Mark Stacy - Academia.edu (original) (raw)
Papers by Mark Stacy
Journal of Neurology Neurosurgery and Psychiatry, 2000
Annals of neurology, Jan 10, 2015
A 12-month double-blind sham-surgery-controlled trial assessing adeno-associated virus type 2 (AA... more A 12-month double-blind sham-surgery-controlled trial assessing adeno-associated virus type 2 (AAV2)-neurturin injected into the putamen bilaterally failed to meet its primary endpoint, but showed positive results for the primary endpoint in the subgroup of subjects followed for 18 months and for several secondary endpoints. Analysis of postmortem tissue suggested impaired axonal transport of neurturin from putamen to substantia nigra. In the present study, we tested the safety and efficacy of AAV2-neurturin delivered to putamen and substantia nigra. We performed a 15- to 24-month, multicenter, double-blind trial in patients with advanced Parkinson disease (PD) who were randomly assigned to receive bilateral AAV2-neurturin injected bilaterally into the substantia nigra (2.0 × 10(11) vector genomes) and putamen (1.0 × 10(12) vector genomes) or sham surgery. The primary endpoint was change from baseline to final visit performed at the time the last enrolled subject completed the 15-mo...
Clinical neuropharmacology
We have previously reported that the use of a 32-symptom Wearing-off Questionnaire (WOQ-32) ident... more We have previously reported that the use of a 32-symptom Wearing-off Questionnaire (WOQ-32) identified wearing off more frequently than a clinician's evaluation or the complications subscale of the Unified Parkinson Disease Rating Scale (UPDRS). However, this prototype tool was not designed for clinical practice and required simplification for daily use. Although wearing off is a commonly understood concept among neurologists caring for Parkinson disease patients, there are a number of definitions in the literature. For the purpose of this study and to include both motor and nonmotor parkinsonian symptoms, wearing off was defined as a generally predictable recurrence of motor and nonmotor symptoms that precedes scheduled doses of anti-parkinsonian medication and usually improves after those doses. Using this definition, retrospective analysis and expert opinion were used to identify the 9 most predictive and relevant of the symptoms previously identified as part of the WOQ-32. T...
We previously reported that the use of a specifically designed Wearing-Off Questionnaire (WOQ) id... more We previously reported that the use of a specifically designed Wearing-Off Questionnaire (WOQ) identified symptoms of wearing-off more frequently than standard assessments conducted by movement disorder specialists during a routine office visit. In the previous study we used a WOQ of 32 symptoms; however this tool was not designed for daily use. In this paper we describe the retrospective development of a simpler, 19-symptom WOQ more suitable for routine clinical use.
Movement Disorders, 2007
The purpose of this study was to evaluate interrater and intrarater reliability of the Fahn-Tolos... more The purpose of this study was to evaluate interrater and intrarater reliability of the Fahn-Tolosa-Marin Tremor Rating Scale (TRS) in essential tremor (ET). Proper treatment of ET is contingent upon correct assessment of the severity, loss of function, and disability related to tremor. Videotape recordings of 17 subjects with ET evaluated with the TRS were produced and sent to 59 raters. Once the raters returned the videotape and completed the score sheet, they were mailed a second tape with the same recordings presented in a different order. In the interrater reliability evaluation, modified Kappa statistics for seven tremor type composites ranged from 0.10 to 0.65 in the first videotape and 0.17 to 0.62 in the second videotape. Interrater reliabilities were greater for Part A items (magnitude of tremor in different body parts) than for Part B items (tremor in writing and drawings) of the TRS. The average Spearman correlation was 0.87, indicating very good consistency between the two videotapes, but correlations for Part A were somewhat better than for Part B. It is best when the same rater performs repeated measures of tremor on a patient, particularly when judging tremor in handwriting and drawings. Training of raters on use of the TRS would help standardize judgement.
Current Treatment Options in Neurology, 2007
Impulse control disorders (ICDs) are a set of behaviors, including pathologic gambling, hypersexu... more Impulse control disorders (ICDs) are a set of behaviors, including pathologic gambling, hypersexuality, compulsive shopping, compulsive eating, and punding, which are now recognized to occur in a subset of patients with Parkinson's disease (PD). Although the underlying pathophysiology of these behaviors is poorly understood, they appear to be associated with the use, and sometimes overuse, of dopaminergic agents prescribed for the treatment of the motor symptoms of PD. At present, there are limited data to support any particular therapeutic strategy. Approaches worth considering in the management of the PD patient with an ICD include reduction or discontinuation of dopamine agonist therapy, trials of various pharmacologic agents, psychosocial interventions, and deep brain stimulation of the subthalamic nucleus. However, the management of each patient must be tailored for the particular clinical setting, and the development of evidence-based treatment strategies awaits future prospective studies and randomized controlled trials.
