Assessing illness-related uncertainty in relapsing-remitting multiple sclerosis: A psychometric analysis of the Mishel Uncertainty of Illness Scale.

A multicenter study involving 204 adults with relapsing-remitting multiple sclerosis (RRMS) assessed the dimensionality and item characteristics of the Mishel-Uncertainty of Illness Scale (MUIS), a generic self-assessment tool. Mokken analysis identified two dimensions in the MUIS with an appropriate item and overall scale scalability after excluding nonclassifiable items. A refined 12-item MUIS, employing a grade response model, effectively discriminated uncertainty levels among RRMS patients (likelihood ratio test p-value = .03). These findings suggest the potential value of the 12-item MUIS as a reliable measure for assessing uncertainty associated with the course of illness in RRMS.

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.

Effectiveness of Dimethyl Fumarate in Real-World Clinical Practice and Strategy to Minimize Adverse Effects and Use of Healthcare Resources.

BACKGROUND: Dimethyl fumarate (DMF) has shown efficacy in reducing relapse rates in patients with multiple sclerosis (MS). However, associated adverse effects (AE) such as gastrointestinal (GI) AE, flushing and lymphopenia are the main cause of treatment discontinuation. The aim of this study was to evaluate the effectiveness of DMF, and to assess strategies to reduce treatment discontinuation rates in routine clinical practice. PATIENTS AND METHODS: Ninety patients started DMF treatment between August 2015 and February 2020. Prior to DMF therapy, patients received written information regarding treatment and the management of AE, along with medical prescriptions. Clinical and analytical data were collected at clinical visits performed at least 6-monthly, and disease progression was evaluated by brain magnetic resonance imaging (MRI). RESULTS: Prior to DMF, 78.7% of patients had an annualized relapse rate (ARR) of 1.07 (range: 1-3) and median Expanded Disability Status Scale (EDSS) score of 1.0 (range: 0-2). At final follow-up, ARR and median EDSS scores were significantly reduced to 0.09 (range: 0-2; p< 0.001) and 0 (range: 0-1.625; p< 0.001), respectively. Just over one quarter of patients with brain MRI (26.8% of 71 patients) showed improvement in disease activity based on MRI evaluation. Lymphopenia was associated with previous treatment lines (p=0.042) and longer disease duration (p=0.032). A total of twelve patients abandoned DMF treatment, mainly due to lymphopenia (7.9%), but none did it because of GI AE or flushing. CONCLUSION: In our series, DMF showed high clinical and radiological efficacy. Providing patients with complete information prior to treatment on the management of associated AE helps them to better understand what to expect, improves tolerance and reduces clinical and telephone consultations, which may help to reduce the use and cost of healthcare resources.

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)

Long-term effectiveness of glatiramer acetate in clinical practice conditions.

Glatiramer acetate currently represents one of the main treatments for relapsing-remitting multiple sclerosis (RRMS). However, the information available about its long-term effect in clinical practice is still limited. Thus, this multicenter retrospective cohort study aimed to assess the long-term effectiveness of glatiramer acetate in this setting. The study population included RRMS patients treated with glatiramer acetate for at least 5 years after its marketing authorization and the primary endpoint was long-term clinical effectiveness, defined as absence of disability progression for at least five consecutive years. A total of 149 patients were included into the study, who had received glatiramer acetate for a mean of 6.9 ± 1.4 years (5 years, n=149; 6 years, n=112; 7 years, n=63; 8 years, n=32; 9 years, n=21). More than 85% of patients remained free from disability progression through years 1 to 9 of glatiramer acetate treatment, and 75.2% showed absence of disability progression for at least five consecutive years. Expanded Disability Status Scale (EDSS) scores were maintained, with most patients showing stable/improved EDSS and 92.6% sustaining EDSS <6. Decreased annual relapse rates and increased proportion of relapse-free patients were maintained during the whole glatiramer acetate treatment compared to the year prior to its authorization (p<0.001). The number of gadolinium-enhanced T1-weighted lesions also decreased from pre-glatiramer-acetate assessment to last follow-up whilst on glatiramer acetate (p<0.05). In conclusion, administration of glatiramer acetate shows long-term clinical effectiveness for RRMS treatment; its effect under clinical practice conditions slowed disability progression and reduced relapse occurrence for up to 9 years.

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...

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

Introducción. La enfermedad de Parkinson (EP) se asocia a síntomas emocionales y conductuales que contribuyen a la morbilidad y pérdida de calidad de vida de los pacientes. Entre ellos destacan la depresión, la ansiedad y el trastorno del control de los impulsos. Desarrollo. El correcto abordaje de la EP pasa por reconocer y tratar diversos síntomas neuropsiquiátricos. Los trastornos afectivos pueden constituir síntomas iniciales de la enfermedad, tienen elevada prevalencia y una etiopatogenia compleja. Los trastornos del control de los impulsos no suelen ser una queja espontánea del paciente, por lo que la indagación acerca de estos síntomas puede ser la única forma de detectar y manejar un serio problema sociofamiliar. El tratamiento farmacológico de estos trastornos es difícil, al tener que preservar el control de los síntomas motores. El apoyo psicológico desde etapas tempranas y a lo largo del proceso evolutivo de la EP resulta fundamental. Conclusiones. Es necesario que el neurólogo y profesionales implicados en el tratamiento de los pacientes con EP estén atentos a la aparición de las manifestaciones emocionales y conductuales de esta enfermedad. Ello redundará en un correcto tratamiento del paciente y una mejor adaptación de su ntorno familiar y social (AU)

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 (AU)

Localization and functional significance of striatal neurons immunoreactive to aromatic L-amino acid decarboxylase or tyrosine hydroxylase in rat Parkinsonian models.

