Parkinson Disease: Kleiner-Fisman G

Miyasaki JM, Shannon K, Voon V, Ravina B, Kleiner-Fisman G, Anderson K, Shulman LM, Gronseth G, Weiner WJ, Anonymous00046. · University of Toronto, Canada. · Neurology. · Pubmed #16606910 No free full text.

Abstract: OBJECTIVE: To make evidence-based treatment recommendations for patients with Parkinson disease (PD) with dementia, depression, and psychosis based on these questions: 1) What tools are effective to screen for depression, psychosis, and dementia in PD? 2) What are effective treatments for depression and psychosis in PD? 3) What are effective treatments for PD dementia or dementia with Lewy bodies (DLB)? METHODS: A nine-member multispecialty committee evaluated available evidence from a structured literature review using MEDLINE, and the Cochrane Database of Health and Psychosocial Instruments from 1966 to 2004. Additional articles were identified by panel members. RESULTS: The Beck Depression Inventory-I, Hamilton Depression Rating Scale, and Montgomery Asberg Depression Rating Scale should be considered to screen for depression in PD (Level B). The Mini-Mental State Examination and the Cambridge Cognitive Examination should be considered to screen for dementia in PD (Level B). Amitriptyline may be considered to treat depression in PD without dementia (Level C). For psychosis in PD, clozapine should be considered (Level B), quetiapine may be considered (Level C), but olanzapine should not be considered (Level B). Donepezil or rivastigmine should be considered for dementia in PD (Level B) and rivastigmine should be considered for DLB (Level B). CONCLUSIONS: Screening tools are available for depression and dementia in patients with PD, but more specific validated tools are needed. There are no widely used, validated tools for psychosis screening in Parkinson disease (PD). Clozapine successfully treats psychosis in PD. Cholinesterase inhibitors are effective treatments for dementia in PD, but improvement is modest and motor side effects may occur.

Kleiner-Fisman G, Herzog J, Fisman DN, Tamma F, Lyons KE, Pahwa R, Lang AE, Deuschl G. · Parkinson's Disease Research Education and Clinical Center, Philadelphia VA Hospital, Philadelphia, Pennsylvania 19104, USA. · Mov Disord. · Pubmed #16892449 No free full text.

Abstract: Subthalamic nucleus (STN) deep brain stimulation (DBS) is currently the most common therapeutic surgical procedure for patients with Parkinson's disease (PD) who have failed medical management. However, a recent summary of clinical evidence on the effectiveness of STN DBS is lacking. We report the results of such a systematic review and meta-analysis. A comprehensive review of the literature using Medline and Ovid databases from 1993 until 2004 was conducted. Estimates of change in absolute Unified Parkinson's Disease Rating Scale (UPDRS) scores after surgery were generated using random-effects models. Sources of heterogeneity were explored with meta-regression models, and the possibility of publication bias was evaluated. Patient demographics, reduction in medication requirements, change in dyskinesia, daily offs, quality of life, and a ratio of postoperative improvement from stimulation compared to preoperative improvement by medication from each study were tabulated and average scores were calculated. Adverse effects from each study were summarized. Thirty-seven cohorts were included in the review. Twenty-two studies with estimates of standard errors were included in the meta-analysis. The estimated decreases in absolute UPDRS II (activities of daily living) and III (motor) scores after surgery in the stimulation ON/medication off state compared to preoperative medication off state were 13.35 (95% CI: 10.85-15.85; 50%) and 27.55 (95% CI: 24.23-30.87; 52%), respectively. Average reduction in L-dopa equivalents following surgery was 55.9% (95% CI: 50%-61.8%). Average reduction in dyskinesia following surgery was 69.1% (95% CI: 62.0%-76.2%). Average reduction in daily off periods was 68.2% (95% CI: 57.6%-78.9%). Average improvement in quality of life using PDQ-39 was 34.5% +/- 15.3%. Univariable regression showed improvements in UPDRS III scores were significantly greater in studies with higher baseline UPDRS III off scores, increasing disease duration prior to surgery, earlier year of publication, and higher baseline L-dopa responsiveness. Average baseline UPDRS III off scores were significantly lower (i.e., suggesting milder disease) in later than in earlier studies. In multivariable regression, L-dopa responsiveness, higher baseline motor scores, and disease duration were independent predictors of greater change in motor score. No evidence of publication bias in the available literature was found. The most common serious adverse event related to surgery was intracranial hemorrhage in 3.9% of patients. Psychiatric sequelae were common. Synthesis of the available literature indicates that STN DBS improves motor activity and activities of daily living in advanced PD. Differences between available studies likely reflect differences in patient populations and follow-up periods. These data provide an estimate of the magnitude of the treatment effects and emphasize the need for controlled and randomized studies.

