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1.  Levodopa-Carbidopa Intestinal Gel in Advanced Parkinson'd Disease: Final 12-Month, Open-Label Results 
Movement Disorders  2014;30(4):500-509.
Motor complications in Parkinson's disease (PD) are associated with long-term oral levodopa treatment and linked to pulsatile dopaminergic stimulation. l-dopa-carbidopa intestinal gel (LCIG) is delivered continuously by percutaneous endoscopic gastrojejunostomy tube (PEG-J), which reduces l-dopa-plasma–level fluctuations and can translate to reduced motor complications. We present final results of the largest international, prospective, 54-week, open-label LCIG study. PD patients with severe motor fluctuations (>3 h/day “off” time) despite optimized therapy received LCIG monotherapy. Additional PD medications were allowed >28 days post-LCIG initiation. Safety was the primary endpoint measured through adverse events (AEs), device complications, and number of completers. Secondary endpoints included diary-assessed off time, “on” time with/without troublesome dyskinesia, UPDRS, and health-related quality-of-life (HRQoL) outcomes. Of 354 enrolled patients, 324 (91.5%) received PEG-J and 272 (76.8%) completed the study. Most AEs were mild/moderate and transient; complication of device insertion (34.9%) was the most common. Twenty-seven (7.6%) patients withdrew because of AEs. Serious AEs occurred in 105 (32.4%), most commonly complication of device insertion (6.5%). Mean daily off time decreased by 4.4 h/65.6% (P < 0.001). On time without troublesome dyskinesia increased by 4.8 h/62.9% (P < 0.001); on time with troublesome dyskinesia decreased by 0.4 h/22.5% (P = 0.023). Improvements persisted from week 4 through study completion. UPDRS and HRQoL outcomes were also improved throughout. In the advanced PD population, LCIG's safety profile consisted primarily of AEs associated with the device/procedure, l-dopa/carbidopa, and advanced PD. LCIG was generally well tolerated and demonstrated clinically significant improvements in motor function, daily activities, and HRQoL sustained over 54 weeks. © 2014 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
PMCID: PMC4674978  PMID: 25545465
dyskinesia; infusion; levodopa-carbidopa intestinal gel; “off” time; percutaneous endoscopic gastrojejunostomy
2.  Binge Eating in Parkinson Disease: Prevalence, Correlates, and the Contribution of Deep Brain Stimulation 
Of 96 Parkinson’s disease (PD) patients at the University of Florida Movement Disorders Center, one (1%) met diagnostic criteria for binge eating disorder (BED). Eight (8.3%) exhibited subthreshold BED. Psychometric criteria classified problem gambling in 17.8%, hoarding in 8.3%, 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% vs. 29%). No more overeaters than non-overeaters were taking a dopamine agonist (44% vs. 41%). More overeaters had a history of subthalamic DBS (44% vs. 14%). History of DBS was the only independent predictor of overeating.
PMCID: PMC3075093  PMID: 21304139
Parkinson’s disease; binge eating; impulse control disorders
3.  The Frequency of Nonmotor Symptoms among Advanced Parkinson Patients May Depend on Instrument Used for Assessment 
Parkinson's Disease  2011;2011:290195.
Background. Nonmotor symptoms (NMS) of Parkinson's disease (PD) may be more debilitating than motor symptoms. The purpose of this study was to determine the frequency and corecognition of NMS among our advanced PD cohort (patients considered for deep brain stimulation (DBS)) and caregivers. Methods. NMS-Questionnaire (NMS-Q), a self-administered screening questionnaire, and NMS Assessment-Scale (NMS-S), a clinician-administered scale, were administered to PD patients and caregivers. Results. We enrolled 33 PD patients (23 males, 10 females) and caregivers. The most frequent NMS among patients using NMS-Q were gastrointestinal (87.9%), sleep (84.9%), and urinary (72.7%), while the most frequent symptoms using NMS-S were sleep (90.9%), gastrointestinal (75.8%), and mood (75.8%). Patient/caregiver scoring correlations for NMS-Q and NMS-S were 0.670 (P < 0.0001) and 0.527 (P = 0.0016), respectively. Conclusion The frequency of NMS among advanced PD patients and correlation between patients and caregivers varied with the instrument used. The overall correlation between patient and caregiver was greater with NMS-Q than NMS-S.
