Triple therapy with deferiprone, idebenone and riboflavin in Friedreich's ataxia - open-label trial.

OBJECTIVES: The objective of the study was to test the efficacy, safety and tolerability of triple therapy with deferiprone, idebenone and riboflavin in Friedreich's ataxia (FRDA) patients in a clinical pilot study. PATIENTS AND METHODS: Patients included in this study were 10 males and three females, 14-61 years of age (average 30.2 ± 12.1), diagnosed with FRDA with normal ventricular function. Patients were treated with triple therapy with deferiprone at 5-25 mg/kg/day, idebenone at 10-20 mg/kg/day and riboflavin at 10-15 mg/kg/day for 15-45 months. The efficacy of this triple therapy was assessed by change from baseline on the scale for the assessment and rating of ataxia (SARA) and by the change from baseline in echocardiogram parameters. RESULTS: Four patients discontinued due to adverse events (AEs) related with deferiprone. The annual worsening rate (AWR) was estimated in this series as 0.96 (CI 95%: 0.462-1.608) SARA score, whereas AWR for our FRDA cohort was estimated as 2.05 ± 1.23 SARA score. LVMI only decreased by 6.5 g/m(2) (6.2%) at the end of the first year of therapy. LVEF remained stable, except in case of three patients. CONCLUSION: Our results seem to indicate some uncertain benefit on the neurological and heart functions of this triple therapy in FRDA.

Epidemiology of ataxia and hereditary spastic paraplegia in Spain: A cross-sectional study.

INTRODUCTION: Ataxia and hereditary spastic paraplegia are rare neurodegenerative syndromes. We aimed to determine the prevalence of these disorders in Spain in 2019. PATIENTS AND METHODS: We conducted a cross-sectional, multicentre, retrospective, descriptive study of patients with ataxia and hereditary spastic paraplegia in Spain between March 2018 and December 2019. RESULTS: We gathered data from a total of 1933 patients from 11 autonomous communities, provided by 47 neurologists or geneticists. Mean (SD) age in our sample was 53.64 (20.51) years; 938 patients were men (48.5%) and 995 were women (51.5%). The genetic defect was unidentified in 920 patients (47.6%). A total of 1371 patients (70.9%) had ataxia and 562 (29.1%) had hereditary spastic paraplegia. Prevalence rates for ataxia and hereditary spastic paraplegia were estimated at 5.48 and 2.24 cases per 100 000 population, respectively. The most frequent type of dominant ataxia in our sample was SCA3, and the most frequent recessive ataxia was Friedreich ataxia. The most frequent type of dominant hereditary spastic paraplegia in our sample was SPG4, and the most frequent recessive type was SPG7. CONCLUSIONS: In our sample, the estimated prevalence of ataxia and hereditary spastic paraplegia was 7.73 cases per 100 000 population. This rate is similar to those reported for other countries. Genetic diagnosis was not available in 47.6% of cases. Despite these limitations, our study provides useful data for estimating the necessary healthcare resources for these patients, raising awareness of these diseases, determining the most frequent causal mutations for local screening programmes, and promoting the development of clinical trials.

Do cerebral venous thrombosis risk factors influence the development of an associated venous infarction?

INTRODUCTION: Cerebral venous thrombosis (CVT) is a multifactorial process with a wide clinical spectrum and many associated risk factors (RF) that could be complicated with venous infarction (VI). We study the influence of RF in the developing of venous infarction in patients with CVT. PATIENTS AND METHODS: An observational study with consecutive inclusion of patients with CVT diagnosis admitted to the Stroke Unit of a Neurology Department between 1995 and 2007. RF were identified and their distribution according to the presence of VI was analysed. RESULTS: A total of 52 patients were included (37 female; 71.15%) with mean age of 46.73 years (range 18-78 years). The most frequent RF associated with CVT were thrombophilia (26.92%) and oral contraceptives (OC) (25% of all the patients and in 35.13% of females). The most frequent RF in patients with venous infarction was thrombophilia (40.9%), whilst in the CVT group without venous infarction the use of oral contraceptives predominated (26.7% of the total sample; 38% of females), with thrombophilic states only being detected in 16.5%. No cases of venous infarction were found in the group of patients with oral contraceptives but without an associated thrombophilic state. CONCLUSION: There appears to be a different profile of associated RF in patients with venous infarction associated to CVT, with the presence of thrombophilia prevailing.

