Parkinson Disease: Oertel W

Horstink M, Tolosa E, Bonuccelli U, Deuschl G, Friedman A, Kanovsky P, Larsen JP, Lees A, Oertel W, Poewe W, Rascol O, Sampaio C, Anonymous00036, Anonymous00037. · Department of Neurology, Radboud University Medical Centre, Nijmegen, The Netherlands. · Eur J Neurol. · Pubmed #17038032 No free full text.

Abstract: To provide evidence-based recommendations for the management of late (complicated) Parkinson's disease (PD), based on a review of the literature. Complicated PD refers to patients suffering from the classical motor syndrome of PD along with other motor or non-motor complications, either disease-related (e.g. freezing) or treatment-related (e.g. dyskinesias or hallucinations). MEDLINE, Cochrane Library and INAHTA database literature searches were conducted. National guidelines were requested from all EFNS societies. Non-European guidelines were searched for using MEDLINE. Part II of the guidelines deals with treatment of motor and neuropsychiatric complications and autonomic disturbances. For each topic, a list of therapeutic interventions is provided, including classification of evidence. Following this, recommendations for management are given, alongside ratings of efficacy. Classifications of evidence and ratings of efficacy are made according to EFNS guidance. In cases where there is insufficient scientific evidence, a consensus statement ('good practice point') is made.

Horstink M, Tolosa E, Bonuccelli U, Deuschl G, Friedman A, Kanovsky P, Larsen JP, Lees A, Oertel W, Poewe W, Rascol O, Sampaio C, Anonymous00034, Anonymous00035. · Department of Neurology, Radboud University Medical Centre, Nijmegen, The Netherlands. · Eur J Neurol. · Pubmed #17038031 No free full text.

Abstract: The aim of the study was to provide evidence-based recommendations for the management of early (uncomplicated) Parkinson's disease (PD), based on a review of the literature. Uncomplicated PD refers to patients suffering from the classical motor syndrome of PD only, without treatment-induced motor complications and without neuropsychiatric or autonomic problems. MEDLINE, Cochrane Library and International Network of Agencies for Health Technology Assessment (INAHTA) database literature searches were conducted. National guidelines were requested from all European Federation of Neurological Societies (EFNS) societies. Non-European guidelines were searched for using MEDLINE. Part I of the guidelines deals with prevention of disease progression, symptomatic treatment of motor features (parkinsonism), and prevention of motor and neuropsychiatric complications of therapy. For each topic, a list of therapeutic interventions is provided, including classification of evidence. Following this, recommendations for management are given, alongside ratings of efficacy. Classifications of evidence and ratings of efficacy are made according to EFNS guidance. In cases where there is insufficient scientific evidence, a consensus statement (good practice point) is made.

Ludolph AC, Kassubek J, Landwehrmeyer BG, Mandelkow E, Mandelkow EM, Burn DJ, Caparros-Lefebvre D, Frey KA, de Yebenes JG, Gasser T, Heutink P, Höglinger G, Jamrozik Z, Jellinger KA, Kazantsev A, Kretzschmar H, Lang AE, Litvan I, Lucas JJ, McGeer PL, Melquist S, Oertel W, Otto M, Paviour D, Reum T, Saint-Raymond A, Steele JC, Tolnay M, Tumani H, van Swieten JC, Vanier MT, Vonsattel JP, Wagner S, Wszolek ZK, Anonymous00107. · Department of Neurology, University of Ulm, Ulm, Germany. · Eur J Neurol. · Pubmed #19364361 No free full text.

Abstract: Tauopathies with parkinsonism represent a spectrum of disease entities unified by the pathologic accumulation of hyperphosphorylated tau protein fragments within the central nervous system. These pathologic characteristics suggest shared pathogenetic pathways and possible molecular targets for disease-modifying therapeutic interventions. Natural history studies, for instance, in progressive supranuclear palsy, frontotemporal dementia with parkinsonism linked to chromosome 17, corticobasal degeneration, and Niemann-Pick disease type C as well as in amyotrophic lateral sclerosis/Parkinson-dementia complex permit clinical characterization of the disease phenotypes and are crucial to the development and validation of biological markers for differential diagnostics and disease monitoring, for example, by use of neuroimaging or proteomic approaches. The wide pathologic and clinical spectrum of the tauopathies with parkinsonism is reviewed in this article, and perspectives on future advances in the understanding of the pathogenesis are given, together with potential therapeutic strategies.