Robinson K, Dennison A, Roalf D, Noorigian J, Cianci H, Bunting-Perry L, Moberg P, Kleiner-Fisman G, Martine R, Duda J, Jaggi J, Stern M. · Department of Rehabilitation Medicine, University of Pennsylvania, Philadelphia, PA, USA. · NeuroRehabilitation. · Pubmed #16340098 No free full text.

Abstract: OBJECTIVE: To identify falling risk factors that are potentially modifiable among individuals who have idiopathic Parkinson's disease. DESIGN: A between group comparison of 19 fallers and 21 nonfallers who have Parkinson's disease, across an array of variables that have been identified as falling risk factors among the elderly and among those who have Parkinson's disease. RESULTS: Several variables were demonstrated significantly to distinguish fallers: disease duration and severity; dyskinesias associated with the use of dopaminergic agents; freezing; postural instability; depression; fear of falling; impaired fine motor control and motor planning in the feet; decreased proximal strength and muscular endurance in the legs; and a higher level of disability. CONCLUSIONS: Several of these variables can be viewed a potentially modifiable during a future intervention trial that aims to reduce falls in those who have Parkinson's disease using multidimensional risk factor modification.

Weintraub D, Newberg AB, Cary MS, Siderowf AD, Moberg PJ, Kleiner-Fisman G, Duda JE, Stern MB, Mozley D, Katz IR. · Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. · J Nucl Med. · Pubmed #15695780 links to  free full text

Abstract: We studied the correlation of striatal dopamine transporter (DAT) imaging with anxiety and depression symptoms in Parkinson's disease (PD). METHODS: Patients with idiopathic PD (n = 76) and age-matched healthy volunteers (n = 46) underwent SPECT brain scans with (99m)Tc-TRODAT-1, a radiolabeled tropane that selectively binds to the DAT. TRODAT-1 distribution volume ratios, a reflection of DAT availability, were calculated from the SPECT scan data for 6 regions of interest (ROIs) in the caudate and putamen. The association between neuropsychiatric symptoms (anxiety, depression, and fatigue) and DAT availability was explored for both subject groups, and the impact of disease severity on this association was examined in the PD group. RESULTS: PD patients showed lower DAT availability than did healthy volunteers in all examined regions (for all ROIs, P < 0.001). In PD patients, higher individual affective measures (for anxiety, r = -0.30 and P = 0.01; and for depression, r = -0.24 and P = 0.05) and total affect scores (r = -0.31; P = 0.01) were associated with diminished left anterior putamen DAT availability. The association between total affect scores and DAT availability was present only in the subset of patients with less severe PD (r = -0.35; P = 0.04), but subjects with the highest DAT availability did not show high total affect scores. No association between neuropsychiatric measures and DAT availability was found in the controls. CONCLUSION: These preliminary findings suggest that decreased DAT availability may be necessary for but not invariably associated with the development of affective symptoms in PD. This suggestion is consistent with previous research showing a link between depression and basal ganglia impairment, particularly involving the left hemisphere, and extends this finding to include anxiety.

