Alemtuzumab treatment in real clinical practice: Experience in a multicenter cohort.

BACKGROUND: Alemtuzumab is a highly effective treatment for relapsing remitting multiple sclerosis (RRMS), but in recent years safety-related concerns had emerged due to description of novel serious side effects not registered in CARE-MS I and CARE-MS II phase 3 studies, nor in TOPAZ extension study. Data about alemtuzumab use in real clinical practice are limited and based mainly on retrospective studies with small sample sizes. Therefore, more information about effectiveness and safety of alemtuzumab in this context is needed. METHODS: A multicenter observational prospective study to investigate effectivity and safety of alemtuzumab in a real-world setting was performed. Primary endpoints were the change in annualized relapse rate (ARR), and in disability measured by EDSS score. Secondary endpoints were the cumulative probability of confirmed 6-month disability improvement and worsening. Disability worsening and disability improvement were considered when the EDSS score was increased or decreased, respectively, in 1 point if baseline EDSS score was <5.0, or in 0.5 point if baseline EDSS score was ≥5.5, confirmed over 6 months. Other secondary endpoint was the proportion of patients who achieved NEDA-3 status (absence of clinical relapses, disability EDSS progression, and MRI disease activity as depicted by new/enlarging T2 lesions or Gadolinium enhancing T1 lesions). Adverse events also were recorded. RESULTS: A total of 195 RRMS patients (70% female) who started alemtuzumab treatment were included. Mean of follow-up was 2.38 years. Alemtuzumab significantly reduced the annualized relapse rate from baseline with risk reductions of 86%, 83.5%, and 84%, at 12, 24, and 36 months of follow-up respectively (Friedman test, p-value < 0.05 for all comparisons). Alemtuzumab also significantly reduced EDSS score over one and two years after starting alemtuzumab treatment (Friedman test, p-value<0.001 for both comparisons). A high proportion of patients presented confirmed 6-month stability or disability improvement (92%, 82%, and 79%, over 1, 2 and 3 years of follow-up respectively). The proportion of patients who retained NEDA-3 status at 12, 24 and 36 months were 61%, 49%, and 42%, respectively. Baseline characteristics associated with a lower probability of achieving NEDA-3 were younger age, sex female, high ARR, elevated number of previous treatments, and switch from a second line therapy. Infusion related reactions were the most frequent adverse event observed. The most common infections were urinary tract infections (50%), and upper respiratory tract infections (19%) over the 3 years of follow- up. Secondary thyroid autoimmunity was developed in 18.5% of patients. CONCLUSION: Alemtuzumab has demonstrated in real clinical practice high effectiveness in controlling multiple sclerosis activity, and no unexpected adverse events were observed.

[Fingolimod: effectiveness and safety in routine clinical practice. An observational, retrospective, multi-centre study in Galicia]. / Fingolimod: efectividad y seguridad en la practica clinica habitual. Estudio observacional, retrospectivo y multicentrico en Galicia.

INTRODUCTION: The effectiveness and safety of fingolimod in patients with relapsing-remitting multiple sclerosis (RRMS) have been proven in clinical trials. Yet, due to their limitations, it is important to know how it behaves under everyday clinical practice conditions. Hence, the aim of this study is to evaluate the effectiveness and safety of fingolimod after 12 months' usage in clinical practice in Galicia. PATIENTS AND METHODS: We conducted a retrospective, multi-centre study (n = 8) of patients with RRMS who were treated with one or more doses of fingolimod, 0.5 mg/day. Effectiveness was assessed -annualised relapse rate (ARR), changes in the score on the Expanded Disability Status Scale (EDSS), percentage of patients free from relapses, free from progression of disability and free from activity in resonance- for the total number of patients and according to previous treatment. Safety was assessed based on the percentage of patients who withdrew and presented adverse side effects. RESULTS: After 12 months' use, fingolimod reduced the ARR by 87% (1.7 to 0.23; p < 0.0001) and, consequently, 81% of patients were free from relapses. The score was reduced by 9%. In all, 91% of patients were free from progression of disability and 72% were free from resonance activity. No signs of disease activity were found in 43% of the patients. Most of the benefits of fingolimod differed depending on previous treatment. About a third of the patients reported adverse side effects, but only 2% of them withdrew for this reason. CONCLUSIONS: In clinical practice, most of the results on the effectiveness of the clinical trials conducted with fingolimod were observed during the first 12 months of treatment. A better safety profile was observed than that reported in the clinical trials.

