Parkinson Disease: Tolosa E

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.

Tolosa E, Gaig C, Santamaría J, Compta Y. · Parkinson's Disease and Movement Disorders Unit, Institut Clínic de Neurosciències, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Hospital Clínic de Barcelona, Barcelona 08036, Spain. · Neurology. · Pubmed #19221308 No free full text.

Abstract: Clinical, neuroimaging, and pathologic studies have provided data suggesting that a variety of nonmotor symptoms can precede the classic motor features of Parkinson disease (PD) by years and, perhaps, even decades. The period when these symptoms arise can be referred to as the "premotor phase" of the disease. Here, we review the evidence supporting the occurrence of olfactory dysfunction, dysautonomia, and mood and sleep disorders, in this premotor phase of PD. These symptoms are well known in established PD and when presenting early, in the premotor phase, should be potentially considered as an integral part of the disease process. Even though information on the premotor phase of PD is rapidly accumulating, the diagnosis of premotor PD remains elusive at this time. Should a safe and effective treatment with disease-modifying or neuroprotective potential in PD become available, identifying individuals in the premotor phase will become a serious priority.

Poewe W, Gauthier S, Aarsland D, Leverenz JB, Barone P, Weintraub D, Tolosa E, Dubois B. · Department of Neurology, Medical University Innsbruck, Innsbruck, Austria. · Int J Clin Pract. · Pubmed #18822028 links to  free full text

Abstract: Parkinson's disease (PD) has long been considered predominantly a motor disorder. However, its frequent association with dementia, which contributes significantly to the morbidity and mortality of the condition, is gaining increasing recognition. PD dementia (PDD) has a unique clinical profile and neuropathology, distinct from Alzheimer's disease (AD). Cholinergic deficits, a feature of both AD and PDD, underlie the rationale for cholinesterase inhibitor therapy in both conditions. In clinical practice, it is important that PDD should be recognised and appropriately treated. This review aims to outline the recently proposed clinical diagnostic criteria for PDD and to summarise the guidelines/recommendations published since 2006 on the use of cholinesterase inhibitors in the management of PDD. Although the cholinesterase inhibitor rivastigmine has recently been approved for the management of PDD, there remains a need for the development of novel therapies that can affect key mechanisms of the disease or prevent/delay patients with PD and mild cognitive impairment from progressing to PDD.

Caballol N, Martí MJ, Tolosa E. · Parkinson's Disease and Movement Disorders Unit, Neurology Service, Institut Clínic de Neurociencies, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic Universitari, University of Barcelona, Barcelona, Spain. · Mov Disord. · Pubmed #18175397 No free full text.

Abstract: Impairment in different cognitive domains such as executive functions, language, memory, and visuospatial skills occurs frequently in Parkinson disease (PD) even in the early stages of the disease. Although frank dementia (Parkinson disease dementia, PDD) is less frequent, risk for developing dementia is two to six times greater than the prevalence rate in general population and it increases in relation to disease duration. Clinically, dementia in PD is characterized by uninsidious onset and slowly progressive cognitive decline, with a predominant dysexecutive syndrome accompanied frequently by a variety of behavioral symptoms such as hallucinations, depression, anxiety, and excessive daytime sleepiness. Although the exact pathophysiology and neurobiological basis of PDD is not known, dementia in PD probably develops as a result of progressive involvement of subcortical and cortical structures by Lewy-type pathology and associated Alzheimer-like histological changes. Dysfunction of different monoamine transmitter has also been implicated in the cognitive deterioration of PD but reduced cholinergic activity in the cortex is thought to account for the strongest mechanism in the development of dementia. Recent evidence suggests that cholinesterase inhibitors are effective in the treatment of dementia and accompanying behavioral symptoms in PD.

