Dopaminergic agonists in Parkinson's disease.

BACKGROUND: Non-ergoline dopamine agonists (DA) are effective treatments for Parkinson's disease (PD). This review presents the pharmacology, evidence of efficacy and safety profile of pramipexole, ropinirole, and rotigotine, and practical recommendations are given regarding their use in clinical practice. RESULTS: Extended-release formulations of pramipexole and ropinirole and transdermal continuous delivery rotigotine patches are currently available; these may contribute to stabilising of plasma levels. In early PD, the three drugs significantly improve disability scales, delay time to dyskinesia and allow a later introduction of levodopa. In late PD they reduced total 'off'-time, improved Unified Parkinson's Disease Rating Scale (UPDRS) in both 'on' and 'off' state and allowed a reduction in total levodopa dosage. A significant improvement in quality of life scales has also been demonstrated. Extended-release formulations have proved to be non-inferior to the immediate release formulations and are better tolerated (ropinirole). Despite a generally good safety profile, serious adverse events, such as impulse control disorder and sleep attacks, need to be routinely monitored. Although combination therapy has not been addressed in scientific literature, certain combinations, such as apomorphine and another DA, may be helpful. Switching from one DA to another is feasible and safe, although in the first days an overlap of dopaminergic side effects may occur. When treatment with DA is stopped abruptly, dopamine withdrawal syndrome may present. Suspending any DA, especially pramipexole, has been linked to onset of apathy, which may be severe. CONCLUSIONS: New non-ergotine DAs are a valuable option for the treatment of both early and late PD. Despite their good safety profile, serious adverse effects may appear; these effects may have a pathoplastic effect on the course of PD and need to be monitored.

Enfermedad de Parkinson avanzada. Características clínicas y tratamiento. Parte I I / Advanced Parkinson's disease: Clinical characteristics and treatment. Part II

Introducción. Muchos de los pacientes con enfermedad de Parkinson (EP) presentan al cabo de varios años fluctuaciones y discinesias graves que requieren de terapias algo más agresivas como la estimulación cerebral profunda del núcleo subtalámico o globo pálido medial, la infusión continua de apomorfina y la infusión intestinal continua de levodopa-carbidopa. Objetivo: Establecer las indicaciones y resultados de las 3 técnicas disponibles en la actualidad para el tratamiento de la EP avanzada. Desarrollo: Revisión exhaustiva de los datos publicados en la literatura sobre las indicaciones y resultados de la estimulación cerebral profunda del núcleo subtalámico, infusión subcutánea de apomorfina e infusión intestinal continua de levodopa-carbidopa en pacientes con EP avanzada. Conclusiones: Aunque existen numerosos estudios que han descrito la eficacia de cada una de estas 3 técnicas, faltan estudios comparativos que permitan definir el candidato ideal para cada una de las técnicas (AU)

Introduction: Many patients who have had Parkinson's disease (PD) for several years will present severe motor fluctuations and dyskinesias which require more aggressive therapies. The different approaches which are now available include deep brain stimulation of the subthalamic nucleus or medial globus allidus, subcutaneous infusion of apomorphine, and intestinal infusion of levodopa-carbidopa. Objective: To define the indications and results for the 3 available therapies for advanced PD. Development: Exhaustive review of the literature concerning the indications and results of deep brain stimulation, subcutaneous apomorphine infusion and duodenal infusion of levodopa/carbidopa gel to treat patients with advanced Parkinson disease. Conclusions: Although numerous studies have confirmed the efficacy of the 3 different therapies in advanced PD, there are no comparative studies that would allow us to define the best candidate for each technique (AU)

Enfermedad de Parkinson avanzada. Características clínicas y tratamiento (parte I) / Advanced Parkinson’s disease: Clinical characteristics and treatment (part 1)

Introducción: Un porcentaje importante de pacientes con enfermedad de Parkinson (EP) desarrollan complicaciones motoras en forma de fluctuaciones motoras, discinesias y síntomas no motores al cabo de 3-5 años del inicio del tratamiento que resultan de difícil control terapéutico. Esta fase de la enfermedad ha sido definida por algunos autores como fase avanzada de la EP. Objetivo: Definir las características clínicas y los factores de riesgo que condicionan que una EP evolucione a un estadio avanzado. Desarrollo: Este documento de consenso se ha realizado mediante una búsqueda bibliográfica exhaustiva y discusión de los contenidos llevadas a cabo por un grupo de expertos en trastornos del movimiento de la Sociedad Española de Neurología coordinados por dos de los autores (JK y MRL). Conclusiones: La presencia de fluctuaciones motoras y discinesias graves, síntomas motores axiales resistentes a la levodopa y síntomas no motores, como los trastornos cognitivos, representan las principales manifestaciones fenotípicas de una EP Avanzada (AU)

