Patient with STN-DBS 
Tremor and Other Hyperkinetic Movements  2014;4:tre-04-214-4855-1.
Hemiballism/hemichorea commonly occurs as a result of a lesion in the subthalamic region.
Case Report
A 38-year-old male with Parkinson’s disease developed intractable hemiballism in his left extremities due to a small lesion that was located adjacent to the right deep brain stimulation (DBS) lead, 10 months after bilateral subthalamic nucleus (STN)-DBS placement. He underwent a right globus pallidus internus (GPi)-DBS lead implantation. GPi-DBS satisfactorily addressed his hemiballism.
This case offered a unique look at basal ganglia physiology in human hemiballism. GPi-DBS is a reasonable therapeutic option for the treatment of medication refractory hemiballism in the setting of Parkinson’s disease.
PMCID: PMC3918512  PMID: 24587970
Globus pallidus internus; subthalamic nucleus; deep brain stimulation; hemiballism; stroke

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