Dubois B, Burn D, Goetz C, Aarsland D, Brown RG, Broe GA, Dickson D, Duyckaerts C, Cummings J, Gauthier S, Korczyn A, Lees A, Levy R, Litvan I, Mizuno Y, McKeith IG, Olanow CW, Poewe W, Sampaio C, Tolosa E, Emre M. · INSERM-UPMC UMRS 610, Federation of Neurology, AP-HP, Salpêtrière Hospital; Université Paris6, Paris, France. · Mov Disord. · Pubmed #18098298 links to  free full text

Abstract: A preceding article described the clinical features of Parkinson's disease dementia (PD-D) and proposed clinical diagnostic criteria for "probable" and "possible" PD-D. The main focus of this article is to operationalize the diagnosis of PD-D and to propose practical guidelines based on a two level process depending upon the clinical scenario and the expertise of the evaluator involved in the assessment. Level I is aimed primarily at the clinician with no particular expertise in neuropsychological methods, but who requires a simple, pragmatic set of tests that are not excessively time-consuming. Level I can be used alone or in concert with Level II, which is more suitable when there is the need to specify the pattern and the severity on the dementia of PD-D for clinical monitoring, research studies or pharmacological trials. Level II tests can also be proposed when the diagnosis of PD-D remains uncertain or equivocal at the end of a Level I evaluation. Given the lack of evidence-based standards for some tests when applied in this clinical context, we have tried to make practical and unambiguous recommendations, based upon the available literature and the collective experience of the Task Force. We accept, however, that further validation of certain tests and modifications in the recommended cut off values will be required through future studies.

Tolosa E, Compta Y, Gaig C. · Neurology Service, 08036 Barcelona, Catalonia, Spain. · Parkinsonism Relat Disord. · Pubmed #17681839 No free full text.

Abstract: There is growing evidence that a variety of symptoms can precede the classical motor features of Parkinson's disease (PD). The period when these symptoms arise can be referred to as the premotor phase of the disease. Well-documented premotor symptoms in PD include constipation, loss of smell, sleep disturbances such as REM sleep behavior disorder (RBD), and mood disturbances like depression. Diagnostic and therapeutic implications linked to improved identification of these premotor features are discussed.

Emre M, Aarsland D, Brown R, Burn DJ, Duyckaerts C, Mizuno Y, Broe GA, Cummings J, Dickson DW, Gauthier S, Goldman J, Goetz C, Korczyn A, Lees A, Levy R, Litvan I, McKeith I, Olanow W, Poewe W, Quinn N, Sampaio C, Tolosa E, Dubois B. · Department of Neurology, Behavioral Neurology and Movement Disorders Unit, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey. · Mov Disord. · Pubmed #17542011 links to  free full text

Abstract: Dementia has been increasingly more recognized to be a common feature in patients with Parkinson's disease (PD), especially in old age. Specific criteria for the clinical diagnosis of dementia associated with PD (PD-D), however, have been lacking. A Task Force, organized by the Movement Disorder Study, was charged with the development of clinical diagnostic criteria for PD-D. The Task Force members were assigned to sub-committees and performed a systematic review of the literature, based on pre-defined selection criteria, in order to identify the epidemiological, clinical, auxillary, and pathological features of PD-D. Clinical diagnostic criteria were then developed based on these findings and group consensus. The incidence of dementia in PD is increased up to six times, point-prevelance is close to 30%, older age and akinetic-rigid form are associated with higher risk. PD-D is characterized by impairment in attention, memory, executive and visuo-spatial functions, behavioral symptoms such as affective changes, hallucinations, and apathy are frequent. There are no specific ancillary investigations for the diagnosis; the main pathological correlate is Lewy body-type degeneration in cerebral cortex and limbic structures. Based on the characteristic features associated with this condition, clinical diagnostic criteria for probable and possible PD-D are proposed.

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.

Tolosa E, Compta Y. · Neurology Service, Institut de Neurociències, Hospital Clínic i Universitari de Barcelona, c./ Villarroel 170, 08036 Barcelona, Catalonia, Spain. · J Neurol. · Pubmed #17131231 No free full text.

