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1.
J Med Genet ; 60(7): 644-654, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-36446582

RESUMEN

BACKGROUND: KBG syndrome is a highly variable neurodevelopmental disorder and clinical diagnostic criteria have changed as new patients have been reported. Both loss-of-function sequence variants and large deletions (copy number variations, CNVs) involving ANKRD11 cause KBG syndrome, but no genotype-phenotype correlation has been reported. METHODS: 67 patients with KBG syndrome were assessed using a custom phenotypical questionnaire. Manifestations present in >50% of the patients and a 'phenotypical score' were used to perform a genotype-phenotype correlation in 340 patients from our cohort and the literature. RESULTS: Neurodevelopmental delay, macrodontia, triangular face, characteristic ears, nose and eyebrows were the most prevalentf (eatures. 82.8% of the patients had at least one of seven main comorbidities: hearing loss and/or otitis media, visual problems, cryptorchidism, cardiopathy, feeding difficulties and/or seizures. Associations found included a higher phenotypical score in patients with sequence variants compared with CNVs and a higher frequency of triangular face (71.1% vs 42.5% in CNVs). Short stature was more frequent in patients with exon 9 variants (62.5% inside vs 27.8% outside exon 9), and the prevalence of intellectual disability/attention deficit hyperactivity disorder/autism spectrum disorder was lower in patients with the c.1903_1907del variant (70.4% vs 89.4% other variants). Presence of macrodontia and comorbidities were associated with larger deletion sizes and hand anomalies with smaller deletions. CONCLUSION: We present a detailed phenotypical description of KBG syndrome in the largest series reported to date of 67 patients, provide evidence of a genotype-phenotype correlation between some KBG features and specific ANKRD11 variants in 340 patients, and propose updated clinical diagnostic criteria based on our findings.


Asunto(s)
Anomalías Múltiples , Trastorno del Espectro Autista , Enfermedades del Desarrollo Óseo , Discapacidad Intelectual , Anomalías Dentarias , Masculino , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/epidemiología , Discapacidad Intelectual/genética , Anomalías Múltiples/diagnóstico , Enfermedades del Desarrollo Óseo/genética , Anomalías Dentarias/genética , Facies , Trastorno del Espectro Autista/genética , Variaciones en el Número de Copia de ADN , Proteínas Represoras/genética , Deleción Cromosómica , Fenotipo , Factores de Transcripción/genética
2.
Epilepsia ; 64(9): e184-e189, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37335529

RESUMEN

Epilepsy constitutes the most common paroxysmal manifestation of glucose transporter type 1 deficiency (G1D) and is generally considered medication-refractory. It can also prove therapeutic diet-resistant. We examined acetazolamide effects in G1D motivated by several longstanding and recent observations: First, the electrographic spike-waves characteristic of absence seizures often resemble those of G1D and, since the 1950s, they have occasionally been treated successfully with acetazolamide, well before G1D was segregated from absence epilepsy as a distinct syndrome. Second, synaptic inhibitory neuron failure characterizes G1D and, in other experimental models, this can be ameliorated by drugs that modify cellular chloride gradient such as acetazolamide. Third, acetazolamide potently stimulates model cell glucose transport in vitro. Seventeen antiepileptic drug or therapeutic diet-refractory individuals with G1D treated with acetazolamide were thus identified via medical record review complemented by worldwide individual survey. Acetazolamide was tolerated and decreased seizures in 76% of them, with 58% of all persons studied experiencing seizure reductions by more than one-half, including those who first manifested myoclonic-astatic epilepsy or infantile spams. Eighty-eight percent of individuals with G1D continued taking acetazolamide for over 6 months, indicating sustained tolerability and efficacy. The results provide a novel avenue for the treatment and mechanistic investigation of G1D.


Asunto(s)
Acetazolamida , Epilepsia Tipo Ausencia , Humanos , Acetazolamida/uso terapéutico , Transportador de Glucosa de Tipo 1/genética , Anticonvulsivantes/uso terapéutico , Convulsiones/tratamiento farmacológico , Epilepsia Tipo Ausencia/tratamiento farmacológico
3.
Neuropediatrics ; 52(3): 192-200, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33657631

