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1.
Epilepsy Behav ; 116: 107741, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33493803

RESUMEN

The objective of this analysis was to determine possible interactions between lamotrigine (LTG) and coffee or cigarette use. As part of the statistical analysis of factors influencing LTG pharmacokinetics (PK) in the Equigen chronic dose study, we collected prospective data from enrolled patients on their use of coffee and cigarettes. Subjects were part of a crossover replication study of generic LTG products with rigorous blood sampling and were instructed to not change their typical consumption of these products for the duration of the study. A total of 35 subjects were enrolled, with 33 subjects having sufficient data for analysis. Higher consumption of coffee was associated with a significantly lower area under the curve (AUC) and maximum concentration (Cmax) of lamotrigine (LTG). Higher cigarette use did not result in a significant change in AUC or Cmax. Coffee, but not cigarette use, either induces LTG metabolism or inhibits LTG absorption.


Asunto(s)
Fumar Cigarrillos , Epilepsia , Anticonvulsivantes/uso terapéutico , Café , Interacciones Farmacológicas , Epilepsia/tratamiento farmacológico , Humanos , Lamotrigina/uso terapéutico , Estudios Prospectivos , Triazinas/uso terapéutico
2.
Epilepsia ; 58(6): 1005-1014, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28387951

RESUMEN

OBJECTIVE: Evaluate the seizure-reduction response and safety of brain-responsive stimulation in adults with medically intractable partial-onset seizures of neocortical origin. METHODS: Patients with partial seizures of neocortical origin were identified from prospective clinical trials of a brain-responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2-6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events. Additional analyses considered safety and seizure reduction according to lobe and functional area (e.g., eloquent cortex) of seizure onset. RESULTS: There were 126 patients with seizures of neocortical onset. The average follow-up was 6.1 implant years. The median percent seizure reduction was 70% in patients with frontal and parietal seizure onsets, 58% in those with temporal neocortical onsets, and 51% in those with multilobar onsets (last observation carried forward [LOCF] analysis). Twenty-six percent of patients experienced at least one seizure-free period of 6 months or longer and 14% experienced at least one seizure-free period of 1 year or longer. Patients with lesions on magnetic resonance imaging (MRI; 77% reduction, LOCF) and those with normal MRI findings (45% reduction, LOCF) benefitted, although the treatment response was more robust in patients with an MRI lesion (p = 0.02, generalized estimating equation [GEE]). There were no differences in the seizure reduction in patients with and without prior epilepsy surgery or vagus nerve stimulation. Stimulation parameters used for treatment did not cause acute or chronic neurologic deficits, even in eloquent cortical areas. The rates of infection (0.017 per patient implant year) and perioperative hemorrhage (0.8%) were not greater than with other neurostimulation devices. SIGNIFICANCE: Brain-responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including adults with seizures of neocortical onset, and those with onsets from eloquent cortex.


Asunto(s)
Corteza Cerebral/fisiopatología , Estimulación Encefálica Profunda/métodos , Epilepsia Refractaria/fisiopatología , Epilepsia Refractaria/terapia , Terapia por Estimulación Eléctrica/métodos , Electroencefalografía , Neocórtex/fisiopatología , Adolescente , Adulto , Mapeo Encefálico , Estimulación Encefálica Profunda/instrumentación , Terapia por Estimulación Eléctrica/instrumentación , Electrodos Implantados , Epilepsias Parciales/fisiopatología , Epilepsias Parciales/terapia , Epilepsia Parcial Compleja/fisiopatología , Epilepsia Parcial Compleja/terapia , Epilepsia Parcial Motora/fisiopatología , Epilepsia Parcial Motora/terapia , Epilepsia Tónico-Clónica/fisiopatología , Epilepsia Tónico-Clónica/terapia , Estudios de Factibilidad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven
3.
Hum Mol Genet ; 23(16): 4357-70, 2014 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-24698976