Abstract: Dystonia can occasionally be found in idiopathic Parkinson's disease. It is very uncommon in untreated patients and is more frequently seen as a complication of its treatment. In this review, the various types of dystonia occurring in PD, the differential diagnosis with other parkinsonian syndromes associated with dystonia and treatments available are revised. Dystonia unrelated to treatment can be typical (blepharospasm, torticollis), atypical (parkinsonian writer's cramp, camptocormia, anismus), or occurring in earlyonset Parkinson disease (the so-called kinesigenic foot dystonia, considered a hallmark of early-onset Parkinson's disease). Early and prominent dystonia in untreated patients with parkinsonism should raise the suspicion of other entities other than Parkinson's disease, such as progressive supranuclear palsy, multiple system atrophy or corticobasal degeneration. In patients on chronic dopaminergic treatment, peak-dose dystonia, diphasic dystonia and off-dystonia can be seen. The later constitutes the major dystonic feature of chronic levodopa therapy, and a wide variety of strategies are available to manage this complication. Among them, deep brain stimulation of the subthalamic nucleus has proved to be the most effective one. Dystonic reactions (mainly involving oculomotor cranial nerves and limbs) in operated patients (especially carriers of deep brain stimulation (DBS) devices) are increasingly being reported, constituting a new type of dystonia in patients with Parkinson's disease: dystonia linked to surgical treatment.

Tolosa E, Wenning G, Poewe W. · Neurology Service, Hospital Clinic, University of Barcelona, Barcelona, Spain. · Lancet Neurol. · Pubmed #16361025 No free full text.

Abstract: The correct diagnosis of Parkinson's disease is important for prognostic and therapeutic reasons and is essential for clinical research. Investigations of the diagnostic accuracy for the disease and other forms of parkinsonism in community-based samples of patients taking antiparkinsonian medication confirmed a diagnosis of parkinsonism in only 74% of patients and clinically probable Parkinson's disease in 53% of patients. Clinicopathological studies based on brain bank material from the UK and Canada have shown that clinicians diagnose the disease incorrectly in about 25% of patients. In these studies, the most common reasons for misdiagnosis were presence of essential tremor, vascular parkinsonism, and atypical parkinsonian syndromes. Infrequent diagnostic errors included Alzheimer's disease, dementia with Lewy bodies, and drug-induced parkinsonism. Increasing knowledge of the heterogeneous clinical presentation of the various parkinsonisms has resulted in improved diagnostic accuracy of the various parkinsonian syndromes in specialised movement-disorder units. Also genetic testing and various other ancillary tests, such as olfactory testing, MRI, and dopamine-transporter single-photon-emission computed-tomography imaging, help with clinical diagnostic decisions.

Castro A, Valldeoriola F, Linazasoro G, Rodriguez-Oroz MC, Stochi F, Marin C, Rodriguez M, Vaamonde J, Jenner P, Alvarez L, Pavon N, Macias R, Luquin MR, Hernandez B, Grandas F, Gimenez-Roldan S, Tolosa E, Obeso JA. · Servicio de Neurología, Hospital Xeral de Galicia, Santiago de Compostela. · Neurologia. · Pubmed #15891947 links to  free full text

Abstract: Levodopa remains the mainstay treatment for Parkinson's disease (PD). Chronic treatment is associated with motor complications (MC) that marred the clinical benefit of levodopa. These problems and experimental data in cell cultures indicating a neurotoxic effect of levodopa have led to the idea of delaying the introduction of levodopa treatment for as long as possible. We here review recent data regarding the mechanism of action of levodopa and its application in clinical practice on the light of the marketing of the combination levodopa-carbidopa- entacapone. Accumulated evidence indicates that MC are mainly the consequence of disease severity governing the degree of dopaminergic depletion and the "pulsatile" dopaminergic stimulation provided by levodopa short plasma half-life. There is no in vivo or clinical evidence of a relevant neurotoxic effect of levodopa. In fact, the recent ELLDOPA study may suggest a neuroprotective effect. Entacapone reduces homocysteine plasma levels which could provide a mechanism to reduce cell death in PD. Currently, the combination levodopa-carbidopa-entacapone is particularly indicated for the treatment of "wearing off" fluctuations. Experimental evidence suggests that early treatment with levodopa-carbidopa-entacapone may substantially ameliorate the incidence of MC. Such a clinical study in "de novo" patients is underway. At present, the combination levodopa-carbidopa-entacapone is indicated when levodopa is judged necessary.