Moberg PJ, Balderston CC, Rick JH, Roalf DR, Weintraub D, Kleiner-Fisman G, Stern MB, Duda JE. · Parkinson's Disease Research, Education, and Clinical Center, Philadelphia Veterans Affairs Medical Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. · Cogn Behav Neurol. · Pubmed #17846512 No free full text.

Abstract: OBJECTIVE: To examine phenylthiocarbamide (PTC) sensitivity in Parkinson disease (PD) patients and healthy volunteers to determine whether taster status represented a simple vulnerability marker for PD. BACKGROUND: The inability to taste PTC has been associated with a number of medical illnesses not typically associated with taste impairment. Abnormalities in the function/expression of G protein-signaling pathways have been implicated in PTC perception and also in dopamine expression and regulation in PD. No study has yet probed whether PTC tasting is disrupted in PD. METHOD: PTC sensitivity was assessed in a small sample of 36 male PD patients and 20 healthy male comparison subjects using a standardized psychophysical method. RESULTS: A higher proportion of nontasters were found in patients relative to healthy comparison subjects. These differences were not explained by alterations in perception of basic taste intensity or age. Among patients, nontasters and tasters of PTC did not differ with regard to duration of illness, age of onset, severity of motor symptoms, or overall illness severity. CONCLUSIONS: These data suggest an increase in the frequency of PTC nontaster status in PD. As phenotypic variation in PTC sensitivity is genetic in origin, this may represent a surrogate risk factor for the development of PD.

Kleiner-Fisman G, Fisman DN. · Parkinson's disease Clinical Center, Philadelphia VA Hospital, University of Pennsylvania, USA. · Arch Neurol. · Pubmed #17420306 links to  free full text

Abstract: OBJECTIVE: To determine risk factors for pedal edema among patients with Parkinson disease (PD) using pramipexole hydrochloride therapy. DESIGN: A retrospective medical record review. SETTING: Philadelphia Veterans Administration Parkinson's Disease Research, Education and Clinical Center (PADRECC). PATIENTS: All consecutive patients at the PADRECC receiving pramipexole from December 2002 to December 2004. MAIN OUTCOME MEASURES: Bivariable and multivariable logistic regression models were used to identify comorbid illnesses, demographic characteristics, other medications, and PD features associated with increased risk of pedal edema among individuals taking pramipexole. Estimation of time to development of pedal edema in individuals taking pramipexole was performed using Kaplan-Meier survival methods and multivariable Cox proportional hazards models. RESULTS: Two hundred thirty-seven PADRECC patients received pramipexole and met criteria for inclusion in the analysis. Of these, 38 (16%) developed pedal edema. Multivariable regression models identified idiopathic PD (odds ratio [OR], 4.80; 95% confidence interval [CI], 1.54-14.98; P = .007), history of coronary artery disease (OR, 3.35; 95% CI, 1.51-7.46; P = .003), and history of diabetes mellitus (OR, 3.12; 95% CI, 1.01-9.60; P = .05) as strong independent risk factors for development of edema. There was no relationship between dose of pramipexole and incidence and severity of pedal edema. The risk of development of pedal edema was 7.7% (95% CI, 4.5%-12.9%) in the first year after initiation of pramipexole therapy, with more rapid development of edema among those with a history of coronary artery disease. CONCLUSIONS: Pedal edema is a relatively common outcome in patients with PD receiving pramipexole. History of coronary artery disease increases the risk for developing edema.

Liang GS, Chou KL, Baltuch GH, Jaggi JL, Loveland-Jones C, Leng L, Maccarone H, Hurtig HI, Colcher A, Stern MB, Kleiner-Fisman G, Simuni T, Siderowf AD. · The Parkinson's Institute, Sunnyvale, CA, USA. · Stereotact Funct Neurosurg. · Pubmed #17063043 No free full text.

