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Estimates of the spectrum and frequency of pathogenic variants in Parkinson's disease (PD) in different populations are currently limited and biased. Furthermore, although therapeutic modification of several genetic targets has reached the clinical trial stage, a major obstacle in conducting these trials is that PD patients are largely unaware of their genetic status and, therefore, cannot be recruited. Expanding the number of investigated PD-related genes and including genes related to disorders with overlapping clinical features in large, well-phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene-targeted clinical trials. The Rostock Parkinson's disease (ROPAD) study is an observational clinical study aiming to determine the frequency and spectrum of genetic variants contributing to PD in a large international cohort. We investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap in a group of 12 580 PD patients from 16 countries [62.3% male; 92.0% White; 27.0% positive family history (FH+), median age at onset (AAO) 59 years] using a next-generation sequencing panel. Altogether, in 1864 (14.8%) ROPAD participants (58.1% male; 91.0% White, 35.5% FH+, median AAO 55 years), a PD-relevant genetic test (PDGT) was positive based on GBA1 risk variants (10.4%) or pathogenic/likely pathogenic variants in LRRK2 (2.9%), PRKN (0.9%), SNCA (0.2%) or PINK1 (0.1%) or a combination of two genetic findings in two genes (∼0.2%). Of note, the adjusted positive PDGT fraction, i.e. the fraction of positive PDGTs per country weighted by the fraction of the population of the world that they represent, was 14.5%. Positive PDGTs were identified in 19.9% of patients with an AAO ≤ 50 years, in 19.5% of patients with FH+ and in 26.9% with an AAO ≤ 50 years and FH+. In comparison to the idiopathic PD group (6846 patients with benign variants), the positive PDGT group had a significantly lower AAO (4 years, P = 9 × 10-34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 × 10-35). Female patients were 22% more likely to have a positive PDGT (P = 3 × 10-4), and for individuals with FH+ this likelihood was 55% higher (P = 1 × 10-14). About 0.8% of the ROPAD participants had positive genetic testing findings in parkinsonism-, dystonia/dyskinesia- or dementia-related genes. In the emerging era of gene-targeted PD clinical trials, our finding that ∼15% of patients harbour potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. Thus, the insights from the ROPAD study allow for data-driven, differential genetic counselling across the spectrum of different AAOs and family histories and promote a possible policy change in the application of genetic testing as a routine part of patient evaluation and care in PD., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Idiopathic Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide. It affects the nervous system, causing motor and non-motor symptomatology. However, its clinical diagnosis remains dependent on the expertise of clinicians, as perceptual clinical scales are often used. Gait stability is one of the most relevant motor signs in PD. Nonetheless, it is usually not reported or quantified, possibly due to its unclear meaning and the high variability of metrics used in the literature. This work aims to identify a reliable and objective indicator that clinicians can use to assess patients in realistic contexts. We focused on the Largest Lyapunov Exponent (LLE), being the most common metric used in previous research works to quantify gait stability. The short and long-term LLEs were calculated in a group of 34 healthy and 42 participants diagnosed with PD. The long-term LLE extracted from the chest, right arm and right foot sensors showed statistical differences between subjects with PD and healthy control (HC) subjects, showing that the HC subjects are more stable than PD patients, whereas the short-term LLE showed the opposite results. Further investigation is required to clarify the reliability of this metric to detect and rate gait stability in people affected with PD.Clinical Relevance- This study is the first step towards the identification of an objective methodology to assess gait stability in clinical settings. Achieving this goal will contribute to improve the understanding and support the diagnosis of gait disorders that cause gait stability problems.

Safinamide is a new add-on drug to levodopa for the treatment of Parkinson's disease (PD) with motor fluctuations. Due to the recent incorporation of safinamide into routine clinical practice, no post-authorisation phase IV studies on the safety of safinamide have been conducted to date. This study provides clinical management guidelines for safinamide based on the opinion of a group of experts in movement disorders. This project was developed in 2 phases: 16 local meetings in phase 1 and a national meeting in phase 2. The meetings followed a pre-established agenda. The present clinical practice guidelines are based on the main conclusions reached during the national meeting. The group concluded that safinamide is effective in reducing motor and non-motor fluctuations. PD patients with mild-to-moderate fluctuations benefit most from treatment, although the drug may also improve the clinical status of patients with advanced PD. The dose of other dopaminergic drugs may be reduced after introducing safinamide, which would contribute to reducing such adverse reactions as impulse control disorder. At doses higher than those usually prescribed, safinamide may also improve dyskinesia. The experts agreed that safinamide is well tolerated and causes few adverse reactions when compared with placebo., (Copyright © 2020. Published by Elsevier España, S.L.U.)