RESUMEN

OBJECTIVE: The study aimed to describe the cases of neurological disease related to the outbreak of enterovirus (EV) in three regions in Northern Spain during 2016. MATERIALS AND METHODS: Multicenter retrospective observational study. Clinical, radiological, and microbiological data were analyzed from patients younger than 15 years with confirmed EV-associated neurological disease admitted to 10 hospitals of Asturias, Cantabria, and Castile and Leon between January 1 and December 31, 2016. RESULTS: Fifty-five patients were included. Median age was 24 months (interquartile range = 18.5 months). Fifteen patients were classified as aseptic meningitis (27.3%). In total, 37 cases presented brainstem encephalitis (67.3%), 25 of them due to EV-A71 with excellent prognosis (84.6% asymptomatic 2 months following the onset). Three cases of acute flaccid myelitis (5.5%) by EV-D68 were reported and presented persistent paresis 2 months following the onset. Microbiological diagnosis by reverse transcriptase polymerase chain reaction was performed in all cases, finding EV in cerebrospinal fluid in meningitis, but not in brainstem encephalitis and acute flaccid myelitis, where EV was found in respiratory or rectal samples. Step therapy was administrated with intravenous immunoglobulin (IVIG; 32.7%), methylprednisolone (10%), and plasmapheresis (3.6%). Four patients received fluoxetine (7.3%). Twenty patients needed to be admitted to pediatric intensive care unit (36.4%). CONCLUSION: Clinical, microbiological, and radiological diagnosis is essential in outbreaks of EV neurological disease, taking into account that it can be difficult to identify EV-A71 and EV-D68 in CSF, requiring throat or rectal samples. There is not specific treatment to these conditions and the efficacy and understanding of the mechanism of action of immune-modulatory treatment (IVIG, corticosteroids, and plasmapheresis) is limited.


Asunto(s)
Enterovirus Humano D , Infecciones por Enterovirus , Mielitis , Niño , Brotes de Enfermedades , Infecciones por Enterovirus/diagnóstico , Infecciones por Enterovirus/epidemiología , Infecciones por Enterovirus/terapia , Humanos , Lactante , Mielitis/complicaciones , Mielitis/epidemiología , Mielitis/terapia , España/epidemiología
4.
Int J Mol Sci ; 22(23)2021 Nov 23.
Artículo en Inglés | MEDLINE | ID: mdl-34884460

RESUMEN

BACKGROUND: GRIN-related disorders (GRD), the so-called grinpathies, is a group of rare encephalopathies caused by mutations affecting GRIN genes (mostly GRIN1, GRIN2A and GRIN2B genes), which encode for the GluN subunit of the N-methyl D-aspartate (NMDA) type ionotropic glutamate receptors. A growing number of functional studies indicate that GRIN-encoded GluN1 subunit disturbances can be dichotomically classified into gain- and loss-of-function, although intermediate complex scenarios are often present. METHODS: In this study, we aimed to delineate the structural and functional alterations of GRIN1 disease-associated variants, and their correlations with clinical symptoms in a Spanish cohort of 15 paediatric encephalopathy patients harbouring these variants. RESULTS: Patients harbouring GRIN1 disease-associated variants have been clinically deeply-phenotyped. Further, using computational and in vitro approaches, we identified different critical checkpoints affecting GluN1 biogenesis (protein stability, subunit assembly and surface trafficking) and/or NMDAR biophysical properties, and their association with GRD clinical symptoms. CONCLUSIONS: Our findings show a strong correlation between GRIN1 variants-associated structural and functional outcomes. This structural-functional stratification provides relevant insights of genotype-phenotype association, contributing to future precision medicine of GRIN1-related encephalopathies.


Asunto(s)
Encefalopatías/patología , Mutación , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/genética , Receptores de N-Metil-D-Aspartato/química , Receptores de N-Metil-D-Aspartato/genética , Adolescente , Animales , Encefalopatías/genética , Células COS , Niño , Preescolar , Chlorocebus aethiops , Estudios de Cohortes , Femenino , Células HEK293 , Humanos , Lactante , Masculino , Modelos Moleculares , Conformación Proteica , España
5.
Am J Med Genet A ; 182(1): 257-267, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31769173

RESUMEN

"An International Meeting on Wolf-Hirschhorn Syndrome (WHS)" was held at The University Hospital La Paz in Madrid, Spain (October 13-14, 2017). One hundred and twenty-five people, including physicians, scientists and affected families, attended the meeting. Parent and patient advocates from the Spanish Association of WHS opened the meeting with a panel discussion to set the stage regarding their hopes and expectations for therapeutic advances. In keeping with the theme on therapeutic development, the sessions followed a progression from description of the phenotype and definition of therapeutic endpoints, to definition of genomic changes. These proceedings will review the major points of discussion.


Asunto(s)
Cromosomas Humanos Par 4/inmunología , Discapacidades del Desarrollo/genética , Convulsiones/genética , Síndrome de Wolf-Hirschhorn/genética , Deleción Cromosómica , Cromosomas Humanos Par 4/genética , Discapacidades del Desarrollo/epidemiología , Discapacidades del Desarrollo/patología , Femenino , Humanos , Fenotipo , Convulsiones/epidemiología , Convulsiones/terapia , España/epidemiología , Síndrome de Wolf-Hirschhorn/epidemiología , Síndrome de Wolf-Hirschhorn/terapia
6.
Medicina (B Aires) ; 79(Suppl 1): 4-9, 2019.
Artículo en Español | MEDLINE | ID: mdl-30776272

RESUMEN

Autism spectrum disorders are a heterogeneous group of disorders that share the presence of two core symptoms: problems in social interaction / communication and the tendency to present restricted interests and repetitive behavior. Over the last years, several epidemiologic studies have been published by different authors in diverse countries, having all of them shown two common characteristics: a global increase in the prevalence rates of autism spectrum disorders, and the existence of a great geographical variability no only between geographical areas, but also within the same geographical areas. At the present manuscript, we analyze some of the most recent prevalence data published in USA and some European countries (including Spain). All of them show different prevalence rates, ranging from 1/59 children with autism spectrum disorders in the USA to 1/806 in Portugal. In a second part, we briefly describe some of the current scientific hypotheses that try to explain this variability.