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2002
Journal of the Neurological Sciences, 2015
The Cervical Dystonia Patient Registry for Observation of OnabotulinumtoxinA Efficacy (CD PROBE; ... more The Cervical Dystonia Patient Registry for Observation of OnabotulinumtoxinA Efficacy (CD PROBE; NCT00836017) is a prospective, observational, multicenter, real-world registry designed to assess the safety, effectiveness, and treatment utilization following multiple treatments of onabotulinumtoxinA. Subjects were naïve to botulinum toxin, new to practice, or had not received toxin in ≥16weeks if in a clinical trial. Dosages and treatment intervals varied due to the real-world design. Descriptive and inferential statistics evaluated changes over 3 treatments. 1046 subjects enrolled. Subjects were 74.4% female, 63.5% toxin-naïve, mean age 58.0±14.7years. The mean dose over 2481 treatment sessions was 189.8±87.1U, with average treatment intervals of 14.6 and 15.1weeks. The mean Toronto Western Spasmodic Torticollis Rating Scale Total score in subjects who completed all assessments (n=479) decreased from 39.2 at baseline to 27.1 at final visit (P<.0001). A high percentage of physicians reported improvement in Clinician Global Impression of Change after initial assessment; this significantly increased at final assessment (n=479, 91.2% vs 95.0%; P<.0001). Similarly, a high percentage of subjects reported improvement in Patient Global Impression of Change after initial assessment, which significantly increased at final assessment (n=470, 83.0% vs 91.7%; P<.0001). Significant reductions in all Cervical Dystonia Impact Profile-58 scores were observed (n=407). Overall, 26.2% of subjects reported adverse events, including muscular weakness (7.0%) and dysphagia (6.4%). Results indicate robust improvement in clinical ratings and excellent tolerability following onabotulinumtoxinA treatment of CD.
Movement disorders : official journal of the Movement Disorder Society, 2015
Impulse control disorders (ICDs), including compulsive gambling, buying, sexual behavior, and eat... more Impulse control disorders (ICDs), including compulsive gambling, buying, sexual behavior, and eating, are a serious and increasingly recognized psychiatric complication in Parkinson's disease (PD). Other impulsive-compulsive behaviors (ICBs) have been described in PD, including punding (stereotyped, repetitive, purposeless behaviors) and dopamine dysregulation syndrome (DDS; compulsive PD medication overuse). ICDs have been most closely related to the use of dopamine agonists (DAs), perhaps more so at higher doses; in contrast, DDS is primarily associated with shorter-acting, higher-potency dopaminergic medications, such as apomorphine and levodopa. Possible risk factors for ICDs include male sex, younger age and younger age at PD onset, a pre-PD history of ICDs, and a personal or family history of substance abuse, bipolar disorder, or gambling problems. Given the paucity of treatment options and potentially serious consequences, it is critical for PD patients to be monitored cl...
Acta Neuropathologica, 2014
disease and Alzheimer disease, were evident in all subjects. We evaluated areas that may be relev... more disease and Alzheimer disease, were evident in all subjects. We evaluated areas that may be relevant to rDP separately from those affected by the comorbid conditions. Anatomical areas identified as potential targets of I758S mutation were globus pallidus, subthalamic nucleus, red nucleus, inferior olivary nucleus, cerebellar Purkinje and granule cell layers, and dentate nucleus. Involvement of subcortical white matter tracts was also evident. Furthermore, in the spinal cord, a loss of dorsal column fibers was noted. This study has identified rDP-associated pathology in neuronal populations, which are part of complex motor and sensory loops. Their involvement would cause an interruption of cerebral and cerebellar connections which are essential for maintenance of motor control.
JAMA neurology, 2014
Convergent biological, epidemiological, and clinical data identified urate elevation as a candida... more Convergent biological, epidemiological, and clinical data identified urate elevation as a candidate strategy for slowing disability progression in Parkinson disease (PD). To determine the safety, tolerability, and urate-elevating capability of the urate precursor inosine in early PD and to assess its suitability and potential design features for a disease-modification trial. The Safety of Urate Elevation in PD (SURE-PD) study, a randomized, double-blind, placebo-controlled, dose-ranging trial of inosine, enrolled participants from 2009 to 2011 and followed them for up to 25 months at outpatient visits to 17 credentialed clinical study sites of the Parkinson Study Group across the United States. Seventy-five consenting adults (mean age, 62 years; 55% women) with early PD not yet requiring symptomatic treatment and a serum urate concentration less than 6 mg/dL (the approximate population median) were enrolled. Participants were randomized to 1 of 3 treatment arms: placebo or inosine t...