Oertel W, Ross JS, Eggert K, Adler G. · Philipps-University Marburg, Marburg, Germany. · Neurology. · Pubmed #17646621 No free full text.

Abstract: Transdermal patches are used for the treatment of various diseases including neurologic and psychiatric disorders such as Parkinson disease (PD), major depression, and attention deficit hyperactivity disorder. They are believed to offer many advantages over conventional oral therapies. By providing smoother, continuous drug delivery and steadier plasma levels, patches may reduce the incidence of side effects, thus making optimal therapeutic doses easier to attain and potentially improving treatment efficacy and compliance. Drug delivery systems such as patches that are more patient- and caregiver-friendly may enable patients to continue treatment for longer periods and to attain greater, more sustained treatment benefits. To date, approved therapies for Alzheimer disease (AD), including cholinesterase inhibitors and memantine, are orally administered. Potential advantages associated with patches provide a therapeutic rationale to offer additional benefits in AD patients. Rivastigmine is well suited to patch administration because it is a small, potent molecule that is both lipophilic and hydrophilic. A rivastigmine patch has been developed and may provide a promising new approach to dementia therapy.

Iranzo A, Comella CL, Santamaria J, Oertel W. · Neurology Service, Hospital Clínic and Institut D'Investigació Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. · Mov Disord. · Pubmed #17534950 No free full text.

Abstract: The pathophysiology of restless legs syndrome (RLS) is associated with central dopaminergic system dysfunction leading to speculations that RLS may be common in those neurodegenerative diseases with dopaminergic cell loss. However, since RLS is a very common condition, the co-occurrence with less frequent disorders such as the neurodegenerative diseases might be a matter of chance. Currently, no data suggests that patients with sporadic and familial RLS are at increased risk for developing a neurodegenerative disease. In particular, whether RLS is associated with Parkinson's disease has not been established. Only a few studies have directly addressed this issue, and these have methodological limitations yielding conflicting results. Few studies have assessed the frequency of RLS in other neurodegenerative disorders. In several autosomal dominant spinocerebellar ataxias, particularly in Machado-Joseph disease, a higher frequency of RLS is reported than could be accounted for in the general population. Two anecdotal publications have reported the presence of RLS in patients with Huntington's disease and hereditary spastic paraparesis. There are no studies that have examined the association between RLS and other neurodegenerative diseases, such as Alzheimer's disease, frontotemporal dementia, dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration. .

Scherfler C, Schwarz J, Antonini A, Grosset D, Valldeoriola F, Marek K, Oertel W, Tolosa E, Lees AJ, Poewe W. · Department of Neurology, Innsbruck Medical University, Innsbruck, Austria. · Mov Disord. · Pubmed #17486648 No free full text.

Abstract: The diagnosis of idiopathic Parkinson's disease (PD) can be achieved with high degrees of accuracy in cases with full expression of classical clinical features. However, diagnostic uncertainty remains in early disease with subtle or ambiguous signs. Functional imaging has been suggested to increase the diagnostic yield in parkinsonian syndromes with uncertain clinical classification. Loss of striatal dopamine nerve terminal function, a hallmark of neurodegenerative parkinsonism, is strongly related to decreases of dopamine transporter (DAT) density, which can be measured by single photon emission computed tomography (SPECT). The use of DAT-SPECT facilitates the differential diagnosis in patients with isolated tremor symptoms not fulfilling PD or essential tremor criteria, drug-induced, psychogenic and vascular parkinsonism as well as dementia when associated with parkinsonism. This review addresses the value of DAT-SPECT in early differential diagnosis, and its potential as a screening tool for subjects at risk of developing PD as well as issues around the assessment of disease progression.

von Campenhausen S, Bornschein B, Wick R, Bötzel K, Sampaio C, Poewe W, Oertel W, Siebert U, Berger K, Dodel R. · Department of Neurology, Friedrich-Wilhelms-University, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany. · Eur Neuropsychopharmacol. · Pubmed #15963700 No free full text.

