[Clinical experience in the treatment of motor fluctuations in Parkinson's disease. Delphi consensus of a group of experts in movement disorders]. / Experiencia clínica en el tratamiento de las fluctuaciones motoras en la enfermedad de Parkinson. Consenso Delphi de un grupo de expertos en trastornos del movimiento.

INTRODUCTION: Motor fluctuations are one of the most common complications of Parkinson's disease and their treatment is still a complex matter. Therefore, from the Neurology Movement Disorders Group we present our clinical experience in the treatment of these complications, with the intention of it being useful in decision-making in daily clinical practice. DEVELOPMENT: Nineteen questions were developed based on a literature review and an open survey answered by members of this group. These issues were discussed in two phases, using the Delphi methodology. Considering the results of the survey, levodopa dose adjustment and dopamine agonists are the option with the best efficacy/tolerability ratio in the treatment of motor fluctuations. Rotigotine is useful in the motor fluctuations associated with gastroparesis, and intermittent subcutaneous apomorphine has positive effects in patients with unpredictable off periods. The most relevant adverse effect associated with dopamine agonists is impulse control disorder. Catechol-O-methyltransferase inhibitors are useful in the initial stages of motor fluctuations, especially in wearing off. Monoamine oxidase inhibitors are generally drugs that are well-tolerated and useful in motor fluctuations. If these measures are not effective, second-line treatments should be indicated on a case-by-case basis. CONCLUSION: The clinical profile of patients with Parkinson's disease is paramount in deciding the most appropriate therapy for the treatment of motor fluctuations.

TITLE: Experiencia clínica en el tratamiento de las fluctuaciones motoras en la enfermedad de Parkinson. Consenso Delphi de un grupo de expertos en trastornos del movimiento.Introducción. Las fluctuaciones motoras son una de las complicaciones más frecuentes en la enfermedad de Parkinson y su tratamiento sigue siendo complejo. Por ello, desde el Grupo de Trastornos del Movimiento de la Asociación Madrileña de Neurología presentamos nuestra experiencia clínica en el tratamiento de estas complicaciones, con la intención de que sea de utilidad en la toma de decisiones en la práctica clínica diaria. Desarrollo. Se elaboraron 19 preguntas a partir de una revisión bibliográfica y una encuesta abierta respondida por los miembros de dicho grupo. Dichas cuestiones se debatieron en dos fases, utilizando la metodología Delphi. Considerando los resultados de la encuesta, el ajuste de la dosis de levodopa y los agonistas dopaminérgicos son la opción con mejor relación eficacia/tolerabilidad en el tratamiento de las fluctuaciones motoras. La rotigotina es útil en las fluctuaciones motoras asociadas a gastroparesia, y la apomorfina subcutánea intermitente, en pacientes con off impredecible. El efecto adverso más relevante asociado a los agonistas dopaminérgicos es el trastorno del control de impulsos. Los inhibidores de la catecol-O-metiltransferasa son útiles en las fluctuaciones motoras de inicio, especialmente en el wearing off. Los inhibidores de la monoaminooxidasa son fármacos, en general, bien tolerados y útiles en las fluctuaciones motoras. En caso de que estas medidas no resulten eficaces, se deben indicar terapias de segunda línea de manera individualizada. Conclusión. El perfil clínico del paciente con enfermedad de Parkinson es primordial para decidir la terapia más adecuada en el tratamiento de las fluctuaciones motoras.

[Myths and evidence on the use of botulinum toxin: neuropharmacology and dystonia]. / Mitos y evidencias en el empleo de la toxina botulinica: neurofarmacologia y distonias.