Los trastornos del espectro autista (TEA) engloban a un grupo heterogéneo de trastornos del neurodesarrollo que tienen en común la presencia de problemas para la interacción/comunicación social y la tendencia a mostrar intereses restringidos o conductas repetitivas. Diversos estudios epidemiológicos realizados en diferentes países en los últimos años han mostrado de forma consistente dos características: el incremento progresivo en la prevalencia de los TEA a nivel mundial y la existencia de una gran variabilidad geográfica entre territorios y dentro de un mismo territorio. En el presente artículo analizamos los datos de prevalencia más recientemente publicados en EE.UU. y en diversos países de Europa (incluyendo España), que muestran tasas de prevalencia muy variables, con un rango que abarca desde 1/59 niños con trastornos del espectro autista en EE. UU., hasta 1/806 en Portugal. En un segundo tiempo describimos brevemente algunas de las principales hipótesis que intentan explicar esta variabilidad.


Asunto(s)
Trastorno del Espectro Autista/epidemiología , Factores de Edad , Trastorno del Espectro Autista/diagnóstico , Demografía/tendencias , Europa (Continente)/epidemiología , Humanos , Prevalencia , Proyectos de Investigación/normas , España/epidemiología , Estados Unidos/epidemiología
7.
Rev Esp Enferm Dig ; 110(1): 30-34, 2018 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-29106289

RESUMEN

INTRODUCTION: Benign biliary diseases are traditionally treated using plastic stents. However, fully covered self-expanding metal stents are currently gaining acceptance for the treatment of these pathologies. OBJECTIVE: To assess the effectiveness and complications associated with the placement of temporary endoscopic fully covered self-expanding metal stents for the treatment of benign biliary diseases. MATERIALS AND METHODS: This was a retrospective and observational study using a prospective database from a tertiary care center from March 2012 to May 2016. Some patients that had a fully covered metal stent due to a benign biliary disease were also included. The indications, resolution, technical success rates and adverse events were documented. RESULTS: 31 patients were included with a total of 34 stents inserted. The indications were as follows: 8 (25%) post cholecystectomy biliary stenoses, 11 (31%) large or multiple choledocholithiasis, 3 (8.3%) biliary fistulas, 2 (6%) post-liver transplant stenoses, 2 (8.3%) papillary stenoses, 2 (6%) perforations and 2 (6%) bleeds. The global resolution success rate of the stents for all pathologies was 88%, this included 87.5% (7/8) in post cholecystectomy stenoses, 73% (8/11) in large choledocholithiasis and 100% for the remaining indications. Thirty-three of 34 stents were removed after an average of 133 days (ranging from 10 to 180 days). No complications were registered. CONCLUSION: Fully covered self-expanding metal stents are an effective and reliable alternative for the resolution of benign biliary diseases.


Asunto(s)
Enfermedades de las Vías Biliares/terapia , Stents Metálicos Autoexpandibles , Adulto , Anciano , Anciano de 80 o más Años , Colangiopancreatografia Retrógrada Endoscópica , Bases de Datos Factuales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento
8.
Ann Neurol ; 75(2): 317-23, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24318406

RESUMEN

In 5 prospectively diagnosed patients with relapsing post-herpes simplex encephalitis (HSE), N-methyl-D-aspartate receptor (NMDAR) antibodies were identified. Antibody synthesis started 1 to 4 weeks after HSE, preceding the neurological relapse. Three of 5 patients improved postimmunotherapy, 1 spontaneously, and 1 has started to improve. Two additional patients with NMDAR antibodies, 9 with unknown neuronal surface antibodies, and 1 with NMDAR and unknown antibodies, were identified during retrospective assessment of 34 HSE patients; the frequency of autoantibodies increased over time (serum, p=0.004; cerebrospinal fluid, p=0.04). The 3 retrospectively identified NMDAR antibody-positive patients also had evidence of relapsing post-HSE. Overall, these findings indicate that HSE triggers NMDAR antibodies and potentially other brain autoimmunity.


Asunto(s)
Autoinmunidad/fisiología , Encéfalo/fisiopatología , Encefalitis por Herpes Simple/patología , Animales , Preescolar , Encefalitis por Herpes Simple/sangre , Encefalitis por Herpes Simple/líquido cefalorraquídeo , Femenino , Células HEK293 , Humanos , Lactante , Masculino , Estudios Prospectivos , Ratas , Receptores de N-Metil-D-Aspartato/sangre , Estudios Retrospectivos , Transfección , Adulto Joven
9.
J Neurooncol ; 118(2): 205-223, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24771286