Outcome of patients with amyotrophic lateral sclerosis attending in a multidisciplinary care unit.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a disease with very poor prognosis, and a mortality of 50% at 18 months after diagnosis. Multidisciplinary units attempt to improve the quality of life and survival of patients with ALS. The aim of this study is to evaluate every 3 months, over a 24-month period, the outcome of patients treated at the ALS unit since the time of diagnosis. MATERIAL AND METHODS: We performed a prospective observational study of patients treated in the ALS unit following a clinical pathway since the time of diagnosis with quarterly reviews from 2006 to 2010. The age of onset, functional impairment (ALSFRS-r), impairment of respiratory function, dysphagia and signs of depression and/or cognitive impairment were evaluated in relation to the initial location symptoms (bulbar [B], upper limbs [UL], lower limbs [LL]). RESULTS: A total of 42 patients (30 males and 12 females) were evaluated (mean age at onset of 57.97 years old, SD 14.56). There was an even distribution by location of onset of symptoms (B 14 patients, UL 14, LL 14.) Functional impairment (B -26,89 points, UL -22,48 points, LL -22,66 points), the need for use of BIPAP (B 64.28%; UL 35.71%; LL 50%), the presence of dysphagia (B 85.71; UL 42.85; LL 71.42%), signs of depression (B 78.57%; UL 35.71%; LL 64.28%) and cognitive impairment (B 42.85%; UL 21.42; LL 35.71%) was higher at 24 months of progression in patients with bulbar onset. There was no difference in mortality data (23.80% overall). CONCLUSIONS: The treatment in multidisciplinary units does not change the neurological progression of the disease, but increases the survival of ALS patients regardless of their initial onset, emphasising the use of multidisciplinary care.

Previous statins treatment and risk of post-stroke infections.

INTRODUCTION: Clinical and laboratory studies have attributed an inmuno-supressor effect to the statins. Furthermore, the administration of simvastatin in the acute onset of stroke has been associated with an increased infection frequency. Our objective is to assess the influence of statins previous treatment on infection after ischemic stroke. PATIENTS AND METHODS: Observational study of patients with ischaemic stroke hospitalised in a Stroke Unit. Demographic data, vascular risk factors, stroke severity, stroke subtype and previous statins treatment were evaluated. The following infections were registered: pneumonia, urinary tract infection, pseudomembranous colitis and sepsis. The patients were classified into two groups, depending on previous statin treatment. RESULTS: A total of 2045 patients were included (1165 were male, aged 69.05±12.5 years). Of these, 306 (15%) patients were receiving statins prior to stroke. These patients had more frequently arterial hypertension, DM, peripheral arterial disease and hypercholesterolaemia than the patients who were not treated with statins (P<0001). There was no statistically significant difference between overall in-hospital infection frequency between patients treated with statins and those with no statins treatment, (11.8% vs. 13%), nor in individual infection type: pneumonia (7.8% vs. 10.2%), urinary tract infection (4.2% vs. 2.8%), pseudomembranous colitis (0.3% vs. 0.7%) and sepsis (2.6% vs. 4.4%). In the atherothrombotic stroke subtype, statins were associated with a lower frequency of sepsis (unadjusted OR, 0.949; 95% CI; 0.928-0.971). CONCLUSIONS: Previous treatment with statins does not appear to influence the frequency of in-hospital infections in patients with ischaemic stroke.

Epidemiology of ataxia and hereditary spastic paraplegia in Spain: a cross-sectional study. / Mapa epidemiológico transversal de las ataxias y paraparesias espásticas hereditarias en España.