Abstract: OBJECTIVE: To provide an overview on the prevalence and incidence of Parkinson's disease (PD) in selected European countries. BACKGROUND: PD is a common disease of unknown etiology. Accurate information on the epidemiology of PD is critical to inform health policy. An aging population will lead to more patients with PD; thus, the high financial burden PD places on society will increase. MATERIAL AND METHODS: A systematic literature search was performed to identify studies on the prevalence and incidence of PD in the following European countries: Austria, the Czech Republic, France, Germany, Italy, The Netherlands, Portugal, Spain, Sweden and United Kingdom. Only published studies were included. Abstracts, reviews, meta-analyses and letters to the editor were excluded. There were no language restrictions. Data were extracted using a standardized assessment form, and evidence tables were used to systematically report and compare the data. RESULTS: Of 39 identified studies, most (87%) reported estimates of PD prevalence rates, while only a few (13%) reported estimates of PD annual incidence rates. Crude prevalence rate estimates ranged from 65.6 per 100,000 to 12,500 per 100,000 and annual incidence estimates ranged from 5 per 100,000 to 346 per 100,000. No publications could be identified for Austria or the Czech Republic. DISCUSSION AND CONCLUSION: The observed variations in prevalence and incidence rates may result from environmental or genetic factors, but might also be a consequence of differences in methodologies for case ascertainment, diagnostic criteria, or age distributions of the study populations. The comparability of existing studies is limited.

Agid Y, Ahlskog E, Albanese A, Calne D, Chase T, De Yebenes J, Factor S, Fahn S, Gershanik O, Goetz C, Koller W, Kurth M, Lang A, Lees A, Lewitt P, Marsden D, Melamed E, Michel PP, Mizuno Y, Obeso J, Oertel W, Olanow W, Poewe W, Pollak P, Tolosa E. · INSERM U 289 & Fédération de Neurologie, Hôpital de la Salpêtrière-47, Paris, France. · Mov Disord. · Pubmed #10584663 No free full text.

This publication has no abstract.

Rascol O, Brooks DJ, Melamed E, Oertel W, Poewe W, Stocchi F, Tolosa E, Anonymous00092. · Clinical Investigation Centre, Department of Clinical Pharmacology, University Hospital, Toulouse, France. · Lancet. · Pubmed #15766996 No free full text.

Abstract: BACKGROUND: Rasagiline mesylate is a novel drug for Parkinson's disease with selective, irreversible monoamine oxidase B (MAO-B) inhibitor activity, and is effective as monotherapy in early disease. This study investigated rasagiline efficacy and safety in levodopa-treated patients with Parkinson's disease and motor fluctuations. METHODS: In an 18-week, double-blind, multicentre (74 hospitals and academic centres in Israel, Argentina, and Europe) trial, 687 outpatients were randomly assigned to oral rasagiline (231 individuals; 1 mg once daily), entacapone (227; 200 mg with every levodopa dose), or placebo (229). Primary outcome was change in total daily off-time (intention-to-treat population). Other measures included the clinical global improvement (CGI) score and unified Parkinson's disease rating scale (UPDRS) scores. Analysis was by intention to treat. FINDINGS: 88 (13%) patients who were assigned treatment did not complete the study (23 rasagiline, 30 entacapone, 35 placebo), mainly because of withdrawal of consent (n=34) and adverse events (n=34). Both rasagiline and entacapone reduced mean daily off-time (-1.18 h rasagiline and -1.2 h entacapone vs placebo -0.4 h; p=0.0001, p<0.0001, respectively) and increased daily on-time without troublesome dyskinesia (0.85 h vs placebo 0.03 h; p=0.0005 for both). We recorded significant mean improvements in CGI scores (-0.86 rasagiline and -0.72 entacapone vs -0.37 placebo; p<0.0001, p=0.0002, respectively). Changes in UPDRS scores also significantly improved for activities of daily living during off-time (-1.71 and -1.38 vs placebo; p<0.0001, p=0.0006, respectively) and motor function during on-time (-2.94 and -2.73 vs placebo; both p<0.0001). Frequency of adverse events was similar for all treatments. INTERPRETATION: Once-daily rasagiline reduces mean daily off-time and improves symptoms of Parkinson's disease in levodopa-treated patients with motor fluctuations, an effect similar to that of entacapone.