RESUMEN

Tuberous sclerosis complex (TSC) is a genetic condition with multisystem involvement, characterized by the development of tumors and other abnormalities in organs such as the brain, retina, skin, heart, kidneys, and lungs. Most patients have neuropathological abnormalities such as cortical tubers, white matter radial migration lines, subependymal nodules, and subependymal giant cell astrocytomas (SEGAs). These lesions are associated with different neurological manifestations that are frequently associated with TSC. These manifestations consist of epilepsy, intellectual disability, and neurobehavioral and psychiatric problems, including autism spectrum disorder. Hydrocephalus may also develop in patients with SEGAs due to ventricular obstruction, when this usually slow-growing tumor reaches sufficient size. Surgery has been the classical approach to treat SEGAs, although this treatment is associated with substantial morbidity and does not completely prevent tumor recurrence. Recently, the mammalian target of rapamycin (mTOR) inhibitor, everolimus, has been approved by the Food and Drug Administration and the European Medicines Agency for the treatment of patients with SEGAs associated with TSC. However, the treatment of SEGAs with these agents requires the development of guidelines that establish a differential diagnosis between SENs and SEGAs, in which neuroradiological examinations play an essential role. With the aim of improving the neuroradiological diagnosis and follow-up of the neuropathological abnormalities associated with TSC, a group of experts in this field has reviewed different aspects related to these issues and put together, a series of statements and recommendations intended to provide guidance to specialists involved in the management of TSC.


Asunto(s)
Encefalopatías/diagnóstico por imagen , Encefalopatías/etiología , Encéfalo/diagnóstico por imagen , Neuroimagen/métodos , Esclerosis Tuberosa/complicaciones , Esclerosis Tuberosa/diagnóstico por imagen , Astrocitoma/diagnóstico , Astrocitoma/diagnóstico por imagen , Astrocitoma/terapia , Encéfalo/patología , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/terapia , Diagnóstico Diferencial , Humanos , Radiografía , Ultrasonografía Prenatal
10.
J Pediatr ; 162(4): 850-856.e2, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23164315

RESUMEN

OBJECTIVE: To report the clinical features of 20 pediatric patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. STUDY DESIGN: Review of clinical data, long-term follow-up, and immunologic studies performed in a single center in Spain in the last 4 years. RESULTS: The median age of the patients was 13 years (range, 8 months-18 years), 70% were female. In 12 patients (60%), the initial symptoms were neurologic, usually dyskinesias or seizures, and in the other 40% psychiatric. One month into the disease, all patients had involuntary movements and alterations of behavior and speech. All patients received steroids, intravenous immunoglobulin or plasma exchange, and 7 rituximab or cyclophosphamide. With a median follow up of 17.5 months, 85% had substantial recovery, 10% moderate or severe deficits, and 1 died. Three patients had previous episodes compatible with anti-NMDAR encephalitis, 2 of them with additional relapses after the diagnosis of the disorder. Ovarian teratoma was identified in 2 patients, 1 at onset of encephalitis and the other 1 year later. Two novel observations (1 patient each) include, the identification of an electroencephalographic pattern ("extreme delta brush") considered characteristic of this disorder, and the development of anti-NMDAR encephalitis as post herpes simplex encephalitis choreoathetosis. CONCLUSIONS: The initial symptoms of pediatric anti-NMDAR encephalitis vary from those of the adults (more neurologic and less psychiatric in children), the development of a mono-symptomatic illness is extremely rare (except in relapses), and most patients respond to treatment. Our study suggests a link between post herpes simplex encephalitis choreoathetosis and anti-NMDAR encephalitis.


Asunto(s)
Encefalitis Antirreceptor N-Metil-D-Aspartato/sangre , Encefalitis Antirreceptor N-Metil-D-Aspartato/diagnóstico , Adolescente , Encéfalo/patología , Niño , Preescolar , Femenino , Humanos , Inmunoterapia/métodos , Lactante , Imagen por Resonancia Magnética/métodos , Masculino , Pediatría/métodos , España , Factores de Tiempo , Resultado del Tratamiento
11.
Pediatr Neurol ; 148: 198-205, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37652816

RESUMEN

We offer a primer to the modifiability of genetic neurological disease, particularly during development. One goal is to harness several unexpected observations made in the course of experimental gene modification or therapy into an explanatory conceptual context based on biological first principles. To this end, we anchor growing, disparate reports of unusual or untoward effects to a plausible framework wherein genes exhibit different degrees of modifiability and may result, when mutated or therapeutically modified, in unsuspected consequences. We propose that genetic pathogenic variant effects and modifiability depend on the number and complexity of associated protein-protein or higher-order interactions. Thus, gene malleability may range from that characteristic of the favorably modifiable primarily structural genes that subserve relatively invariant or circumscribed phenomena such as cell shape to that typical of some transcription factors, which are less functionally predictable when altered. The latter may be expressed developmentally, in compartmentalized manner, or only intermittently and yet exert vastly ramified influences sometimes circumscribed only to select species. We also argue that genetic diseases may steer the organism toward often poorly understood biological end points and co-opt multiple processes into hardly modifiable biology. Addition or modification of genes to approximate a normal state not previously experienced by the organism may lead to further aberration due to extraneous interference with the native biology of the disease state. Therefore, an understanding as perspicuous as possible of gene function, regulation, modifiability, and biological directionality down to seemingly minute but disease-relevant consequences is a prerequisite to intervention. Although we provide some groundwork steps to such an understanding, this may occasionally prove unattainable.