RESUMEN

Cerebral cavernous malformations (CCMs) are vascular lesions affecting the central nervous system. CCM occurs either sporadically or in an inherited, autosomal dominant manner. Constitutional (germline) mutations in any of three genes, KRIT1, CCM2 and PDCD10, can cause the inherited form. Analysis of CCM lesions from inherited cases revealed biallelic somatic mutations, indicating that CCM follows a Knudsonian two-hit mutation mechanism. It is still unknown, however, if the sporadic cases of CCM also follow this genetic mechanism. We extracted DNA from 11 surgically excised lesions from sporadic CCM patients, and sequenced the three CCM genes in each specimen using a next-generation sequencing approach. Four sporadic CCM lesion samples (36%) were found to contain novel somatic mutations. Three of the lesions contained a single somatic mutation, and one lesion contained two biallelic somatic mutations. Herein, we also describe evidence of somatic mosaicism in a patient presenting with over 130 CCM lesions localized to one hemisphere of the brain. Finally, in a lesion regrowth sample, we found that the regrown CCM lesion contained the same somatic mutation as the original lesion. Together, these data bolster the idea that all forms of CCM have a genetic underpinning of the two-hit mutation mechanism in the known CCM genes. Recent studies have found aberrant Rho kinase activation in inherited CCM pathogenesis, and we present evidence that this pathway is activated in sporadic CCM patients. These results suggest that all CCM patients, including those with the more common sporadic form, are potentially amenable to the same therapy.


Asunto(s)
Proteínas Reguladoras de la Apoptosis/genética , Proteínas Portadoras/genética , Neoplasias del Sistema Nervioso Central/genética , Hemangioma Cavernoso del Sistema Nervioso Central/genética , Proteínas de la Membrana/genética , Proteínas Asociadas a Microtúbulos/genética , Mutación , Proteínas Proto-Oncogénicas/genética , Neoplasias del Sistema Nervioso Central/patología , Células Endoteliales/metabolismo , Hemangioma Cavernoso del Sistema Nervioso Central/patología , Humanos , Proteína KRIT1 , Quinasas Asociadas a rho/metabolismo
4.
Epilepsia ; 56(6): 959-67, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25988840

RESUMEN

OBJECTIVE: Patients with suspected mesial temporal lobe (MTL) epilepsy typically undergo inpatient video-electroencephalography (EEG) monitoring with scalp and/or intracranial electrodes for 1 to 2 weeks to localize and lateralize the seizure focus or foci. Chronic ambulatory electrocorticography (ECoG) in patients with MTL epilepsy may provide additional information about seizure lateralization. This analysis describes data obtained from chronic ambulatory ECoG in patients with suspected bilateral MTL epilepsy in order to assess the time required to determine the seizure lateralization and whether this information could influence treatment decisions. METHODS: Ambulatory ECoG was reviewed in patients with suspected bilateral MTL epilepsy who were among a larger cohort with intractable epilepsy participating in a randomized controlled trial of responsive neurostimulation. Subjects were implanted with bilateral MTL leads and a cranially implanted neurostimulator programmed to detect abnormal interictal and ictal ECoG activity. ECoG data stored by the neurostimulator were reviewed to determine the lateralization of electrographic seizures and the interval of time until independent bilateral MTL electrographic seizures were recorded. RESULTS: Eighty-two subjects were implanted with bilateral MTL leads and followed for 4.7 years on average (median 4.9 years). Independent bilateral MTL electrographic seizures were recorded in 84%. The average time to record bilateral electrographic seizures in the ambulatory setting was 41.6 days (median 13 days, range 0-376 days). Sixteen percent had only unilateral electrographic seizures after an average of 4.6 years of recording. SIGNIFICANCE: About one third of the subjects implanted with bilateral MTL electrodes required >1 month of chronic ambulatory ECoG before the first contralateral MTL electrographic seizure was recorded. Some patients with suspected bilateral MTL seizures had only unilateral electrographic seizures. Chronic ambulatory ECoG in patients with suspected bilateral MTL seizures provides data in a naturalistic setting, may complement data from inpatient video-EEG monitoring, and can contribute to treatment decisions.