TITLE: Fingolimod: efectividad y seguridad en la practica clinica habitual. Estudio observacional, retrospectivo y multicentrico en Galicia.Introduccion. La efectividad y seguridad del fingolimod en pacientes con esclerosis multiple remitente recurrente (EMRR) se demostro en ensayos clinicos. Sin embargo, por las limitaciones de estos, es importante saber como se comporta en condiciones de practica clinica habitual. Asi, el objetivo de este estudio es evaluar la efectividad y seguridad del fingolimod despues de 12 meses de uso en la practica clinica en Galicia. Pacientes y metodos. Estudio retrospectivo y multicentrico (n = 8) de pacientes con EMRR y tratados con una o mas dosis de fingolimod, 0,5 mg/dia. Se evaluo la efectividad ­tasa anualizada de brotes (TAB), cambio en la puntuacion de la escala expandida del estado de discapacidad (EDSS), porcentaje de pacientes libres de brotes, libres de progresion de discapacidad y libres de actividad en resonancia­ para el total de pacientes y segun tratamiento previo. Se evaluo la seguridad a partir del porcentaje de pacientes que discontinuaron y que presentaron efectos adversos. Resultados. Despues de 12 meses de uso, el fingolimod redujo un 87% la TAB (de 1,7 a 0,23; p < 0,0001) y, en consecuencia, un 81% de pacientes estuvo libre de brotes. La puntuacion de la EDSS disminuyo un 9%. Un 91% de pacientes estuvo libre de progresion de discapacidad y un 72%, libre de actividad en resonancia. En el 43% de los pacientes no se evidenciaron signos de la actividad de la enfermedad. La mayoria de los beneficios del fingolimod difirieron segun el tratamiento previo. Alrededor de un tercio de los pacientes comunicaron efectos adversos, pero solo el 2% discontinuo debido a ellos. Conclusiones. La mayoria de los resultados de efectividad de los ensayos clinicos del fingolimod se observa durante los 12 primeros meses de tratamiento en la practica clinica. Se observo un mejor perfil de seguridad al comunicado en los ensayos clinicos.

Bases anatómicas, fisiopatológicas y neuroquímicas de los síndromes rígido-acinéticos / Anatomical, pathophysiological and neurochemical bases of rigid-akinetic syndrome

Introducción. Los síndromes rígido-acinéticos incluyen un grupo heterogéneo de patologías agrupados por una serie de síntomas comunes en las esferas motora, cognitiva y emocional. Desarrollo. Los ganglios basales están constituidos por un grupo de estructuras anatómicamente dispersas que se conectan entre sí y con diversas estructuras formando un entramado de redes funcionales. Las lesiones en estos circuitos producen síntomas en las esferas motora, cognitiva y emocional. En la enfermedad de Parkinson, el síndrome rígido-acinético más conocido y estudiado, actualmente sólo pueden explicarse del conjunto de sus síntomas el temblor y la bradicinesia. Los síndromes rígido-acinéticos se consideran hoy enfermedades neurodegenerativas que afectan a múltiples estructuras y sistemas del sistema nervioso central y periférico. Una gran parte de estos pueden agruparse dentro de las sinucleinopatías y las taupatías, aunque en ocasiones los hallazgos anatomopatológicos entre ambas se solapan. Conclusiones. Es preciso un mayor conocimiento del funcionamiento del sistema nervioso y los procesos de degeneración neuronal para poder obtener nuevas estrategias terapéuticas más eficaces (AU)

Introduction. The rigid-akinetic syndromes include a heterogeneous collection of pathologies grouped by a series of common symptoms that appear in the motor, cognitive and emotional spheres. Development. The basal ganglia are made up of a group of anatomically dispersed structures that are nonetheless connected to each other and with several other structures to form a cluster of functional networks. Lesions in these circuits produce symptoms in the motor, cognitive and emotional spheres. Of all the syndromes that occur in Parkinson's disease, which is the best-known and most widely studied rigid-akinetic syndrome, only tremor and bradykinesia can presently be explained. Rigid-akinetic syndromes are nowadays considered to be neurodegenerative diseases that affect a number of structures and systems within the central and peripheral nervous system. Many of these can be included within the groups of synucleinopathies and tauopathies, although on occasions the pathological findings overlap between the two. Conclusions. Further knowledge of the functioning of the nervous system and the processes involved in neuronal degeneration is needed to be able to produce new, more effective therapeutic strategies (AU)

[Disorders affecting the emotional sphere and impulse control in Parkinson's disease]. / Alteraciones de la esfera emocional y el control de los impulsos en la enfermedad de Parkinson.