INTRODUCTION: Botulinum toxin type A (BTA) is a bacterial endotoxin, whose therapeutic use has had a dramatic impact on different neurological disorders, such as dystonia and spasticity. AIM: To analyze and summarize different questions about the use of BTA in our clinical practice. DEVELOPMENT: A group of experts in neurology developed a list of topics related with the use of BTA. Two groups were considered: neuropharmacology and dystonia. A literature search at PubMed, mainly for English language articles published up to June 2016 was performed. The manuscript was structured as a questionnaire that includes those questions that, according to the panel opinion, could generate more controversy or doubt. The initial draft was reviewed by the expert panel members to allow modifications, and after subsequent revisions for achieving the highest degree of consensus, the final text was then validated. Different questions about diverse aspects of neuropharmacology, such as mechanism of action, bioequivalence of the different preparations, immunogenicity, etc. were included. Regarding dystonia, the document included questions about methods of evaluation, cervical dystonia, blepharospasm, etc. CONCLUSION: This review does not pretend to be a guide, but rather a tool for continuous training of residents and specialists in neurology, about different specific areas of the management of BTA.

TITLE: Mitos y evidencias en el empleo de la toxina botulinica: neurofarmacologia y distonias.Introduccion. La toxina botulinica de tipo A (TBA) ha supuesto una verdadera revolucion terapeutica en neurologia, y en la actualidad es el tratamiento rutinario en las distonias focales y la espasticidad. Objetivo. Plantear, revisar y responder cuestiones controvertidas en relacion con la neurofarmacologia de la TBA y su uso en las distonias en la practica clinica habitual. Desarrollo. Un grupo de expertos en trastornos del movimiento reviso una lista de temas controvertidos relacionados con la farmacologia de la TBA y su uso en las distonias. Revisamos la bibliografia e incluimos articulos relevantes especialmente en ingles, pero tambien, si su importancia lo merece, en castellano y en frances, hasta junio de 2016. El documento se estructuro como un cuestionario que incluyo las preguntas que podrian generar mayor controversia o duda. El borrador inicial del documento fue revisado por los miembros del panel y se realizaron las modificaciones necesarias hasta alcanzar el mayor grado de consenso. Incluimos preguntas sobre diferentes aspectos de la neurofarmacologia, especialmente el mecanismo de accion, la bioequivalencia de los diferentes preparados y la inmunogenicidad. En relacion con el subapartado de las distonias, se incluyeron aspectos sobre la evaluacion y el tratamiento de las distonias focales. Conclusiones. Esta revision no pretende ser una guia, sino una herramienta practica destinada a neurologos y medicos internos residentes interesados en esta area, dentro de diferentes ambitos especificos del manejo de la TBA.

Cancer stem cell drugs target K-ras signaling in a stemness context.

Cancer stem cells (CSCs) are considered to be responsible for treatment relapse and have therefore become a major target in cancer research. Salinomycin is the most established CSC inhibitor. However, its primary mechanistic target is still unclear, impeding the discovery of compounds with similar anti-CSC activity. Here, we show that salinomycin very specifically interferes with the activity of K-ras4B, but not H-ras, by disrupting its nanoscale membrane organization. We found that caveolae negatively regulate the sensitivity to this drug. On the basis of this novel mechanistic insight, we defined a K-ras-associated and stem cell-derived gene expression signature that predicts the drug response of cancer cells to salinomycin. Consistent with therapy resistance of CSC, 8% of tumor samples in the TCGA-database displayed our signature and were associated with a significantly higher mortality. Using our K-ras-specific screening platform, we identified several new candidate CSC drugs. Two of these, ophiobolin A and conglobatin A, possessed a similar or higher potency than salinomycin. Finally, we established that the most potent compound, ophiobolin A, exerts its K-ras4B-specific activity through inactivation of calmodulin. Our data suggest that specific interference with the K-ras4B/calmodulin interaction selectively inhibits CSC.

Antidepressants in Parkinson's disease. Recommendations by the movement disorder study group of the Neurological Association of Madrid. / Antidepresivos en la enfermedad de Parkinson. Recomendaciones del grupo de trastornos del movimiento de la Asociación Madrileña de Neurología.