Tolosa E, Coelho M, Gallardo M. · Parkinson's Disease and Movement Disorders Unit, Neurology Service, Institut Clinic Malaltias del Sistema Nervios, Hospital Clínic Universitari, University of Barcelona, Spain. · Mov Disord. · Pubmed #14531043 No free full text.

Abstract: Parkinson's syndrome (PS) is frequently encountered in disorders associated with prominent degeneration of the nigrostriatal pathway as in Parkinson's disease, multisystem atrophy, and progressive supranuclear palsy (presynaptic PS). Drug-induced parkinsonism, a common, underdiagnosed health problem and psychogenic parkinsonism are causes of Parkinson's syndrome which, evidence suggests, occurs without degeneration of nigrostriatal structures. We review clinical features and results of DAT imaging in drug-induced parkinsonism and psychogenic parkinsonism. These two conditions normally give normal striatal DAT imaging results; an abnormal result in either case could exclude both conditions, corroborating a diagnosis of organic parkinsonism in uncertain cases.

Tolosa E. · Neurology Service, ICMSN, Banco de Tejidos Neurológicos, Hospital Clinico, University of Barcelona, Barcelona, Spain. · J Neural Transm Suppl. · Pubmed #12830929 No free full text.

Abstract: Numerous advances have taken place in the pharmacological management of Parkinson disease (PD) in recent years. Some of the more clinically relevant will be discussed in the text that follows. New drugs have been developed to treat or prevent the motor fluctuations and dyskinesias that occur frequently with the continuous use of levodopa. Such drugs include the catechol-O-methyl-transferase (COMT) inhibitors, such as tolcapone and entecapone, and new dopamine (DA) agonists with long half lives such as cabergoline, pramipexole or ropirinole. Also new, atyical, antipsychotics have appeared which have revolutionized the treatment of PD since they allow us to control hallucinations and other psychotic behaviour without worsening of motor function. Finally preliminary reports suggest that cholinesterase inhibitors, such as rivastigmine, can be usefull in the management of cognitive impairment in PD, one of the most difficult clinical problems encountered in the management of this neurodegenerative disorder.

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.

Tolosa E, Molinuevo JL, Valldeoriola F, Pastor P. · Servicio de Neurología, Hospital Clínic i Universitari, Universitat de Barcelona. · Neurologia. · Pubmed #10377729 No free full text.

Abstract: The dopamine precursor, levodopa, and the synthetic dopamine agonists are drugs widely used to alleviate the motor symptoms of idiopathic Parkinson's disease. Recently, several molecules which act on different pharmacological receptors implied in Parkinson's disease pathophysiology, have been developed to be applied as a treatment for its motor and cognitive symptoms. This paper discusses these novel therapeutical strategies, their mechanism of action, and their potential applications. To facilitate its lecture, the article has been structured in several sections. In the first section, drugs acting on dopamine metabolism are described, in the next part recent studies on new dopamine agonists and drugs acting on non-dopamine neuronal receptors are analysed, and finally the role of trophic factors for the treatment of Parkinson's disease is discussed.

Olanow CW, Hauser RA, Jankovic J, Langston W, Lang A, Poewe W, Tolosa E, Stocchi F, Melamed E, Eyal E, Rascol O. · Department of Neurology, Mount Sinai School of Medicine, New York, New York 10029, USA. · Mov Disord. · Pubmed #18932271 No free full text.