Objectives: To compare the characteristics of patients undergoing treatment with continuous intestinal infusion of levodopa-carbidopa (CIILC) for advanced Parkinson's disease and the data on the effectiveness and safety of CIILC in the different autonomous communities (AC) of Spain., Methods: A retrospective, longitudinal, observational study was carried out into 177 patients from 11 CAs who underwent CIILC between January 2006 and December 2011. We analysed data on patients' clinical and demographic characteristics, variables related to effectiveness (changes in off time/on time with or without disabling dyskinesia; changes in Hoehn and Yahr scale and Unified Parkinson's Disease Rating Scale scores; non-motor symptoms; and Clinical Global Impression scale scores) and safety (adverse events), and the rate of CIILC discontinuation., Results: Significant differences were observed between CAs for several baseline variables: duration of disease progression prior to CIILC onset, off time (34.9-59.7%) and on time (2.6-48.0%; with or without disabling dyskinesia), Hoehn and Yahr score during on time, Unified Parkinson's Disease Rating Scale-III score during both on and off time, presence of≥ 4 motor symptoms, and CIILC dose. Significant differences were observed during follow-up (> 24 months in 9 of the 11 CAs studied) for the percentage of off time and on time without disabling dyskinesia, adverse events frequency, and Clinical Global Impression scores. The rate of CIILC discontinuation was between 20-40% in 9 CAs (78 and 80% in remaining 2 CAs)., Conclusions: This study reveals a marked variability between CAs in terms of patient selection and CIILC safety and effectiveness. These results may have been influenced by patients' baseline characteristics, the availability of multidisciplinary teams, and clinical experience., (Copyright © 2017 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.)

We analyzed the frequency of intermediate alleles (IAs) in the ATXN1, ATXN2, and HTT genes in several neurodegenerative diseases. The study included 1126 patients with Alzheimer's disease (AD), 440 patients with frontotemporal dementia (FTD), and 610 patients with Parkinson's disease. In all cohorts, we genotyped ATXN1 and ATXN2 CAG repeats. In addition, in the FTD cohort, we determined the number of HTT CAG repeats. The frequency of HTT IAs was higher in patients with FTD (6.9%) versus controls (2.9%) and in the C9orf72 expansion noncarriers (7.2%) versus controls (2.9%), although the difference was nonsignificant after correction for multiple testing. Compared with controls, progressive nonfluent aphasia (PNFA) groups showed a significantly higher frequency of HTT IAs (13.6% vs. 2.9% controls). For the ATXN2 gene, we observed an increase in IA frequency in AD cases (AD 4.1% vs. controls 1.8%) and in the behavioral FTD group (4.8% vs. 1.8%). For the ATXN1 gene, we found a significant increase of IAs in patients with PNFA (18.6%) versus controls (6.7%). In conclusion, our work suggests that the HTT and ATXN1 IAS may contribute to PNFA pathogenesis and point to a link between ATXN2 IAS and AD., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Levodopa-carbidopa intestinal gel (LCIG) is effective in the treatment of advanced Parkinson's disease (PD). However, the patients' profile that might benefit from treatment with LCIG has not been characterized., Objective: This retrospective study explored the influence of disease duration (DD) on the effectiveness of LCIG and identified factors associated with treatment discontinuation in a cohort of advanced PD patients., Methods: Patients initiating LCIG therapy between Jan-2006 and Dec-2011 in 18 Spanish centers were included. Effectiveness in treating motor symptoms (MSs), non-motor symptoms (NMSs), and adverse events (AEs) occurrence was compared in DD≥10 or <10 years and LCIG continuation/discontinuation groups. Factors associated with LCIG discontinuation were evaluated using univariate and multivariate analyses., Results: Overall, 177 PD patients were included (52.5% male; mean age 70.6±8.4 years; mean LCIG duration 35.6±18.6 months). Patients with DD≥10 years (n = 125) experienced less reduction in "off" time (-29%) than those with DD <10 years (-38%; n = 51; p = 0.021), and reported more severe AEs (32.8% vs. 17.6%; p = 0.043). DD did not significantly influence changes in NMSs or discontinuation rates. Fifty-four patients discontinued LCIG therapy, factors associated with discontinuation were higher percentages of waking day in the "off" state (OR, 1.028; 95% CI, 1.002-1.055; p = 0.0360) and in the "on" state with troublesome dyskinesia (OR, 1.032; 95% CI, 1.002-1.064; p = 0.0376) at baseline., Conclusions: Advanced PD patients with DD <10 years might benefit more from treatment with LCIG than patients with a longer DD. Although MSs severity at baseline was statistically associated with LCIG discontinuation, the probability was very low with little clinical significance.

