Effectiveness and Safety of Teriflunomide in Relapsing-Remitting Multiple Sclerosis and Improvements in Quality of Life: Results from the Real-World TERICARE Study.

INTRODUCTION: Teriflunomide is a once-daily oral immunomodulator approved for relapsing forms of multiple sclerosis (MS) or relapsing-remitting multiple sclerosis (RRMS; depending on the local label), based on extensive evidence from clinical trials and a real-world setting on efficacy, tolerability and patient-reported benefits. The TERICARE study assessed the impact of teriflunomide treatment over 2 years on health-related quality of life (HRQoL) and some of the most common and disabling symptoms of MS, such as fatigue and depression. METHODS: This prospective observational study in Spain included RRMS patients treated with teriflunomide for ≤ 4 weeks. The following patient-reported outcomes (PROs) were collected at baseline and every 6 months for 2 years: the 29-item Multiple Sclerosis Impact Scale version 2 (MSIS-29), the 21-item Modified Fatigue Impact Scale (MFIS-21), the Beck Depression Inventory (BDI-II), the Short Form (SF)-Qualiveen and the Treatment Satisfaction Questionnaire for Medication v1.4 (TSQM). Annualised relapse rate (ARR), disability progression according to the Expanded Disability Status Scale (EDSS), and no evidence of disease activity (NEDA-3) were also assessed. RESULTS: A total of 325 patients were analysed. Patients had a mean (SD) age of 43.2 years (10.4), a mean baseline EDSS score of 1.75 (1.5), a mean number of relapses in the past 2 years of 1.5 (0.7), and 64% had received prior disease-modifying therapy (DMT). Patients showed significant improvements in the psychological domain of MSIS-29 from 35.9 (26.6) at baseline to 29.4 (25.5) at 18 months (p = 0.004) and 29.0 (24.6) at 24 months (p = 0.002). Levels of fatigue and depression were also reduced. After 2 years of treatment with teriflunomide, ARR was reduced to 0.17 (95% CI 0.14-0.21) from the baseline of 0.42 (95% CI 0.38-0.48), representing a 60.1% reduction. Mean EDSS scores remained stable during the study, and 79.9% of patients showed no disability progression. 54.7% of patients achieved NEDA-3 in the first 12 months, which increased to 61.4% during months 12-24. Patients reported increased satisfaction with treatment over the course of the study, regardless of whether they were DMT naive or not. CONCLUSION: Teriflunomide improves psychological aspects of HRQoL and maintains low levels of fatigue and depression. Treatment with teriflunomide over 2 years is effective in reducing ARR and disability progression.

Glucose metabolism in lean patients with mild type 2 diabetes mellitus: evidence for insulin-sensitive and insulin-resistant variants.