Introduction: A large percentage of patients with Parkinson’s disease (PD) develop motor fluctuations, dyskinesias, and severe non-motor symptoms within 3 to 5 years of starting dopaminergic therapy, and these motor complications are refractory to treatment. Several authors refer to this stage of the disease as advanced Parkinson’s disease. Objective: To define the clinical manifestations of advanced PD and the risk factors for reaching this stage of the disease. Development: This consensus document has been prepared by using an exhaustive literature search and by discussion of the contents by an expert group on movement disorders of the Sociedad Española de Neurología (Spanish Neurology Society), coordinated by two of the authors (JK and MRL). Conclusions: Severe motor fluctuations and dyskinesias, axial motor symptoms resistant to levodopa, and cognitive decline are the main signs in the clinical phenotype of advanced PD (AU)

Advanced Parkinson's disease: clinical characteristics and treatment. Part II.

INTRODUCTION: Many patients who have had Parkinson's disease (PD) for several years will present severe motor fluctuations and dyskinesias which require more aggressive therapies. The different approaches which are now available include deep brain stimulation of the subthalamic nucleus or medial globus pallidus, subcutaneous infusion of apomorphine, and intestinal infusion of levodopa-carbidopa. OBJECTIVE: To define the indications and results for the 3 available therapies for advanced PD. DEVELOPMENT: Exhaustive review of the literature concerning the indications and results of deep brain stimulation, subcutaneous apomorphine infusion and duodenal infusion of levodopa/carbidopa gel to treat patients with advanced Parkinson disease. CONCLUSIONS: Although numerous studies have confirmed the efficacy of the 3 different therapies in advanced PD, there are no comparative studies that would allow us to define the best candidate for each technique.

[Advanced Parkinson's disease: clinical characteristics and treatment (part 1)]. / Enfermedad de Parkinson avanzada. Características clínicas y tratamiento (parte I).

INTRODUCTION: A large percentage of patients with Parkinson's disease (PD) develop motor fluctuations, dyskinesias, and severe non-motor symptoms within 3 to 5 years of starting dopaminergic therapy, and these motor complications are refractory to treatment. Several authors refer to this stage of the disease as advanced Parkinson's disease. OBJECTIVE: To define the clinical manifestations of advanced PD and the risk factors for reaching this stage of the disease. DEVELOPMENT: This consensus document has been prepared by using an exhaustive literature search and by discussion of the contents by an expert group on movement disorders of the Sociedad Española de Neurología (Spanish Neurology Society), coordinated by two of the authors (JK and MRL). CONCLUSIONS: Severe motor fluctuations and dyskinesias, axial motor symptoms resistant to levodopa, and cognitive decline are the main signs in the clinical phenotype of advanced PD.

Efficacy and safety of pallidal stimulation in primary dystonia: results of the Spanish multicentric study.

BACKGROUND: Dystonia is a complex clinical syndrome originated by a wide range of aetiologies. The diagnosis of dystonia is made after the evaluation of aetiological, phenomenological and genetic factors. Medications, except in patients with dopa-responsive dystonia, are of limited efficacy. Botulinum toxin injections are not applicable to patients with generalised dystonia, since many muscular groups contribute to disability. Clinical studies in children and adults with primary generalised dystonia (PGD) have reported beneficial effects of bilateral GPi deep brain stimulation (DBS) in both motor symptoms and disability produced by dystonia as well as a favourable impact of DBS in the health-related quality of life (HRQoL). Some clinical aspects of GPi stimulation in primary dystonia still remain controversial such as the influence of disease duration or age at onset in determining the postoperative clinical outcome. RESULTS: The authors report the results of a multicentric study designed to assess the tolerability and clinical effects of bilateral pallidal DBS on motor impairment, functional disability, quality of life, pain and mood in patients with medically refractory primary generalised or segmental dystonia.