INTRODUCTION: Parkinson's disease (PD) is associated with mood and behavioral symptoms contributing to morbidity and reduced quality of life of the patients. Most characteristic are depression, anxiety and impulse control disorder. DEVELOPMENT: Identification and treatment of neuropsychiatric symptoms is necessary for an appropriate management of PD. Affective symptoms may be the initial manifestation of PD, are highly prevalent and pathogenically complex. Impulse control disorders are usually not a spontaneous complaint, so asking about these symptoms may be the only way to detect and treat a serious socio-familial problem. Pharmacological treatment of these manifestations is difficult to balance with an adequate control of motor symptoms. Psychological support from early stages and throughout the evolution of PD is fundamental. CONCLUSIONS: Neurologist and other healthcare professionals treating PD patients need to be aware of behavioral and emotional manifestations of the disease. This will lead to an appropriate patient management and better adaptation of the familial and social situation.

Ictus isquémico y cefalea sexual / Ischaemic stroke and sexual headache

No disponible

Síndrome de Guillain-Barré que complica una infección del tracto urinario por Escherichia coli / Guillain-Barré syndrome complicating a urinary tract infection due to Escherichia coli

No disponible

No disponible

[Endovascular treatment of carotid disease in patients at high surgical risk]. / Tratamiento endovascular de la enfermedad carotídea en pacientes de alto riesgo.

AIMS: To analyse the perioperative morbi-mortality rates during the first 30 days following endovascular therapy in patients with carotid stenosis and important risk factors for surgery. We also sought to determine the survival rate, the percentage of patients that were stroke-free and the percentage of cases of restenosis during the follow-up period. PATIENTS AND METHODS: A retrospective study was conducted on a series of 100 patients with symptomatic > 50% and asymptomatic > 70% carotid stenosis, who underwent endovascular therapy between January 2000 and December 2006 because of the important risk factors they presented. Monitoring was clinical and was performed by means of carotid Doppler scanning. RESULTS: The mean age of the sample: 72.2 years (46-86). Perioperative morbi-mortality of the series: 6% (confidence interval, CI 95% = 0.8-11.2) and in the symptomatic stenosis group: 5.7% (CI 95% = 1.8-12.9). The mean follow-up time was 23.4 months (0-94). Total mortality of the series during the follow-up was 7% (CI 95% = 1.4-12.5). The probability of survival at 3 and 5 years is 93 and 89%, respectively. At one year, 98.9% of the patients remained stroke-free. Restenosis of the stent occurred in 5% (CI 95% = 1.6-11.2). The probability of restenosis not occurring was 96.75% at 6 months and 94% at 3 years. CONCLUSIONS: Stent angioplasty is an effective form of treatment in carotid stenosis in patients with important risk factors for surgery and it is therefore important to fulfil patient selection protocols and avoid perioperative complications.

Tratamiento endovascular de la enfermedad carotídea en pacientes de alto riesgo / Endovascular treatment of carotid disease in patients at high surgical risk