Obesity and type 2 diabetes mellitus (DM2) are 2 closely related syndromes, with obesity occurring in 70% to 80% of DM2 patients. Both syndromes are characterized by insulin resistance (IR). However, the metabolic characteristics of lean DM2 patients are not clearly defined, a fact attributed to the heterogeneity of the diabetes syndrome. Our objective was to study glucose metabolism in lean DM2 patients, in terms both of the basal and the insulin-stimulated states, and particularly, to investigate whether 2 subpopulations of diabetic patients are identifiable on the basis of degree of IR. Sixteen nonobese (body mass index [BMI] less than 27 kg. m(-2)) DM2 subjects with light to moderate fasting hyperglycemia were studied. Ten healthy subjects were used as a control group, with no family history of DM2 and matched by age, sex, and BMI in the diabetic group. All participants underwent an intravenous glucose tolerance test with frequent sampling over 180 minutes. Insulin sensitivity (IS) and glucose effectiveness at zero insulin (GEZI) were calculated using Bergman's minimal model. Non-insulin-mediated glucose uptakes (NIMGU) and insulin-mediated glucose uptakes (IMGU) were calculated for the basal (F) and insulin-stimulated states at 11.1 mmol/L of glucose (11.1). The beta-cell function was calculated via the acute insulin response to glucose (AIRg). Clustering techniques were used to identify subpopulations of DM2 patients on the basis of insulin sensitivity. The group of DM2 patients was characterized by both IR (IS index, 6.23 +/- 4.68 v 12.75 +/- 7.74 x 10(-5). min(-1). (pmol. L(-1))(-1), P <.01) and insulin secretion abnormalities (AIRg, 336 +/- 456 v 1,912 +/- 1,293 pmol/L. min, P <.0001), but showed similar values for GEZI (0.011 +/- 0.005 v 0.011 +/- 0.007 min(-1), not significant [NS]) in comparison to the control group. For the basal state, no differences were found between the DM2 patients and control subjects for NIMGU(F) (0.13 +/- 0.07 v 0.08 +/- 0.05 mmol/kg. min, NS) or for IMGU(F) (0.05 +/- 0.04 v 0.05 +/- 0.02 mmol/kg. min, NS). For the insulin-stimulated state, the DM2 patients showed a reduction of approximately 50% in the IMGU(11.1) value (0.20 +/- 0.17 v 0.38 +/- 0.24 mmol/kg. min, P <.05), but no significant differences were found for NIMGU(11.1) (0.19 +/- 0.09 v 0.20 +/- 0.12 mmol/kg. min, NS) in relation to the control group. Using the clustering technique, it was possible to identify 2 subpopulations of DM2 patients, a DM-IS group (n = 6) that was insulin sensitive (IS index, 11.70 +/- 2.40 x 10(-5). min(-1). (pmol. L(-1))(-1)) and a DM-IR group (n = 10) that was insulin resistant (IS index, 3.02 +/- 1.60 x 10(-5). min(-1). (pmol. L(-1))(-1)). The DM-IS group was characterized by an absence of IR, diminished GEZI, and a reduction in AIRg; whereas the DM-IR group was characterized by IR and a reduction in AIRg, but normal GEZI. We conclude that (1) as a group, DM2 patients are characterized by IR and beta-cell dysfunction, but normal NIMGU; (2) two subpopulations of DM2 patients can be identified on the basis of insulin sensitivity, with the DM-IS group further characterized by diminished GEZI; and finally, (3) deterioration in the pancreatic response to glucose stimulus is a sine qua non condition for a profound alteration in glucose metabolism in DM2 patients.

Disartria y disfagia aisladas como forma de presentación de un ictus isquémico agudo lacunar bilateral y simultáneo / Isolated dysarthria and dysphagia as the presenting symptoms of simultaneous bilateral acute lagunar ischaemic stroke

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[CADASIL: brief report on a family with a new p.G296C mutation in exon 6 of the Notch-3 gene]. / CADASIL: comunicación de una familia con una nueva mutación p.G296C en el exón 6 del gen Notch-3.

INTRODUCTION: CADASIL is a dominant autosomal inborn systemic arteriopathy, whose genetic anomaly is located in the Notch-3 gene of chromosome 19. It is clinically characterised by migraine with aura, recurrent stroke and cognitive deterioration, and is one of the causes of strokes among the young. CASE REPORT: The propositus was a 57-year-old male who presented a clinical picture of dysarthria, loss of strength in the left extremities and alterations affecting balance with dysmetry in the left extremities, related with an acute ischaemic stroke in the cerebellar peduncle. An ultrastructural study of a biopsy specimen of the skin revealed the electron-dense deposits that characterise CADASIL. The genetic analysis identified a new mutation for this disease in codon 296 of exon 6 in the Notch-3 gene that produces a change of amino acid, from glycine to cysteine in protein (p.G296C). CONCLUSIONS: This communication reports the case of a family with CADASIL that was a carrier of a new p.G296C mutation located in exon 6 of the Notch-3 gene.