INTRODUCTION: Ataxia and hereditary spastic paraplegia are rare neurodegenerative syndromes. We aimed to determine the prevalence of these disorders in Spain in 2019. PATIENTS AND METHODS: We conducted a cross-sectional, multicentre, retrospective, descriptive study of patients with ataxia and hereditary spastic paraplegia in Spain between March 2018 and December 2019. RESULTS: We gathered data from a total of 1.809 patients from 11 autonomous communities, provided by 47 neurologists or geneticists. Mean (SD) age in our sample was 53.64 (20.51) years; 920 patients were men (50.8%) and 889 were women (49.2%). The genetic defect was unidentified in 920 patients (47.6%). A total of 1371 patients (70.9%) had ataxia and 562 (29.1%) had hereditary spastic paraplegia. Prevalence rates for ataxia and hereditary spastic paraplegia were estimated at 5.48 and 2.24 cases per 100 000 population, respectively. The most frequent type of dominant ataxia in our sample was SCA3, and the most frequent recessive ataxia was Friedreich ataxia. The most frequent type of dominant hereditary spastic paraplegia in our sample was SPG4, and the most frequent recessive type was SPG7. CONCLUSIONS: In our sample, the estimated prevalence of ataxia and hereditary spastic paraplegia was 7.73 cases per 100 000 population. This rate is similar to those reported for other countries. Genetic diagnosis was not available in 47.6% of cases. Despite these limitations, our study provides useful data for estimating the necessary healthcare resources for these patients, raising awareness of these diseases, determining the most frequent causal mutations for local screening programmes, and promoting the development of clinical trials.

Circulating miR-323-3p is a biomarker for cardiomyopathy and an indicator of phenotypic variability in Friedreich's ataxia patients.

MicroRNAs (miRNAs) are noncoding RNAs that contribute to gene expression modulation by regulating important cellular pathways. In this study, we used small RNA sequencing to identify a series of circulating miRNAs in blood samples taken from Friedreich's ataxia patients. We were thus able to develop a miRNA biomarker signature to differentiate Friedreich's ataxia (FRDA) patients from healthy people. Most research on FDRA has focused on understanding the role of frataxin in the mitochondria, and a whole molecular view of pathological pathways underlying FRDA therefore remains to be elucidated. We found seven differentially expressed miRNAs, and we propose that these miRNAs represent key mechanisms in the modulation of several signalling pathways that regulate the physiopathology of FRDA. If this is the case, miRNAs can be used to characterize phenotypic variation in FRDA and stratify patients' risk of cardiomyopathy. In this study, we identify miR-323-3p as a candidate marker for phenotypic differentiation in FRDA patients suffering from cardiomyopathy. We propose the use of dynamic miRNAs as biomarkers for phenotypic characterization and prognosis of FRDA.

Ophthalmic features of Friedreich ataxia.

PURPOSE: To describe ocular abnormalities in patients with Friedreich ataxia (FRDA). METHODS: Patients diagnosed with FRDA by genetic analysis were invited to participate in a prospective cohort. The patients included underwent an extensive ophthalmologic examination, including low-contrast Sloan letter charts test and retinal nerve fiber layer (RNFL) thickness analysis by optical coherence tomography (OCT). RESULTS: Twenty-three patients agreed to participate. In all, 19 patients (83%) had a visual acuity of at least 0.8 in both eyes. Fundus examination showed diffuse optic nerve pallor in four patients. However, OCT showed a decreased mean peripapillary RNFL thickness in all but three adult cases and one teenager. The RNFL thickness was found to have a positive correlation with visual acuity (P=0.001) and contrast sensitivity (P=0.001) and a negative correlation with time elapsed from diagnosis (P=0.001). CONCLUSIONS: OCT and low contrast test sensitivity show that the visual pathway is affected in FRDA. However, in most patients there is no significant visual impairment. In a small proportion of patients visual acuity declines with disease progression. This study provides a better understanding of the ophthalmic features of FRDA.