JAMA Neurology, 2014
Coenzyme Q10 (CoQ10), an antioxidant that supports mitochondrial function, has been shown in prec... more Coenzyme Q10 (CoQ10), an antioxidant that supports mitochondrial function, has been shown in preclinical Parkinson disease (PD) models to reduce the loss of dopamine neurons, and was safe and well tolerated in early-phase human studies. A previous phase II study suggested possible clinical benefit. To examine whether CoQ10 could slow disease progression in early PD. A phase III randomized, placebo-controlled, double-blind clinical trial at 67 North American sites consisting of participants 30 years of age or older who received a diagnosis of PD within 5 years and who had the following inclusion criteria: the presence of a rest tremor, bradykinesia, and rigidity; a modified Hoehn and Yahr stage of 2.5 or less; and no anticipated need for dopaminergic therapy within 3 months. Exclusion criteria included the use of any PD medication within 60 days, the use of any symptomatic PD medication for more than 90 days, atypical or drug-induced parkinsonism, a Unified Parkinson's Disease Rating Scale (UPDRS) rest tremor score of 3 or greater for any limb, a Mini-Mental State Examination score of 25 or less, a history of stroke, the use of certain supplements, and substantial recent exposure to CoQ10. Of 696 participants screened, 78 were found to be ineligible, and 18 declined participation. The remaining 600 participants were randomly assigned to receive placebo, 1200 mg/d of CoQ10, or 2400 mg/d of CoQ10; all participants received 1200 IU/d of vitamin E. Participants were observed for 16 months or until a disability requiring dopaminergic treatment. The prospectively defined primary outcome measure was the change in total UPDRS score (Parts I-III) from baseline to final visit. The study was powered to detect a 3-point difference between an active treatment and placebo. The baseline characteristics of the participants were well balanced, the mean age was 62.5 years, 66% of participants were male, and the mean baseline total UPDRS score was 22.7. A total of 267 participants required treatment (94 received placebo, 87 received 1200 mg/d of CoQ10, and 86 received 2400 mg/d of CoQ10), and 65 participants (29 who received placebo, 19 who received 1200 mg/d of CoQ10, and 17 who received 2400 mg/d of CoQ10) withdrew prematurely. Treatments were well tolerated with no safety concerns. The study was terminated after a prespecified futility criterion was reached. At study termination, both active treatment groups showed slight adverse trends relative to placebo. Adjusted mean changes (worsening) in total UPDRS scores from baseline to final visit were 6.9 points (placebo), 7.5 points (1200 mg/d of CoQ10; P = .49 relative to placebo), and 8.0 points (2400 mg/d of CoQ10; P = .21 relative to placebo). Coenzyme Q10 was safe and well tolerated in this population, but showed no…
Neurology, 2008
This review updates understanding and research on blepharospasm, a subtype of focal dystonia. Top... more This review updates understanding and research on blepharospasm, a subtype of focal dystonia. Topics covered include clinical aspects, pathology, pathophysiology, animal models, dry eye, photophobia, epidemiology, genetics, and treatment. Blepharospasm should be differentiated from apraxia of eyelid opening. New insights into pathology and pathophysiology are derived from different types of imaging, including magnetic resonance studies. Physiologic studies indicate increased plasticity and trigeminal sensitization. While botulinum neurotoxin injections are the mainstay of therapy, other therapies are on the horizon. Neurology ® 2008;71:1275-1282 GLOSSARY BFMDRS ϭ Burke-Fahn-Marsden dystonia rating scale; BoNT ϭ botulinum neurotoxin; DBS ϭ deep brain stimulation; DTI ϭ diffusion tensor imaging; FDG ϭ 18 fluorodeoxyglucose; VBM ϭ voxel-based morphometry.
Neurology, 2005
To determine whether people with Parkinson disease (PD) are less likely to report a history of ci... more To determine whether people with Parkinson disease (PD) are less likely to report a history of cigarette smoking than their unaffected siblings. Previous studies reported that individuals with PD are half as likely to have smoked as those unaffected by PD. Other studies reported that smoking modified the risk of PD due to polymorphisms in the MAO-B and nNOS genes. Thus, genetic studies of PD should consider confounding or interaction with smoking history as well. The authors have collected detailed smoking histories on a family-based case-control sample ascertained for genetic studies of PD. In a matched case-control study of 140 sibships, individuals with PD (n = 143) were compared to sibling controls (n = 168). Cigarette smoking history was collected by a structured telephone interview. Conditional logistic regression was used to examine the relationship between smoking and PD while controlling for confounding by age and sex. Ever smoking, current smoking, and increasing duration (in years), dose (in packs/day), and intensity (in pack-years) of smoking were significantly inversely associated with PD (p < 0.05). The association was not modified by sex, age at onset, or recency of exposure. Consistent with previous studies, individuals with Parkinson disease are significantly less likely to have smoked regularly than their unaffected siblings. This association was detected even though discordant sibling pairs are more likely to be overmatched for environmental exposures than unmatched case and control groups.
Neurology, 2006
In this multicenter study of 100 patients with cervical dystonia, we examined the immunogenicity ... more In this multicenter study of 100 patients with cervical dystonia, we examined the immunogenicity of botulinum toxin type B (BTX-B) and correlated the clinical response with the presence of blocking antibodies (Abs) using a novel mouse protection assay. One-third of the patients who were negative for BTX-B Abs at baseline became positive for BTX-B Abs at last visit. Thus, the high antigenicity of BTX-B limits its long-term efficacy.