PMCID: PMC3144664  PMID: 21808724
4.  Course, prognosis, and management of psychosis in Parkinson’s disease: Are current treatments really effective? 
CNS spectrums  2008;13(3 Suppl 4):26-33.
It is essential to recognize and treat psychosis in Parkinson disease (PD) for several reasons. Multiple studies have shown that psychosis in PD patients is a strong risk factor for nursing home placement. Psychosis may be the single greatest stress for caretakers of PD patients, it is often persistent, and its presence markedly increases the risk of mortality.
Treatment of psychotic symptoms should occur only after potential medical and environmental causes of delirium have been eliminated or addressed. Initial pharmacologic changes should include limiting the patient’s anti-PD medications to those that are necessary to preserve motor function. Should that fail, an atypical antipsychotic agent is presently the treatment of choice. An emerging treatment option is the use of acetylcholinesterase inhibitors. This article reviews what is currently known about the course, prognosis and treatment strategies in PD psychosis.
PMCID: PMC3045851  PMID: 18323764
5.  A Review of the Pathophysiology and Treatment of Psychosis in Parkinson’s Disease 
Drugs & aging  2008;25(8):665-682.
Psychotic symptoms in Parkinson’s disease (PD) are relatively common, and in addition to being a disturbance to patients’ daily lives, they have consistently been shown to be associated with poor outcome. Our understanding of the pathophysiology of psychosis in PD has expanded dramatically over the past fifteen years, from an initial interpretation of symptoms as dopaminergic drug side effects to the current view of a complex interplay of extrinsic and disease-related factors. The present article reviews the unique clinical features of psychosis as expressed in PD, associated risk factors, and current theories behind its pathogenesis, including medications, visual processing deficits, sleep disturbances, genetics, and neurochemical and structural abnormalities. Finally, we review both traditional and emergent management strategies for PD psychosis, including antipsychotic agents, cholinesterase inhibitors, electroconvulsive therapy (ECT), and other pharmacological and psychological interventions.
PMCID: PMC3045853  PMID: 18665659
6.  Double-Blind, Double-Dummy, Randomized Study of Continuous Intrajejunal Infusion of Levodopa-Carbidopa Intestinal Gel in Advanced Parkinson's Disease 
The Lancet. Neurology  2013;13(2):141-149.
Levodopa is the most effective therapy for Parkinson's disease (PD), but chronic treatment is associated with the development of potentially disabling motor complications. Experimental studies suggest that motor complications are due to non-physiologic, intermittent administration of the drug, and can be reduced with continuous delivery. Levodopa-carbidopa intestinal gel (LCIG) is a form of levodopa that can be delivered continuously through an intrajejunal percutaneous tube.
We performed a 12-week double-blind, double-dummy, double-titration, multi-center trial to evaluate the efficacy and safety of LCIG compared to optimized, oral, immediate-release levodopa-carbidopa (LC-IR) in advanced PD patients with motor complications. The primary endpoint was change from baseline to final visit in motor “Off” time. Motor “On” time without troublesome dyskinesia was the key secondary endpoint.
71 patients with advanced PD were randomized to receive continuous LCIG infusion plus placebo LC-IR capsules (n=37) or to receive LC-IR capsules plus continuous placebo LCIG infusion (n=34). Both groups were titrated to optimal effect. 93% of subjects (n=66) completed the trial. In comparison to LC-IR, LCIG significantly reduced “Off” time by a mean (±SE) of 1·91±0·57 hours (P=0·0015) and increased “On” time without troublesome dyskinesia by a mean of 1·86±0·65 hours (P=0·006). Adverse events were primarily related to the surgical procedure and the device, and while potentially serious, were not associated with residual deficit or mortality.
In comparison to standard oral LC-IR, LCIG significantly reduced “Off” time and increased “On” time without troublesome dyskinesia in patients with advanced PD. Adverse events were largely due to the procedure and the device. Benefits are of greater magnitude than have been obtained with medical therapies to date, and represent the first demonstration of the benefit of continuous levodopa delivery in a double-blind controlled study.