Eggert K, Schrader C, Hahn M, Stamelou M, Rüssmann A, Dengler R, Oertel W, Odin P. · Department of Neurology, Philipps-University of Marburg, Marburg, Germany. · Clin Neuropharmacol. · Pubmed #18520982 No free full text.

Abstract: OBJECTIVES: We report here on the experience with continuous jejunal levodopa infusion in 13 German parkinsonian patients who have motor and nonmotor complications despite individually optimized oral treatment. The tolerability, efficacy, and the need for dose adjustment of levodopa infusion were followed-up prospectively. Thereby, we describe clinically relevant details for how to successfully initiate and handle this new treatment strategy. METHODS: Thirteen patients with advanced Parkinson disease (PD) who have motor fluctuations and dyskinesia were switched off their conventional PD medication to continuous levodopa infusion and followed-up within a maximum period of 12 months. RESULTS: Time in "off" represented a mean of 50% (+/-14; n = 13) of awake time before levodopa infusion and was reduced to a mean of 11% (+/-9; n = 11) of awake time after 6 months. Time in "on with disabling dyskinesias" represented a mean of 17% (+/-15; n = 13) of awake time before levodopa infusion and was reduced to a mean of 3% (+/-6; n= 11) of awake time after 6 months, thereby increasing the time in good "on" state. A positive effect on nonmotor symptoms (anxiety, sleep disturbances) was also observed. In most cases, dose adjustment was required within the first 6 months (predominantly after months 1-3). The therapy was safe and effective. However, problems with the technical device were common. CONCLUSIONS: Continuous jejunal levodopa infusion is an effective and feasible alternative treatment option for patients with advanced PD who can cope with and tolerate the device.

Köllensperger M, Geser F, Seppi K, Stampfer-Kountchev M, Sawires M, Scherfler C, Boesch S, Mueller J, Koukouni V, Quinn N, Pellecchia MT, Barone P, Schimke N, Dodel R, Oertel W, Dupont E, Østergaard K, Daniels C, Deuschl G, Gurevich T, Giladi N, Coelho M, Sampaio C, Nilsson C, Widner H, Sorbo FD, Albanese A, Cardozo A, Tolosa E, Abele M, Klockgether T, Kamm C, Gasser T, Djaldetti R, Colosimo C, Meco G, Schrag A, Poewe W, Wenning GK, Anonymous00007. · Section for Clinical Neurobiology, Department of Neurology, Innsbruck Medical University, Austria. · Mov Disord. · Pubmed #18442131 No free full text.

Abstract: The clinical diagnosis of multiple system atrophy (MSA) is fraught with difficulty and there are no pathognomonic features to discriminate the parkinsonian variant (MSA-P) from Parkinson's disease (PD). Besides the poor response to levodopa, and the additional presence of pyramidal or cerebellar signs (ataxia) or autonomic failure as major diagnostic criteria, certain other clinical features known as "red flags" or warning signs may raise the clinical suspicion of MSA. To study the diagnostic role of these features in MSA-P versus PD patients, a standardized red flag check list (RFCL) developed by the European MSA Study Group (EMSA-SG) was administered to 57 patients with probable MSA-P and 116 patients with probable PD diagnosed according to established criteria. Those red flags with a specifity over 95% were selected for further analysis. Factor analysis was applied to reduce the number of red flags. The resulting set was then applied to 17 patients with possible MSA-P who on follow-up fulfilled criteria of probable MSA-P. Red flags were grouped into related categories. With two or more of six red flag categories present specificity was 98.3% and sensitivity was 84.2% in our cohort. When applying these criteria to patients with possible MSA-P, 76.5% of them would have been correctly diagnosed as probable MSA-P 15.9 (+/-7.0) months earlier than with the Consensus criteria alone. We propose a combination of two out of six red flag categories as additional diagnostic criteria for probable MSA-P.