Movement Disorders, 2008
Maintenance of symptom control in Parkinson&a... more Maintenance of symptom control in Parkinson's disease (PD) requires continuous titration of medication and addition of multiple therapies over the course of the disease. Adherence to medication is vital to symptom control and key to maximizing the efficacy of existing therapies. However, adherence is compromised by a variety of factors, including motor symptoms, complex dosing regimens, multiple medications, and lack of patient/physician awareness of the impact and prevalence of suboptimal adherence. This retrospective, longitudinal cohort study assessed the prevalence of suboptimal adherence [measured as the medication possession ratio (MPR)] to PD medications, and its impact on the worsening of PD symptoms (measured as increase in monotherapy dose, augmentation of therapy, PD-related emergency department visit, or hospitalization), in a Medicare Health Maintenance Organization population in the United States. Irrespective of the MPR threshold chosen, a high percentage of patients were categorized as suboptimally adherent to their PD medications, and patients with suboptimal adherence to their PD medications had higher risks of worsening of PD symptoms, compared with those who were adherent. Increased awareness of both the magnitude and impact of suboptimal adherence to PD medications, coupled with dosage simplification and a unified effort by healthcare professionals and patients, may improve adherence to PD medications and ultimately improve symptom control.
Movement Disorders, 2008
We present a video report of a patient with advanced non-Wilsonian cirrhotic liver disease who de... more We present a video report of a patient with advanced non-Wilsonian cirrhotic liver disease who developed extraocular muscle dystonia (oculogyric crisis) and severe orofaciolingual dyskinesias. Acquired hepatocerebral degeneration causes choreic movements, especially of cranial muscles, but dystonic ocular spasm is an infrequent manifestation of this disorder. This case illustrates that AHD should be considered in the differential diagnosis of extraocular muscle dystonia.
Movement Disorders, 2013
A B S T R AC T : AFQ056 is a novel, selective metabotropic glutamate receptor 5 antagonist. This ... more A B S T R AC T : AFQ056 is a novel, selective metabotropic glutamate receptor 5 antagonist. This was a 13-week, double-blind, placebo-controlled study. Patients with Parkinson's disease and moderate-tosevere levodopa (L-dopa)-induced dyskinesia who were receiving stable L-dopa/anti-parkinsonian treatment and were not currently receiving amantadine were randomized to receive either AFQ056 (at doses of 20, 50, 100, 150, or 200 mg daily) or placebo (1:1:1:1:2:3 ratio) for 12 weeks. The primary outcome was the modified Abnormal Involuntary Movements Scale. Secondary outcomes included the 26-item Parkinson's Disease Dyskinesia Scale, the Patient's/Clinician's Global Impression of Change, and the Unified Parkinson's Disease Rating Scale parts III (motor evaluation) and IV (severity of motor complications). Safety was assessed. In total, 98 of 133 (73.7%) AFQ056-treated patients and 47 of 64 (73.4%) patients in the placebo group completed the study. Baseline characteristics were comparable. Patients randomized to AFQ056 200 mg daily administered in 2 doses demonstrated significant improvements at Week 12 on the modified Abnormal Involuntary Movements Scale compared with placebo (difference, 22.8; 95% confidence interval [CI], 25.2, 20.4; P 5 0.007). Based on final actual doses, there was a dose-response relationship on the modified Abnormal Involuntary Movements Scale, with 200 mg daily demonstrating the most robust effect (difference, 23.6; 95% CI, 27.0, 20.3; P 5 0.012). Improvements in dyskinesia were supported by change on Unified have served on AFQ056 advisory board(s). Alain Destee received honoraria for consultancy from Novartis in the context of Clinical Drug development programs for Parkinson's disease. Werner Poewe has received honoraria for consultancy and lecture fees from Novartis AG in the context of clinical drug development programs for Parkinson's disease.
Movement Disorders, 2005
This study compares the sensitivity of a Patient Questionnaire versus information gathered by cli... more This study compares the sensitivity of a Patient Questionnaire versus information gathered by clinicians at a routine clinic visit in recognizing symptoms of wearing-off in early Parkinson's disease (PD). This Patient Questionnaire, containing 32 items representing a wide spectrum of motor and nonmotor wearing-off symptoms, was administered to subjects attending two PD clinics. The Patient Questionnaire results were compared to the information gathered by the clinician from the Unified Parkinson's Disease Rating Scale (UPDRS) Part IV, Question 36 and from a specific Clinical Assessment Question regarding loss of medication efficacy, wearing-off, sleepiness, dyskinesias, psychiatric complications, morning akinesia, other dopaminergic side effects, or none of the above. Examiners were blinded to study hypothesis and survey contents. Three hundred consecutive subjects with PD of Ͻ5 years duration were evaluated; the mean subject age was 72 Ϯ 9.6 years and 60.2% were men. Subjects reporting wearing-off were significantly younger (69.9 vs. 74.7 years) and differed regarding duration of PD symptoms (3.7 vs. 3.1 years). Wearingoff was found in 181 subjects (62.6%) by one or more of the three measures. The most sensitive tool was the Patient Questionnaire, with 165 subjects (57.1%) indicating symptoms of wearing-off. Question 36 of the UPDRS was positive in 127 subjects (43.9%), and the Clinical Assessment Question identified 85 subjects (29.4%) as experiencing wearing-off. All of these results were found to differ significantly. The mean number of wearing-off symptoms reported by the 165 subjects indicating wearing-off on the clinical survey was 6.25, with tremor being the most common motor feature and tiredness the most common nonmotor feature.