Migraña episódica frecuente y péptido relacionado con el gen de la calcitonina. Influencia del tratamiento con topiramato y zonisamida en los niveles del péptido / Frequent episodic migraine and calcitonin gene-related peptide. Influence of treatment with topiramate and zonisamide on levels of the peptide

Introducción. La fisiopatología del dolor en la migraña se relaciona con la activación del sistema trigeminovascular por medio de la liberación de neuropéptidos vasoactivos, y el más importante es el péptido relacionado con el gen de la calcitonina (CGRP), que causa una inflamación neurógena en los vasos leptomeníngeos. Objetivo. Investigar si el CGRP está incrementado en la migraña episódica frecuente y si el tratamiento preventivo con topiramato o zonisamida modifica sus niveles. Sujetos y métodos. Se estudiaron 28 pacientes con migraña episódica con o sin aura, cumpliendo los criterios de la Sociedad Internacional de Cefaleas, con una frecuencia de 4-14 días/mes. En todos los pacientes se determinaron los niveles plasmáticos del CGRP durante un período intercrítico (> 72 h sin dolor). Los pacientes se aleatorizaron en dos grupos de tratamiento, uno con 50 mg/día de topiramato y otro con 50 mg/día de zonisamida, durante tres meses. Al finalizar el período activo se analizó nuevamente el nivel del CGRP. El grupo control lo constituyeron nueve sujetos sanos. Resultados. El CGRP fue significativamente superior en el grupo de migraña episódica comparado con el grupo control (50,61 ± 22,5 pg/mL frente a 34,96 ± 17,03 pg/mL; p = 0,037). Después del tratamiento con neuromoduladores no se hallaron diferencias significativas en el nivel de CGRP (46,11 ± 24,2 pg/mL basal frente a 47,5 ± 24,88 pg/mL postratamiento). Tampoco se hallaron diferencias al analizar los grupos de topiramato y zonisamida de forma individualizada. Conclusiones. El nivel plasmático del CGRP está incrementado en la migraña episódica y sus niveles no son modificados por el tratamiento con dosis bajas de topiramato o zonisamida (AU)

Introduction. The pathophysiology of pain in migraine is related to the activation of the trigeminovascular system by releasing vasoactive neuropeptides, the most important of which is calcitonin gene-related peptide (CGRP), which causes a neurogenic inflammation in the leptomeningeal vessels. Aim. To study whether CGRP is increased in frequent episodic migraine and whether preventive treatment with topiramate or zonisamide modifies its levels. Subjects and methods. We studied 28 patients with episodic migraine with or without aura, in accordance with the International Headache Society criteria, with a frequency of 4-14 days/month. Plasma levels of CGRP were determined in all the patients during an interictal period (> 72 hours without pain). Patients were divided at random into two treatment groups, one with 50 mg/day of topiramate and the other with 50 mg/day of zonisamide, for three months. At the end of the active period the CGRP level was analysed again. The control group consisted of nine healthy subjects. Results. CGRP was significantly higher in the episodic migraine group than in the control group (50.61 ± 22.5 pg/mL versus 34.96 ± 17.03 pg/mL; p = 0.037). After treatment with neuromodulators no significant differences were found in the level of CGRP (46.11 ± 24.2 pg/mL basal versus 47.5 ± 24.88 pg/mL post-treatment). Neither were any differences found on analysing the topiramate and zonisamide groups individually. Conclusions. The plasma level of CGRP is increased in episodic migraine, and its levels are not modified by treatment with low doses of topiramate or zonisamide (AU)

Cefalea trigeminoautonómica secundaria a un hematoma intraorbitario espontáneo / Trigeminal-autonomic cephalgia secondary to a spontaneous intra-orbital haematoma

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Fingolimod: efectividad y seguridad en la práctica clínica habitual. Estudio observacional, retrospectivo y multicéntrico en Galicia / Fingolimod: effectiveness and safety in routine clinical practice. An observational, retrospective, multi-centre study in Galicia