"SARAgrama": una propuesta de representación gráfica en la evolución de las ataxias / "SARAgraph": a proposed graphic system for representing ataxia progression

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[Mixed hereditary polyposis with atypical extracolonic manifestations]. / Poliposis hereditaria mixta con manifestaciones extracolónicas atípicas.

We present the case of a 31 year-old-man with mixed hereditary polyposis and atypical extracolonic manifestations, as patent ductus arteriosus and mental retardation, with cranial hyperostosis. This is an extremely uncommon polyposis syndrome and has a moderate risk to progress to colon cancer.

¿Influyen los factores de riesgo de trombosis venosa cerebral en el desarrollo de infarto venoso asociado? / Do cerebral venous thrombosis risk factors influence the development of an associated venous infarction?

Introducción: La trombosis venosa cerebral (TVC) es un proceso multifactorial con amplio espectro clínico y de factores de riesgo (FR), que puede presentar o no infarto venoso. Estudiamos los FR que influyen en el desarrollo del infarto venoso en pacientes con diagnóstico de TVC.Pacientes y métodos: Estudio observacional con inclusión de pacientes consecutivos con diagnóstico de TVC atendidos por la Unidad de Ictus del servicio de Neurología entre los años 1995 y 2007. Se identifican los FR y se analiza su distribución en función de la presencia del infarto venoso.Resultados: Se incluyeron 52 pacientes (37 mujeres; 71,15%) con edad media de 46,73 años (18-78 años). Los factores de riesgo de TVC más frecuentes fueron los estados de hipercoagulabilidad hereditarios (26,92%) y el uso de anticonceptivos orales (ACO) (25% del total muestral y 35,13% de las mujeres). Entre los FR identificados en pacientes con infarto venoso predominan los trastornos de hipercoagulabilidad hereditarios (40,9%) mientras que en los casos sin infarto venoso, el factor más frecuente es el uso de ACO (26,7%; 38% de las mujeres), estando presentes los estados de hipercoagulabilidad sólo en el 16,5%. No observamos ningún caso de infarto venoso con tratamiento ACO y sin estado de hipercoagulabilidad asociado. Conclusiones: En los pacientes con infarto venoso asociado a TVC parece existir un diferente perfil de factores de riesgo asociado, predominando la presencia de estados protrombóticos hereditarios (AU)

Introduction: Cerebral venous thrombosis (CVT) is a multifactorial process with a wide clinical spectrum and many associated risk factors (RF) that could be complicated with venous infarction (VI). We study the influence of RF in the developing of venous infarction in patients with CVT.Patients and methods: An observational study with consecutive inclusion of patients with CVT diagnosis admitted to the Stroke Unit of a Neurology Department between 1995 and 2007. RF were identified and their distribution according to the presence of VI was analysed. Results: A total of 52 patients were included (37 female; 71.15%) with mean age of 46.73 years (range 18-78 years). The most frequent RF associated with CVT were thrombophilia (26.92%) and oral contraceptives (OC) (25% of all the patients and in 35.13% of females). The most frequent RF in patients with venous infarction was thrombophilia (40.9%), whilst in the CVT group without venous infarction the use of oral contraceptives predominated (26.7% of the total sample; 38% of females), with thrombophilic states only being detected in 16.5%. No cases of venous infarction were found in the group of patients with oral contraceptives but without an associated thrombophilic state. Conclusion: There appears to be a different profile of associated RF in patients with venous infarction associated to CVT, with the presence of thrombophilia prevailing (AU)

Tratamiento previo con estatinas y riesgo de complicaciones infecciosas tras un infarto cerebral agudo / Previous statins treatment and risk of post-stroke infections