Abstract: BACKGROUND: In patients with advanced Parkinson's disease (PD), deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been shown to improve motor function and decrease medication requirements in the short term. However, the long-term benefits of DBS are not yet established. OBJECTIVE: It was the aim of this study to evaluate long-term outcomes of patients with PD treated with bilateral DBS of the STN. DESIGN AND METHODS: Thirty-three subjects who had bilateral STN DBS were followed prospectively after surgery. We evaluated subjects, using the Unified Parkinson's Disease Rating Scale (UPDRS), preoperatively, 12 months after surgery and at a long-term follow-up visit. Ratings were performed on and off dopaminergic medications. We compared postoperative UPDRS scores, dyskinesia ratings and medication dosages with preoperative values. RESULTS: Twenty-seven subjects had evaluations beyond 18 months (median 33.7 months). Total UPDRS scores in the 'medication-off' state were improved by 37% (p < 0.001) at 12 months and 17.7% (p = 0.0051) at the long-term evaluation. Medication-off state UPDRS part III scores were significantly improved at both 1 year and at the last evaluation (37.6 and 29.3%; p < 0.001). Dopaminergic medication requirements were decreased by 35.3% (p < 0.001) during the first postoperative year and remained below preoperative levels at the long-term evaluation. Average duration of 'off' time remained decreased by about 40% at both 1 year and at the time of last evaluation. Subjects had a sustained reduction in dyskinesia severity (88.6% at 1 year and 68.8% at last evaluation). CONCLUSIONS: In this cohort of subjects with advanced PD, bilateral STN stimulation improved 'off' medication motor function, reduced time spent in the medication-off state and reduced medication requirements for up to 4 years after surgery. We conclude that STN DBS is an effective long-term therapy for selected patients with advanced PD.

Deuschl G, Herzog J, Kleiner-Fisman G, Kubu C, Lozano AM, Lyons KE, Rodriguez-Oroz MC, Tamma F, Tröster AI, Vitek JL, Volkmann J, Voon V. · Department of Neurology, Christian-Albrechts-Universität Kiel, Kiel, Germany. · Mov Disord. · Pubmed #16810719 No free full text.

Abstract: Numerous factors need to be taken into account when managing a patient with Parkinson's disease (PD) after deep brain stimulation (DBS). Questions such as when to begin programming, how to conduct a programming screen, how to assess the effects of programming, and how to titrate stimulation and medication for each of the targeted sites need to be addressed. Follow-up care should be determined, including patient adjustments of stimulation, timing of follow-up visits and telephone contact with the patient, and stimulation and medication conditions during the follow-up assessments. A management plan for problems that can arise after DBS such as weight gain, dyskinesia, axial symptoms, speech dysfunction, muscle contractions, paresthesia, eyelid, ocular and visual disturbances, and behavioral and cognitive problems should be developed. Long-term complications such as infection or erosion, loss of effect, intermittent stimulation, tolerance, and pain or discomfort can develop and need to be managed. Other factors that need consideration are social and job-related factors, development of dementia, general medical issues, and lifestyle changes. This report from the Consensus on Deep Brain Stimulation for Parkinson's Disease, a project commissioned by the Congress of Neurological Surgeons and the Movement Disorder Society, outlines answers to a series of questions developed to address all aspects of DBS postoperative management and decision-making with a systematic overview of the literature (until mid-2004) and by the expert opinion of the authors. The report has been endorsed by the Scientific Issues Committee of the Movement Disorder Society and the American Society of Stereotactic and Functional Neurosurgery.

Kleiner-Fisman G, Fisman DN, Zamir O, Dostrovsky JO, Sime E, Saint-Cyr JA, Lozano AM, Lang AE. · Division of Neurology, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada. · Mov Disord. · Pubmed #15390008 No free full text.