Riedel O, Klotsche J, Spottke A, Deuschl G, Förstl H, Henn F, Heuser I, Oertel W, Reichmann H, Riederer P, Trenkwalder C, Dodel R, Wittchen HU. · Institute of Clinical Psychology and Psychotherapy, Technical University of Dresden, Chemnitzer Strasse 46, Dresden, Germany. · J Neurol. · Pubmed #18204803 No free full text.

Abstract: BACKGROUND: Parkinson's disease (PD) is often accompanied by non-motor complications, such as dementia, depression, and psychotic symptoms, which worsen the prognosis and increase the personal and socioeconomic burden of disease. Prevalence estimates of these complications are quite variable and are lacking for the outpatient care sector. METHODS: As part of a larger, nationwide, cross-sectional epidemiological study in n = 315 neurological outpatient settings in Germany, this paper estimates the frequency of dementia and cognitive impairment in n = 873 outpatients meeting the UK Brain Bank criteria for idiopathic PD. Assessments were based on a clinical interview and neuropsychological assessments, including the Hoehn & Yahr rating and Unified Parkinson's Disease Rating Scale (UPDRS). Cognitive impairment was assessed by the Mini-Mental State Exam (MMSE), Clock Drawing Test (CDT) and the Parkinson Neuropsychometric Dementia Assessment (PANDA) and the clinician's diagnosis of dementia was based on the diagnostic criteria of DSMIV. RESULTS: Using standardized cutoff scores, the prevalence of cognitive impairment in the study sample as measured by various methods was 17.5% by MMSE (< or = 24), 41.8% by CDT (> or = 3), 43.6% by PANDA (< or = 14), and 28.6% met the DSM-IV criteria for dementia. All estimates increased with age and PD severity. Gender was an inconsistent contributor while illness duration had no significant impact on cognition. Multiple regression analyses revealed PD severity to be the strongest predictor of dementia risk (OR = 4.3; 95% CI: 2.1-9.1), while neuropsychiatric syndromes had independent, although modest additional contributions (OR = 2.5, 95% CI: 1.6-3.8). CONCLUSION: Estimates of cognitive impairment and dementia in PD patients are largely dependent on the diagnostic measure used. Using established clinical diagnostic standards for dementia the overall rate on routine outpatient neurological care is 28.6%, but using more sensitive neuropsychological measures, rates for cognitive impairment might be up to 2-fold higher. The MMSE revealed strikingly low sensitivity. Neuropsychiatric syndromes, in addition to PD severity and age, have an independent--although modest--additional contribution to patients' risk for cognitive impairment and dementia.

Oertel W, Poewe W, Wolters E, De Deyn PP, Emre M, Kirsch C, Hsu C, Tekin S, Lane R. · Department of Neurology, Philipps University, Marburg, Germany. · Drug Saf. · Pubmed #18095748 No free full text.