INTRODUCTION: Although antidepressants are widely used in Parkinson's disease (PD), few well-designed studies to support their efficacy have been conducted. DEVELOPMENT: These clinical guidelines are based on a review of the literature and the results of an AMN movement disorder study group survey. CONCLUSIONS: Evidence suggests that nortriptyline, venlafaxine, paroxetine, and citalopram may be useful in treating depression in PD, although studies on paroxetine and citalopram yield conflicting results. In clinical practice, however, selective serotonin reuptake inhibitors are usually considered the treatment of choice. Duloxetine may be an alternative to venlafaxine, although the evidence for this is less, and venlafaxine plus mirtazapine may be useful in drug-resistant cases. Furthermore, citalopram may be indicated for the treatment of anxiety, atomoxetine for hypersomnia, trazodone and mirtazapine for insomnia and psychosis, and bupropion for apathy. In general, antidepressants are well tolerated in PD. However, clinicians should consider the anticholinergic effect of tricyclic antidepressants, the impact of serotonin-norepinephrine reuptake inhibitors on blood pressure, the extrapyramidal effects of antidepressants, and any potential interactions between monoamine oxidase B inhibitors and other antidepressants.

Hemifacial spasm, vertebrobasilar dolichoectasia and neurofibromatosis type 1.

Hemifacial spasm (HFS) is usually produced by compression of the facial nerve by tortuous blood vessels at the root exit zone, including vertebrobasilar dolichoectasia (VBD). Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with a variety of symptoms, affecting mainly the skin and nervous system. Cerebrovascular abnormalities are becoming a recognized complication of the disease and the most constantly described lesions are stenosis and occlusions affecting the internal carotid artery. VBD has rarely been associated with NF1. We report a 38-year-old female patient with HFS produced by VBD with NF1 presenting with other cerebrovascular abnormalities associated with this disease. We discuss the possible association between these three entities, assuming that a causal relationship may be established and that VBD is part of the spectrum of vascular abnormalities caused by NF1 in this patient.

[Galantamine therapy in dementia associated with CADASIL]. / Tratamiento con galantamina en la demencia asociada a CADASIL.

INTRODUCTION: Cholinergic neuronal impairment has been suggested in cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencefalopathy (CADASIL). Cholinomimetic therapy could be useful. CASE REPORTS: Four patients with CADASIL and dementia were treated with the acetylcholinesterase inhibitor galantamine and we assessed cognitive, behavioral, functional and the caregiver burden aspects. Three patients showed either mild improvement or stabilization in the behavior and caregiver burden. CONCLUSION: Our results suggest some benefit from galantamine treatment and they could support the existence of a cholinergic deficit in CADASIL.

[Adult-onset subacute sclerosing panencephalitis: clinicopathological findings]. / Panencefalitis esclerosante subaguda de comienzo en la edad adulta: hallazgos clinicopatológicos.

INTRODUCTION: Subacute sclerosing panencephalitis is a disease affecting the central nervous system that is produced by persistent infection by a defective measles virus. This disease is very infrequent and its incidence has gone down even further in western countries since the introduction of generalised measles vaccinations. Onset of the disease is usually during infancy or adolescence. Reports of cases beginning during adulthood are scarce. CASE REPORT: We describe the case of a 30-year-old female with a slowly progressive subacute clinical picture consisting in behavioural disorders, with defrontalisation, cortico-subcortical cognitive impairment, long tract signs and visual disorders, which led the patient into a vegetative state. Four years after the onset of symptoms the patient died. The different electroencephalogram recordings performed did not show any periodic activity and magnetic resonance imaging of the head revealed cerebral atrophy with hyperintense lesions in T2 sequences in white matter. The histological study of the brain showed a chronic inflammatory infiltration with neuronal loss and demyelination, as well as intranuclear inclusions and neurofibrillary degeneration. CONCLUSIONS: The appearance of subacute sclerosing panencephalitis in adulthood is exceptional. Diagnosis requires a high degree of clinical suspicion, above all in the absence of typical symptoms, such as myoclonias or periodic complexes in EEG recordings.