PMCID: PMC4643396  PMID: 24361112
Parkinson's disease; Levodopa/Carbidopa Intestinal Gel; Motor fluctuations
7.  Prevalence of hypersexual behavior in Parkinson’s disease patients: Not restricted to males and dopamine agonist use 
This study investigates the prevalence and demographic characteristics of hypersexuality in Parkinson’s disease (PD). Impulse control disorders in PD patients have been associated with dopamine agonist therapy. Moreover, hypersexuality and pathological gambling have been associated with males, while females may be inherently thought to be more likely to participate in compulsive shopping and binge-eating behaviors. In this study, a screening mail-in survey was sent to all PD patients at a single Movement Disorders Center. One hundred forty one of 400 (35.3%) research packets were returned completed. Fifteen of 141 patients met initial screening criteria for hypersexual behavior. After detailed interview, only 6/141 (4.3%) of PD patients met criteria for pathologic hypersexual behavior. These behaviors included: compulsive masturbation, prostitution, and paraphilias. Patients with a younger age of PD onset were more likely to exhibit hypersexual behavior. Unlike previous report, no significant association was found between hypersexuality and gender or dopamine agonist use. Rather, this study suggests that physicians should be vigilant for hypersexual behavior in all PD patients, regardless of gender and PD medication regimen. Ultimately, given the innate sensitivity of the topic and survey limitations, it is very likely that hypersexual behavior in our cohort, as it is in the general PD population, has been under-reported.
PMCID: PMC2840579  PMID: 20360887
Parkinson’s disease; hypersexuality; impulsive behavior; dopamine agonists
8.  Role of rasagiline in treating Parkinson’s disease: Effect on disease progression 
Rasagiline is a second generation, selective, irreversible monoamine oxidase type B (MAO-B) inhibitor. It has demonstrated efficacy in monotherapy for early Parkinson’s disease (PD) patients in one large randomized, placebo-controlled trial (TVP-1012 in Early Monotherapy for Parkinson’s Disease Outpatients), and has shown ability to reduce off time in more advanced PD patients with motor fluctuations in two large placebo-controlled trials (Parkinson’s Rasagiline: Efficacy and Safety in the Treatment of “Off”, and Lasting Effect in Adjunct Therapy With Rasagiline Given Once Daily). Preclinical data abound to suggest potential for neuroprotection by this compound against a variety of neurotoxic insults in cell cultures and in animals. The lack of amphetamine metabolites provides an advantage over the first generation MAO-B inhibitor selegiline. One large trial has investigated the potential for disease modification in PD patients (Attenuation of Disease progression with Azilect Given Once-daily) and preliminary results maintain some possible advantage to earlier initiation of the 1 mg/day dose. The clinical significance of the difference detected remains a consideration.
PMCID: PMC2695242  PMID: 19753135
rasagiline; Parkinson’s disease; neuroprotection; selegiline
9.  Cognitive decline tracks motor progression and not disease duration in Parkinson patients 
We performed an analysis of prospectively-acquired cross sectional data on 106 Parkinson disease (PD) patients who underwent comprehensive neuropsychological testing and the Unified Parkinson Disease Rating Scale (UPDRS) motor scale. A significant correlation between the UPDRS motor and neuropsychological tests in all cognitive domains except for general intelligence and visuo-spatial function was seen. In this study, cognitive decline within this PD cohort correlated with motor impairment but not disease duration. Our findings suggest that overall cognitive impairment (except visuospatial dysfunction) may track motor progression in PD more than duration of disease. Longitudinal studies are needed to confirm our results.
PMCID: PMC2656340  PMID: 19300633
Parkinson; dementia; cognition; visual-spatial dysfunction
10.  The four As associated with pathological Parkinson disease gamblers: anxiety, anger, age, and agonists 
Several studies have related pathological gambling in PD to dopamine agonist therapy. A mail-in survey was sent to PD patients seen at the University of Florida Movement Disorders Center to determine gambling frequency and behavior, and any lifestyle or environmental factors associated with compulsive gambling in PD. 462 surveys were sent and 127 completed surveys were returned, of which ten were from patients who met criteria for compulsive gambling. All ten were taking dopamine agonists coincident with the compulsive gambling. Compulsive gamblers were younger, and psychological distress measures revealed that compulsive gamblers exhibited higher levels of anxiety, anger, and confusion. Thus in this cohort, we have uncovered the several characteristics of the most likely PD compulsive gambler, namely: (young) age, “angry”, “anxious”, and using a (dopamine) agonist.