Asunto(s)
Ondas Encefálicas/fisiología , Electrocardiografía Ambulatoria , Epilepsia del Lóbulo Temporal/patología , Epilepsia del Lóbulo Temporal/fisiopatología , Lateralidad Funcional/fisiología , Adolescente , Adulto , Electrodos Implantados , Femenino , Hipocampo/patología , Hipocampo/fisiopatología , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto Joven
5.
Cancer Invest ; 28(5): 544-53, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20014946

RESUMEN

Chemotherapeutic agents produce persistent difficulties in memory through an unknown mechanism. We tested the hypothesis that chemotherapeutic agents readily able to cross the blood-brain barrier (cyclophosphamide and fluorouracil), as opposed to those not known to readily cross the barrier (paclitaxel and doxorubicin), reduce neural cell proliferation following chemotherapy. We found that 5-bromo-2-deoxyuridine labeling following chemotherapy given to C57BL/6 mice revealed a similar reduction in neural cell proliferation in the dentate gyrus for all four agents. Insulin-like growth factor 1, a molecule implicated in promoting neurogenesis, counteracted the effects of high doses of chemotherapy on neural cell proliferation.


Asunto(s)
Antineoplásicos/toxicidad , Barrera Hematoencefálica , Giro Dentado/efectos de los fármacos , Factor I del Crecimiento Similar a la Insulina/farmacología , Animales , Antineoplásicos/metabolismo , Bromodesoxiuridina/metabolismo , Proliferación Celular/efectos de los fármacos , Ciclofosfamida/toxicidad , Doxorrubicina/toxicidad , Fluorouracilo/toxicidad , Humanos , Ratones , Ratones Endogámicos C57BL , Neurogénesis/efectos de los fármacos , Neuronas/efectos de los fármacos , Paclitaxel/toxicidad , Pérdida de Peso
6.
Neurology ; 95(9): e1244-e1256, 2020 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-32690786

RESUMEN

OBJECTIVE: To prospectively evaluate safety and efficacy of brain-responsive neurostimulation in adults with medically intractable focal onset seizures (FOS) over 9 years. METHODS: Adults treated with brain-responsive neurostimulation in 2-year feasibility or randomized controlled trials were enrolled in a long-term prospective open label trial (LTT) to assess safety, efficacy, and quality of life (QOL) over an additional 7 years. Safety was assessed as adverse events (AEs), efficacy as median percent change in seizure frequency and responder rate, and QOL with the Quality of Life in Epilepsy (QOLIE-89) inventory. RESULTS: Of 256 patients treated in the initial trials, 230 participated in the LTT. At 9 years, the median percent reduction in seizure frequency was 75% (p < 0.0001, Wilcoxon signed rank), responder rate was 73%, and 35% had a ≥90% reduction in seizure frequency. We found that 18.4% (47 of 256) experienced ≥1 year of seizure freedom, with 62% (29 of 47) seizure-free at the last follow-up and an average seizure-free period of 3.2 years (range 1.04-9.6 years). Overall QOL and epilepsy-targeted and cognitive domains of QOLIE-89 remained significantly improved (p < 0.05). There were no serious AEs related to stimulation, and the sudden unexplained death in epilepsy (SUDEP) rate was significantly lower than predefined comparators (p < 0.05, 1-tailed χ2). CONCLUSIONS: Adjunctive brain-responsive neurostimulation provides significant and sustained reductions in the frequency of FOS with improved QOL. Stimulation was well tolerated; implantation-related AEs were typical of other neurostimulation devices; and SUDEP rates were low. CLINICALTRIALSGOV IDENTIFIER: NCT00572195. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that brain-responsive neurostimulation significantly reduces focal seizures with acceptable safety over 9 years.


