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Parkinson's disease (PD) is a chronic progressive and irreversible disease and the second most common neurodegenerative disease worldwide. In Spain, it affects around 120.000-150.000 individuals, and its prevalence is estimated to increase in the future. PD has a great impact on patients' and caregivers' lives and also entails a substantial socioeconomic burden. The aim of the present study was to examine the current situation and the 10-year PD forecast for Spain in order to optimize and design future management strategies. This study was performed using the modified Delphi method to try to obtain a consensus among a panel of movement disorders experts. According to the panel, future PD management will improve diagnostic capacity and follow-up, it will include multidisciplinary teams, and innovative treatments will be developed. The expansion of new technologies and studies on biomarkers will have an impact on future PD management, leading to more accurate diagnoses, prognoses, and individualized therapies. However, the socio-economic impact of the disease will continue to be significant by 2030, especially for patients in advanced stages. This study highlighted the unmet needs in diagnosis and treatment and how crucial it is to establish recommendations for future diagnostic and therapeutic management of PD.

La safinamida es un nuevo fármaco para el tratamiento de pacientes con enfermedad de Parkinson (EP) con fluctuaciones como tratamiento complementario a levodopa. Dado que por el momento aún no existen estudios de fase IV postautorización debido a la reciente incorporación de la safinamida a la práctica clínica habitual, el interés de este proyecto radica en el desarrollo de una guía de manejo clínico de la safinamida basada en las opiniones de expertos de trastornos del movimiento. Este proyecto se desarrolló en 2 fases: una primera fase que constó de 16 reuniones locales y una segunda fase que consistió en una reunión nacional. Dichas reuniones siguieron un guion de trabajo preestablecido. Tras la reunión nacional se recopilaron las principales conclusiones de los expertos, que han supuesto la base para redactar la presente guía clínica. Se concluyó que la safinamida es eficaz en la reducción de las fluctuaciones motoras y no motoras. Los pacientes con EP con fluctuaciones leves-moderadas son los que más se benefician del tratamiento, si bien el fármaco puede contribuir a mejorar diversos problemas clínicos en pacientes con EP avanzada. Se ha destacado la posibilidad de reducir la dosis de otros fármacos dopaminérgicos tras la introducción de la safinamida, lo cual contribuiría a reducir efectos adversos como el trastorno de control de impulsos. Se hipotetizó sobre el posible efecto de la safinamida sobre la mejoría de las discinesias a dosis más altas de las habitualmente utilizadas. Se ha consensuado que la safinamida es bien tolerada y presenta un perfil de efectos adversos favorable frente a placebo. 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.

Background: Multimodal Neuro-Monitoring advances the treatment of patients through continuous monitoring of different parameters and generates high volumes of electronically available data [ref:1]. One possibility to analyze this “tsunami” of data is Visual Analytics (VA) which[for full text, please go to the a.m. URL], 64. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie e.V. (GMDS)

Open-label extensions [studies SP516 (NCT00501969) and SP715 (NCT00594386)] of the CLEOPATRA-PD and PREFER studies were conducted to evaluate the safety, tolerability and efficacy of the dopaminergic agonist, rotigotine, over several years of follow-up in patients with advanced Parkinson’s disease (PD). Eligible subjects completing the double-blind trials received open-label adjunctive rotigotine (≤16 mg/24 h) for up to 4 and 6 years in Studies SP516 and SP715, respectively. Safety and tolerability were assessed using adverse events, vital signs and laboratory parameters, and efficacy assessed using the unified Parkinson’s disease rating scale (UPDRS). Of the 395 and 258 patients enrolled in the SP516 and SP715 studies, 48 and 45 % completed, respectively. Adverse events were typically dopaminergic effects [e.g., somnolence (18–25 %/patient-year), insomnia (5–7 %/patient-year), dyskinesias (4–8 %/patient-year) and hallucinations (4–8 %/patient-year)], or related to the transdermal application of a patch (application site reactions: 14–15 %/patient-year). There were no clinically relevant changes in vital signs or laboratory parameters in either study. Mean UPDRS part II (activities of daily living) and part III (motor function) total scores improved from double-blind baseline during dose titration, then gradually declined over the maintenance period. In study SP516, mean UPDRS part II and III total scores were 0.8 points above and 2.8 points below double-blind baseline, respectively, at end of treatment. In study SP715, mean UPDRS part II and III total scores were 4.1 points above and 0.2 points below baseline, respectively, at end of treatment. In these open-label studies, adjunctive rotigotine was efficacious with an acceptable safety and tolerability profile in patients with advanced PD for up to 6 years.