PMCID: PMC2654528  PMID: 19300546
Parkinson; gambling; compulsive behavior; dopamine agonist; anxiety
11.  Mild cognitive impairment in Parkinson’s disease: the challenge and the promise 
This review addresses the literature surrounding Parkinson’s disease (PD) and mild cognitive impairment (MCI). It discusses the neuropsychological, pharmaceutical, and pathological overlap, the socioeconomic impact of PD and MCI, and the value of recognizing, understanding, and treating MCI in PD. It is concluded from this review that MCI in PD does exist and should be considered in clinical and research investigations. Due to the lack of accepted clinical criteria, an inclusive operating definition of MCI in PD is proposed. Research guidelines for studying the presence of MCI in PD and evaluating the efficacy of pharmaceutical interventions are also suggested.
PMCID: PMC2426819  PMID: 18568128
Parkinson’s, dementia; mild cognitive impairment; therapy; cognition
12.  Observational Study of IncobotulinumtoxinA for Cervical Dystonia or Blepharospasm (XCiDaBLE): Interim Results for the First 170 Subjects with Blepharospasm 
XCiDaBLE is a large, prospective, observational “naturalistic” study evaluating Xeomin® for Cervical Dystonia or BLEpharospasm in the United States. We report the interim results from the blepharospasm cohort of XCiDaBLE.
Subjects (≥18 years old) with blepharospasm were followed for two treatment cycles of incobotulinumtoxinA and monitored for 4 weeks after injection via interactive voice/web response system (IVRS/IWRS). The investigator-reported scale includes the Clinical Global Impression Scale-Severity subscale (CGI-S). Patient-reported outcome measures include the Patient Global Impression Scale-Severity (PGI-S) and -Improvement (PGI-I) subscales, Jankovic Rating Scale (JRS), SF-12v2® health survey, and Work Productivity and Activity Impairment questionnaire. Subjects are seen by the investigator at baseline (including the first injection), during the second injection, and at a final study visit (12 weeks after the second injection).
One hundred seventy subjects were included in this interim analysis. The majority of subjects were female (77.1%) and white (91.8%), and had previously been treated with botulinum toxins (96.5%). The mean total dose (both eyes) was 71.5 U of incobotulinumtoxinA for the first injection. PGI-S, PGI-I, and JRS scores were significantly improved 4 weeks after treatment (all p<0.0001). No differences were noted in either quality of life (QoL) or work productivity in this short assessment period. No unexpected adverse events occurred.
This is an interim study and assessment method based on an IVRS/IWRS. In this predominantly toxin-experienced cohort, significant benefits in specific and global measures of disease severity were seen in the immediate post-incobotulinumtoxinA injection period. It will be interesting to see if there are improvements in QoL with consistent individualized injections over a longer period.
PMCID: PMC4107228  PMID: 25120942
Open label; prospective; blepharospasm; incobotulinumtoxinA; Jankovic Rating Scale; Xeomin
13.  A Novel DYT-5 Mutation with Phenotypic Variability within a Colombian Family 
Tremor and Other Hyperkinetic Movements  2013;3:tre-03-138-4462-2.
DYT-5 dystonia usually presents as a dopa-responsive dystonia (DRD) with early or late parkinsonian manifestations and/or dystonic features. Genetically, these patients have been described as having a wide array of independent mutations in the guanosine triphosphate cyclohydrolase 1 gene (GCH1), and these patients may also have a wide array of clinical manifestations.
A Colombian family with six affected female members was characterized.
Three members, including the index case, revealed mild parkinsonism, whereas three granddaughters of the index case showed severe generalized dystonia. No men were affected. There was anticipation, and a female predominance was uncovered. Treatment with levodopa was generally effective except in a case with severe skeletal deformities and contractions. Detailed genetic analysis in the index case revealed a new mutation in exon 1 of GCH1 (c.159delG).
This study revealed a new mutation of GCH1 that resulted in heterogeneous clinical presentations of DRD within a large family.
PMCID: PMC3822405  PMID: 24255805
DRD, dopamine; Parkinson's disease; dystonia, genetics
14.  Unilateral deep brain stimulation surgery in Parkinson’s disease improves ipsilateral symptoms regardless of laterality 
Parkinsonism & related disorders  2011;17(10):745-748.