[Anticoagulant treatment in hemorrhagic brains infarts due to large sinus venous thrombosis]. / Anticoagulación en infartos cerebrales hemorrágicos por extensa trombosis de senos venosos.

Cerebral venous and sinus thrombosis is an infrequent condition which presents with a wide spectrum of signs and a variable mode of onset. Sinus thrombosis may cause isolated intracranial hypertension but also may cause cerebral venous infarcts, which are frequently hemorrhagic. Treatment with antithrombotic agents is controversial because there is only one randomised controlled trial with unfractionated heparin. We report a 46- years-old man complaining of progressive headache, paraparesis and dysphasia. After admission, his neurological status worsened and he developed tetraparesis, depressed level of consciousness and seizures. A cranial computarized tomography (CT) scan showed multiple hyperdensities suggestive of hemorrhagic infarcts. Magnetic resonance imaging (MRI) study confirmed extensive cerebral venous thrombosis. Unfractionated heparin was administered for two weeks followed by acenocumarol. Within a few days his neurological status improved, and five weeks after admission the patient only hadd slight neurological deficit. After 11 years of follow-up, he has had a complete recovery. The G20210A mutation in the prothrombin gene was detected as a likely risk factor for venous thrombosis. Therapeutical and diagnosis aspects are discussed. We review the previous literature on the topic.

[CADASIL: a case with clinical, radiological, histological and genetic diagnoses]. / CADASIL: un caso con diagnóstico clínico, radiológico, histológico y genético.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare inherited cerebrovascular disease. The onset of clinical symptoms occurs with migraine with aura, transient ischemic attacks, recurrent subcortical ischemic infarcts, neuropsychiatric changes reaching subcortical dementia. Brain magnetic resonance images show multiple deep cerebral infarcts in white matter and basal ganglia and diffuse leukoencephalopathy. Neuropathologic hallmark consists of deposition of small electron dense granular patches related to the basement membrane of vascular smooth muscle cells with degeneration of smooth muscle cells and media and luminal obliteration. Recently, the genetic characteristics of this disorder have been reported. Missense mutations in notch3 gene localized in chromosome 19 are involved in its pathogenesis. Only three families from Spain have been reported. Here we describe a patient with typical clinical symptoms, neuroimaging and pathology of CADASIL. C406T (Arg110Cys) mutation in notch3 gene was found. We comment on the clinical symptoms of different members of the patient's family.

[Pharmaceutical care in people who have had acute coronary episodes (TOMCOR study)]. / Atención farmacéutica en personas que han sufrido episodios coronarios agudos (Estudio TOMCOR).

BACKGROUND: This study evaluates the effects on coronary patients of a new practice in community pharmacies called Pharmaceutical Care (PhC) as compared to the traditional pattern of pharmacy practice. It attempts to ascertain whether pharmaceutical care is feasible in addition to ascertaining differences in effectiveness for coronary patients' pharmacotherapeutic health outcomes, potentially attributable to PhC. METHODS: A randomized prospective controlled-intervention study was conducted in 83 community pharmacies in the provinces of Asturias, Barcelona, Madrid and Biscay in a one-year monitoring of the drug-use of 735 patients at the start of the study (330 intervention patients and 405 control) and 600 at the end. RESULTS: Differences were fund in favor of the intervention group in: a) the use of health care services as a morbidity indicator such as frequency of hospital emergency room visits 1.27 I (CI95%; 1.10-1.44) and 1.63 C (CI95%; 1.36-1.90) or average length-of-stay in Intensive Care Units 2.46 I (CI95%; 1.56-3.36) and 5.87 C (CI95%; 3.57-8.17), both due to coronary causes; b) health-related quality of life score (physical functioning dimension difference of 4.7 (p < 0.05); c) average patient knowledge of coronary heart disease risk factors having improved by 10% (p < 0002-0.007 depending on dimension); d) patient knowledge of the name and identification of their drugs having improved by 10% (p < 0.001) along with their subjective perception of the antiagregans drugs relative importance having improved by 12% (p < 0.009) and effects of beta-blockers having improved by 25% (p < 0.02); e) average satisfaction with pharmaceutical care service and perception of pharmacist's professional competence having improved by 2% (p < 0.000 to 0.05 depending on dimension). CONCLUSIONS: A decrease in emergency health care demand due to coronary causes, a fewer number of patient hospitalizations and a shorter length-of-stay in Coronary Intensive Care Units due to hospitalization regarding coronary patients on pharmaceutical care would suggest that patients who suffered an acute coronary heart episode made a better use of drugs and would tend to be less ill. Furthermore, coronary patients who received pharmaceutical care services showed a better knowledge of the reasons for their pharmacotherapy and therefore took better advantage of health care resources and improved their health condition.