Calidad de vida en la enfermedad de Alzheimer / Quality of life in Alzheimer´s disease

Introducción. La calidad de vida es un concepto de creciente interés cuya evaluación complementa la valoración clínica tradicional, de interés fundamentalmente en ámbitos de organización de la asistencia. Presentamos un estudio de calidad de vida en la enfermedad de Alzheimer y su relación con medidas cognitivas y funcionales. Pacientes y métodos. Se evalúa la calidad de vida mediante la escala EQ-5D en una muestra de casos de enfermedad de Alzheimer diagnosticados con criterios del National Institute of Neurologic, Communicative Disorders and Stroke-Alzheimer’s Disease and Related Disorders Association que han donado muestra de sangre para el Banco Nacional de ADN, en los que se ha determinado también el estadio de la escala de deterioro global, y se ha efectuado un test de fluencia verbal y el test minimental de Folstein. Se realizó un análisis clásico, contraste de variables mediante chi al cuadrado para las proporciones y t de Student para las medias,y estimación de r para los modelos de regresión en las variables cuantitativas. Se determinó la tarifa social mediante el programa SPSS v. 11. Resultados. Se analizan 141 casos, con una relación de 2 a 1 entre mujer y varón, y una edad media de 76,2 años. Los aspectos de cuidado personal, actividad y, en menor medida, motilidad se ven afectados en la enfermedad de Alzheimer, pero no parecen hacerlo los aspectos de dolor y ansiedad. Existe relación entre calidad de vida, escalas funcionales y escalas cognitivas. Los aspectos funcionales se correlacionan mejor que los cognitivos con la calidad de vida. Conclusiones. La calidad de vida se evalúa en la enfermedad de Alzheimer mediante escalas generales, como EQ-5D. Los aspectos cognitivos no parecen aportar información relevante en relación con la calidad de vida que no se aporte ya por los aspectos funcionales (AU)

Introduction. Quality of life is a concept that is receiving increasing amounts of attention; its assessment complements the traditional clinical evaluation, which is of special interest in areas related with healthcare organisation. Here, we present a study on quality of life in Alzheimer’s disease and its relationship with cognitive and functional measures. Patients and methods. Quality of life was evaluated by means of the EQ-5D scale in a sample of cases of Alzheimer’s disease (diagnosed according to criteria established by the National Institute of Neurologic, Communicative Disorders and Stroke-Alzheimer’s Disease and Related Disorders Association) that donated blood samples for the National DNA Bank. The status of the global deterioration scale was determined and a verbal fluency test and the Folstein minimental test were also carried out. A classic analysis, variable contrast by means of chi-square for proportions and Student’s t test for measurements were conducted, as well as estimation of r for the regression models in the quantitative variables. The social rate was determined using the software application SPSS v. 11. Results. Altogether 141 cases were analysed, with a male to female ratio of 2:1, and a mean age of 76.2 years. Aspects such as personal hygiene, activity and, to a lesser extent, motility are affected in Alzheimer’s disease, but pain and anxiety aspects do not seem to be affected. There is a relationship between quality of life, functional scales and cognitive scales. Functional aspects correlate with quality of life better than cognitive ones. Conclusions. Quality of life is evaluated in Alzheimer’s disease using general scales, such as EQ-5D. Cognitive aspects do not appear to provide relevant information about quality of life that is not already provided by the functional aspects (AU)

[Quality of life in Alzheimer's disease]. / Calidad de vida en la enfermedad de Alzheimer.

INTRODUCTION: Quality of life is a concept that is receiving increasing amounts of attention; its assessment complements the traditional clinical evaluation, which is of special interest in areas related with healthcare organisation. Here, we present a study on quality of life in Alzheimer's disease and its relationship with cognitive and functional measures. PATIENTS AND METHODS: Quality of life was evaluated by means of the EQ-5D scale in a sample of cases of Alzheimer's disease (diagnosed according to criteria established by the National Institute of Neurologic, Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association) that donated blood samples for the National DNA Bank. The status of the global deterioration scale was determined and a verbal fluency test and the Folstein minimental test were also carried out. A classic analysis, variable contrast by means of chi-square for proportions and Student's t test for measurements were conducted, as well as estimation of r for the regression models in the quantitative variables. The social rate was determined using the software application SPSS v. 11. RESULTS: Altogether 141 cases were analysed, with a male to female ratio of 2:1, and a mean age of 76.2 years. Aspects such as personal hygiene, activity and, to a lesser extent, motility are affected in Alzheimer's disease, but pain and anxiety aspects do not seem to be affected. There is a relationship between quality of life, functional scales and cognitive scales. Functional aspects correlate with quality of life better than cognitive ones. CONCLUSIONS: Quality of life is evaluated in Alzheimer's disease using general scales, such as EQ-5D. Cognitive aspects do not appear to provide relevant information about quality of life that is not already provided by the functional aspects.