Abstract: BACKGROUND AND AIM: Rivastigmine is now widely approved for the treatment of mild to moderately severe dementia in Parkinson's disease (PDD). However, since anticholinergic drugs have a role in the management of tremor in patients with Parkinson's disease (PD), concerns have been raised that the use of cholinergic drugs might worsen PD. The current analyses were performed to examine the potential of rivastigmine to affect tremor and other motor symptoms in patients with PDD. METHODS: The safety profile of rivastigmine was evaluated using a database from a 24-week, randomized, double-blind, placebo-controlled trial in 541 PDD patients (362 randomized to rivastigmine, 179 to placebo), and 334 PDD patients who subsequently entered an open-label 24-week extension on rivastigmine. RESULTS: During the double-blind trial, the adverse event (AE) of emerging or worsening tremor was reported in 10.2% of patients in the rivastigmine group, compared with 3.9% in the placebo group (p = 0.012). Tremor was most frequently reported during the titration phase of rivastigmine treatment, although this was not reflected in total motor Unified Parkinson's Disease Rating Scale (UPDRS) part III scores. Dose dependence of this AE was not observed. At the end of the double-blind phase, six (1.7%) rivastigmine-treated patients had discontinued the study because of tremor. In the open-label extension in which all patients received rivastigmine, tremor was reported by 6.9% of patients: 3.8% and 12.2% of whom had previously received double-blind rivastigmine and placebo, respectively (p = 0.006), suggesting that first exposure to rivastigmine leads to a transient increase in tremor. Three (0.9%) of the 334 patients who entered the open-label extension phase discontinued because of tremor. Incidences of worsening parkinsonism, bradykinesia and rigidity were all <5% in both treatment groups (all p-values not statistically significant, rivastigmine vs placebo). In the 48-week observation of rivastigmine treatment, there was no evidence of adverse long-term motor outcomes. Post-hoc analysis showed that similar improvements in the symptoms of dementia, including the ability to perform activities of daily living, were seen regardless of whether exacerbation of tremor was reported during the study. CONCLUSION: Rivastigmine did not induce clinically significant exacerbation of motor dysfunction in patients with PDD. Rest tremor incidence as an AE was a transient phenomenon during dose titration of rivastigmine. There was no indication that exposure to long-term rivastigmine was associated with a worsening of PD.

Eggert K, Wüllner U, Antony G, Gasser T, Janetzky B, Klein C, Schöls L, Oertel W. · Department of Neurology, Philipps-University of Marburg, Marburg, Germany. · Mov Disord. · Pubmed #17230444 No free full text.

Abstract: Parkinson's disease (PD) is the second most common neurodegenerative disease. Although 10 gene loci have been identified to cause a Parkinsonian syndrome, these loci account only for a minority of PD patients. Large, systematic research programs are required to collect, store, and analyze DNA samples and clinical information to support further discovery of additional genetic components of PD or other movement disorders. Such programs facilitate research into the relationship between genotype and phenotype. The German Competence Network on Parkinson's disease (CNP) initiated the Gene Bank Parkinson's Disease Germany (GEPARD), providing an administrative and scientific infrastructure for the storage of DNA and clinical data that are electronically accessible and protective of patient rights. In this article, we offer guidance on how to establish a framework for a clinical genetic data and DNA bank, and describe GEPARD as a model that may be useful to other local, national, and international research groups developing similar programs.

Stacy M, Hauser R, Oertel W, Schapira A, Sethi K, Stocchi F, Tolosa E. · Division of Neurology, Duke University Medical School, Durham, North Carolina 27705, USA. · Clin Neuropharmacol. · Pubmed #17095894 No free full text.

Abstract: 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. The resulting 9-symptom questionnaire (WOQ-9) identified 158 (95.8%) of the 165 subjects captured by the 32-Symptom Wearing-off Questionnaire as having wearing off, excluding 7 subjects reporting only balance difficulty (n = 3), numbness (n = 2), difficulty standing (n = 1), and abdominal discomfort (n = 1). Subjects reporting wearing off with the WOQ-9 were significantly younger, had been longer diagnosed with Parkinson disease, experienced a longer duration of levodopa therapy, exhibited a higher UPDRS total score, had higher levodopa equivalent dosages, and increased dyskinesia compared with patients not identified as wearing off with the WOQ-9. No statistical differences were noted with respect to sex, UPDRS subsection scores, Schwab & England Scale, or Hoehn & Yahr Scale.