Researchers have consistently observed in right-handed individuals across normal and disease states that the ‘dominant’ left hemisphere has greater ipsilateral control of the left side than the right hemisphere has over the right. We sought to determine whether this ipsilateral influence of the dominant hemisphere reported in Parkinson’s disease extends to treatments such as deep brain stimulation (DBS) and whether it affects outcome. We hypothesised that among Parkinson right-handers, unilateral left DBS would provide greater ipsilateral motor improvement compared with the ipsilateral motor improvement experienced on the right side.
A total of 73 Parkinson patients who underwent unilateral DBS of the subthalamic nucleus (STN) or globus palidus internus (GPi) participated. Left and right ‘composite scores’, were computed by separately adding all items on the left and right side from the motor section of the Unified Parkinson Disease Rating Scale. The change in the pre- and 4-month post-implantation score was the primary outcome measure. The mean motor scores improved by 4.96 ± 11.79 points (p < 0.001) post-surgery on the ipsilateral side of the DBS implantation. Regression analyses revealed that the side (left vs. right) and target (STN vs. GPi) did not significantly contribute in the effect of ipsilateral motor improvement (p = 0.3557).
While DBS on the ‘dominant’ left side failed to exert a greater ipsilateral influence compared with DBS on the non-dominant right side, significant ipsilateral motor improvements were observed after unilateral stimulation regardless of site of implantation and laterality.
PMCID: PMC3791592  PMID: 21856205
Unilateral DBS; STN; GPi; Parkinson’s disease; UPDRS
15.  DBS Candidates That Fall Short on a Levodopa Challenge Test 
The neurologist  2011;17(5):263-268.
Candidacy for deep brain stimulation (DBS) in Parkinson disease (PD) is typically assessed by the preoperative motor response to levodopa along with an interdisciplinary evaluation. However, recent cases treated at our institution have achieved good outcomes with DBS despite a sub-30% improvement in motor scores. The aim of this study was to examine the outcomes of DBS in a subset of patients who failed to reach the 30% motor improvement threshold.
A review of all DBS patients treated at the University of Florida Movement Disorders Center between 2002 and 2009 was performed utilizing a DBS database. All patients with sub-30% improvement in Unified Parkinson Disease Rating Scale Part III after dopaminergic medication administration were included.
Nine patients were identified; DBS was performed for severe dyskinesia (n = 5), “on/off motor” fluctuations (n = 1) and medication-refractory tremor (n = 3). The target symptoms were improved in all patients. Postoperatively, scores on the Unified Parkinson Disease Rating Scale Part II and III and subscores on Parkinson disease questionnaire-39 improved (P < 0.05).
Although motor response to levodopa remains the primary selection criteria for DBS candidacy in Parkinson disease, patients who do not meet the 30% threshold and have disabling symptoms may still benefit from DBS. Select patients with severe dyskinesia, “on/off” motor fluctuations, and/or medication-refractory tremor may experience significant benefits from DBS and should be considered on a case by case basis through an interdisciplinary team evaluation.
PMCID: PMC3789884  PMID: 21881468
deep brain stimulation; Parkinson disease; levodopa challenge test; dyskinesia; on-off motor fluctuations; tremor; quality of life
16.  A randomized, double-blind study of repeated incobotulinumtoxinA (Xeomin®) in cervical dystonia 
Journal of Neural Transmission  2013;120(12):1699-1707.
IncobotulinumtoxinA (Xeomin®, NT 201), a preparation without accessory (complexing) proteins, has shown comparable efficacy and safety to onabotulinumtoxinA in treating cervical dystonia (CD). This study evaluated the efficacy and safety of repeated incobotulinumtoxinA injections in subjects with CD. Following a ≤20-week placebo-controlled, randomized, double-blind, single-dose main period, subjects could enter a ≤68-week prospective, randomized, double-blind, repeated-dose, flexible-interval (minimum 6 weeks) extension period with 240 U or 120 U of incobotulinumtoxinA (≤5 injections). Outcome measures included the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) and adverse events (AEs). Of 219 subjects completing the main period, 214 were randomized in the extension period to receive incobotulinumtoxinA 240 U (n = 111) or 120 U (n = 103); 169 subjects completed the extension period, with 90 receiving five injection sessions. Both doses of incobotulinumtoxinA provided statistically significant and clinically relevant improvements in mean TWSTRS-Total, -Severity, -Disability, and -Pain scores, from each injection session to respective 4-week follow-up visits. The most frequently reported AE was dysphagia (240 U: 23.4 %; 120 U: 12.6 %), which did not result in any study withdrawals. There was no impact of injection interval on the incidence of AEs (post hoc analysis). A major limitation of this study was the fixed dose design requested by regulatory authorities, which does not reflect clinical practice. However, repeated incobotulinumtoxinA injections (240 or 120 U; flexible intervals) provided sustained efficacy and were well tolerated, with no unexpected safety risks following repeated injections. The incidence of AEs was similar in subjects requiring repeated injections at shorter intervals (≤12 weeks) compared with those treated using longer intervals (>12 weeks).