[Neuroprotection in Parkinson's disease: analysis though group of experts' methodology]. / Neuroprotección en la enfermedad de Parkinson: análisis a través de la metodología de informadores clave.

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.

[Diagnosis of vascular parkinsonism: correlation of the symptoms with neuroimaging and utility of SPECT with 123I-ioflupane]. / Diagnóstico del parkinsonismo vascular: correlación de la clínica con la neuroimagen y la utilidad de la SPECT con 123I-ioflupano.

INTRODUCTION: The concept of vascular parkinsonism (VP) has evolved since it was introduced by Critchley. The relationships between the clinical manifestations and neuroimagining of patients with VP to determine the utility of SPECT in its diagnosis have been established. MATERIAL AND METHODS: Retrospective study of patients with suspicion of VP according to Ziljmans 2004 criteria. RESULTS: A total of 22 patients were included. The most frequent risk factor was AHT. The most frequent manifestations were: bradykinesis, followed by gait disorder. Response to L-dopa was related with symptoms in lower limbs (p=0.014). The most frequent alterations on the magnetic resonance imaging were: atrophy with ventricular dilation followed by white matter lesions. The Hachinski scale was related with acute onset (p=0.022) and territorial infarction (p=0.039), and the Winikates with subcortical- paraventricular white matter lesions (p=0.036), and both with gender (male) (p=0.031), and stroke background (p=0.022). Alteration in gait was associated with paraventricular white matter lesions (p = 0.043), and other manifestations with lesions in the medulla (p=0,020). Tremor was associated with bilateral involvement of putamens in SPECT (p=0.039), strategic lesion with putamen involvement (p = 0.028) and lesions of periventricular white matter lesions with SPECT type 1 and 2 (p=0.045). There were no significant relationships of the SPECT with response to L-dopa or with the scales. Discussion. The different relationships between symptoms, scales and neuroimagin show the complexity of the subject and the need to use all of them in the diagnosis of VP.

Unique origin and low penetrance of the 946delGAG mutation in Valencian DYT1 families.

Mutations in the DYT1 gene cause idiopathic torsion dystonia (ITD) transmitted in families as an autosomal dominant trait with incomplete penetrance. The most common mutation, 946delGAG, has been observed in populations with different ethnic and geographic origins. We have investigated 40 individuals from 22 unrelated families with ITD originating from the Land of Valencia, Spain, for the presence of this mutation and we found 5 patients and 6 unaffected subjects from 4 families who were carriers of the mutation. This finding indicates that 18% of families may be diagnosed as DYT1 and that penetrance is reduced. We detected two different geographic and linguistic origins of the Valencian families. However, by haplotype analysis using D9S1260, D9S1261, D9S63 and D9S1262 as flanking markers, we demonstrated that all affected and unaffected carriers shared a common chromosome confirming identical origin of the mutation in the four families. We postulate a unique origin for the 946delGAG mutation in the Land of Valencia and, based on linguistic criterion, we propose that the mutation might have occurred at the beginning of the second millennium. Genetic analysis of another family from Castilla-La Mancha showed a different haplotype segregating with the disease, suggesting that at least two distinct mutational events for the 946delGAG mutation have occurred in Spain.

[Results of a program of presymptomatic diagnosis of Huntington's disease: evaluation of a 6 year period]. / Resultados de un programa de diagnóstico presintomático en la enfermedad de Huntington: evaluación de un período de 6 años.

OBJECTIVE: To know the uptake of predictive testing of Huntington's disease, the characteristics of the applicants, as well as the consequences for them. METHODS: Prospective observational study between January of 1994 and December of 1999 of the predictive testing applicants who entered in the protocol consisted of: informative interview, psychiatric interview, blood extraction for molecular study, as well as outcome and follow-up interviews. RESULTS: There were 87 applicants with a 50% risk. The mean age of the applicants was 28 years (SD = 7). Thirty one per cent already had children in the moment of predictive testing. The application rate according to the estimate population with 50% risk for the Comunidad Valenciana is 13,4%. The rate varies depending on the access to the information of the population in risk, being of 24,7% when they have direct access and of 8,3% when they do not have it (p < 0,01). Forty per cent did not come to the post-outcome visit, the positive or negative result for the mutation not influencing over it. Only 6,8% had some adverse event in the six years of follow-up all being slight. CONCLUSIONS: The application rate is determined by the access to the information of the population in risk. The fulfilment of the protocol designed for presymptomatic diagnosis of Huntington's disease keeps the adverse events presentation to a minimum.

Action hand dystonia after cortical parietal infarction.