Deuschl G, Schade-Brittinger C, Krack P, Volkmann J, Schäfer H, Bötzel K, Daniels C, Deutschländer A, Dillmann U, Eisner W, Gruber D, Hamel W, Herzog J, Hilker R, Klebe S, Kloss M, Koy J, Krause M, Kupsch A, Lorenz D, Lorenzl S, Mehdorn HM, Moringlane JR, Oertel W, Pinsker MO, Reichmann H, Reuss A, Schneider GH, Schnitzler A, Steude U, Sturm V, Timmermann L, Tronnier V, Trottenberg T, Wojtecki L, Wolf E, Poewe W, Voges J, Anonymous00228. · Christian Albrechts University, Kiel, Germany. · N Engl J Med. · Pubmed #16943402 links to  free full text

Abstract: BACKGROUND: Neurostimulation of the subthalamic nucleus reduces levodopa-related motor complications in advanced Parkinson's disease. We compared this treatment plus medication with medical management. METHODS: In this randomized-pairs trial, we enrolled 156 patients with advanced Parkinson's disease and severe motor symptoms. The primary end points were the changes from baseline to six months in the quality of life, as assessed by the Parkinson's Disease Questionnaire (PDQ-39), and the severity of symptoms without medication, according to the Unified Parkinson's Disease Rating Scale, part III (UPDRS-III). RESULTS: Pairwise comparisons showed that neurostimulation, as compared with medication alone, caused greater improvements from baseline to six months in the PDQ-39 (50 of 78 pairs, P=0.02) and the UPDRS-III (55 of 78, P<0.001), with mean improvements of 9.5 and 19.6 points, respectively. Neurostimulation resulted in improvements of 24 to 38 percent in the PDQ-39 subscales for mobility, activities of daily living, emotional well-being, stigma, and bodily discomfort. Serious adverse events were more common with neurostimulation than with medication alone (13 percent vs. 4 percent, P<0.04) and included a fatal intracerebral hemorrhage. The overall frequency of adverse events was higher in the medication group (64 percent vs. 50 percent, P=0.08). CONCLUSIONS: In this six-month study of patients under 75 years of age with severe motor complications of Parkinson's disease, neurostimulation of the subthalamic nucleus was more effective than medical management alone. (ClinicalTrials.gov number, NCT00196911 [ClinicalTrials.gov].).

Schrag A, Geser F, Stampfer-Kountchev M, Seppi K, Sawires M, Köllensperger M, Scherfler C, Quinn N, Pellecchia MT, Barone P, Del Sorbo F, Albanese A, Ostergaard K, Dupont E, Cardozo A, Tolosa E, Nilsson CF, Widner H, Lindvall O, Giladi N, Gurevich T, Daniels C, Deuschl G, Coelho M, Sampaio C, Abele M, Klockgether T, Schimke N, Eggert KM, Oertel W, Djaldetti R, Colosimo C, Meco G, Poewe W, Wenning GK, Anonymous00441. · Department of Clinical Neurosciences, Royal Free & University College Medical School, London, United Kingdom. · Mov Disord. · Pubmed #16502399 No free full text.

Abstract: Although multiple system atrophy (MSA) is a neurodegenerative disorder leading to progressive disability and decreased life expectancy, little is known about patients' own evaluation of their illness and factors associated with poor health-related quality of life (Hr-QoL). We, therefore, assessed Hr-QoL and its determinants in MSA. The following scales were applied to 115 patients in the European MSA-Study Group (EMSA-SG) Natural History Study: Medical Outcome Study Short Form (SF-36), EQ-5D, Beck Depression Inventory (BDI), Mini-Mental state examination (MMSE), Unified MSA Rating Scale (UMSARS), Hoehn & Yahr (H&Y) Parkinson's disease staging scale, Composite Autonomic Symptom Scale (COMPASS), and Parkinson's Disease Sleep Scale (PDSS). Forty-six percent of patients had moderate to severe depression (BDI > or = 17); Hr-QoL scores on the SF-36 and EQ-5D were significantly impaired. Pain, the only domain with similar scores in MSA and published PD patients, was reported more frequently in patients with MSA-P (predominantly parkinsonian motor subtype) than MSA-C (predominantly cerebellar motor subtype; 76% vs. 50%; P = 0.005). Hr-QoL scores correlated most strongly with UMSARS motor, COMPASS, and BDI scores but not with MMSE scores, age at onset, or disease duration. The COMPASS and UMSARS activities of daily living scores were moderate-to-strong predictors for the SF-36 physical summary score and the BDI and UMSARS motor scores for the SF-36 mental summary score. This report is the first study to show that Hr-QoL is significantly impaired in MSA. Although not all possible factors related to impaired Hr-QoL in MSA could be assessed, autonomic dysfunction, motor impairment, and depression were most closely associated with poor Hr-QoL, and therapeutic management, therefore, should concentrate upon these aspects of the disease.