PMCID: PMC3834167  PMID: 23779062
Dystonia; Xeomin; IncobotulinumtoxinA; NT 201; Botulinum toxin
17.  Solvent Exposures and Parkinson’s Disease Risk in Twins 
Annals of Neurology  2011;71(6):776-784.
Several case reports have linked solvent exposure to Parkinson’s disease (PD), but few studies have assessed associations with specific agents using an analytic epidemiologic design. We tested the hypothesis that exposure to specific solvents is associated with PD risk using a discordant twin pair design.
99 twin pairs discordant for PD ascertained from the National Academy of Science/National Research Council (NAS/NRC) World War II Veteran Twins Cohort were interviewed regarding lifetime occupations and hobbies using detailed job-task-specific questionnaires. Exposures to 6 specific solvents selected a priori were estimated by expert raters unaware of case status.
Ever exposure to trichloroethylene (TCE) was associated with significantly increased risk of PD (OR 6.1, 95%CI 1.2 – 33; p = 0.034), and exposure to perchloroethylene (PERC) and carbon tetrachloride (CCl4) tended toward significance (respectively: OR 10.5, 95%CI 0.97-113, p = 0.053; OR 2.3, 95%CI 0.9-6.1, p = 0.088). Results were similar for estimates of exposure duration and cumulative lifetime exposure.
Exposure to specific solvents may increase risk of PD. TCE is the most common organic contaminant in groundwater, and PERC and CCl4 are also ubiquitous in the environment. Our findings require replication in other populations with well-characterized exposures, but the potential public health implications are substantial.
PMCID: PMC3366287  PMID: 22083847
18.  Levodopa—carbidopa intestinal gel in advanced Parkinson’s disease open-label study: Interim results 
Parkinsonism & related disorders  2013;19(3):339-345.
Levodopa–carbidopa intestinal gel (LCIG) delivered continuously via percutaneous endoscopic gastrojejunostomy (PEG-J) tube has been reported, mainly in small open-label studies, to significantly alleviate motor complications in Parkinson’s disease (PD). A prospective open-label, 54-week, international study of LCIG is ongoing in advanced PD patients experiencing motor fluctuations despite optimized pharmacologic therapy. Pre-planned interim analyses were conducted on all enrolled patients (n = 192) who had their PEG-J tube inserted at least 12 weeks before data cutoff (July 30, 2010). Outcomes include the 24-h patient diary of motor fluctuations, Unified Parkinson’s Disease Rating Scale (UPDRS), Clinical Global Impression-Improvement (CGI-I), Parkinson’s Disease Questionnaire (PDQ-39), and safety evaluations. Patients (average PD duration 12.4 yrs) were taking at least one PD medication at baseline. The mean (±SD) exposure to LCIG was 256.7 (±126.0) days. Baseline mean “Off” time was 6.7 h/day. “Off” time was reduced by a mean of 3.9 (±3.2) h/day and “On” time without troublesome dyskinesia was increased by 4.6 (±3.5) h/day at Week 12 compared to baseline. For the 168 patients (87.5%) reporting any adverse event (AE), the most common were abdominal pain (30.7%), complication of device insertion (21.4%), and procedural pain (17.7%). Serious AEs occurred in 60 (31.3%) patients. Twenty-four (12.5%) patients discontinued, including 14 (7.3%) due to AEs. Four (2.1%) patients died (none deemed related to LCIG). Interim results from this advanced PD cohort demonstrate that LCIG produced meaningful clinical improvements. LCIG was generally well-tolerated; however, device and procedural complications, while generally of mild severity, were common.