«Apuntes en Neurologia» is an initiative in which prominent national and international leaders, with broad academic recognition, came together to synthesise the most outstanding clinical aspects within their area of interest and to discuss the latest developments in a more accessible language. Understanding the factors that affect the onset and progression of any neurological disease through a review is important to be able to develop strategies to reduce the burden of these diseases. Moreover, knowledge of the clinical aspects is essential to solve the problems of daily clinical practice. The data collected here reflect the weight of evidence and some of them anticipate a promising future in the treatment of these diseases. This first edition focuses on common paroxysmal neurological disorders such as migraine, epilepsy and sleep disorders, as well as neurodegenerative disorders such as Parkinson's disease and cognitive impairment. These are clearly different pathologies, although some of them such as migraine and epilepsy, may share clinical symptoms. Sleep disorders, however, are important manifestations of neurodegenerative diseases that are sometimes clinically apparent long before the onset of other neurological symptoms. After recalling pathophysiology and diagnosis, the current review focuses on bringing together the main advances in five of the major neurological diseases.

Inertial measurement units (IMUs) have a long-lasting popularity in a variety of industrial applications from navigation systems to guidance and robotics. Their use in clinical practice is now becoming more common, thanks to miniaturization and the ability to integrate on-board computational and decision-support features. IMU-based gait analysis is a paradigm of this evolving process, and in this study its use for the assessment of Parkinson's disease (PD) is comprehensively analyzed. Data coming from 25 individuals with different levels of PD symptoms severity and an equal number of age-matched healthy individuals were included into a set of 6 different machine learning (ML) techniques, processing 18 different configurations of gait parameters taken from 8 IMU sensors. Classification accuracy was calculated for each configuration and ML technique, adding two meta-classifiers based on the results obtained from all individual techniques through majority of voting, with two different weighting schemes. Average classification accuracy ranged between 63% and 80% among classifiers and increased up to 96% for one meta-classifier configuration. Configurations based on a statistical preselection process showed the highest average classification accuracy. When reducing the number of sensors, features based on the joint range of motion were more accurate than those based on spatio-temporal parameters. In particular, best results were obtained with the knee range of motion, calculated with four IMUs, placed bilaterally. The obtained findings provide data-driven evidence on which combination of sensor configurations and classification methods to be used during IMU-based gait analysis to grade the severity level of PD.

Background: The effect of subthalamic deep brain stimulation on balance in Parkinson's disease remains unclear., Objective: To evaluate the effect of subthalamic nucleus stimulation on balance in Parkinson's disease using posturography., Methods: 16 patients (9 women) who underwent subthalamic deep brain stimulation [mean age 59.6 years (46-70); mean disease duration 15.6 years (7-25); mean duration of subthalamic stimulation 32.1 months (3.0-69.6)] and 13 healthy age-matched controls were evaluated using a static posturography analysis. Patients were assessed under four conditions: 1) off medication/off stimulation; 2) off medication/on stimulation; 3) on medication/off stimulation and 4) on medication/on stimulation in ten experimental paradigms, some reproducing common situations of daily living. The displacement of the centre of pressure was analyzed using 14 posturographic parameters. The Mann-Whitney test was used to compare patients with controls. The Wilcoxon signed rank test was used to compare patients under different clinical conditions., Results: Patients off medication/off stimulation showed larger and more rapid displacements of the centre of pressure than controls in most paradigms (p<0.05), particularly when performing a dual task. Subthalamic stimulation alone reduced the lateral excursion and anterior-posterior velocity of the centre of pressure in quite stance paradigms (p<0.05). Subthalamic stimulation combined with antiparkinsonian medication did not induce statistically significant changes in posturagraphic measures in any experimental paradigm., Conclusions: Although subthalamic stimulation alone may induce some positive effect on balance, subthalamic stimulation in addition to antiparkinsonian medication, which is the usual treatment in clinical practice, did not modify balance as assessed by static posturography in patients with Parkinson's disease., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Aim: To assess long-term effectiveness and tolerability of levodopa-carbidopa intestinal gel (LCIG) in Spanish patients with advanced Parkinson's disease., Patients & Methods: This was an observational, multicenter, cross-sectional, retrospective study., Results: Data of 177 patients were analyzed. LCIG treatment led to a reduction in the percentage of daily 'off' time (16.2 vs 47.6% before LCIG), an increase in the percentage of daily 'on' time without disabling dyskinesia (55.6 vs 21.6%). Most patients experienced improvements in freezing of gait, tremor, dizziness, fatigue or flat mood. Adverse events related to levodopa, gastrostomy and technical issues were reported in 36.2, 42.4 and 43.5% of patients, respectively., Conclusion: This study confirms the long-term effectiveness and safety profile of LCIG in patients with advanced Parkinson's disease.

Subcutaneous infusion of apomorphine is a useful treatment for motor and nonmotor complications in Parkinson's disease patients and improves the patient's quality of life. An adequate selection of suitable candidates is crucial for obtaining the best results with this therapy. Parkinsonian patients with severe biphasic dyskinesias, demented or having experienced serious neuropsychiatric side effects with other dopamine agonists should not be offered this treatment. The therapeutic effect of continuous apomorphine infusion is reviewed and practical recommendations on its use are provided.