INTRODUCCIÓN: La efectividad y seguridad del fingolimod en pacientes con esclerosis múltiple remitente recurrente (EMRR) se demostró en ensayos clínicos. Sin embargo, por las limitaciones de éstos, es importante saber cómo se comporta en condiciones de práctica clínica habitual. Así, el objetivo de este estudio es evaluar la efectividad y seguridad del fingolimod después de 12 meses de uso en la práctica clínica en Galicia. PACIENTES Y MÉTODOS: Estudio retrospectivo y multicéntrico (n = 8) de pacientes con EMRR y tratados con una o más dosis de fingolimod, 0,5 mg/día. Se evaluó la efectividad -tasa anualizada de brotes (TAB), cambio en la puntuación de la escala expandida del estado de discapacidad (EDSS), porcentaje de pacientes libres de brotes, libres de progresión de discapacidad y libres de actividad en resonancia- para el total de pacientes y según tratamiento previo. Se evaluó la seguridad a partir del porcentaje de pacientes que discontinuaron y que presentaron efectos adversos. RESULTADOS: Después 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 puntuación de la EDSS disminuyó un 9%. Un 91% de pacientes estuvo libre de progresión 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 mayoría de los beneficios del fingolimod difirieron según el tratamiento previo. Alrededor de un tercio de los pacientes comunicaron efectos adversos, pero sólo el 2% discontinuó debido a ellos. CONCLUSIONES: La mayoría de los resultados de efectividad de los ensayos clínicos del fingolimod se observa durante los 12 primeros meses de tratamiento en la práctica clínica. Se observó un mejor perfil de seguridad al comunicado en los ensayos clínicos

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 (AU)

Trombosis venosa cerebral en adultos en el Complejo Hospitalario-Universitario De A Coruña España: revisión clínico-radiológica de 48 casos diagnosticados entre 1995 Y 2005 / Cerebral vein thrombosis in adults in the Hospital-University of A Coruña Spain: clinico-radiological review of 48 cases diagnosed between 1995 and 2005

Introducción. La trombosis venosa cerebral es una patología del sistema nervioso central cuya incidencia es aún desconocida. El diagnostico es difícil, teniendo en cuenta que las manifestaciones neurológicas así como su etiología pueden ser extremadamente variables. Objetivos: conocer la etiología, clínica y pronóstico de las trombosis de los senos venosos cerebrales en el Complejo Hospitalario Universitario Juan Canalejo de A Coruna. Pacientes y métodos: se revisaron de forma retrospectiva los casos diagnosticados de TVC desde 1995 a 2005. Se registro la etiología, las manifestaciones clínicas, los signos radiológicos en la TAC en el momento del ingreso, el tratamiento aplicado y el pronóstico a los 6 meses empleando la escala modificada de Rankin. Resultados: se registraron 48 casos de los cuales 27 eran mujeres y 21 hombres; el rango de edad fue de 21 a 88 años, con una mediana de 43 años. La etiología infecciosa estuvo presente en cinco casos equivalente al 10,4%). En pacientes jóvenes (<43 años) los trastornos de la coagulación y/o la toma de anticonceptivos hormonales se constato en el 66,7% de los casos, mientras que en los mayores de 43 años la etiología neoplásica se encontró en el 29% y no pudo identificarse en el 45,8%. El síntoma más frecuente fue la cefalea en el 72,9%. En la tomografía axial computarizada el signo radiológico mas frecuente fue la hiperdensidad de uno o varios senos venosos (62,5%), pero fue estrictamente normal en el 20% de los casos. Treinta y cuatro pacientes recibieron tratamiento anticoagulante con buena evolución, así el 75% presento puntuación en la escala modificada de Rankin ≤1 a los seis meses. Ocho pacientes (16,7%) fallecieron, pero la mortalidad estuvo fuertemente relacionada con la patología de base de los mismos (50% cáncer). Conclusiones: en pacientes jóvenes predomina la etiología por anticonceptivos y los trastornos de la coagulación, en cambio, a partir de la sexta década dominan las neoplasias subyacentes y causas indeterminadas. El tratamiento anticoagulante es eficaz y seguro. El pronóstico es excelente en la mayoría de los casos...