Abstract: A neuroprotective therapy is the single most important unmet medical need in Parkinson's disease. Several promising agents in the laboratory have been tested in the clinic, but none has been established in clinical trials to have a disease modifying effect despite positive results because of potential confounding symptomatic or pharmacologic effects. The delayed start design was developed to try to avoid a symptomatic confound when testing a putative neuroprotective therapy. In this study design, patients are randomly assigned to study drug or placebo in the first phase of the study, and both groups receive the active drug in the second phase. If benefits seen at the end of phase I persist through the end of phase II, they cannot be readily explained by a symptomatic effect (as patients in both groups are receiving the same medication) and benefits in the early start group must relate to the early initiation of the treatment. Although the precise mechanism responsible for such an effect can be debated, positive results in a delayed start study indicate that patients who receive early treatment have a better outcome than those where the treatment is delayed. We are using the delayed start design to assess the potential disease modifying effects of rasagiline in a prospective double blind controlled trial (the ADAGIO study). We here describe the rationale for the study and baseline characteristics of the 1,176 patients who have been enrolled into the trial.

Poewe WH, Rascol O, Quinn N, Tolosa E, Oertel WH, Martignoni E, Rupp M, Boroojerdi B, Anonymous00326. · Department of Neurology, Innsbruck Medical University, Innsbruck, Austria. · Lancet Neurol. · Pubmed #17509486 No free full text.

Abstract: BACKGROUND: Continuous dopaminergic drug delivery is an unmet medical need in advanced Parkinson's disease. The aim of this trial-Clinical Efficacy of Pramipexole And Transdermal Rotigotine in Advanced PD (CLEOPATRA-PD)-was to assess the efficacy of adjunct treatment with rotigotine in comparison with placebo and with pramipexole in levodopa-treated patients with advanced Parkinson's disease and wearing-off type motor fluctuations. METHODS: In this randomised controlled trial, eligible participants were randomly assigned to receive either rotigotine (up to 16 mg/24 h as a transdermal patch), pramipexole (up to 4.5 mg/day orally), or placebo for 6 months. Primary efficacy variables were absolute change in total hours "off" (assessed by home diaries) from baseline to end of study and responder rate (defined as the proportion of patients with >or=30% reduction in absolute off time per day). Analyses were done by intention to treat. This trial is registered with the US National Institutes of Health clinical trials database (ClinicalTrials.gov), number NCT00244387. FINDINGS: 204 patients were randomly assigned to receive rotigotine, 201 to receive pramipexole, and 101 to receive placebo; 427 (84%) completed the trial. The number of discontinuations in each group was similar; most were for adverse events. The mean dose of rotigotine was 12.95 mg/24 h (SD 3.54), the mean dose of pramipexole was 3.1 mg/day (1.24). Mean absolute change in off time from baseline was -2.5 h (SE 0.20) with rotigotine, -2.8 h (0.20) with pramipexole, and -0.9 h (0.29) with placebo. The absolute change in off time from baseline compared with placebo was -1.58 h (95% CI -2.27 to -0.90; p<0.0001) for rotigotine and -1.94 h (-2.63 to -1.25; p<0.0001) for pramipexole. Responder rates were 67% (134 of 200 patients) for pramipexole, 59.7% (120 of 201 patients) for rotigotine, and 35% (35 of 100 patients) for placebo. INTERPRETATION: In terms of change in absolute off time, rotigotine was non-inferior to pramipexole. Continuous delivery of rotigotine as transdermal patches could offer similar efficacy to oral pramipexole in patients with fluctuating Parkinson's disease over 6 months of treatment.

Kumru H, Santamaria J, Valldeoriola F, Marti MJ, Tolosa E. · Neurology Service, Hospital Clínic de Barcelona and Institut d'Investigacions Biomèdiques August Pi i Sunyer , Universitat de Barcelona, Barcelona, Spain. · Mov Disord. · Pubmed #16972276 No free full text.

Abstract: Body weight changes occur during the clinical course of Parkinson's disease (PD) and with surgical treatment, but the effect of dopaminergic treatment on weight is unknown. Body mass index (BMI), Hamilton depression scale score (HDS), and Unified Parkinson's Disease Rating Scale III (UPRS-III) were measured before and 3 months after starting pramipexole in 28 PD patients. Pramipexole produced a significant weight increase, as well as motor and mood improvement (P <0.001). HDS and BMI changes were mildly related (P = 0.05). A direct effect of pramipexole on limbic D(3) receptors involved in the control of feeding may be responsible for weight gain in PD.