A 46-year-old patient with a pure left cortical infarct affecting mainly the gyrus postcentralis developed action dystonia in the right hand. Mechanisms involved in the genesis of focal secondary dystonia are discussed with emphasis on abnormal cortical sensory processing.

[Descriptive study of a serie of patients affected by progressive supranuclear palsy]. / Análisis descriptivo de una serie de pacientes afectados de parálisis supranuclear progresiva.

INTRODUCTION: Progressive supranuclear palsy is a neurodegenerative disorder affecting diverse neurologic systems. The actual treatment response is poor in most patients. OBJECTIVE: review of a long series of patients affected by PSP in several aspects. PATIENTS AND METHODS: A series of patients was reviewed by means of the register questionnaire of PSP in Spain (from PSP Disabling Rating Scale and Staging System). This is carried out on the patients when the diagnostic is done. It was achieved a descriptive of the patients, in several aspects, and an evaluation of the treatment in relation to the dose and the duration. RESULTS: In general, the age of diagnostic is 66 years, there is not neurological illness in the family, falls and disorders of gait are the most representative parameters. The neuroimage shows fronto temporal atrophy. The treatment response is poor, despite the dose and the duration. CONCLUSIONS: Our series confirms the typical dates of the illness an the poor response to treatment with L Dopa.

Polyradiculoneuritis after botulinum toxin therapy for cervical dystonia.

A 40-year-old man with cervical dystonia developed an acute inflammatory demyelinating polyradiculoneuritis after botulinum toxin type A treatment. Some cases of idiopathic brachial plexopathy and polyradiculoneuritis have been reported to date. Although a causal relationship is not firmly established, the clinical temporal profile suggests a pathogenic relationship. In patients with cervical dystonia, further use of type A botulinum toxin should be considered contraindicated, and the use of another type of botulinum toxin should be taken into consideration.

[Entacapone: is it useful as complimentary treatment with levodopa?]. / Entacapona: es útil como tratamiento complementario a la levodopa?

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.

Drug-induced tardive syndromes.

We reviewed the database of five Movement Disorders Units to establish drugs responsible for tardive syndromes or TS (tardive dyskinesia, dystonia, akathisia, tremor, tics or tourettism, and myoclonus). The diagnostic criteria for TS included: (1) appearance of persistent dyskinesia, dystonia, akathisia, tremor, tics or tourettism, or myoclonus, related to prolonged drug exposure, (2) exclusion of other possible causes of these movement disorders. One-hundred patients fulfilled the diagnostic criteria for TS (26 males, 74 females, mean age 69.4+/-15.8 years). TS were related to 1, 2, 3, 4 and 5 drugs in 58, 27, 9, 5 and 1 patients, respectively. The most frequently offending drugs were antipsychotic drugs, substituted benzamides, thietylperazine and calcium-channel blockers. Seventy-two patients had buccolinguomasticatory syndrome, 30 had tremor, 22 akathisia and 16 dystonia (35 patients had a combination of at least two of these TS). Forty-two patients had coexistent parkinsonism. The TS disappeared following withdrawal of the offending drug in 40 cases. Old age and being female were more frequently associated with TS, with the exception of tardive dystonia. Substituted benzamides, calcium-channel blockers and thiethylperazine (a neuroleptic used for vertigo) were a frequent cause of TS in our series.

[Outpatient care of patients with Parkinson disease]. / Asistencia extrahospitalaria a pacientes con enfermedad de Parkinson.

INTRODUCTION: Some neurology clinics have been set up in specialist centres during the last ten years and their activities described. The group of patients with Parkinson's disease attended in the clinics of specialist centres have the distinguishing feature of where they are treated, which makes them different to other groups with the same disorder. OBJECTIVE: In this article we describe the general data of neurological attention for patients with Parkinson's disease, seen in two clinics belonging to specialist centres. PATIENTS AND METHODS: This article is based on records of patients made by neurologists of two structured centres in Hospital La Fe. RESULTS: In a period of 18 months 228 patients with Parkinson's disease were recorded out of a total case register of 5,101. Patients with Parkinson's disease made up between 4% and 5% of the patients attending the clinic. Between 30% and 50% of the patients seen in these clinics were evaluated only once during the period recorded. CONCLUSIONS: There seems to be a large number of cases recorded and these represent 70% of the estimated number of cases in the area. It seems that some patients do not keep in contact with the neurologist. Differences in function noted in clinics of specialist centres, between each other and compared with hospitals, are due to specific organizations and structures.