Background: A Task Force was convened by the EFNS/MDS-ES Scientist Panel on Parkinson's disease (PD) and other movement disorders to systemically review relevant publications on the diagnosis of PD., Methods: Following the EFNS instruction for the preparation of neurological diagnostic guidelines, recommendation levels have been generated for diagnostic criteria and investigations., Results: For the clinical diagnosis, we recommend the use of the Queen Square Brain Bank criteria (Level B). Genetic testing for specific mutations is recommended on an individual basis (Level B), taking into account specific features (i.e. family history and age of onset). We recommend olfactory testing to differentiate PD from other parkinsonian disorders including recessive forms (Level A). Screening for pre-motor PD with olfactory testing requires additional tests due to limited specificity. Drug challenge tests are not recommended for the diagnosis in de novo parkinsonian patients. There is an insufficient evidence to support their role in the differential diagnosis between PD and other parkinsonian syndromes. We recommend an assessment of cognition and a screening for REM sleep behaviour disorder, psychotic manifestations and severe depression in the initial evaluation of suspected PD cases (Level A). Transcranial sonography is recommended for the differentiation of PD from atypical and secondary parkinsonian disorders (Level A), for the early diagnosis of PD and in the detection of subjects at risk for PD (Level A), although the technique is so far not universally used and requires some expertise. Because specificity of TCS for the development of PD is limited, TCS should be used in conjunction with other screening tests. Conventional magnetic resonance imaging and diffusion-weighted imaging at 1.5 T are recommended as neuroimaging tools that can support a diagnosis of multiple system atrophy (MSA) or progressive supranuclear palsy versus PD on the basis of regional atrophy and signal change as well as diffusivity patterns (Level A). DaTscan SPECT is registered in Europe and the United States for the differential diagnosis between degenerative parkinsonisms and essential tremor (Level A). More specifically, DaTscan is indicated in the presence of significant diagnostic uncertainty such as parkinsonism associated with neuroleptic exposure and atypical tremor manifestations such as isolated unilateral postural tremor. Studies of [(123) I]MIBG/SPECT cardiac uptake may be used to identify patients with PD versus controls and MSA patients (Level A). All other SPECT imaging studies do not fulfil registration standards and cannot be recommended for routine clinical use. At the moment, no conclusion can be drawn as to diagnostic efficacy of autonomic function tests, neurophysiological tests and positron emission tomography imaging in PD., Conclusions: The diagnosis of PD is still largely based on the correct identification of its clinical features. Selected investigations (genetic, olfactory, and neuroimaging studies) have an ancillary role in confirming the diagnosis, and some of them could be possibly used in the near future to identify subjects in a pre-symptomatic phase of the disease., (© 2012 The Author(s) European Journal of Neurology © 2012 EFNS.)

Freezing of gait is an episodic gait disorder that may occur in patients with Parkinson's disease. The risk factors for this disorder are poorly understood. To determine the relevant risk factors for this condition, we screened 160 consecutive patients with Parkinson's disease for freezing of gait and assessed 36 potentially related variables. Freezers and non-freezers were compared using statistical univariate analysis, followed by bivariate and multivariate logistic regression, receiver operating characteristics curves and Kaplan-Meier estimates. Seventy-one patients (44.4%) reported freezing of gait. At onset, the mean disease duration was 8.1±6.3years. Freezers experienced falls more frequently than non-freezers (57.7% vs 23.6%, p<0.001). Disease duration was the independent variable most associated with freezing of gait (OR=1.10, 95% CI=1.01-1.19, p=0.020). Its specificity was 77%, but its sensitivity was low, and Hoehn and Yahr staging and the UPDRS (part III) score showed similar accuracy to that of disease duration in predicting freezers. Previous antiparkinsonian treatments and predominant motor signs (tremor/akinesia-rigidity subtypes) at the onset of Parkinson's disease were not related to freezing of gait. Patients who developed Parkinson's disease before the age of 60years experienced freezing of gait earlier than older patients (log-rank, p<0.005). Freezing of gait is a common and disabling motor complication of Parkinson's disease that is related to the progression of the disease. It is not primarily associated with dopamine replacement therapy and may occur early in young patients., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Dopamine dysregulation syndrome is a complication of the dopaminergic treatment for Parkinson's disease, probably related to sensitization of the mesolimbic dopamine system. The relationship between dopamine dysregulation syndrome and deep brain stimulation of the subthalamic nucleus remains unclear. We report three patients with Parkinson's disease who developed de novo dopamine dysregulation syndrome after deep brain stimulation of the subthalamic nucleus. We hypothesized that the combined effect of dopaminergic replacement therapy and deep brain stimulation on the limbic territory of the subthalamic nucleus could have precipitated the dopamine dysregulation syndrome in these patients, by inducing hyperstimulation of the mesolimbic dopamine system. The outcome of postoperative dopamine dysregulation syndrome is poor despite deep brain stimulation adjustments, attempts to reduce the dose of dopaminergic drugs and the addition of quetiapine or antidepressants., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objective: To study the possible relationship between central levodopa influx and short-term antiparkinsonian and dyskinetic responses to levodopa in patients with Parkinson disease., Methods: The clinical response to a single oral dose of standard and controlled-release levodopa/carbidopa was assessed in 12 patients with Parkinson disease complicated with motor fluctuations and dyskinesias. Plasma concentrations of levodopa and large neutral amino acids were determined, and the theoretical central levodopa influx was calculated using a model based on competitive inhibition of substrates to cross the blood-brain barrier., Results: The mean (SD) central levodopa influxes at the onset of the antiparkinsonian clinical effect were 19.7 (10.9 x 10(-3) and 19.1 (7.4 x 10(-3) nmol min(-1) g(-)1 (P >0.1) for standard and controlled-release levodopa, respectively. The mean (SD) central levodopa influxes at the onset of choreic dyskinesias were 20.1 (8.2 x 10 (-3) and 19.9 (10.8 x 10(-3) nmol min (-1) g(-)1 (P 9 0.1) for standard and controlled-release levodopa, respectively. During the tests, choreic dyskinesias were associated with a central levodopa influx of 10 x 10(-3) nmol min(-1) g(-1) or greater, and foot dystonia occurred with a central levodopa influx less than 9 x 10(-3) nmol min(-1) g(-1)., Conclusions: The clinical response to levodopa in patients with advanced Parkinson disease may be related to central levodopa influx. We found no differences in the central levodopa influx threshold for clinical improvement with different levodopa formulations. The central levodopa influxes at the onset of choreic dyskinesias and antiparkinsonian effect were similar. Choreic dyskinesias and foot dystonia were associated with high and low central levodopa influx, respectively.