Journal of Neurology Neurosurgery and Psychiatry, 2000
Annals of neurology, Jan 10, 2015
A 12-month double-blind sham-surgery-controlled trial assessing adeno-associated virus type 2 (AA... more A 12-month double-blind sham-surgery-controlled trial assessing adeno-associated virus type 2 (AAV2)-neurturin injected into the putamen bilaterally failed to meet its primary endpoint, but showed positive results for the primary endpoint in the subgroup of subjects followed for 18 months and for several secondary endpoints. Analysis of postmortem tissue suggested impaired axonal transport of neurturin from putamen to substantia nigra. In the present study, we tested the safety and efficacy of AAV2-neurturin delivered to putamen and substantia nigra. We performed a 15- to 24-month, multicenter, double-blind trial in patients with advanced Parkinson disease (PD) who were randomly assigned to receive bilateral AAV2-neurturin injected bilaterally into the substantia nigra (2.0 × 10(11) vector genomes) and putamen (1.0 × 10(12) vector genomes) or sham surgery. The primary endpoint was change from baseline to final visit performed at the time the last enrolled subject completed the 15-mo...
Clinical neuropharmacology
We have previously reported that the use of a 32-symptom Wearing-off Questionnaire (WOQ-32) ident... more We have previously reported that the use of a 32-symptom Wearing-off Questionnaire (WOQ-32) identified wearing off more frequently than a clinician's evaluation or the complications subscale of the Unified Parkinson Disease Rating Scale (UPDRS). However, this prototype tool was not designed for clinical practice and required simplification for daily use. Although wearing off is a commonly understood concept among neurologists caring for Parkinson disease patients, there are a number of definitions in the literature. For the purpose of this study and to include both motor and nonmotor parkinsonian symptoms, wearing off was defined as a generally predictable recurrence of motor and nonmotor symptoms that precedes scheduled doses of anti-parkinsonian medication and usually improves after those doses. Using this definition, retrospective analysis and expert opinion were used to identify the 9 most predictive and relevant of the symptoms previously identified as part of the WOQ-32. T...
We previously reported that the use of a specifically designed Wearing-Off Questionnaire (WOQ) id... more We previously reported that the use of a specifically designed Wearing-Off Questionnaire (WOQ) identified symptoms of wearing-off more frequently than standard assessments conducted by movement disorder specialists during a routine office visit. In the previous study we used a WOQ of 32 symptoms; however this tool was not designed for daily use. In this paper we describe the retrospective development of a simpler, 19-symptom WOQ more suitable for routine clinical use.
Movement Disorders, 2007
The purpose of this study was to evaluate interrater and intrarater reliability of the Fahn-Tolos... more The purpose of this study was to evaluate interrater and intrarater reliability of the Fahn-Tolosa-Marin Tremor Rating Scale (TRS) in essential tremor (ET). Proper treatment of ET is contingent upon correct assessment of the severity, loss of function, and disability related to tremor. Videotape recordings of 17 subjects with ET evaluated with the TRS were produced and sent to 59 raters. Once the raters returned the videotape and completed the score sheet, they were mailed a second tape with the same recordings presented in a different order. In the interrater reliability evaluation, modified Kappa statistics for seven tremor type composites ranged from 0.10 to 0.65 in the first videotape and 0.17 to 0.62 in the second videotape. Interrater reliabilities were greater for Part A items (magnitude of tremor in different body parts) than for Part B items (tremor in writing and drawings) of the TRS. The average Spearman correlation was 0.87, indicating very good consistency between the two videotapes, but correlations for Part A were somewhat better than for Part B. It is best when the same rater performs repeated measures of tremor on a patient, particularly when judging tremor in handwriting and drawings. Training of raters on use of the TRS would help standardize judgement.
Current Treatment Options in Neurology, 2007
Impulse control disorders (ICDs) are a set of behaviors, including pathologic gambling, hypersexu... more Impulse control disorders (ICDs) are a set of behaviors, including pathologic gambling, hypersexuality, compulsive shopping, compulsive eating, and punding, which are now recognized to occur in a subset of patients with Parkinson's disease (PD). Although the underlying pathophysiology of these behaviors is poorly understood, they appear to be associated with the use, and sometimes overuse, of dopaminergic agents prescribed for the treatment of the motor symptoms of PD. At present, there are limited data to support any particular therapeutic strategy. Approaches worth considering in the management of the PD patient with an ICD include reduction or discontinuation of dopamine agonist therapy, trials of various pharmacologic agents, psychosocial interventions, and deep brain stimulation of the subthalamic nucleus. However, the management of each patient must be tailored for the particular clinical setting, and the development of evidence-based treatment strategies awaits future prospective studies and randomized controlled trials.