Introducción y objetivo: Diversos estudios clínicos y experimentales atribuyen un efecto inmunosupresor a las estatinas y la administración de simvastatina en la fase aguda del ictus se ha asociado a mayor frecuencia de infecciones durante el ingreso. Nuestro objetivo es comprobar si el consumo previo de estatinas influye en la aparición de complicaciones infecciosas intrahospitalarias tras un infarto cerebral (IC). Pacientes y métodos: Estudio observacional incluyendo pacientes con IC ingresados en la Unidad de Ictus. Se analizan: datos demográficos, factores de riesgo vascular, gravedad al ingreso, subtipo etiológico de infarto cerebral y consumo previo de estatinas. Se ha estudiado la aparición de las siguientes complicaciones infecciosas durante la hospitalización: neumonía, infección urinaria, colitis pseudomembranosa y sepsis de cualquier origen agrupando a los enfermos en dos grupos: pacientes que previamente tomaban o no estatinas. Resultados: Se incluyeron 2.045 pacientes (1.162 varones) con edad media de 69,05 años (DE 12,5). El 15% (306 pacientes) tomaba estatinas previamente al IC. Dichos pacientes presentaban con mayor frecuencia que los que no lo hacían (p<0,0001) antecedente de HTA, DM, arteriopatía periférica e hipercolesterolemia. La frecuencia de infección intrahospitalaria fue similar en ambos grupos, tanto evaluada de manera global (11,8% vs 13%, p=0,643) como al analizar cada una de las infecciones separadamente. En el subgrupo de IC aterotrombótico, las estatinas se asociaron con una menor frecuencia de sepsis (OR no ajustado 0,949, IC 95% [0,928 – 0,971]). Conclusiones: El tratamiento previo con estatinas parece no influir en la frecuencia de complicaciones infecciosas intrahospitalarias tras un IC agudo (AU)

Introduction: Clinical and laboratory studies have attributed an inmuno-supressor effect to the statins. Furthermore, the administration of simvastatin in the acute onset of stroke has been associated with an increased infection frequency. Our objective is to assess the influence of statins previous treatment on infection after ischemic stroke. Patients and methods: Observational study of patients with ischaemic stroke hospitalised in a Stroke Unit. Demographic data, vascular risk factors, stroke severity, stroke subtype and previous statins treatment were evaluated. The following infections were registered: pneumonia, urinary tract infection, pseudomembranous colitis and sepsis. The patients were classified into two groups, depending on previous statin treatment. Results: A total of 2045 patients were included (1165 were male, aged 69.05±12.5 years). Of these, 306 (15%) patients were receiving statins prior to stroke. These patients had more frequently arterial hypertension, DM, peripheral arterial disease and hypercholesterolaemia than the patients who were not treated with statins (P < 0001). There was no statistically significant difference between overall in-hospital infection frequency between patients treated with statins and those with no statins treatment, (11.8% vs. 13%), nor in individual infection type: pneumonia (7.8% vs. 10.2%), urinary tract infection (4.2% vs. 2.8%), pseudomembranous colitis (0.3% vs. 0.7%) and sepsis (2.6% vs. 4.4%). In the atherothrombotic stroke subtype, statins were associated with a lower frequency of sepsis (unadjusted OR, 0.949; 95% CI; 0.928-0.971). Conclusions: Previous treatment with statins does not appear to influence the frequency of in-hospital infections in patients with ischaemic stroke (AU)

Evolución de pacientes con esclerosis lateral amiotrófica atendidos en una unidad multidisciplinar / Outcome of patients with amyotrophic lateral sclerosis attending in a multidisciplinary care unit