Gerhard A, Pavese N, Hotton G, Turkheimer F, Es M, Hammers A, Eggert K, Oertel W, Banati RB, Brooks DJ. · MRC Clinical Sciences Centre and Division of Neuroscience, Faculty of Medicine, Imperial College, London, UK. · Neurobiol Dis. · Pubmed #16182554 No free full text.

Abstract: Idiopathic Parkinson's disease (PD) is a neurodegenerative disorder associated with akinesia, tremor and rigidity. While the characteristic Lewy body pathology targets pigmented and other brainstem nuclei at post-mortem, activated microglia are found in both subcortical and cortical areas. [11C](R)-PK11195 is a positron emission tomography (PET) marker of peripheral benzodiazepine sites (PBBS), which are selectively expressed by activated microglia. We examined 18 PD patients clinically and with [11C](R)-PK11195 and [18F]-dopa PET. Compared to 11 normal controls, the PD patients showed significantly increased mean levels of [11C](R)-PK11195 binding in the pons, basal ganglia and frontal and temporal cortical regions. Eight PD patients were examined longitudinally, and their [11C](R)-PK11195 signal remained stable over 2 years. Levels of microglial activation did not correlate with clinical severity or putamen [18F]-dopa uptake. Our in vivo findings confirm that widespread microglial activation is associated with the pathological process in PD. The absence of significant longitudinal changes suggests that microglia are activated early in the disease process, and levels then remain relatively static, possibly driving the disease via cytokine release.

Stacy M, Bowron A, Guttman M, Hauser R, Hughes K, Larsen JP, LeWitt P, Oertel W, Quinn N, Sethi K, Stocchi F. · Duke University Medical Center, 932 Morreene Road, Durham, NC 27705, USA. · Mov Disord. · Pubmed #15719426 No free full text.

Abstract: 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 <5 years duration were evaluated; the mean subject age was 72 +/- 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). Wearing-off 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.

Piccini P, Lindvall O, Björklund A, Brundin P, Hagell P, Ceravolo R, Oertel W, Quinn N, Samuel M, Rehncrona S, Widner H, Brooks DJ. · Medical Research Council Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, London, UK. · Ann Neurol. · Pubmed #11079531 No free full text.

Abstract: Intrastriatal transplantation of dopaminergic neurones aims to repair the selective loss of nigrostriatal projections and the consequent dysfunction of striatocortical circuitries in Parkinson's disease (PD). Here, we have studied the effects of bilateral human embryonic dopaminergic grafts on the movement-related activation of frontal cortical areas in 4 PD patients using H2 15O positron emission tomography and a joystick movement task. At 6.5 months after transplantation, mean striatal dopamine storage capacity as measured by 18F-dopa positron emission tomography was already significantly elevated in these patients. This was associated with a modest clinical improvement on the Unified Parkinson's Disease Rating Scale, whereas the impaired cortical activation was unchanged. At 18 months after surgery, there was further significant clinical improvement in the absence of any additional increase in striatal 18F-dopa uptake. Rostral supplementary motor and dorsal prefrontal cortical activation during performance of joystick movements had significantly improved, however. Our data suggest that the function of the graft goes beyond that of a simple dopamine delivery system and that functional integration of the grafted neurones within the host brain is necessary to produce substantial clinical recovery in PD.