Pintor L, Baillès E, Valldeoriola F, Tolosa E, Martí MJ, de Pablo J. · Servicio de Psiquiatría, Instituto Clínico de Neurociencias, Hospital Clínico de Barcelona, 08036 Barcelona, Spain. · Gen Hosp Psychiatry. · Pubmed #16377367 No free full text.

Abstract: OBJECTIVE: The aim of this study is to evaluate response to reboxetine in a 4-month follow-up study on depression in Parkinson's disease (PD), and to assess its tolerability profile. METHODS: A prospective 4-month follow-up study was performed in 17 PD patients with a major depressive episode. The intensity of depressive symptoms was evaluated mainly with the Hamilton Rating Scale for Depression (HAM-D), and PD was assessed with the Unified Parkinson Disease Rating Scale (UPDRS). RESULTS: Reboxetine causes a progressive decrease in depressive symptoms in PD patients; the initial score of 16.76 (2.68) on HAM-D decreased to 5.85 (2.42) at 4 months (P < .002). Mean UPDRS scores did not show a statistically significant increase: 18.18 (2.6) at the beginning and 18.25 (2.4) at the end of the follow-up period (P = .8). CONCLUSIONS: Reboxetine, as first choice treatment for major depressive episodes in PD patients, seems to be effective in progressively improving depressive symptoms over the first 4 months of treatment until complete remission. Reboxetine does not seem to increase PD symptoms, whereas patients' quality of life improves.

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.

Molinuevo JL, Valldeoriola F, Tolosa E, Rumia J, Valls-Sole J, Roldan H, Ferrer E. · Servei de Neurologia, Hospital Clinic Universitari, Villarroel 170, Barcelona 08036, Spain. · Arch Neurol. · Pubmed #10891980 links to  free full text

Abstract: CONTEXT: Subthalamic nucleus (STN) stimulation may be effective in ameliorating parkinsonian symptoms even to the extent to permit levodopa withdrawal. OBJECTIVES: To analyze the efficacy of STN stimulation in patients with Parkinson disease (PD) and to determine if levodopa may be withdrawn after surgery. DESIGN: Before-after trial. SETTING: Referral center, hospitalized care. PATIENTS: Fifteen patients with advanced PD. INTERVENTIONS: Microelectrode-guided bilateral STN high-frequency stimulation. OUTCOME MEASURES: Before surgery patients were evaluated in off-medication and on-medication conditions. Dopaminergic drug dosages were reduced after surgery, aiming for complete withdrawal. Six months after surgery, patients were reeavaluated in off- and on-medication conditions, with the stimulation turned on and off. RESULTS: Total Unified Parkinson's Disease Rating Scale (UPDRS) motor score in the off-medication condition improved by 65.9%; and axial symptoms, bradykinesia, rigidity, and tremor improved by 65.8%, 60.4%, 66.1%, and 81.1%, respectively. UPDRS part II scores were reduced by 71.8% and Schwab and England scores improved by 45.3%. Levodopa was withdrawn in 8 patients and the overall levodopa dose was reduced 80.4%. "Off" time was reduced 89.7% and the severity of dyskinesias decreased 80.6% after surgery. All results reached significance (P<.001). Stimulation of the STN achieved antiparkinsonian effect similar to that of treatment with levodopa. No life-threatening adverse effects occurred. CONCLUSIONS: Bilateral STN stimulation safely improves all parkinsonian symptoms, decreases or eliminates the need for levodopa, and ameliorates motor fluctuations and dyskinesias. Complete withdrawal of levodopa is feasible with this technique and the overall motor effect of STN stimulation is quantitatively comparable to that obtained with levodopa.

Alegret M, Vendrell P, Junqué C, Valldeoriola F, Nobbe FA, Rumià J, Tolosa E. · Department of Psychiatry and Clinical Psychobiology, University of Barcelona, IDIBAPS: Institut d'Investigacions Biomèdiques August Pi i Sunyer, Passeig de la Vall d'Hebron, 171 08035, Barcelona, Spain. · Neuropsychologia. · Pubmed #10689039 No free full text.