Plexopatía braquial en variceladel adulto. Presentación de un caso / Brachial plexopathy in varicella of the adults. A case report

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Alternate-day dosing of aspirin in atrial fibrillation. LASAF Pilot Study Group.

BACKGROUND: In inhibiting platelet function, aspirin seems to reduce the risk of cerebrovascular accidents, death, and acute coronary events in patients with nonrheumatic atrial fibrillation. Aspirin given on alternate days might have the advantage of not hindering prostacyclin synthesis. Thus a study was performed to evaluate whether aspirin used in this way might improve the results reported with daily treatment. METHODS: To test this hypothesis 285 patients (age range 40 to 82 years) with primary atrial fibrillation were randomly allocated in an open multicenter trial to 3 groups: (1) group A1, treated with 125 mg aspirin daily (n = 104); (2) group A2, treated with 125 mg aspirin on alternate days (n = 90), (3) group C (controls), who were not treated with anticoagulants or platelet inhibitors (n = 91). RESULTS: Inclusion took place from January 1990 to July 1994, and follow-up ended in May 1996 (range 1 to 62 months). Sudden cardiac death in association with heart failure or angina was the most common final event: 4.8%, 1.1%, and 6.6% in groups A1, A2, and C, respectively. Both cardiovascular mortality rate and the incidence of main events were reduced, in relative terms, by 80% (1. 1% in group A2 vs 6.6% in group C). The differences were smaller between group A1 and C but did not reach statistical significance. The reduction of main cardiovascular events between groups A1 and A2 was statistically significant (7.7% vs 2.2% = 5.5%; 95% confidence limits 1%, 11%; P <.05). The difference did not reach statistical significance when other end points were analyzed. CONCLUSION: In this trial low-dose aspirin given on alternate days seemed to be an efficient intervention in preventing major cardiovascular events. Regarding strokes, however, aspirin was less efficient. Mortality rate in the 3 groups as a whole was associated with heart failure and the development of ischemic heart disease.

[The etiology and associated risk factors in a sample of 300 patients with atrial fibrillation]. / Estudio de la etiología y factores de riesgo asociados en una muestra de 300 pacientes con fibrilación auricular.