Introduction: Currently used antiparkinsonian drugs neither stop nor slow-down the progressive nature of the disease. The final phase of PD is characterized by the presence of symptoms and signs resistant to dopaminergic agents, such as depression, dementia, freezing and falls. Therefore, it is urgent to develop therapies able to positively modify this outcome. Despite neuroprotection is a research priority in PD, no effective strategies have been found so far., Method: A key informants study was conducted. A group of experts in PD fulfilled a questionnaire of 10 questions to explore the most important topics related to neuroprotection. Afterwards a consensus about the current situation of neuroprotection in PD was established and future directions of development were suggested., Results: Most of the answers emphasized the need of new concepts, the limitations of animal models and the difficulties in the difficulties in demonstrating a neuroprotective effects in humans owing to a lack of biomarkers. Some of the experts believe that we are already exerting a disease modifying effect., Conclusions: The concept of neuroprotection should be widened. Animal models should be improved. A reliable biomarker to start neuroprotective therapies long before the appearance of motor symptoms and to evaluate the neuroprotective effect of any therapy should be urgently developed.

Unlabelled: A literature review was conducted to assess risk of cardiac valve regurgitation (CVR) associated with use of ergot-derived and non-ergot dopamine agonists (DAs) in patients with Parkinson's disease (PD)., Inclusion Criteria: case-control/observational studies of >10 patients with PD treated with DAs, including a control group and assessment of incidence/risk of CVR. Of the 166 publications identified, 14 met all inclusion criteria and included 1,750 patients. In 11 of the studies, a significant increase in CVR frequency of any severity (at the aortic, mitral or tricuspid valve) in the ergot group vs. the non-ergot or control group was described. No study reported increased risk of CVR for non-ergot DAs, compared with controls. In the studies identified in the literature, the use of ergot-derived DAs (pergolide and cabergoline) in patients with PD was associated with increased risk of CVR. Increased risk of CVR was not associated with the use of non-ergot DAs.

To evaluate the long-term effects of entacapone on both mean daily 'on' time and health-related quality of life (QoL) in patients with Parkinson's disease (PD) experiencing 'end-of-dose' motor fluctuations and the benefits of an early therapeutic intervention. A prospective, multicenter, observational, 12-month study was performed with an initial 3-month intervention phase, consisting of a phone call to half of the patients from randomly selected investigators to assess if dose adjustment was necessary. Effectiveness was determined by home diaries ('on' time), subscales II and III of the Unified Parkinson's Disease Rating Scale (UPDRS), and the Parkinson's Disease Questionnaire (PDQ-8). After 3 months of treatment, 4.0% of the intervention group patients discontinued the study, versus 18.4% in the control group (P < 0.01). The improvement in 'on' time was significantly increased since the 3-month visit (21%, P < 0.0001) until the end of the study (23% at 12 months, P < 0.0001). Entacapone also induced significant reductions in the UPDRS scores for subscales II and III and in the PDQ-8 score. 11.2% of patients experienced at least one adverse reaction. This study confirms the effectiveness of entacapone in reducing motor fluctuations by increasing 'on' time, and in improving QoL of PD patients. An early adjustment of entacapone and levodopa doses reduces the number of treatment discontinuations during the first months of treatment.