Abstract: In Parkinson's disease, cognitive performance can vary according to levodopa levels (on-off states). Both positive and negative effects of dopaminergic stimulation have been reported. Pallidotomy is also able to change cognitive performance, in addition to levodopa pharmacokinetics. The aim of this investigation was to study the effects of pallidotomy on cognitive on-off fluctuations in Parkinson's disease. A brief neuropsychological battery was administered to 15 PD patients during on and off states before and after surgery. Before pallidotomy, patients performed better in the on condition on Trail Making test B; after pallidotomy levodopa no longer improved performance, and the interaction between surgery and state was significant. In relation to the difference between preoperative and postoperative performance in Trail Making B test, there was a significant postsurgical improvement only in off state. Verbal fluency decreased after pallidotomy in both on and off conditions. Our results suggest that pallidotomy can change the effects of levodopa on neuropsychological functions.

Koller WC, Hutton JT, Tolosa E, Capilldeo R. · Department of Neurology, University of Miami, FL, USA. · Neurology. · Pubmed #10496260 No free full text.

Abstract: OBJECTIVE: To compare effects of immediate-release (IR) and sustained-release (CR) carbidopa/levodopa in levodopa-naive PD patients. BACKGROUND: It was hypothesized that the long-acting preparation would be associated with fewer long-term complications. METHODS: A total of 618 patients were studied in 36 centers worldwide in a blinded, randomized parallel study. Measures of efficacy and adverse reactions were recorded at 3-month intervals for 5 years. Motor fluctuations and dyskinesias were evaluated by a patient diary and a physician-recorded questionnaire. The Nottingham Health Profile (NHP) was used to evaluate quality of life. RESULTS: Approximately 60% of patients completed the trial. After 5 years, the mean dose of IR was 426 mg/day, and the bioavailable dose of CR was 510 mg/day (mean dose, 736 mg/day). After 5 years, 20.6% of the IR group and 21.8% of the CR group had motor fluctuations or dyskinesia. Sixteen percent of both groups had changes in motor response by the questionnaire's definition. There was no significant difference between the two treatment groups. Disability scores and the motor score of the Unified Parkinson Disease Rating Scale (UPDRS) were highest at baseline, improved with therapy, and thereafter worsened over time to reach baseline scoring at the end of 5 years. The CR group was superior to IR for the Activities of Daily Living subsection of the UPDRS for all 5 years and for emotional reactivity and social isolation on the NHP; however, this may have resulted from higher doses of CR that were used. CONCLUSION: Despite the progressive nature of PD, both the immediate-release and sustained-release carbidopa/levodopa formulations maintained a similar level of control in PD after 5 years compared with baseline. Additionally, the low incidence of motor fluctuations or dyskinesia was not significantly different between the treatment groups and may be partly attributed to the relatively low doses of levodopa used throughout the 5-year study.

Antonini A, Tolosa E. · Parkinson Institute Milan, Istituti Clinici di Perfezionamento, Via Bignami 1, Milan, Italy. · Expert Rev Neurother. · Pubmed #19496689 No free full text.

Abstract: The continuous infusion of levodopa or apomorphine represents a good therapeutic option for advanced Parkinson's disease as this approach provides constant dopaminergic stimulations and is a good alternative to deep brain stimulation. While apomorphine provides a similar level of motor benefit to levodopa, its long-term use is limited by compliance and injection site skin reactions. The administration of levodopa/carbidopa by continuous duodenal infusion allows replacement of all oral medications and permits achievement of a satisfactory therapeutic response paralleled by a reduction in motor complication severity. However, compared with apomorphine, it is more invasive as it requires a percutaneous endoscopic gastrostomy. In this review we discuss the advantages and limitations of these procedures and how they compare to deep brain stimulation. We also address the issue of selection criteria and propose clinical characteristics of candidates to help the clinician choose the most suitable option for their patients.