PMCID: PMC3661282  PMID: 23287001
Parkinson’s disease; Levodopa–carbidopa intestinal gel; Motor fluctuations; PEG-J procedure; Pump administration
19.  Prospective Study Evaluating IncobotulinumtoxinA for Cervical Dystonia or Blepharospasm: Interim Results from the First 145 Subjects with Cervical Dystonia 
Tremor and Other Hyperkinetic Movements  2013;3:tre-03-139-2924-1.
We report the interim results from XCiDaBLE, a large, prospective, observational “naturalistic” study evaluating Xeomin® (incobotulinumtoxinA) for Cervical Dystonia or BLEpharospasm in the United States.
Subjects (≥ 18 years old) with cervical dystonia (CD) are followed for two treatment cycles and monitored via Interactive Voice/Web Response. The subject's physician must have chosen to treat with incobotulinumtoxinA prior to and independent of enrollment in this study. Subject-reported scales include the Subject Global Impression-Severity and Improvement and Cervical Dystonia Impact Profile (CDIP-58), and Work Productivity and Quality of Life (QoL) are assessed by means of an employment questionnaire and work history and the SF-12v2 Health Survey (SF-12v2). Subjects are seen by the investigator for three visits, which include a baseline visit (including the first injection), a second injection visit, and a final study visit (12 weeks after the second injection).
This ongoing study includes 145 subjects with a diagnosis of CD. The majority were female (82.3%) and white (91.0%) and had previously been treated with botulinum toxins (77.2%). There were 106 employed at the time of disease onset, but 12.6 years later only 44% were still employed at the time of enrolment into the study, and 20% were either receiving or seeking disability benefits. The mean total dose/treatment of CD was 225.2 units for the first injection. The CDIP-58 total score was significantly improved 4 weeks after the first injection compared to baseline (p≤0.0001). Most subjects noted improvement in their global impression assessment. No new or unexpected adverse events occurred.
The results from these interim analyses confirm previous controlled, single-dose studies of incobotulinumtoxinA in terms of efficacy and safety.
PMCID: PMC3638085  PMID: 23724362
incobotulinumtoxinA; botulinum toxin type A; NT 201; cervical dystonia; CDIP-58
20.  Sustained efficacy and safety of repeated incobotulinumtoxinA (Xeomin®) injections in blepharospasm 
Journal of Neural Transmission  2013;120(9):1345-1353.
IncobotulinumtoxinA (Xeomin®, NT 201) is a purified botulinum toxin type A free from accessory (complexing) proteins. Previous studies evaluated single sets of incobotulinumtoxinA injections for the treatment of blepharospasm. Individualized injection intervals and other potential determinants of efficacy and safety need to be evaluated in a prospective, longitudinal study. Subjects with blepharospasm who completed a ≤20 weeks double-blind, placebo-controlled main period entered a ≤69 weeks open-label extension period (OLEX) and received ≤5 additional incobotulinumtoxinA treatments at flexible doses (≤50 U per eye) and flexible injection intervals (minimum of 6 weeks). Outcome measures included Jankovic Rating Scale (JRS) (sumscore, severity subscore and frequency subscore), Blepharospasm Disability Index, and adverse events. All 102 subjects who completed the main period entered the OLEX; 82 subjects completed the study, 56 received the maximum five injections. From each injection visit to a control visit 6 weeks later, investigator-rated JRS sumscores and subscores, and patient-rated Blepharospasm Disability Index were significantly improved (p ≤ 0.001 for all). All scores were still significantly improved at trial termination compared with the first injection visit (p < 0.05 for all). The most frequently reported adverse events were eyelid ptosis (31.4 %) and dry eye symptoms (17.6 %). The injection interval had no impact on the incidence of adverse events (post hoc analysis). No subject developed neutralizing antibodies during the study. Repeated incobotulinumtoxinA injections, administered at flexible doses and injection intervals from 6 to 20 weeks according to subjects’ needs, provide sustained efficacy in the treatment of blepharospasm with no new or unexpected safety risks.
PMCID: PMC3751217  PMID: 23435927
Blepharospasm; Botulinum toxin; IncobotulinumtoxinA; Dystonia; Xeomin
21.  SNCA Variants Are Associated with Increased Risk for Multiple System Atrophy 
Annals of neurology  2009;65(5):610-614.
To test whether the synucleinopathies Parkinson’s 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 Parkinson’s 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).