PURPOSE: To analyze the etiology and the prevalence of risk factors in patients with atrial fibrillation. PATIENTS AND METHODS: Applying an unpaired case controlled study, we examined 300 consecutive patients (143 men) with atrial fibrillation and a mean age of 66 +/- 8 years. This group is compared with a control group of 700 patients (mean age 64 +/- 12 years). RESULTS: In the group with atrial fibrillation the etiology in 32% was arterial hypertension, in 20% coronary heart disease, in 13% valvular heart disease, in 11% heart failure, in 4% hyperthyroidism and in 20% idiopathic. 50% presented hypertension, 29% tobaccoism, 26% left ventricular hypertrophy, 20% consumption of alcohol, 19% hypercholesterolemia and 16% diabetes. Compared with the control group, patients with atrial fibrillation had coronary heart disease (p < 0.05), VHD (p < 0.01), myocardiopathy (p < 0.05), HT (p < 0.001), left ventricular hypertrophy (p < 0.001), diabetes (p < 0.01) and alcohol consumption (p < 0.01) more frequently. In the multivariant analysis heart failure (odds ratio 2.1 [1.2-3.3]), the valvular heart disease (odds ratio 2.2 [1.4-3.5]), the coronary heart disease (odds ratio 1.8 [1.2-2.6]), the arterial hypertension (odds ratio 1.7 [1.2-2.3]), the left ventricular hypertrophy (odds ratio 2.6 [1.7-3.8]), the diabetes (odds ratio 1.9 [1.2-2.9]) and alcoholic habits (odds ratio 2 [1.3-3.9]) were independent risk factors for atrial fibrillation in our population. CONCLUSIONS: Atrial fibrillation in our study, is more frequent in patients with arterial hypertension, coronary heart disease or valvular heart disease. There are other risk factors such as arterial hypertension, diabetes and consumption of alcohol too, the modification of which could diminish the risk of the appearance of atrial fibrillation.

[Coronary spasm and heart arrest caused by ventricular fibrillation]. / Espasmo coronario y parada cardíaca por fibrilación ventricular.

We report the cases of three young men, heavy smokers, without previous heart disease and who were resuscitated after cardiac arrest due to ventricular fibrillation attributed to coronary spasm. All of them complained of atypical chest pain and the exercise testing, echocardiogram and coronary angiography were normal. The first case was diagnosed by Holter monitoring and by provocative testing with intracoronary ergonovine; the second by provocative testing with intracoronary acetylcholine and the third by Holter monitoring. The patients were treated with a calcium antagonist and/or nitrates and in the follow up they remained asymptomatic.

Plasma lipids, HDL and apolipoproteins, and coronary heart disease in men less than 50 years old. A case-control study.

OBJECTIVE: To determine the predictive value of lipoproteins for early coronary heart disease in men less than 50 years old from southern Europe. METHODS AND RESULTS: One hundred and fifty-seven men less than 50 years old were consecutively evaluated for symptoms of coronary heart disease in a tertiary referral hospital. A group of 415 male miners with mean age of 41 +/- 8 years without clinical or electrocardiographic evidence of coronary disease served as controls. Blood samples were taken by venipuncture as soon as possible after admission to the hospital from cases and after 12 hours of fasting in controls. Plasma concentrations of total cholesterol (TChol), HDL-cholesterol (HDLChol), triglycerides (TG), apoproteins A1 and B and Lp(a) were determined. The odds ratios, as estimators of relative risk, were computed using the Mantel-Haenszel procedure. The odds ratios from highest to lowest were a TChol/HDLChol ratio equal to or greater than 5: 10.7 (95% confidence interval (CI) 6.1 to 18.8), TG > 2.25 mmol.l-1 and HDLChol < 0.9 mmol.l-1: 7.4 (95% CI 3.9 to 14.1), HDLChol < 0.9 mmol.l-1: 6.9 (95% CI 4.5 to 10.6), TG > 2.25 mmol.l-1: 3.3 (95% CI 2.0 to 5.3), Lp(a) > 30 mg.dl-1: 2.7 (95% CI 1.8 to 4.1), Apo B > 120 mg.dl-1: 2.4 (95% CI 1.3 to 4.2), non-HDLChol > 5.2 mmol.l-1: 2.2 (CI 1.4 to 3.3), TChol > 6.5 mmol.l-1: 1 (95% CI 0.6 to 1.6), TChol > 5.2 mmol.l-1: 0.9 (95% CI 0.6 to 1.3). CONCLUSIONS: This study indicates that in males less than 50 years a ratio TChol/HDLChol > or = 5 presents the greatest risk power for early coronary heart disease. Plasma concentrations of TChol alone did not demonstrate to have value as risk factor for cardiovascular disease.