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2002
Journal of the Neurological Sciences, 2015
The Cervical Dystonia Patient Registry for Observation of OnabotulinumtoxinA Efficacy (CD PROBE; ... more The Cervical Dystonia Patient Registry for Observation of OnabotulinumtoxinA Efficacy (CD PROBE; NCT00836017) is a prospective, observational, multicenter, real-world registry designed to assess the safety, effectiveness, and treatment utilization following multiple treatments of onabotulinumtoxinA. Subjects were naïve to botulinum toxin, new to practice, or had not received toxin in ≥16weeks if in a clinical trial. Dosages and treatment intervals varied due to the real-world design. Descriptive and inferential statistics evaluated changes over 3 treatments. 1046 subjects enrolled. Subjects were 74.4% female, 63.5% toxin-naïve, mean age 58.0±14.7years. The mean dose over 2481 treatment sessions was 189.8±87.1U, with average treatment intervals of 14.6 and 15.1weeks. The mean Toronto Western Spasmodic Torticollis Rating Scale Total score in subjects who completed all assessments (n=479) decreased from 39.2 at baseline to 27.1 at final visit (P<.0001). A high percentage of physicians reported improvement in Clinician Global Impression of Change after initial assessment; this significantly increased at final assessment (n=479, 91.2% vs 95.0%; P<.0001). Similarly, a high percentage of subjects reported improvement in Patient Global Impression of Change after initial assessment, which significantly increased at final assessment (n=470, 83.0% vs 91.7%; P<.0001). Significant reductions in all Cervical Dystonia Impact Profile-58 scores were observed (n=407). Overall, 26.2% of subjects reported adverse events, including muscular weakness (7.0%) and dysphagia (6.4%). Results indicate robust improvement in clinical ratings and excellent tolerability following onabotulinumtoxinA treatment of CD.
Movement disorders : official journal of the Movement Disorder Society, 2015
Impulse control disorders (ICDs), including compulsive gambling, buying, sexual behavior, and eat... more Impulse control disorders (ICDs), including compulsive gambling, buying, sexual behavior, and eating, are a serious and increasingly recognized psychiatric complication in Parkinson's disease (PD). Other impulsive-compulsive behaviors (ICBs) have been described in PD, including punding (stereotyped, repetitive, purposeless behaviors) and dopamine dysregulation syndrome (DDS; compulsive PD medication overuse). ICDs have been most closely related to the use of dopamine agonists (DAs), perhaps more so at higher doses; in contrast, DDS is primarily associated with shorter-acting, higher-potency dopaminergic medications, such as apomorphine and levodopa. Possible risk factors for ICDs include male sex, younger age and younger age at PD onset, a pre-PD history of ICDs, and a personal or family history of substance abuse, bipolar disorder, or gambling problems. Given the paucity of treatment options and potentially serious consequences, it is critical for PD patients to be monitored cl...
Acta Neuropathologica, 2014
disease and Alzheimer disease, were evident in all subjects. We evaluated areas that may be relev... more disease and Alzheimer disease, were evident in all subjects. We evaluated areas that may be relevant to rDP separately from those affected by the comorbid conditions. Anatomical areas identified as potential targets of I758S mutation were globus pallidus, subthalamic nucleus, red nucleus, inferior olivary nucleus, cerebellar Purkinje and granule cell layers, and dentate nucleus. Involvement of subcortical white matter tracts was also evident. Furthermore, in the spinal cord, a loss of dorsal column fibers was noted. This study has identified rDP-associated pathology in neuronal populations, which are part of complex motor and sensory loops. Their involvement would cause an interruption of cerebral and cerebellar connections which are essential for maintenance of motor control.
JAMA neurology, 2014
Convergent biological, epidemiological, and clinical data identified urate elevation as a candida... more Convergent biological, epidemiological, and clinical data identified urate elevation as a candidate strategy for slowing disability progression in Parkinson disease (PD). To determine the safety, tolerability, and urate-elevating capability of the urate precursor inosine in early PD and to assess its suitability and potential design features for a disease-modification trial. The Safety of Urate Elevation in PD (SURE-PD) study, a randomized, double-blind, placebo-controlled, dose-ranging trial of inosine, enrolled participants from 2009 to 2011 and followed them for up to 25 months at outpatient visits to 17 credentialed clinical study sites of the Parkinson Study Group across the United States. Seventy-five consenting adults (mean age, 62 years; 55% women) with early PD not yet requiring symptomatic treatment and a serum urate concentration less than 6 mg/dL (the approximate population median) were enrolled. Participants were randomized to 1 of 3 treatment arms: placebo or inosine t...