12.
Sci Rep ; 13(1): 3465, 2023 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-36859467

RESUMEN

Augmentation of anaplerosis, or replenishment of carbon lost during intermediary metabolic transitions, is desirable in energy metabolism defects. Triheptanoin, the triglyceride of 7-carbon heptanoic acid, is anaplerotic via direct oxidation or 5-carbon ketone body generation. In this context, triheptanoin can be used to treat Glucose transporter type 1 deficiency encephalopathy (G1D). An oral triheptanoin dose of 1 g/Kg/day supplies near 35% of the total caloric intake and impacted epilepsy and cognition in G1D. This provided the motivation to establish a maximum, potentially greater dose. Using a 3 + 3 dose-finding approach useful in oncology, we studied three age groups: 4-6, 6.8-10 and 11-16 years old. This allowed us to arrive at a maximum tolerated dose of 45% of daily caloric intake for each group. Safety was ascertained via analytical blood measures. One dose-limiting toxicity, occurring in 1 of 6 subjects, was encountered in the middle age group in the context of frequently reduced gastrointestinal tolerance for all groups. Ketonemia following triheptanoin was determined in another group of G1D subjects. In them, ß-ketopentanoate and ß-hydroxypentanoate concentrations were robustly but variably increased. These results enable the rigorous clinical investigation of triheptanoin in G1D by providing dosing and initial tolerability, safety and ketonemic potential.ClinicalTrials.gov registration: NCT03041363, first registration 02/02/2017.


Asunto(s)
Cetosis , Persona de Mediana Edad , Humanos , Preescolar , Transportador de Glucosa de Tipo 1 , Carbono , Triglicéridos
13.
Sci Rep ; 13(1): 8951, 2023 06 02.
Artículo en Inglés | MEDLINE | ID: mdl-37268656

RESUMEN

Fuel influx and metabolism replenish carbon lost during normal neural activity. Ketogenic diets studied in epilepsy, dementia and other disorders do not sustain such replenishment because their ketone body derivatives contain four carbon atoms and are thus devoid of this anaplerotic or net carbon donor capacity. Yet, in these diseases carbon depletion is often inferred from cerebral fluorodeoxyglucose-positron emission tomography. Further, ketogenic diets may prove incompletely therapeutic. These deficiencies provide the motivation for complementation with anaplerotic fuel. However, there are few anaplerotic precursors consumable in clinically sufficient quantities besides those that supply glucose. Five-carbon ketones, stemming from metabolism of the food supplement triheptanoin, are anaplerotic. Triheptanoin can favorably affect Glucose transporter type 1 deficiency (G1D), a carbon-deficiency encephalopathy. However, the triheptanoin constituent heptanoate can compete with ketogenic diet-derived octanoate for metabolism in animals. It can also fuel neoglucogenesis, thus preempting ketosis. These uncertainties can be further accentuated by individual variability in ketogenesis. Therefore, human investigation is essential. Consequently, we examined the compatibility of triheptanoin at maximum tolerable dose with the ketogenic diet in 10 G1D individuals using clinical and electroencephalographic analyses, glycemia, and four- and five-carbon ketosis. 4 of 8 of subjects with pre-triheptanoin beta-hydroxybutyrate levels greater than 2 mM demonstrated a significant reduction in ketosis after triheptanoin. Changes in this and the other measures allowed us to deem the two treatments compatible in the same number of individuals, or 50% of persons in significant beta-hydroxybutyrate ketosis. These results inform the development of individualized anaplerotic modifications to the ketogenic diet.ClinicalTrials.gov registration NCT03301532, first registration: 04/10/2017.


Asunto(s)
Dieta Cetogénica , Cetosis , Animales , Humanos , Transportador de Glucosa de Tipo 1 , Ácido 3-Hidroxibutírico , Cuerpos Cetónicos
14.
Neurol Ther ; 12(1): 89-105, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36269538