Introduction. Cerebral venous thrombosis is a pathology of the central nervous system which incident is still unknown. The diagnosis is difficult because the neurological manifestations and its etiology may be extremely varied. Objectives. The aim of our study was to ascertain the etiology, the clinical manifestations and the prognosis of the cases of Cerebral venous thrombosis diagnosed at our Hospital. Patients and Methods. It was reviewed retrospectively all histories of the patients who were diagnosed of cerebral venous thrombosis from 1995 to 2005. It was recorded the etiological factors, the clinical manifestations, the radiological signs in the computed tomography scan at admission, the treatment administered and the prognosis at six months was classified in accordance with the modified Rankin scale (mRS). Results. We reviewed 48 cases (27 females; 21 males). The age range was 21 to 88 years old, with a median at 43 years. The infectious etiology was present in five patients (10,4%). In the young group (<43years), coagulation diseases and/or oral hormone contraceptives were involved in 66,7% of the cases, whereas in the age group (≥43 years), an underlying neoplasm was identified in 29% of the cases and no etiological factor in 45,8%. Headache was the most frequent symptom (72,9%). The most frequently observed radiological sign in the computed tomography scan was hyperdensity in one or more venous sinuses (62.5%), but it was normal in 20% of the cases. 34 patients received anticoagulant treatment with a good evolution, so 75% presented mRS ≤1 at six months. Death occurred in 8 patients (16,7%), although it was closely related to their basic condition (50% neoplasm). Conclusions. In young population, the most frequently etiologies are contraceptives and coagulation disease and in people older than 60 years, the underlying neoplasm and cases of unknown etiology prevail. The anticoagulant treatment is effective and safe. The prognosis was excellent in the most of the cases...

Miopatía por deficiencia de mioadenilato desaminasa desencadenada por el tratamiento con atorvastatina / Myopathy due to deficiency of desaminase myoadenilate induced by atorvastatine

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Síndrome radiológico aislado: dilema clínico y terapéutico / Radiologically isolated syndrome: a clinical and therapeutic dilemma

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CADASIL: comunicación de una familia con una nueva mutación p. G296C en el exón 6 del gen Notch- 3 / CADASIL: brief report on a family with a new p. G296C mutation in exon 6 of the Notch- 3 gene

Introducción. CADASIL es una arteriopatía sistémica de herencia autosómica dominante, cuya anomalía genética se sitúa en el gen Notch-3 del cromosoma 19, y se caracteriza clínicamente por migraña con aura, ictus de repetición y deterioro cognitivo, y es causante de la ocurrencia de ictus en la población joven. Caso clínico. El caso propositus es un varón de 57 años que presentó un cuadro de disartria, pérdida de fuerza en las extremidades izquierdas y alteración del equilibrio con dismetría en las extremidades izquierdas, en relación con un ictus isquémico agudo en el pedúnculo cerebeloso. El estudio ultraestructural de la biopsia de piel identificó los depósitos de material electrón densos típicos del CADASIL. El análisis genético identificó una nueva mutación para esta enfermedad en el codón 296 del exón 6 del gen Notch-3 que produce un cambio aminoacídico de glicina a cisteína en la proteína (p.G296C). Conclusión. Se comunica el caso de una familia afectada de CADASIL, portadora de una nueva mutación p.G296C situada en el exón 6 del gen Notch-3 (AU)

Introduction. CADASIL is a dominant autosomal inborn systemic arteriopathy, whose genetic anomaly is located in the Notch-3 gene of chromosome 19. It is clinically characterised by migraine with aura, recurrent stroke and cognitive deterioration, and is one of the causes of strokes among the young. Case report. The propositus was a 57-year-old male who presented a clinical picture of dysarthria, loss of strength in the left extremities and alterations affecting balance with dysmetry in the left extremities, related with an acute ischaemic stroke in the cerebellar peduncle. An ultrastructural study of a biopsy specimen of the skin revealed the electron-dense deposits that characterise CADASIL. The genetic analysis identified a new mutation for this disease in codon 296 of exon 6 in the Notch-3 gene that produces a change of amino acid, from glycine to cysteine in protein (p.G296C). Conclusions. This communication reports the case of a family with CADASIL that was a carrier of a new p.G296C mutation located in exon 6 of the Notch-3 gene (AU)