Summary 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.

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.Following the EFNS instruction for the preparation of neurological diagnostic guidelines, recommendation levels have been generated for diagnostic criteria and investigations.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.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.

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.

Item does not contain fulltext 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. 19 p.

Two hundred and seventy-two patients with idiopathic blepharospasm were reviewed to establish the role of local eye disease in their illness. The majority of patients (57%) had symptoms at the onset of their illness such as dryness of the eyes, grittiness, irritation or photophobia suggesting eye lid or ocular surface disease. Detailed ophthalmological examination at the time of presentation had been carried out in 170 of the 272 cases; 64% of these patients had ocular symptoms, and 40% had demonstrable ocular surface or eye lid pathology. Such pathology was usually bilateral, chronic and resistant to local treatment. Blepharospasm developed in these patients after a long latent period, often of many years. Unilateral pathology was acute, normally responded well to local treatment, but was followed by the development of bilateral blepharospasm usually within six months. Amongst all 272 patients, those without ocular symptoms at presentation rarely developed them subsequently; if they did, there were no abnormal signs. The data suggest that ophthalmological disorders may trigger idiopathic blepharospasm in a substantial proportion of cases predisposed to develop this condition.

Critical Care Medicine is a relatively young and high-tech branch in modern medicine that combines clinical skills, powerful drugs and sophisticated mechanical devices to support the function of vital organs. This allows patients to survive a variety of previously lethal insults such asmultiple trauma, extensive surgery or severe infections. Despite this dedicated care, mortality among critically ill patients who require intensive care for more than a few days remains around 20% worldwide. Critical illness affects millions of patients each year worldwide, and consumesa large fraction of health care resources. It is therefore of great interest to detect those patients most vulnerable to specific organ deterioration as early as possible, in order to administer dedicated therapies earlier and hopefully prevent the chronic and lethal phases of critical illness. The typical ICU generates vast amounts of data from several monitoring systems for each patient. At the department of Intensive Care Medicine of the university hospital Leuven, this data is electronically collected as time series of varying resolutions and integrated in apatient data management system (PDMS). Using data mining and machine learning techniques, clinically relevant prediction models have already been developed from the PDMS data. It is now the time to transition early detection models into intelligent warning systems to be used for decision support by the physician, on the daily evaluation of the individual ICU patients. With the help of an interdisciplinary research team, I will conduct my PhD first by acquiring the knowledge and skills required to perform in-depth analysis of clinical and research databases collected at Leuven hospital ICU or gathered in international collaboration with other ICU's. Second, I will develop novel models for early detectionof organ-specific critical illness. Finally, the ultimate goal will be to translate these models into bedside tools to be used at the bedside of the ICU patient, and to validate them in a prospective observational clinical trial. status: published