PMCID: PMC3520128  PMID: 19475667
22.  The Prevalence of Fatigue Following Deep Brain Stimulation Surgery in Parkinson's Disease and Association with Quality of Life 
Parkinson's Disease  2012;2012:769506.
Fatigue is a common and disabling nonmotor symptom seen in Parkinson's disease (PD). While deep brain stimulation surgery (DBS) improves motor symptoms, it has also been associated with non-motor side effects. To date no study has utilized standardized instruments to evaluate fatigue following DBS surgery. Our objective was to determine the prevalence of fatigue following DBS surgery in PD its impact on quality of life and explore predictive factors. We recruited 44 PD subjects. At least one year following DBS placement, we administered the Fatigue Severity Scale (FSS), the Parkinson's Disease Questionnaire (PDQ-39), the Beck Depression Inventory, the Beck Anxiety Inventory, the UPDRS, and a neuropsychological battery. Fifty-eight percent of subjects had moderate to severe fatigue. Fatigue was significantly associated with quality of life, depression, and anxiety. Depression preoperatively was the only predictive factor of fatigue. Fatigue is common following DBS surgery and significantly impacts quality of life.
PMCID: PMC3359731  PMID: 22666631
23.  Two McLeod patients with novel mutations in XK 
Journal of the Neurological Sciences  2011;305(1-2):160-164.
McLeod syndrome (MLS) is a rare, X-linked, late-onset, disease involving hematological, brain, and neuromuscular systems, caused by mutations in XK that result in either defective XK or complete loss of XK protein. Acanthocytosis of erythrocytes is a typical feature. We report novel mutations in two patients who exhibited typical clinical characteristics of MLS. The coding and flanking intronic regions of XK were amplified by PCR, sequenced, and compared with the normal XK sequence. XK protein, and its complexed partner protein, Kell, were assessed by Western blot analysis. Patient 1 was found to have a single base insertion, 605insA at 175Ile creating a frame shift within the coding sequence of XK. Patient 2 had a single base substitution in the 3′ splice sequence of intron 2 (IVS2–2a>g). In both cases mutations resulted in the absence of XK protein.
PMCID: PMC3337778  PMID: 21463873
McLeod syndrome; Neuroacanthocytosis; XK protein; Kell protein; Acanthocytosis; McLeod blood group; Kx erythrocyte antigen; Kell blood group antigens
24.  Effect of Deep Brain Stimulation on Parkinson's Nonmotor Symptoms following Unilateral DBS: A Pilot Study 
Parkinson's Disease  2011;2011:507416.
Parkinson's disease (PD) management has traditionally focused largely on motor symptoms. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and globus pallidus internus (GPi) are effective treatments for motor symptoms. Nonmotor symptoms (NMSs) may also profoundly affect the quality of life. The purpose of this pilot study was to evaluate NMS changes pre- and post-DBS utilizing two recently developed questionnaires. Methods. NMS-Q (questionnaire) and NMS-S (scale) were administered to PD patients before/after unilateral DBS (STN/GPi targets). Results. Ten PD patients (9 STN implants, 1 GPi implant) were included. The three most frequent NMS symptoms identified utilizing NMS-Q in pre-surgical patients were gastrointestinal (100%), sleep (100%), and urinary (90%). NMS sleep subscore significantly decreased (−1.6 points ± 1.8, P = 0.03). The three most frequent NMS symptoms identified in pre-surgical patients using NMS-S were gastrointestinal (90%), mood (80%), and cardiovascular (80%). The largest mean decrease of NMS scores was seen in miscellaneous symptoms (pain, anosmia, weight change, and sweating) (−7 points ± 8.7), and cardiovascular/falls (−1.9, P = 0.02). Conclusion. Non-motor symptoms improved on two separate questionnaires following unilateral DBS for PD. Future studies are needed to confirm these findings and determine their clinical significance as well as to examine the strengths/weaknesses of each questionnaire/scale.
PMCID: PMC3246796  PMID: 22220288
25.  Differential Response of Dystonia and Parkinsonism following Globus Pallidus Internus Deep Brain Stimulation in X-Linked Dystonia-Parkinsonism (Lubag) 
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.
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.
PMCID: PMC2969112  PMID: 20714213
X-linked dystonia-parkinsonism; Globus pallidus internus; Cognitive impairment; Medication-resistant parkinsonism

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