Abstract: Unilateral pallidotomy is an effective treatment for contralateral parkinsonism and dyskinesia, yet symptoms progress in many patients. Little is known about whether such patients obtain a useful response to subsequent bilateral subthalamic nucleus deep brain stimulation (STN DBS). Changes in Unified Parkinson's Disease Rating Scale (UPDRS) Motor and Activities of Daily Living (ADL) scores, medication requirements, and dyskinesias were measured. Clinical outcomes were compared to patients with de novo STN DBS. Neuronal recordings were performed. STN DBS resulted in a significant reduction in UPDRS Motor scores (42.1%; 95% confidence interval [CI], 26.9-57.4; P = 0.03), comparable with de novo STN DBS surgery (41%; 95% CI, 26-46%; P < 0.001). There was also less change in dyskinesia duration and disability scores (P = 0.017, 0.005). There were no side-to-side differences clinically or in the STN neuronal firing rates and patterns. Bilateral STN DBS is safe and efficacious in improving motor symptoms in patients with prior pallidotomy.

Horvath J, Fross RD, Kleiner-Fisman G, Lerch R, Stalder H, Liaudat S, Raskoff WJ, Flachsbart KD, Rakowski H, Pache JC, Burkhard PR, Lang AE. · Department of Neurology, University Hospital, Geneva, Switzerland. · Mov Disord. · Pubmed #15197703 No free full text.

Abstract: We report on 4 new cases of valvular heart disease in Parkinson's disease patients treated with the ergot derivative dopamine agonists pergolide and cabergoline. Noninflammatory fibrotic degeneration of cardiac valves has been reported to occur in patients with carcinoid syndrome and to occasionally complicate therapies with the anti-migraine ergot alkaloid ergotamine and methysergide and with the appetite suppressants fenfluramine and dexfenfluramine. In these cases, the pathogenesis is suspected to involve serotonin-mediated abnormal fibrogenesis by means of the 5-HT2B receptors, which are expressed in the fibroblasts of heart valves. Based on strikingly similar echocardiographic and histopathological features, we strongly suspect that ergot-derived dopamine agonists may cause a valvular heart disease nearly identical to that seen in those conditions. These cases add to a rapidly growing and worrying list of similar published reports, suggesting that we may well be facing a novel, yet unrecognized, complication of this class of agents, which are widely used not only in Parkinson's disease but also in restless legs syndrome and various common endocrine dysfunctions. Therefore, until more is known about the true prevalence of this side effect, we propose that an assessment of cardiac function be performed before and in the course of a long-term therapy with ergot derivative dopamine agonists.

Kleiner-Fisman G, Fisman DN, Kahn FI, Sime E, Lozano AM, Lang AE. · Division of Neurology and Neurosurgery, Toronto Western Hospital, University of Toronto, Toronto, Ontario. · Arch Neurol. · Pubmed #14623727 links to  free full text

Abstract: BACKGROUND: Functional neuroimaging studies have demonstrated disturbances in the activity of premotor and motor cortices in Parkinson disease and in animal models of parkinsonism that improve in response to effective basal ganglia surgical therapy. Techniques that directly alter the function of these cortical areas, such as transcranial magnetic stimulation, have been applied in patients with Parkinson disease, with transient improvement in their bradykinesia and gait dysfunction. Recently, a patient with refractory Parkinson disease was claimed to have obtained a marked bilateral clinical benefit from extradural unilateral motor cortical stimulation. We hypothesized that direct cortical stimulation could alleviate the disability of the treatment-refractory parkinsonian symptoms commonly present in MSA. OBJECTIVE: To evaluate the efficacy of motor cortical stimulation in patients with refractory parkinsonism due to multiple system atrophy (MSA). METHODS: Five patients with a diagnosis of MSA with predominant parkinsonism underwent surgery for subdural motor cortical stimulation. MAIN OUTCOME MEASURES: Changes in activities of daily living and motor subscores on the Unified Parkinson's Disease Rating Scale 12 hours after medication withdrawal. Scores at baseline and 3 to 6 months following surgery were compared. RESULTS: All patients had a decline in motor scores at the follow-up evaluations despite the application of a variety of adjustments. The activities of daily living score mildly worsened by 9.7% (95% confidence interval, 32.3 to-13.0; P =.37) and the motor score worsened by 25.6% (95% confidence interval, 58.7 to -7.5; P =.06). Despite objective worsening over time and no deterioration when stimulation was immediately turned off, 3 patients still claimed subjective benefit and requested continued stimulation. No patients suffered adverse effects from the surgery or long-term stimulation, although 1 patient had a stimulation-induced seizure during the initial programming. The range of settings for 4 patients with bipolar configuration and 1 patient with monopolar configuration were as follows: amplitude, 3 to 3.6 V; pulse width, 40 to 90 milliseconds; and pulse rate, 145 to 185 Hz. CONCLUSIONS: Our data suggest that motor cortical stimulation using these parameters fails to improve the motor disability in MSA. Worsening of motor scores was likely a function of disease progression.