RESUMEN

INTRODUCTION: Outcome measures traditionally used in spinal muscular atrophy (SMA) clinical trials are inadequate to assess the full range of disease severity. The aim of this study was to assess the psychometric properties of a set of existing questionnaires and new items, gathering information on the impact of SMA from the patient and caregiver perspectives. METHODS: This was a multicenter, prospective, noninterventional study including patients with a confirmed diagnosis of 5q-autosomal-recessive SMA aged 8 years and above, or their parents (if aged between 2 and 8 years). The set of outcome measurements included the SMA Independence Scale (SMAIS) patient and caregiver versions, the Neuro-QoL Fatigue Computer Adaptive Test (CAT), the Neuro-QoL Pain Short Form-Pediatric Pain, the PROMIS adult Pain Interference CAT, and new items developed by Fundación Atrofia Muscular España: perceived fatigability, breathing and voice, sleep and rest, and vulnerability. Reliability, construct validity, discriminant validity, and sensitivity to change (4 months from baseline) were measured. RESULTS: A total of 113 patients were included (59.3% 2-17 years old, 59.3% male, and 50.4% with SMA type II). Patients required moderate assistance [mean patient and caregiver SMAIS (SD) scores were 31.1 (12.8) and 7.6 (11.1), respectively]. Perceived fatigability was the most impacted domain, followed by vulnerability. Cronbach's alpha coefficient for perceived fatigability, breathing and voice, and vulnerability total scores were 0.92, 0.88, and 0.85, respectively. The exploratory factor analysis identified the main factors considered in the design, except in the sleep and rest domain. All questionnaires were able to discriminate between the Clinical Global Impression-Severity scores and SMA types. Sensitivity to change was only found for the SMAIS caregiver version and vulnerability items. CONCLUSIONS: This set of outcome measures showed adequate reliability, construct validity, and discriminant validity and may constitute a valuable option to measure symptom severity in patients with SMA.

15.
Neurol Ther ; 11(3): 1209-1219, 2022 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-35657490

RESUMEN

INTRODUCTION: There are many uncertainties about treatment selection and expectations regarding therapeutic goals and benefits in the new landscape of spinal muscular atrophy (SMA). Our aim was to assess treatment preferences and expectations of pediatric neurologists caring for patients with SMA. METHODS: DECISIONS-SMA is a non-interventional, cross-sectional pilot study that assessed pediatric neurologists with expertise in SMA from across Spain. Participants were presented with 11 simulated case scenarios of common encounters of patients with SMA type 1 and 2 to assess treatment initiation, escalation, or switches. We also asked for the expected benefit with new therapies for four simulated case scenarios. Participants completed a behavioral battery to address their tolerance to uncertainty and aversion to ambiguity. The primary outcome was therapeutic inertia (TI), defined as the number of simulated scenarios with lack of treatment initiation or escalation when warranted over the total (11) presented cases. RESULTS: A total of 35 participants completed the study. Participants' mean (SD) expectation for achieving an improvement by starting a new therapy for SMA type 1 (case 1, a 5-month-old) and SMA type 2 (case 6, a 1-year-old) were both 59.6% (± 21.8), but declined to 20.2% (± 12.2) for a case scenario of a 16-year-old treatment-naïve patient with long-standing SMA type 2 with severe disability. The mean (SD) TI score was 4.2 (1.7), and 3.29 (1.5) for treatment initiation. Of a total 385 individual responses, TI was observed in 147 (38.2%) of treatment choices. The multivariable analysis showed that lower aversion to ambiguity (p = 0.019) and lower expectation of treatment response (p = 0.007) were associated with higher TI after adjustment for participants' age and years of experience. Older age (p = 0.019), lower years of experience (p = 0.035), lower aversion to ambiguity (p = 0.015), and lower expectation of treatment benefits (p = 0.006) were associated with inertia for treatment initiation. CONCLUSIONS: Pediatric neurologists managing patients with SMA were optimistic regarding treatment improvement in cases with early diagnosis, but had lower expectations when treatment delays and advanced patient age were present. Low aversion to ambiguity, low expectation of treatment benefits, and lower clinical experience were more likely to make suboptimal decisions, resulting in lack of treatment initiation, escalation, and TI.

16.
PLoS One ; 17(2): e0264006, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35167619

RESUMEN

BACKGROUND: The therapeutic landscape for spinal muscular atrophy has changed in the last few years, encompassing respiratory/motor function and life expectancy benefits. However, physicians still have the challenge of tailoring individuals' treatment to therapeutic goals, disease progression, patient/caregiver's preferences, and personal experience to achieve an optimal risk/benefit balance. This study aims to provide insight into the preferred treatment choices of pediatric neurologists managing spinal muscular atrophy in their daily practice and to recognize behavioral factors that may influence decision-making. METHODS: This is a noninterventional, cross-sectional pilot study involving 50 pediatric neurologists managing spinal muscular atrophy in Spain. We designed an online platform that contains 13 simulated case scenarios of common presentations of patients with spinal muscular atrophy. The primary study outcome will be treatment preferences according to the percentages of participants who select treatment initiation when recommended, switch therapies when there is evidence of disease progression, and select treatment discontinuation when disease progression puts patients outside treatment recommendation (11 case scenarios). Secondary outcomes include therapeutic inertia prevalence (11 case scenarios), herding phenomenon prevalence (2 case scenarios), care-related regret prevalence (specific questions) and intensity (10-item Regret Intensity Scale), occupational burnout prevalence (nonproprietary single-item measure), and risk preferences (uncertainty test and risk aversion assessment). CONCLUSIONS: The study findings will contribute to better understand relevant factors associated with therapeutic decisions of pediatric neurologists in spinal muscular atrophy, identifying treatment preferences and evaluating the role of behavioral aspects such as therapeutic inertia, herding, regret, and workplace burnout.