Asunto(s)
Epilepsia Refractaria/terapia , Terapia por Estimulación Eléctrica/métodos , Epilepsias Parciales/terapia , Neuroestimuladores Implantables , Calidad de Vida , Adolescente , Adulto , Anciano , Trastorno Depresivo/epidemiología , Epilepsia Refractaria/fisiopatología , Epilepsia Refractaria/psicología , Epilepsias Parciales/fisiopatología , Epilepsias Parciales/psicología , Femenino , Estudios de Seguimiento , Humanos , Hemorragias Intracraneales/epidemiología , Masculino , Trastornos de la Memoria/epidemiología , Persona de Mediana Edad , Estudios Prospectivos , Infecciones Relacionadas con Prótesis/epidemiología , Ensayos Clínicos Controlados Aleatorios como Asunto , Estado Epiléptico/epidemiología , Muerte Súbita e Inesperada en la Epilepsia/epidemiología , Suicidio/estadística & datos numéricos , Resultado del Tratamiento , Adulto Joven
7.
Stroke ; 39(12): 3222-30, 2008 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-18974380

RESUMEN

BACKGROUND AND PURPOSE: Cavernous malformations of the brain (CMs) cause intracranial hemorrhage, but its reported frequency varies, partly attributable to study design. To improve the validity of future research, we aimed to develop a robust definition of CM hemorrhage. METHODS: We systematically reviewed the published literature (Ovid Medline and Embase to June 1, 2007) for definitions of CM hemorrhage used in studies of the untreated clinical course of >or=20 participants with CM(s), to inform the development of a consensus statement on the clinical and imaging features of CM hemorrhage at a scientific workshop of the Angioma Alliance. RESULTS: A systematic review of 1426 publications about CMs in humans, revealed 15 studies meeting our inclusion criteria. Although 14 (93%) studies provided a definition of CM hemorrhage, data were less complete on the confirmatory type(s) of imaging (87%), whether CM hemorrhage should be clinically symptomatic (73%), and whether hemorrhage had to extend outside the CM or not (47%). We define a CM hemorrhage as requiring acute or subacute onset symptoms (any of: headache, epileptic seizure, impaired consciousness, or new/worsened focal neurological deficit referable to the anatomic location of the CM) accompanied by radiological, pathological, surgical, or rarely only cerebrospinal fluid evidence of recent extra- or intralesional hemorrhage. The definition includes neither an increase in CM diameter without other evidence of recent hemorrhage, nor the existence of a hemosiderin halo. CONCLUSIONS: A consistent approach to clinical and brain imaging classification of CM hemorrhage will improve the external validity of future CM research.


Asunto(s)
Hemorragia Cerebral/etiología , Ensayos Clínicos como Asunto/normas , Malformaciones Arteriovenosas Intracraneales/complicaciones , Algoritmos , Biomarcadores , Hemorragia Cerebral/clasificación , Hemorragia Cerebral/diagnóstico , Hemorragia Cerebral/epidemiología , Trastornos de la Conciencia/etiología , Diagnóstico por Imagen/métodos , Diagnóstico por Imagen/normas , Humanos , Malformaciones Arteriovenosas Intracraneales/diagnóstico , Imagen por Resonancia Magnética , Trastornos del Movimiento/etiología , Convulsiones/etiología , Trastornos de la Sensación/etiología , Tomografía Computarizada por Rayos X
8.
Epilepsy Behav ; 13(4): 693-9, 2008 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-18589000

RESUMEN

Generic substitution of branded antiepileptic drugs (AEDs) has sparked recent debates. We sought to understand perceptions about generic AED substitution and how these guide prescribing. Surveys were conducted among 550 adult patients with self-reported epilepsy and 606 physicians who treat patients with epilepsy. Physicians (88%) were concerned about an increase in breakthrough seizures in patients switched from a brand AED to a generic or among generics. Two-thirds of physicians and 34% of patients have linked breakthrough seizures to generic AED substitution. Physicians (75%) and patients (65%) were also concerned about efficacy. About half of physicians were extremely/very likely to request that brand AEDs not be substituted with a generic. In conclusion, perceptions among physicians and patients do not align with the FDA position that generic AEDs have the same clinical effect and safety profile as branded AEDs. Additional investigation on bioequivalence may help address ongoing concerns and inform policy-making decisions.