Introducción: La esclerosis lateral amiotrófica (ELA) es una enfermedad con muy mal pronóstico, con una mortalidad del 50% a los 18 meses tras el diagnóstico. Las unidades multidisciplinares pretenden mejorar la calidad de vida y la supervivencia de los enfermos de ELA. El objetivo de nuestro estudio es evaluar cada 3 meses la evolución de pacientes atendidos en la unidad de ELA desde el momento del diagnóstico y durante 24 meses. Material y métodos: Se realizó un estudio observacional prospectivo de pacientes atendidos en la unidad de ELA siguiendo una vía clínica desde el momento del diagnóstico y con revisiones trimestrales desde 2006 a 2010. La edad de inicio, el deterioro de la situación funcional (escala ALSFRS-r), el deterioro de la función respiratoria y la aparición de disfagia y de signos de depresión y/o de deterioro cognitivo fueron evaluados en relación con la localización inicial de los síntomas (bulbar [B], miembros superiores [MMSS], miembros inferiores [MMII]). Resultados: 42 pacientes (30V y 12M) fueron evaluados (edad media de inicio±desviación estándar de 57,97±14,56 años). Se encontró una distribución igual por localización de inicio de los síntomas (B 14 pacientes, MMSS 14, MMII 14). El deterioro funcional (B –26,89 pts.; MMSS –22,48 pts.; MMII –22,66 pts.), la necesidad de uso de BIPAP (B 64,28%; MMSS 35,71%, MMII 50%), la presencia de disfagia (B 85,71; MMSS 42.85; MMII 71.42%), de signos de depresión (B 78,57%, MMSS 35,71%; MMII 64,28%) y de deterioro cognitivo (B 42,85%; MMSS 21,42; MMII 35,71%) fue mayor a los 24 meses de evolución en los pacientes de inicio bulbar. No hubo diferencias en los datos de mortalidad (global 23,80%). Conclusiones: El tratamiento en unidades multidisciplinares no varía la evolución neurológica de la enfermedad pero favorece la aplicación de cuidados multidisciplinares e incrementa la supervivencia de los enfermos de ELA independientemente de su forma de inicio (AU)

Introduction: Amyotrophic lateral sclerosis (ALS) is a disease with very poor prognosis, and a mortality of 50% at 18 months after diagnosis. Multidisciplinary units attempt to improve the quality of life and survival of patients with ALS. The aim of this study is to evaluate every 3 months, over a 24-month period, the outcome of patients treated at the ALS unit since the time of diagnosis. Material and methods: We performed a prospective observational study of patients treated in the ALS unit following a clinical pathway since the time of diagnosis with quarterly reviews from 2006 to 2010. The age of onset, functional impairment (ALSFRS-r), impairment of respiratory function, dysphagia and signs of depression and/or cognitive impairment were evaluated in relation to the initial location symptoms (bulbar [B], upper limbs [UL], lower limbs [LL]). Results: A total of 42 patients (30 males and 12 females) were evaluated (mean age at onset of 57.97years old, SD 14.56). There was an even distribution by location of onset of symptoms (B 14 patients, UL 14, LL 14.) Functional impairment (B –26,89 points, UL –22,48 points, LL –22,66 points), the need for use of BIPAP (B 64.28%; UL 35.71%; LL 50%), the presence of dysphagia (B 85.71; UL 42.85; LL 71.42%), signs of depression (B 78.57%; UL 35.71%; LL 64.28%) and cognitive impairment (B 42.85%; UL 21.42; LL 35.71%) was higher at 24 months of progression in patients with bulbar onset. There was no difference in mortality data (23.80% overall). Conclusions: The treatment in multidisciplinary units does not change the neurological progression of the disease, but increases the survival of ALS patients regardless of their initial onset, emphasising the use of multidisciplinary care (AU)

Poliposis hereditaria mixta con manifestaciones extracolónicas atípicas / Mixed hereditary polyposis with atypical extracolonic manifestations

Presentamos un varón de 31 años con poliposis hereditaria mixta y manifestaciones extracolónicas atípicas como ductus arterioso persistente y retraso mental, con hiperostosis craneal. Se trata de un síndrome polipósico extremadamente infrecuente y con riesgo moderado de progresión a desarrollar cáncer de colon

We present the case of a 31 year-old-man with mixed hereditary polyposis and atypical extracolonic manifestations, as patent ductus arteriosus and mental retardation, with cranial hyperostosis. This is an extremely uncommon polyposis syndrome and has a moderate risk to progress to colon cancer