Asunto(s)
Toma de Decisiones Clínicas/métodos , Atrofia Muscular Espinal/terapia , Neurólogos/psicología , Agotamiento Profesional/epidemiología , Estudios Transversales , Progresión de la Enfermedad , Humanos , Prioridad del Paciente , Pediatría , Proyectos Piloto
17.
Lancet Neurol ; 19(3): 234-246, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-32057303

RESUMEN

BACKGROUND: Investigations of myelin oligodendrocyte glycoprotein (MOG) antibodies are usually focused on demyelinating syndromes, but the entire spectrum of MOG antibody-associated syndromes in children is unknown. In this study, we aimed to determine the frequency and distribution of paediatric demyelinating and encephalitic syndromes with MOG antibodies, their response to treatment, and the phenotypes associated with poor prognosis. METHODS: In this prospective observational study, children with demyelinating syndromes and with encephalitis other than acute disseminated encephalomyelitis (ADEM) recruited from 40 secondary and tertiary centres in Spain were investigated for MOG antibodies. All MOG antibody-positive cases were included in our study, which assessed syndromes, treatment and response to treatment (ie, number of relapses), outcomes (measured with the modified Rankin scale [mRS]), and phenotypes associated with poor prognosis. We used Fisher's exact and Wilcoxon rank sum tests to analyse clinical features, and survival Cox regression to analyse time to antibody negativity. FINDINGS: Between June 1, 2013, and Dec 31, 2018, 239 children with demyelinating syndromes (cohort A) and 296 with encephalitis other than ADEM (cohort B) were recruited. 116 patients had MOG antibodies, including 94 (39%) from cohort A and 22 (7%) from cohort B; 57 (49%) were female, with a median age of 6·2 years (IQR 3·7-10·0). Presenting syndromes in these 116 patients included ADEM (46 [68%]), encephalitis other than ADEM (22 [19%]), optic neuritis (20 [17%]), myelitis (13 [11%]), neuromyelitis optica spectrum disorders (six [5%]), and other disorders (nine [8%]). Among the patients with autoimmune encephalitis in cohort B (n=64), MOG antibodies were more common than all neuronal antibodies combined (22 [34%] vs 21 [33%]). After a median follow-up of 42 months (IQR 22-67), 33 (28%) of the 116 patients had relapses, including 17 (17%) of 100 diagnosed at first episode. Steroids, intravenous immunoglobulin, or plasma exchange were used in 100 (86%) patients at diagnosis, and 32 (97%) of 33 at relapses. Rituximab was mainly used at relapses (11 [33%]). 99 (85%) of 116 patients had substantial recovery (mRS <2) and 17 (15%) moderate to severe deficits (mRS >2; one died). Phenotypes of poor prognosis included ADEM-like relapses progressing to leukodystrophy-like features, and extensive cortical encephalitis evolving to atrophy. Time to antibody negativity was longer in patients with relapses (HR 0·18, 95% CI 0·05-0·59). INTERPRETATION: The spectrum of paediatric MOG antibody-associated syndromes is wider than previously reported and includes demyelinating syndromes and encephalitis. Recognition of these disorders has important clinical and prognostic implications. FUNDING: Mutua Madrileña Foundation; ISCIII-Subdirección General de Evaluación y Fomento de la Investigación Sanitaria; Fondo Europeo de Desarrollo Regional; Pediatrics Spanish Society; Departament de Salut, Generalitat de Catalunya; Marato TV3 Foundation; Red Española de Esclerosis Múltiple; La Caixa Foundation; and Fundació CELLEX.


Asunto(s)
Enfermedades Desmielinizantes/inmunología , Encefalitis/inmunología , Glicoproteína Mielina-Oligodendrócito/inmunología , Autoanticuerpos/sangre , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Inmunoglobulina G/sangre , Inmunoglobulinas Intravenosas , Imagen por Resonancia Magnética , Masculino , Glicoproteína Mielina-Oligodendrócito/análisis , Neuromielitis Óptica/sangre , Neuromielitis Óptica/diagnóstico , Neuromielitis Óptica/inmunología , Pediatría , Estudios Prospectivos , España , Síndrome
18.
An Pediatr (Engl Ed) ; 91(6): 415.e1-415.e10, 2019 Dec.
Artículo en Español | MEDLINE | ID: mdl-31708334

RESUMEN

It is estimated that about 70 million people all over the world suffer from epilepsy, half of which are children, in whom the prevalence is around 0.5 to 0.8%. Although there are several therapies, the treatment of epilepsy is based mainly on drugs, which, depending on the year of coming onto the market are classified as first, second, or third generation. In this article, a description is presented on the main characteristics of the latest generation of anti-epileptic drugs (lacosamide, eslicarbazepine acetate, brivaracetam, perampanel, retigabine, everolimus and cannabidiol). These, with the exception of retigabine (is not yet on the market), are considered safe and effective in the paediatric population. Everolimus and cannabidiol have very specific indications (tuberous sclerosis, Dravet syndrome, and Lennox Gastaut syndrome), while the rest are indicated in the management of seizures of focal origin in children from 4 years-old. These new molecules have been developed in order to provide a pharmaceutical profile and tolerance superior to the previously available drugs, and it is forecast that as their use increases, their true potential and profile will widen. Furthermore, for the first time in Paediatric Epileptology, the extrapolation of the efficacy data in adults have been used (together with specific safety and pharmacokinetic studies in the paediatric population), in order to speed up their approval for use in the child population.