Striatal neurons which are immunoreactive (ir) to aromatic L-amino-acid decarboxylase (AADC) or tyrosine hydrodroxylase (TH) may play a role in the decarboxylation of L-DOPA to dopamine (DA) in advanced stages of Parkinson's disease (PD). However, the functional significance of these neurons and the mechanisms responsible for their induction remain to be clarified. In this study, rats were subjected to different types of dopaminergic or serotonergic denervation and L-DOPA injection to study the effects on these neurons. AADC-ir neurons were found in both normal and DA-denervated striata, and no significant differences in their number and distribution were induced following different types of denervation or L-DOPA administration. TH-ir neurons were only found in DA-denervated striata. However, TH-ir neurons did not appear in those areas with maximal DA depletion, but rather were observed near spared or partially lesioned DA terminals. The population of AADC-ir neurons may make a significant contribution to the effects of exogenous L-DOPA in advanced stages of PD. In addition, TH-ir neurons may contribute to these effects, since we have detected AADC-ir in TH-ir neurons using confocal laser scanning microscopy. Finally, neither L-DOPA therapy nor serotonergic denervation induces significant changes in the number or distribution of these neurons.

Effects of (-)-nicotine and (-)-cotinine on 6-hydroxydopamine-induced oxidative stress and neurotoxicity: relevance for Parkinson's disease.

In view of the apparent controversial properties of (-)-nicotine (NIC) in relation to both oxidative stress and neuroprotection, we studied the effects of NIC on hydroxyl radical (*OH) formation, oxidative stress production by 6-hydroxydopamine (6-OHDA) autoxidation in the presence and absence of ascorbate, and 6-OHDA neurotoxicity. Both NIC and (-)-cotinine (COT) exhibited increased *OH production during 6-OHDA autoxidation. Although the same effect was observed in *OH generation by the Fenton reaction (H2O2 + Fe2+), this reaction was completely prevented with the previous incubation of Fe2+ with NIC or COT. Furthermore, both NIC and COT demonstrated a capacity to be able to reduce the TBARS formation provoked in rat brain mitochondrial preparations by 6-OHDA autoxidation. This effect is assumed as a consequence of the action of NIC and COT on lipid peroxidation propagation. We treated with NIC (1mg/kg, i.p.) two 6-OHDA-induced rat models of Parkinson's disease. However, only in one of these models did we obtain clear evidence of a neuroprotective effect of NIC on nigrostriatal terminals, as revealed by immunohistochemistry against tyrosine hydroxylase. Thus, the antioxidant properties of both NIC and COT in relation to the lipid peroxidation induced by 6-OHDA autoxidation, together with their reported capacity to prevent the Fenton reaction, probably by sequestration of Fe2+, may contribute to an understanding of its neuroprotective properties. In addition, the reported capacity of both NIC and COT to increase the production of *OH by 6-OHDA autoxidation might help explain the controversial observation found under different experimental conditions.

Effects of aluminum and zinc on the oxidative stress caused by 6-hydroxydopamine autoxidation: relevance for the pathogenesis of Parkinson's disease.

Aluminum and zinc have been related to the pathogenesis of Parkinson's disease (PD), the former for its neurotoxicity and the latter for its apparent antioxidant properties. 6-Hydroxydopamine (6-OHDA) is an important neurotoxin putatively involved in the pathogenesis of PD, its neurotoxicity often being related to oxidative stress. The potential effect of these metals on the oxidative stress induced by 6-OHDA autoxidation and the potential of ascorbic acid (AA), cysteine, and glutathione to modify this effect were investigated. Both metals, particularly Al3+, induced a significant reduction in *OH production by 6-OHDA autoxidation. The combined action of AA and a metal caused a significant and sustained increase in *OH generation, particularly with Al3+, while the effect of sulfhydryl reductants was limited to only the first few minutes of the reaction. However, both Al3+ and Zn2+ provoked a decrease in the lipid peroxidation induced by 6-OHDA autoxidation using mitochondrial preparations from rat brain, assessed by TBARS formation. In the presence of AA, only Al3+ induced a significant reduction in lipid peroxidation. After intrastriatal injections of 6-OHDA in rats, tyrosine hydroxylase immunohistochemistry revealed that Al3+ reduces 6-OHDA-induced dopaminergic lesion in the striatum, which corroborates the involvement of lipid peroxidation in 6-OHDA neurotoxicity and appears to discard the participation of this mechanism on PD by Al3+ accumulation. The previously reported antioxidant properties of Zn2+ appear to be related to the induction of Zn2+-containing proteins and not to the metal per se.