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.

A large number of patients with Parkinson's disease (PD) experience nocturnal problems that impair their sleep quality. Among them, motor disorders such as tremor, rigidity, akinesia, akathisia, periodic leg movements, painful dystonia, dyskinesias, restless legs syndrome, and rapid eye movement sleep behavior disorder are common. This article reviews the clinical characteristics of some nocturnal motor problems that often induce sleep disruption in PD patients.

Levodopa is the most effective symptomatic agent in the treatment of Parkinson's disease (PD) and the "gold standard" against which new agents must be compared. However, there remain two areas of controversy: (1) whether levodopa is toxic, and (2) whether levodopa directly causes motor complications. Levodopa is toxic to cultured dopamine neurons, and this may be a problem in PD where there is evidence of oxidative stress in the nigra. However, there is little firm evidence to suggest that levodopa is toxic in vivo or in PD. Clinical trials have not clarified this situation. Levodopa is also associated with motor complications. Increasing evidence suggests that they are related, at least in part, to the short half-life of the drug (and its potential to induce pulsatile stimulation of dopamine receptors) rather than to specific properties of the molecule. Treatment strategies that provide more continuous stimulation of dopamine receptors provide reduced motor complications in MPTP monkeys and PD patients. These studies raise the possibility that more continuous and physiological delivery of levodopa might reduce the risk of motor complications. Clinical trials to test this hypothesis are underway. We review current evidence relating to these areas of controversy.

To assess the patterns of drug use in Parkinson's disease in Spain, information about the clinical characteristics and current treatment of 1803 parkinsonian patients was obtained from a nationwide survey, involving 241 physicians with practice based on the different assistance levels of the Spanish National Healthcare System. Approximately 90% of the patients were treated with levodopa, regardless of the characteristics of their physicians, but the use of the other available antiparkinsonian treatments was highly influenced by the medical specialty and interest in movement disorders of the prescribing doctors., (Copyright 2002 Movement Disorder Society)

To identify putative risk factors for levodopa-induced dyskinesias we studied the effect of several clinical variables on the occurrence of dyskinesias in a series of 168 consecutive patients with Parkinson's disease treated for at least 6 months with levodopa. Of these, 108 (64%) developed dyskinesias after a mean duration of levodopa treatment of 51.4 +/- 43.3 months. Patients tended to suffer dyskinesias on the side of the body first affected by Parkinson's disease. The overall probability of developing dyskinesias increased with levodopa treatment duration, about 10% per year during the first 7 years. Univariate and multivariate logistic regression analysis identified the age at onset of Parkinson's disease (OR 0.923; 95% CI 0.883-0.964) and the initial levodopa dose (mean dose of the first 6 months of treatment; OR 1.004; 95% CI 1.002-1.006) as the main independent predictors. Survival curves showed that onset of Parkinson's disease at age 50 years or before (logrank, P < 0.05) and initial levodopa treatment with more than 600 mg/day (logrank, P < 0.05) were associated with a higher risk for the appearance of dyskinesias.

Background: Controlled-release levodopa-carbidopa (CRLC) improves some aspects of Parkinson's disease (PD) in patients previously treated with standard levodopa formulations (SL). However, little is known about the effect of this strategy on the health-related quality of life (QoL)., Objective: To assess the QoL and clinical changes due to the conversion of treatment from SL to CRLC in patients with mild to moderate PD., Patients and Methods: Through the Nottingham Health Profile (NHP), QoL was measured in 276 non-selected PD patients included in a multicenter, open study. Guidelines for switching to CRLC and optimization of treatment were given. Assessment of patients was carried out by means of the Hoehn & Yahr, UPDRS, and Schwab & England scales, and questionnaires for dyskinesias and sleep. Examination of the NHP-Spanish Version-scaling properties by fitting data to the Rasch model, disclosed that 3 NHP scales (Emotional reactions, Pain, and Physical mobility) and the NHP distress index (NHPD) were suitable for efficacy analysis., Results: Comparison of scores at baseline and at the end of the study showed significant improvement (paired Student t-test, p < 0.0001) in all these four scales associated with the change to CRLC. Responsiveness to change of the NHP was high. In the present study, changes in QoL were not contingent to baseline factors such as age, gender, stage of disease or ADL capabilities., Conclusion: Conversion to CRLC significantly improves the QoL of patients with mild to moderate PD.