Critically ill patients are patients who, due to a variety of triggering medical conditions, require vital organ support to avoid imminent death. Despite major progress in intensive care the patients still face a high mortality risk. Moreover, critical illness is hallmarked by features of accelerated aging where many patients experience an adverse legacy of the illness long after hospital discharge. This is mostly described for adults and includes muscle weakness, chronic renal failure despite resolution of acute renal damage, bone loss and fracture risk, neurocognitive impairment and post-traumatic stress disorders. Children, treated in the paediatric intensive care unit (PICU) during crucial developmental phases, show impaired long-term physical and neurocognitive/psychological development and reduced quality of life. The degree to which the developmental impairment was already present or predestined at PICU admission, how much of the legacy was evoked by critical illness and its management, and what the underlying biological mechanisms are, remained unclear. The main objective of this doctoral thesis was thus to gain more insight in the underlying biological processes and modifiable risk factors with regard to the long-term developmental deficit faced by critically ill children. We hypothesised that two intensive care-related interventions during PICU stay could potentially affect the long-term outcome of these critically ill children. These are the exposure to phthalates, which are toxic plasticisers shown to leach from indwelling medical devices, and the nutritional management early during the course of critical illness. We further hypothesised that this legacy of critical illness and its management could be brought about by damage-related changes in DNA methylation or by telomere length alterations. In a first part, we documented the impact of exposure to circulating phthalates during paediatric critical illness on long-term neurocognitive outcome of critically ill children. We demonstrated that plasma concentrations of several phthalate metabolites, which were virtually undetectable in healthy children, were extremely high in critically ill children upon PICU admission. They decreased rapidly, but remained markedly elevated at PICU discharge. Moreover, exposure to circulating phthalate metabolites was independently and robustly associated with the attention deficit observed years after PICU admission. These data underscore the importance to use, whenever possible, medical devices composed of alternative, safer plasticisers or with low phthalate release potential. In a second part, we focused on the nutritional management during PICU stay. Providing artificial nutritional support is thought to be of major importance in an intensive care setting, as the vast majority of critically ill patients are unable to eat normally, particularly while being mechanically ventilated. Observational data have associated malnutrition during critical illness with muscle wasting, weakness and delayed recovery. Consequently, many clinicians have assumed that artificial nutrition via the parenteral route is beneficial for patients' outcome. However, a large randomised controlled clinical study (the "PEPaNIC" trial) showed that withholding of such supplemental parenteral nutrition during the first week of paediatric intensive care reduced the incidence of new infections and accelerated recovery, allowing an earlier PICU discharge. Despite these beneficial short-term effects, concerns have been raised about long-term developmental consequences, possibly mediated by DNA methylation changes or telomere length alterations, of tolerating such a macronutrient deficit. Hence, assessment of the impact on long-term outcome of the children was crucial. In this second part we therefore documented the impact of critical illness and of early initiation of supplemental parenteral nutrition on telomere length alterations and DNA methylation changes during PICU stay, and on long-term health risks, and physical and neurocognitive outcome of PICU survivors. As accelerated telomere shortening could theoretically explain part of the legacy of paediatric critical illness, we quantified telomere length in repeated white blood cell DNA harvested in PICU from patients who were enrolled in the PEPaNIC-trial, as compared with healthy children who never needed intensive care. We found that shorter than normal leukocyte telomeres are present in critically ill children admitted to the PICU. Duration of stay in PICU and early initiation of parenteral nutrition further shortened telomeres, effects that were independent of other determinants and which could predispose these children to adverse long-term health sequelae. As DNA methylation is essential for diverse biological processes such as development and cognition, and nutrition may have a major impact on the epigenome, we investigated whether DNA methylation changes arise during the course of PICU stay and remain present until PICU discharge, and whether these could be affected by the nutritional management strategy in PICU. After adjusting for pre-admission DNA methylation changes and critical illness-induced changes in cell type composition, several genes of potentially high relevance to the long-term legacy of critical illness, such as genes involved in neuronal migration, differentiation and growth, brain development and signaling, processing of amyloid-beta precursor protein, transcriptional regulation, energy metabolism and multiple cellular signalling pathways, were found to be differentially methylated between patients upon PICU discharge and matched controls. Severity of illness and early initiation of parenteral nutrition, independent of its slowing effect on recovery, were found to be significantly associated with a large proportion of the aberrant DNA methylation changes that arose during PICU stay. In a last study, we investigated whether withholding parenteral nutrition during the first week in PICU, an intervention that clearly improved short-term PICU outcome, has an impact on long-term health risks and physical and neurocognitive development. Two years after inclusion in the PEPaNIC randomised controlled trial, we assessed health risks, and physical and neurocognitive development of 786 PICU-survivors who were randomly allocated to late or early initiation of parenteral nutrition in the PICU, in comparison with 405 matched healthy children. Late initiation of parenteral nutrition did not adversely affect survival, physical and neurocognitive development, but improved overall executive functioning, more specifically inhibition, working memory, and meta-cognition. Also externalising behavioural problems and visual-motor integration were improved. Moreover, we found that omitting supplemental parenteral nutrition early during PICU stay partially normalised the long-term neurocognitive legacy of paediatric critical illness. The protective effect of withholding parenteral nutrition was most pronounced in the youngest children. In conclusion, we demonstrated that exposure to phthalates leaching from indwelling plastic medical devices could induce an attention deficit in PICU survivors. Secondly, we showed that telomeres shortened and DNA methylation changes in genes important for neurocognitive development arose during PICU stay, partly explained by early initiation of parenteral nutrition. These changes may predispose critically ill children to adverse long-term health sequelae. Finally, we found that withholding parenteral nutrition during the first week in the PICU did not negatively affect survival, growth or health status 2 years later, and significantly improved several domains of neurocognitive development, hereby partially normalising the long-term neurocognitive legacy of paediatric critical illness. Hence, these data increase our understanding of the factors and the underlying biological processes that may contribute to the impaired development of critically ill children. They will hopefully lead to a change in legislation concerning the use of plasticisers in medical devices and to a change in clinical guidelines in favour of withholding early use of PN during paediatric critical illness, both in order to improve long-term developmental outcomes of millions of PICU survivors worldwide. status: published