JAMA Neurology, 2014
Coenzyme Q10 (CoQ10), an antioxidant that supports mitochondrial function, has been shown in prec... more Coenzyme Q10 (CoQ10), an antioxidant that supports mitochondrial function, has been shown in preclinical Parkinson disease (PD) models to reduce the loss of dopamine neurons, and was safe and well tolerated in early-phase human studies. A previous phase II study suggested possible clinical benefit. To examine whether CoQ10 could slow disease progression in early PD. A phase III randomized, placebo-controlled, double-blind clinical trial at 67 North American sites consisting of participants 30 years of age or older who received a diagnosis of PD within 5 years and who had the following inclusion criteria: the presence of a rest tremor, bradykinesia, and rigidity; a modified Hoehn and Yahr stage of 2.5 or less; and no anticipated need for dopaminergic therapy within 3 months. Exclusion criteria included the use of any PD medication within 60 days, the use of any symptomatic PD medication for more than 90 days, atypical or drug-induced parkinsonism, a Unified Parkinson's Disease Rating Scale (UPDRS) rest tremor score of 3 or greater for any limb, a Mini-Mental State Examination score of 25 or less, a history of stroke, the use of certain supplements, and substantial recent exposure to CoQ10. Of 696 participants screened, 78 were found to be ineligible, and 18 declined participation. The remaining 600 participants were randomly assigned to receive placebo, 1200 mg/d of CoQ10, or 2400 mg/d of CoQ10; all participants received 1200 IU/d of vitamin E. Participants were observed for 16 months or until a disability requiring dopaminergic treatment. The prospectively defined primary outcome measure was the change in total UPDRS score (Parts I-III) from baseline to final visit. The study was powered to detect a 3-point difference between an active treatment and placebo. The baseline characteristics of the participants were well balanced, the mean age was 62.5 years, 66% of participants were male, and the mean baseline total UPDRS score was 22.7. A total of 267 participants required treatment (94 received placebo, 87 received 1200 mg/d of CoQ10, and 86 received 2400 mg/d of CoQ10), and 65 participants (29 who received placebo, 19 who received 1200 mg/d of CoQ10, and 17 who received 2400 mg/d of CoQ10) withdrew prematurely. Treatments were well tolerated with no safety concerns. The study was terminated after a prespecified futility criterion was reached. At study termination, both active treatment groups showed slight adverse trends relative to placebo. Adjusted mean changes (worsening) in total UPDRS scores from baseline to final visit were 6.9 points (placebo), 7.5 points (1200 mg/d of CoQ10; P = .49 relative to placebo), and 8.0 points (2400 mg/d of CoQ10; P = .21 relative to placebo). Coenzyme Q10 was safe and well tolerated in this population, but showed no…
Neurology, 2008
This review updates understanding and research on blepharospasm, a subtype of focal dystonia. Top... more This review updates understanding and research on blepharospasm, a subtype of focal dystonia. Topics covered include clinical aspects, pathology, pathophysiology, animal models, dry eye, photophobia, epidemiology, genetics, and treatment. Blepharospasm should be differentiated from apraxia of eyelid opening. New insights into pathology and pathophysiology are derived from different types of imaging, including magnetic resonance studies. Physiologic studies indicate increased plasticity and trigeminal sensitization. While botulinum neurotoxin injections are the mainstay of therapy, other therapies are on the horizon. Neurology ® 2008;71:1275-1282 GLOSSARY BFMDRS ϭ Burke-Fahn-Marsden dystonia rating scale; BoNT ϭ botulinum neurotoxin; DBS ϭ deep brain stimulation; DTI ϭ diffusion tensor imaging; FDG ϭ 18 fluorodeoxyglucose; VBM ϭ voxel-based morphometry.
Neurology, 2005
To determine whether people with Parkinson disease (PD) are less likely to report a history of ci... more To determine whether people with Parkinson disease (PD) are less likely to report a history of cigarette smoking than their unaffected siblings. Previous studies reported that individuals with PD are half as likely to have smoked as those unaffected by PD. Other studies reported that smoking modified the risk of PD due to polymorphisms in the MAO-B and nNOS genes. Thus, genetic studies of PD should consider confounding or interaction with smoking history as well. The authors have collected detailed smoking histories on a family-based case-control sample ascertained for genetic studies of PD. In a matched case-control study of 140 sibships, individuals with PD (n = 143) were compared to sibling controls (n = 168). Cigarette smoking history was collected by a structured telephone interview. Conditional logistic regression was used to examine the relationship between smoking and PD while controlling for confounding by age and sex. Ever smoking, current smoking, and increasing duration (in years), dose (in packs/day), and intensity (in pack-years) of smoking were significantly inversely associated with PD (p < 0.05). The association was not modified by sex, age at onset, or recency of exposure. Consistent with previous studies, individuals with Parkinson disease are significantly less likely to have smoked regularly than their unaffected siblings. This association was detected even though discordant sibling pairs are more likely to be overmatched for environmental exposures than unmatched case and control groups.
Neurology, 2006
In this multicenter study of 100 patients with cervical dystonia, we examined the immunogenicity ... more In this multicenter study of 100 patients with cervical dystonia, we examined the immunogenicity of botulinum toxin type B (BTX-B) and correlated the clinical response with the presence of blocking antibodies (Abs) using a novel mouse protection assay. One-third of the patients who were negative for BTX-B Abs at baseline became positive for BTX-B Abs at last visit. Thus, the high antigenicity of BTX-B limits its long-term efficacy.
