RESUMEN
Background: Pediatric investigation plans (PIPs) describe how adult drugs can be studied in children. In 2015, PIPs for Amyotrophic Lateral Sclerosis (ALS) became mandatory for European marketing-authorization of adult treatments, unless a waiver is granted by the European Medicines Agency (EMA).Objective: To assess the feasibility of clinical studies on the effect of therapy in children (<18 years) with ALS in Europe.Methods: The EMA database was searched for submitted PIPs in ALS. A questionnaire was sent to 58 European ALS centers to collect the prevalence of pediatric ALS during the past ten years, the recruitment potential for future pediatric trials, and opinions of ALS experts concerning a waiver for ALS.Results: Four PIPs were identified; two were waived and two are planned for the future. In total, 49 (84.5%) centers responded to the questionnaire. The diagnosis of 44,858 patients with ALS was reported by 46 sites; 39 of the patients had an onset < 18 years (prevalence of 0.008 cases per 100,000 or 0.087% of all diagnosed patients). The estimated recruitment potential (47 sites) was 26 pediatric patients within five years. A majority of ALS experts (75.5%) recommend a waiver should apply for ALS due to the low prevalence of pediatric ALS.Conclusions: ALS with an onset before 18 years is extremely rare and may be a distinct entity from adult ALS. Conducting studies on the effect of disease-modifying therapy in pediatric ALS may involve lengthy recruitment periods, high costs, ethical/legal implications, challenges in trial design and limited information.
Asunto(s)
Esclerosis Amiotrófica Lateral , Adulto , Niño , Humanos , Esclerosis Amiotrófica Lateral/diagnóstico , Esclerosis Amiotrófica Lateral/epidemiología , Esclerosis Amiotrófica Lateral/terapia , Estudios de Factibilidad , Europa (Continente) , Bases de Datos Factuales , PrevalenciaRESUMEN
Given the high oxygen consumption of motor neurons, we sought to assess the frequency and prognostic value of arterial hypertension (affecting brain's oxygen supply) in amyotrophic lateral sclerosis (ALS). We consecutively and prospectively included all ALS patients with regular medical follow-up and documented blood pressure measurements and monitored them until death. Vascular factors diagnosed prior to the onset of motor signs in ALS patients were compared with those in a stratified, age- and gender-matched case-control population. The severity of leukoaraiosis on magnetic resonance imaging (MRI) was blindly assessed. Post mortem examinations were performed when authorized. Compared with controls (n = 408), the 102 ALS patients were significantly more likely to display hypertension (41-57%) and current smoking (15-26%). The number of years of hypertension was associated with survival (HR = 1.04 (1.01-1.07)). In a multivariate analysis, leukoaraiosis severity (HR = 1.214 (1.096-1.344)), current smoking (HR = 1.766 (1.085-2.872)) and low vital capacity (HR = 2.422 (1.266-4.633)) remained independent predictors of survival. Post mortem examinations revealed a greater frequency of leukoaraiosis in ALS patients (p = 0.02). In conclusion, the effect of chronic hypertension on survival might be exerted through abnormal neural perfusion. The higher frequency of recent hypertension in ALS patients may be due to a compensatory increase in blood pressure in response to a lower oxygen supply.
Asunto(s)
Esclerosis Amiotrófica Lateral/fisiopatología , Arterias/fisiopatología , Hipertensión/fisiopatología , Anciano , Anciano de 80 o más Años , Esclerosis Amiotrófica Lateral/epidemiología , Autopsia , Estudios de Casos y Controles , Comorbilidad , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Hipertensión/epidemiología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de RiesgoRESUMEN
Detection of enterovirus (EV) in the spinal cord of patients with amyotrophic lateral sclerosis (ALS) has been reported on post mortem central nervous system tissues. In cases of persistent infection, it is very likely that the EV genome might be detected in the cerebrospinal fluid (CSF). A study was conducted in seven French amyotrophic lateral sclerosis (ALS) centres between 1997 and 2002. A total of 242 ALS patients and 354 age- and sex-matched controls (non-ALS patients) were enrolled. A sensitive RT-PCR method was performed on the CSF to assess the presence of EV RNA; 14.5% of ALS patients were positive compared to 7.6% of controls (chi(2) value, 5.31; p = 0.02). Although EV infection has a seasonal pattern, we observed no seasonality in positive detection of the EV genome among ALS patients. There was no significant relationship among ALS patients between the initial clinical form or survival and the result of the RT-PCR. These findings suggest a relationship between the presence of EV sequences in CSF and ALS. Our study is consistent with the hypothesis that persistent EV infection can be one of the multiple factors involved in the development of ALS.
Asunto(s)
Esclerosis Amiotrófica Lateral/líquido cefalorraquídeo , Esclerosis Amiotrófica Lateral/virología , Enterovirus/genética , Genoma Viral/fisiología , ARN Viral/líquido cefalorraquídeo , Anciano , Esclerosis Amiotrófica Lateral/mortalidad , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la EnfermedadRESUMEN
Our objective was to assess the regulation of the hypoxia response of angiogenic and inflammatory factors from 76 cerebrospinal fluids (CSF) of sporadic amyotrophic lateral sclerosis (ALS) patients with different respiratory status. We first analysed the hypoxia response capacity by measuring CSF levels of angiogenin (ANG), VEGF, angiopoietin-2 (ANG-2) and PGE-2 in 40 ALS patients according to their hypoxaemia level and compared it with 40 neurological controls. We then compared the ANG, VEGF, EPO and ANG-2 CSF levels of 36 other ALS patients, divided into three groups with either 1) normoxaemia, 2) intermittent desaturation in the absence of hypoxaemia, or 3) chronic hypoxaemia with or without desaturation. We demonstrated a lack of up-regulation of both ANG and VEGF during hypoxaemia in ALS, compared with hypoxaemic controls. In contrast, PGE-2 and ANG-2 levels were increased in both hypoxaemic ALS patients and controls. ANG and VEGF levels did not increase in patients with long disease durations and with intermittent or chronic hypoxaemia. ANG-2 and EPO levels were up-regulated early in intermittent hypoxaemia and late in chronic hypoxaemia, respectively. Our results suggest alteration of the HIF-1alpha-mediated response to hypoxia during sporadic ALS, whereas the NFK-B pathway seems early activated.