Asunto(s)
Anticonvulsivantes/administración & dosificación , Epilepsia/tratamiento farmacológico , Anticonvulsivantes/efectos adversos , Anticonvulsivantes/farmacología , Niño , Preescolar , Epilepsia/epidemiología , Epilepsia/fisiopatología , Humanos , Prevalencia
19.
Epileptic Disord ; 20(4): 239-256, 2018 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-30078771

RESUMEN

The objective of this study was to gather evidence-based data on the educational needs of neuropediatricians. A needs assessment was conducted to identify the clinical challenges of physicians when diagnosing, medically treating, and managing pediatric patients with epilepsy; which could be addressed through educational interventions. A two-phase mixed-methods approach was used to conduct the needs assessment in Germany, Spain, and the US. Phase 1 consisted of qualitative data collection through multiple sources: a literature review, semi-structured interviews with clinicians and nurses working in pediatric epilepsy, and interpretation and input from faculty experts. Qualitative data were coded (NVivo) and analyzed using a thematic analysis, and findings were then used to design the second phase. Phase 2 consisted of quantitative data collection through an online survey that aimed to validate the identified challenges and underlying causes using a larger sample than in Phase 1. Data from the survey were analyzed using frequency tabulations and chi-square tests (SPSS). A total of 267 participants were included in the study. Phase 1 included 88 participants (neurologists, pediatricians, neuropediatricians, and nurses). Phase 2 included 179 participants (neurologists, pediatricians, and neuropediatricians). The main areas of challenge which emerged from the triangulated data included: the integration of guidelines into practice, identification of epilepsy and epilepsy events, integration of genetic testing into practice, integration of non-pharmacological treatments, transition from pediatric to adult care, and involvement and engagement with caregivers. Underlying causes of these challenges are reported, along with supporting qualitative findings. This study identified the educational needs of physicians working in pediatric epilepsy in Germany, Spain and the USA. Increasingly, educational interventions are required to be evidence-based. The results of this study could be used to design such interventions to support neuropediatricians who wish to specialize in pediatric epileptology, in order to manage the identified challenges.


Asunto(s)
Epilepsia/diagnóstico , Epilepsia/terapia , Neurólogos/estadística & datos numéricos , Pediatras/estadística & datos numéricos , Adulto , Femenino , Alemania , Humanos , Masculino , Persona de Mediana Edad , Neurólogos/educación , Pediatras/educación , España , Estados Unidos
20.
Neurology ; 85(20): 1736-43, 2015 Nov 17.
Artículo en Inglés | MEDLINE | ID: mdl-26491084

RESUMEN

OBJECTIVE: To report 14 patients with immune-mediated relapsing symptoms post-herpes simplex encephalitis (HSE) and to compare the clinical and immunologic features of the teenage and adult group with those of young children. METHODS: Prospective observational study of patients diagnosed between June 2013 and February 2015. Immunologic techniques have been reported previously. RESULTS: Among the teenage and adult group (8 patients, median age 40 years, range 13-69; 5 male), 3 had an acute symptom presentation suggesting a viral relapse, and 5 a presentation contiguous with HSE suggesting a recrudescence of previous deficits. Seven patients developed severe psychiatric/behavioral symptoms disrupting all social interactions, and one refractory status epilepticus. Blepharospasm occurred in one patient. Five patients had CSF antibodies against NMDA receptor (NMDAR) and 3 against unknown neuronal cell surface proteins. In 5/6 patients, the brain MRI showed new areas of contrast enhancement that decreased after immunotherapy and clinical improvement. Immunotherapy was useful in 7/7 patients, sometimes with impressive recoveries, returning to their baseline HSE residual deficits. Compared with the 6 younger children (median age 13 months, range 6-20, all with NMDAR antibodies), the teenagers and adults were less likely to develop choreoathetosis (0/8 vs 6/6, p < 0.01) and decreased level of consciousness (2/8 vs 6/6, p < 0.01) and had longer delays in diagnosis and treatment (interval relapse/antibody testing 85 days, range 17-296, vs 4 days, range 0-33, p = 0.037). CONCLUSION: In teenagers and adults, the immune-mediated relapsing syndrome post-HSE is different from that known in young children as choreoathetosis post-HSE and is underrecognized. Prompt diagnosis is important because immunotherapy can be highly effective.


Asunto(s)
Encefalitis por Herpes Simple/diagnóstico , Encefalitis por Herpes Simple/inmunología , Herpes Simple/diagnóstico , Herpes Simple/inmunología , Adolescente , Adulto , Anciano , Encefalitis por Herpes Simple/tratamiento farmacológico , Femenino , Herpes Simple/tratamiento farmacológico , Humanos , Inmunoterapia/tendencias , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Método Simple Ciego , Adulto Joven
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