Analizar la morbimortalidad perioperatoria durante los primeros 30 días tras la terapia endovascularen pacientes con estenosis carotídea e importantes factores de riesgo para la cirugía, y determinar la supervivencia, el porcentaje de pacientes libres de ictus, así como el porcentaje de reestenosis durante el tiempo de seguimiento. Pacientes y métodos.Se ha realizado un estudio retrospectivo de una serie de 100 pacientes con estenosis carotídeas sintomáticas > 50% y asintomáticas > 70% a los que se realizó terapia endovascular entre enero de 2000 y diciembre de 2006 por presentar importantes factores de riesgo. El seguimiento ha sido clínico mediante Doppler carotídeo. Resultados. Media de edad de la muestra: 72,2 años (rango: 46-86 años). Morbimortalidad perioperatoria de la serie: 6% (IC 95% = 0,8-11,2) y en el grupo de estenosissintomática: 5,7% (IC 95% = 1,8-12,9). El tiempo medio de seguimiento fue de 23,4 meses (rango: 0-94 meses). Lamortalidad total de la serie durante el seguimiento fue del 7% (IC 95% = 1,4-12,5). La probabilidad de supervivencia a los 3 y 5 años es del 93% y 89%, respectivamente. El 98,9% ha permanecido libre de ictus al año. Se produjo reestenosis del stenten el 5% (IC 95% = 1,6-11,2). La probabilidad de que no se produzca reestenosis es del 96,75% a los 6 meses y del 94% a los 3 años. Conclusiones. La angioplastia con stent es un tratamiento efectivo en estenosis carotídea en pacientes con importantes factores de riesgo para la cirugía, de ahí la importancia de realizar protocolos de selección de pacientes y evitar las complicaciones periprocedimiento

To analyse the perioperative morbi-mortality rates during the first 30 days following endovascular therapyin patients with carotid stenosis and important risk factors for surgery. We also sought to determine the survival rate, the percentage of patients that were stroke-free and the percentage of cases of restenosis during the follow-up period. Patients andmethods. A retrospective study was conducted on a series of 100 patients with symptomatic > 50% and asymptomatic > 70% carotid stenosis, who underwent endovascular therapy between January 2000 and December 2006 because of the important risk factors they presented. Monitoring was clinical and was performed by means of carotid Doppler scanning. Results. The mean age of the sample: 72.2 years (46-86). Perioperative morbi-mortality of the series: 6% (confidence interval, CI 95% =0.8-11.2) and in the symptomatic stenosis group: 5.7% (CI 95% = 1.8-12.9). The mean follow-up time was 23.4 months (0-94). Total mortality of the series during the follow-up was 7% (CI 95% = 1.4-12.5). The probability of survival at 3 and 5 years is 93 and 89%, respectively. At one year, 98.9% of the patients remained stroke-free. Restenosis of the stent occurred in 5% (CI95% = 1.6-11.2). The probability of restenosis not occurring was 96.75% at 6 months and 94% at 3 years. Conclusions. Stent angioplasty is an effective form of treatment in carotid stenosis in patients with important risk factors for surgery and it istherefore important to fulfil patient selection protocols and avoid perioperative complications (AU)

Angiotensin type-1-receptor antagonists reduce 6-hydroxydopamine toxicity for dopaminergic neurons.

Angiotensin II activates (via type 1 receptors) NAD(P)H-dependent oxidases, which are a major source of superoxide, and is relevant in the pathogenesis of several cardiovascular diseases and certain degenerative changes associated with ageing. Given that there is a brain renin-angiotensin system and that oxidative stress is a key contributor to Parkinson's disease, we investigated the effects of angiotensin II and angiotensin type 1 (AT(1)) receptor antagonists in the 6-hydroxydopamine model of Parkinson's disease. Rats subjected to intraventricular injection of 6-hydroxydopamine showed bilateral reduction in the number of dopaminergic neurons and terminals. Injection of angiotensin alone did not induce any significant effect. However, angiotensin increased the toxic effect of 6-hydroxydopamine. Rats treated with the AT(1) receptor antagonist ZD 7155 and then 6-hydroxydopamine (with or without exogenous administration of angiotensin) showed a significant reduction in 6-hydroxydopamine-induced oxidative stress (lipid peroxidation and protein oxidation) and dopaminergic degeneration. Dopaminergic degeneration was also reduced by the NAD(P)H inhibitor apocynin. Angiotensin may play a pivotal role, via AT(1) receptors, in increasing the oxidative damage of dopaminergic cells, and treatment with AT(1) antagonists may reduce the progression of Parkinson's disease.

Angiotensin-converting enzyme inhibition reduces oxidative stress and protects dopaminergic neurons in a 6-hydroxydopamine rat model of Parkinsonism.