Movement Disorders, 2008
Maintenance of symptom control in Parkinson&a... more Maintenance of symptom control in Parkinson's disease (PD) requires continuous titration of medication and addition of multiple therapies over the course of the disease. Adherence to medication is vital to symptom control and key to maximizing the efficacy of existing therapies. However, adherence is compromised by a variety of factors, including motor symptoms, complex dosing regimens, multiple medications, and lack of patient/physician awareness of the impact and prevalence of suboptimal adherence. This retrospective, longitudinal cohort study assessed the prevalence of suboptimal adherence [measured as the medication possession ratio (MPR)] to PD medications, and its impact on the worsening of PD symptoms (measured as increase in monotherapy dose, augmentation of therapy, PD-related emergency department visit, or hospitalization), in a Medicare Health Maintenance Organization population in the United States. Irrespective of the MPR threshold chosen, a high percentage of patients were categorized as suboptimally adherent to their PD medications, and patients with suboptimal adherence to their PD medications had higher risks of worsening of PD symptoms, compared with those who were adherent. Increased awareness of both the magnitude and impact of suboptimal adherence to PD medications, coupled with dosage simplification and a unified effort by healthcare professionals and patients, may improve adherence to PD medications and ultimately improve symptom control.
Movement Disorders, 2008
We present a video report of a patient with advanced non-Wilsonian cirrhotic liver disease who de... more We present a video report of a patient with advanced non-Wilsonian cirrhotic liver disease who developed extraocular muscle dystonia (oculogyric crisis) and severe orofaciolingual dyskinesias. Acquired hepatocerebral degeneration causes choreic movements, especially of cranial muscles, but dystonic ocular spasm is an infrequent manifestation of this disorder. This case illustrates that AHD should be considered in the differential diagnosis of extraocular muscle dystonia.
Movement Disorders, 2013
A B S T R AC T : AFQ056 is a novel, selective metabotropic glutamate receptor 5 antagonist. This ... more A B S T R AC T : AFQ056 is a novel, selective metabotropic glutamate receptor 5 antagonist. This was a 13-week, double-blind, placebo-controlled study. Patients with Parkinson's disease and moderate-tosevere levodopa (L-dopa)-induced dyskinesia who were receiving stable L-dopa/anti-parkinsonian treatment and were not currently receiving amantadine were randomized to receive either AFQ056 (at doses of 20, 50, 100, 150, or 200 mg daily) or placebo (1:1:1:1:2:3 ratio) for 12 weeks. The primary outcome was the modified Abnormal Involuntary Movements Scale. Secondary outcomes included the 26-item Parkinson's Disease Dyskinesia Scale, the Patient's/Clinician's Global Impression of Change, and the Unified Parkinson's Disease Rating Scale parts III (motor evaluation) and IV (severity of motor complications). Safety was assessed. In total, 98 of 133 (73.7%) AFQ056-treated patients and 47 of 64 (73.4%) patients in the placebo group completed the study. Baseline characteristics were comparable. Patients randomized to AFQ056 200 mg daily administered in 2 doses demonstrated significant improvements at Week 12 on the modified Abnormal Involuntary Movements Scale compared with placebo (difference, 22.8; 95% confidence interval [CI], 25.2, 20.4; P 5 0.007). Based on final actual doses, there was a dose-response relationship on the modified Abnormal Involuntary Movements Scale, with 200 mg daily demonstrating the most robust effect (difference, 23.6; 95% CI, 27.0, 20.3; P 5 0.012). Improvements in dyskinesia were supported by change on Unified have served on AFQ056 advisory board(s). Alain Destee received honoraria for consultancy from Novartis in the context of Clinical Drug development programs for Parkinson's disease. Werner Poewe has received honoraria for consultancy and lecture fees from Novartis AG in the context of clinical drug development programs for Parkinson's disease.
Movement Disorders, 2005
This study compares the sensitivity of a Patient Questionnaire versus information gathered by cli... more This study compares the sensitivity of a Patient Questionnaire versus information gathered by clinicians at a routine clinic visit in recognizing symptoms of wearing-off in early Parkinson's disease (PD). This Patient Questionnaire, containing 32 items representing a wide spectrum of motor and nonmotor wearing-off symptoms, was administered to subjects attending two PD clinics. The Patient Questionnaire results were compared to the information gathered by the clinician from the Unified Parkinson's Disease Rating Scale (UPDRS) Part IV, Question 36 and from a specific Clinical Assessment Question regarding loss of medication efficacy, wearing-off, sleepiness, dyskinesias, psychiatric complications, morning akinesia, other dopaminergic side effects, or none of the above. Examiners were blinded to study hypothesis and survey contents. Three hundred consecutive subjects with PD of Ͻ5 years duration were evaluated; the mean subject age was 72 Ϯ 9.6 years and 60.2% were men. Subjects reporting wearing-off were significantly younger (69.9 vs. 74.7 years) and differed regarding duration of PD symptoms (3.7 vs. 3.1 years). Wearingoff was found in 181 subjects (62.6%) by one or more of the three measures. The most sensitive tool was the Patient Questionnaire, with 165 subjects (57.1%) indicating symptoms of wearing-off. Question 36 of the UPDRS was positive in 127 subjects (43.9%), and the Clinical Assessment Question identified 85 subjects (29.4%) as experiencing wearing-off. All of these results were found to differ significantly. The mean number of wearing-off symptoms reported by the 165 subjects indicating wearing-off on the clinical survey was 6.25, with tremor being the most common motor feature and tiredness the most common nonmotor feature.