Pramipexol is a novel nonergot dopamine agonist which has high selectivity for intereacting with dopamine D2 receptors (especially with D3 receptor subtype). It has been effective in early Parkinson's disease as monotherapy and as adjunctive therapy with L-dopa in advanced stages of the disease. Clinical improvement can be observed after 3 or 4 weeks of treatment. The adverse events profile of pramipexol is similar, in general, to that of other dopamine receptor agonists, although it can be foreseen that pramipexol should not induce side effects related to the ergot chemical structure such as eritromelalgia, distal vasospasm, retroperitoneal fibrosis or pleural effusions. Nevertheless, the potential advantages of this promising dopamine agonist should be tested in well-designed prospective comparative studies with other available ergot and nonergot dopamine agonists.

Entacapone (Comtan) is a potent, selective inhibitor of peripheral catechol-O-methyltransferase (COMT) with therapeutic potential as an adjuvant to levodopa therapy in patients with Parkinson's disease. Entacapone decreases peripheral conversion of levodopa to 3-O-methyldopa increasing central extracellular levodopa and consequently striatal dopamine concentrations. At doses of 200 mg 2 to 10 times daily coadministered with levodopa/carbidopa or levodopa/benserazide entacapone may increase the duration of clinical response both after the first single dose and after repeated dosing in patients with end-of-dose fluctuations. At this dosage, it has a time to peak-plasma concentration of 1.2 hours and an elimination half life of 3.4 hours. In two multicentric, long-term (approximately 6 month), randomized and placebo-controlled studies, the duration of 'on' time was increased and the duration of 'off time' was decreased in patients who received adjunctive entacapone therapy. Moreover, patients randomized to entacapone reduced their levodopa requirements. In these and other phase III studies, entacapone was generally well tolerated, with few reported adverse events, mainly dyskinesias and gastrointestinal disorders. The dyskinesias were generally well controlled by decreasing the mean daily levodopa dose. Entacapone appears as a clinically significant and beneficial adjunct to levodopa therapy in Parkinson's disease patients with end-of-dose fluctuations.

We present the results of an open, prospective, multicentric study including 450 patients with mild to moderate Parkinson's disease (PD) converted from standard Sinemet to Sinemet CR (controlled release; Dupont Pharma, Pavia, Italy). Patients with complex fluctuations and diphasic dyskinesias were excluded and the conversion was made after some recommendations, depending on the clinical problems and the daily dosage and administration schedule of standard (STD) Sinemet. The condition of more than 60% of the patients improved after the change and 80% of them preferred the CR formulation by the end of the study. We found a moderate, but significant, improvement in most of the efficacy parameters used, such as the Unified Parkinson's Disease Rating Scale (UPDRS), the Schawb and England scale, and dyskinesias and sleep questionnaires. Forty-five patients (10%) discontinued the study due to adverse effects (mainly gastrointestinal disturbances, functional deterioration, and dyskinesias). We conclude that Sinemet CR is a useful and safe therapeutic option in patients with mild and moderate PD. Selection of the patients is the most important outcome factor.

Conversion from standard levodopa to Sinemet CR was performed in a series of 450 patients with Parkinson's disease. Of these, 299 experienced motor complications (group A) and 151 showed stable motor response (group B). There was significant improvement in various parameters of efficacy (Unified Parkinson's Disease Rating Scale, Hoehn-Yahr staging, Schwab-England scale) particularly in those related to functional aspects such as activities of daily living of the Unified Parkinson's Disease Rating Scale, sleep questionnaires and the Nottingham Health Profile. Adverse effects were usually mild or moderate, and only 10% of patients discontinued Sinemet CR due to side effects. Sinemet CR treatment was preferred by 81% of patients in group A and by 73.8% of patients in group B.

More effective measures to control and replace the dopaminergic deficit of Parkinson's disease are being actively sought. One basic problem is how the striatal dopamine loss should be replaced in order to mimic most accurately the physiological state. Animal electrophysiology indicates that the dopaminergic nigrostriatal pathway has a dual tonic and phasic action. Intermittent dopaminergic stimulation is associated with behavioural hyposensitivity both in animal models and in patients with Parkinson's disease. Continuous dopaminergic stimulation provides a tonic background and improves some clinical problems but is also associated with tolerance. None of the available pharmacological approaches can restore the dopamine deficiency of Parkinson's disease to physiological levels. Continuous dopaminergic stimulation for < 24 h, associated with small doses of levodopa or a short-acting dopamine agonist, appears to be the best, albeit imperfect, therapeutic approach until other, more efficacious remedies are developed.

Behavioral hyposensitivity to repeated apomorphine administration occurs in fluctuating parkinsonian patients. To determine to what extent the interval between doses influences the response, we administered equal paired apomorphine injections to 10 fluctuating parkinsonian patients. Subjects received two apomorphine injections at 2-hour and at 4-hour intervals on different days after a 10- to 12-hour overnight period without levodopa. Following apomorphine doses at 2-hour intervals, the duration of response was reduced by 40% (61 versus 42 minutes, p less than 0.001) but was of equal duration when the doses were given at 4-hour intervals. These findings indicate that the interval between doses is a critical determinant of motor response. We postulate a time-dependent period of partial hyposensitivity to pulsatile DA stimulation.