It is now established that the brain possesses a local renin-angiotensin system and that angiotensin II exerts multiple actions in the nervous system, including regulation of striatal dopamine release. Furthermore, angiotensin activates NADPH-dependent oxidases, which are a major source of superoxide, and angiotensin-converting enzyme inhibitors, commonly used in the treatment of hypertension and chronic heart failure, have shown antioxidant properties in several tissues. Oxidative stress is a key contributor to the pathogenesis and progression of Parkinson's disease. In the present study, we treated rats with intraventricular injections of the dopaminergic neurotoxin 6-hydroxydopamine and subcutaneous injections of the angiotensin-converting enzyme inhibitor Captopril to study the possible neuroprotective effect of the latter on the dopaminergic system and on 6-hydroxydopamine-induced oxidative stress. Rats treated with Captopril and 6-hydroxydopamine showed significantly less reduction in the number of dopaminergic neurons (i.e., immunoreactive to tyrosine hydroxylase) in the substantia nigra and in the density of striatal dopaminergic terminals than 6-hydroxydopamine-lesioned rats not treated with Captopril. In addition, Captopril reduced the levels of major oxidative stress indicators (i.e., lipid peroxidation and protein oxidation) in the ventral midbrain and the striatum of 6-hydroxydopamine-lesioned rats. Our results suggest that angiotensin-converting enzyme inhibitors may be useful for treatment of Parkinson's disease and that further investigation should focus on the neuroprotective capacity of these compounds.

Interaction between the noradrenergic and serotonergic systems in locomotor hyperactivity and striatal expression of Fos induced by amphetamine in rats.

It is classically considered that Amphetamine acts by increasing extracellular dopamine levels. However, some data suggest a relevant role of other neurochemical systems. The striatum is of particular interest to the study of this question. We have investigated the involvement of the noradrenergic and serotonergic systems and their possible interaction in the striatal responses to Amphetamine using a double behavioral and immunohistochemical approach (i.e., changes in locomotor activity and striatal expression of Fos). In normal rats, Amphetamine induced locomotor hyperactivity and striatal expression of Fos. Pretreatment with the alpha1-adrenergic-receptor antagonist Prazosin or lesion of the serotonergic system significantly reduced the locomotor hyperactivity and striatal Fos expression induced by Amphetamine. Administration of Prazosin to rats with serotonergic denervation did not produce any further reduction in the Amphetamine-induced locomotor hyperactivity or striatal Fos expression compared with that observed in rats with serotonergic denervation only. Amphetamine did not induce a detectable increase in Fos expression in dopamine-denervated striata, and elicited intense rotation towards the dopamine-denervated side. This suggests that striatal dopamine release is essential in the Amphetamine-induced effects on striatal neurons. However, the noradrenergic system plays an important role, and the serotonergic system is necessary for mediating the effects of the Amphetamine-induced noradrenergic stimulation. Concurrent stimulation of dopaminergic and serotonergic receptors appears necessary to regulate Amphetamine-induced responses in the striatal neurons.

Rat brain cholinergic, dopaminergic, noradrenergic and serotonergic neurons express GABAA receptors derived from the alpha3 subunit.

In order to study the most abundant GABAA receptor subtypes expressed in cholinergic, dopaminergic, noradrenergic and serotonergic neurons (i.e., in neurons of the so-called "global" projection systems), we employed double-immunocytochemical techniques combining the labeling of GABAA receptor alpha1, alpha2 and alpha3 subunit with markers for these cells. Cholinergic neurons in the striatum, habenula, and pedunculo-pontine nucleus were immunonegative for the alpha1 subunit, and most were also alpha2-immunonegative. However, cholinergic neurons in the striatum, septum and pedunculo-pontine nucleus were alpha3 immunopositive. Dopaminergic neurons in the substantia nigra pars compacta were highly immunopositive for the alpha3, and noradrenergic neurons in the locus coeruleus were immunoreactive for the alpha3 and the alpha2-subunit; although neurons of these areas were negative for alpha1. Similarly, serotonergic neurons in raphe also showed a high level of labeling of alpha3, while there was a lack of immunoreactivity for the alpha1-subunit, and only some individual neurons were positive for the alpha2 subunit. As the presence of different alpha-subunits confers specific physiological and pharmacological properties to GABAA receptors, the abundance of receptors containing the alpha3 subunit (and the scarcity of receptor subtypes including the other alpha-subunits studied) may have important implications for the GABAergic regulation of brain "global" or "diffuse" projection systems.