Kleiner-Fisman G, Fisman DN, Sime E, Saint-Cyr JA, Lozano AM, Lang AE. · Division of Neurology and Neurosurgery, Toronto Western Hospital, University of Toronto, Ontario, Canada. · J Neurosurg. · Pubmed #12959435 No free full text.

Abstract: OBJECT: The use of deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been associated with a marked initial improvement in individuals with advanced Parkinson disease (PD). Few data are available on the long-term outcomes of this procedure, however, or whether the initial benefits are sustained over time. The authors present the long-term results of a cohort of 25 individuals who underwent bilateral DBS of the STN between 1996 and 2001 and were followed up for 1 year or longer after implantation of the stimulator. METHODS: Patients were evaluated at baseline and repeatedly after surgery by using the Unified Parkinson's Disease Rating Scale (UPDRS); the scale was applied to patients during periods in which antiparkinsonian medications were effective and periods when their effects had worn off. Postoperative UPDRS total scores and subscores, dyskinesia scores, and drug dosages were compared with baseline values, and changes in the patients' postoperative scores were evaluated to assess the possibility that the effect of DBS diminished over time. In this cohort the median duration of follow-up review was 24 months (range 12-52 months). The combined (ADL and motor) total UPDRS score during the medication-off period improved after 1 year, decreasing by 42% relative to baseline (95% confidence interval [CI 35-50%], p < 0.001) and the motor score decreased by 48% (95% CI 42-55%, p < 0.001). These gains did diminish over time, although a sustained clinical benefit remained at the time of the last evaluation (41% improvement over baseline, 95% CI 31-50%; p < 0.001). Axial subscores at the time of the last evaluation showed only a trend toward improvement (p = 0.08), in contrast to scores for total tremor (p < 0.001), rigidity (p < 0.001), and bradykinesia (p = 0.003), for which highly significant differences from baseline were still present at the time of the last evaluation. Medication requirements diminished substantially, with total medication doses reduced by 38% (95% CI 27-48%, p < 0.001) at 1 year and 36% (95% CI 25-48%, p < 0.001) at the time of the last evaluation; this decrease may have accounted, at least in part, for the significant decrease of 46.4% (95% CI 20.2-72.5%, p = 0.007) in dyskinesia scores obtained by patients during the medication-on period. No preoperative demographic variable, such as the patient's age at the time of disease onset, age at surgery, sex, duration of disease before surgery, preoperative drug dosage, or preoperative severity of dyskinesia, was predictive of long-term outcome. The only predictor of a better outcome was the patient's preoperative response to levodopa. CONCLUSIONS: In this group of patients with advanced PD who underwent bilateral DBS of the STN, sustained improvement in motor function was present a mean of 2 years after the procedure, and sustained reductions in drug requirements were also achieved. Improvements in tremor, rigidity, and bradykinesia were more marked and better sustained over time than improvements in axial symptoms. A good preoperative response to levodopa predicted a good response to surgery.

Lang AE, Kleiner-Fisman G, Saint-Cyr JA, Miyasaki J, Lozano A. · No affiliation provided · Neurology. · Pubmed #12525751 No free full text.

This publication has no abstract.

Kleiner-Fisman G, Saint-Cyr JA, Miyasaki J, Lozano A, Lang AE. · No affiliation provided · Neurology. · Pubmed #12391378 No free full text.

This publication has no abstract.