We studied the histories of 173 patients with Parkinson's disease (1985-1987) chronically treated with levodopa + dopa decarboxylase inhibitor. Ninety four patients had daily motor fluctuations and 79 showed stable motor response. The most significant differences between fluctuating and stable patients were given by age at disease onset and duration of levodopa therapy. Patient with disease onset before 60 had a greater risk (p less than 0.001) of developing fluctuations. Delaying the initiation of levodopa treatment was not associated with a smaller incidence of fluctuations.

Behavioral hyposensitivity to repeated apomorphine administration has been observed in fluctuating parkinsonian patients. To investigate whether a similar phenomenon occurs in patients never treated with levodopa, we studied the response to apomorphine in 20 de novo patients with Parkinson's disease. Six patients showed no or minimal improvement after apomorphine injections (maximal dose 3.5 mg). Fourteen patients responded and were then given up to four repeated subcutaneous injections of apomorphine [minimal effective dose (MED)]. The responses of de novo patients were compared with responses in 10 patients with motor fluctuations previously studied by the same protocol. There was no significant difference in latency and duration of motor responses after repeated apomorphine injections in de novo patients. MED was similar in de novo and fluctuating patients, but duration of improvement induced by each apomorphine bolus was longer in the de novo group. These results indicate that response duration to apomorphine is longer in previously untreated patients and that behavioral tolerance associated with pulsatile dopaminergic stimulation by apomorphine occurs mainly in patients with more advanced disease under chronic levodopa therapy.

Recent studies giving subcutaneous apomorphine or intravenous levodopa boluses have not found clear evidence of behavioral hyposensitivity to repeated dopaminergic stimulation in Parkinson's disease (PD). Here we analyze that data, and review experimental findings in animal models and our previous experience with parkinsonian patients. We conclude that acute tolerance to pulsatile stimulation is likely to play a role in the pathophysiology of motor fluctuations in PD.

Ten patients with Parkinson's disease (PD) with motor fluctuations under levodopa treatment were given repeated equal subcutaneous injections of apomorphine [minimal effective dose (MED)] in 1 day. The MED was defined as the dose of apomorphine necessary to induce at least 60% reduction of motor disability for a minimum period of 10 min. MED was found for each patient in previous study days. In eight a subcutaneous infusion of apomorphine was performed on a different day. Four patients with simple fluctuations ("wearing off") showed a progressive reduction of the motor response to apomorphine injections, but three of the four had a stable response (continuous "on") to apomorphine infusion. Six patients with complicated fluctuations also exhibited a decreasing response to successive apomorphine injections and often completely failed to respond to some of the boluses. The response to a subcutaneous infusion of apomorphine was unstable in three of four cases. These findings indicate that a reduction of striatal dopaminergic receptor sensitivity is associated with repeated "pulsatile" apomorphine administration in parkinsonian patients with oscillations of motor performance. It is suggested that altered regulation of dopaminergic receptor sensitivity following pulsatile stimulation with levodopa may be a relevant phenomenon in the pathogenesis of motor fluctuations in PD.

Complex motor fluctuations and dyskinesias ("on-off" phenomenon) in Parkinson's disease can be corrected by parenteral administration of levodopa, levodopa-methyl-ester, lisuride and apomorphine. Levodopa and levodopa-methyl-ester may only be administered intravenously because of their low solubility. Lisuride and apomorphine are readily absorbed after subcutaneous administration. Repeated or continuous intravenous infusions of levodopa have been given for a few days, using a wearable "jacket-like" pump, with good results. So far, lisuride is the only dopamine agonist used for chronic treatment by continuous infusion. The "on-off" effect is adequately controlled in most patients by subcutaneous lisuride administration (plus oral levodopa). However, adverse effects, particularly psychiatric complications, constitute a major limiting factor for routine applications of this form of treatment. Subcutaneous apomorphine infusion is unlikely to become a standard therapeutic procedure in Parkinson's disease, but it is a very valuable research method to gain further insight into the pathophysiology of motor fluctuations in Parkinson's disease.

Fluctuations and dyskinesias are the 2 main motor complications associated with chronic levodopa therapy. Striatal denervation following degeneration of the substantia nigra dopaminergic projections is probably the major pathophysiologic mechanism underlying motor fluctuations. In addition, pathologic modification of striatal receptors, partially related to the nonphysiologic delivery of levodopa in a discontinuous pulsatile mode, may be responsible for the various types of dyskinesias and sudden "off" episodes. Drugs capable of providing a stable dopaminergic stimulation should be particularly useful for preventing the development of motor complications in patients not yet treated. At the other end of the clinical spectrum, patients with complex fluctuations are the least likely to improve with slow-release levodopa preparations.