Asunto(s)
Anticonvulsivantes/uso terapéutico , Medicamentos Genéricos/uso terapéutico , Epilepsia/tratamiento farmacológico , Epilepsia/psicología , Percepción , Médicos/psicología , Anticonvulsivantes/economía , Medicamentos Genéricos/economía , Epilepsia/economía , Femenino , Encuestas Epidemiológicas , Humanos , Masculino , Equivalencia Terapéutica , Estados Unidos
9.
Hum Mutat ; 27(1): 118, 2006 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-16329096

RESUMEN

Cerebral cavernous malformations (CCMs) are vascular abnormalities of the brain that can result in a variety of neurological disabilities, including stroke and seizures. Linkage analyses using autosomal dominant families manifesting CCMs have identified three different causative loci on chromosomes 7q21.2 (CCM1), 7p13 (CCM2), and 3q25.2-q27 (CCM3). Mutations in the gene Krit1 are responsible for CCM1, mutations in the gene MGC4607 are responsible for CCM2, and mutations in the gene PDCD10 were recently reported to be responsible for CCM3. We report here that sequence analysis of PDCD10 in a panel of 29 probands lacking Krit1 and MGC4607 mutations revealed only three mutations. The frequency of identified mutations in the PDCD10 gene was surprisingly low, especially given that this panel was heavily biased towards non-CCM1, non-CCM2 probands. These data are in stark contrast with the linkage data, which suggests that 40% of inherited cases would be due to mutations in this gene. Interestingly, when examining the haplotypes of previously published CCM3 families, we found a distinct recombination event in one of the largest CCM3 families that excludes the PDCD10 gene. Although there are many potential explanations for this observation, when combined with the apparent under-representation of causative CCM mutations in PDCD10, this recombination event in a CCM3-linked family suggests that there may be an additional CCM gene in the same chromosomal region.


Asunto(s)
Proteínas Reguladoras de la Apoptosis/genética , Hemangioma Cavernoso del Sistema Nervioso Central/genética , Proteínas de la Membrana/genética , Proteínas Asociadas a Microtúbulos/genética , Mutación/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Portadoras/genética , Análisis Mutacional de ADN , Exones/genética , Pruebas Genéticas , Humanos , Proteína KRIT1 , ARN Mensajero/genética , ARN Mensajero/metabolismo
10.
Epilepsy Res ; 127: 195-199, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27619358

RESUMEN

PURPOSE: To determine whether Double Inversion Recovery (DIR) on 3T MRI can enhance detection of epileptogenic lesions Methods: 29 adult patients with DRE were enrolled in a prospective pilot study. Brain MRIs were obtained using a specialized protocol that included: (1) Fast-Spin EchoT2, (2) T2 fluid attenuated inversion recovery (FLAIR), and (3) DIR sequences. Two neuroradiologists blinded to clinical information independently reviewed each sequence in the order listed above for T2-hyperintense lesions. Cortical lesions were determined to be concordant with the epileptic focus based upon available clinical and electrodiagnostic testing. RESULTS: Of 29 studies, 21 had a lesion identified with 13/21 abnormalities being non-specific. Of 8 remaining studies, 3 revealed a lesion only with DIR sequencing. DIR-lesions were concordant with clinical data in 1 subject, non-discordant in 1 subject, and discordant in 1 subject. SIGNIFICANCE: DIR has the potential to be more sensitive in detecting cortically based lesions relative to standard imaging. More data are needed to assess the sensitivity and specificity of DIR, particularly as it pertains to identification of epileptogenic lesions using electrodiagnostic testing and outcome after surgery.


Asunto(s)
Encéfalo/diagnóstico por imagen , Epilepsia Refractaria/diagnóstico por imagen , Imagen por Resonancia Magnética , Adulto , Encéfalo/fisiopatología , Encéfalo/cirugía , Mapeo Encefálico , Epilepsia Refractaria/fisiopatología , Epilepsia Refractaria/cirugía , Electroencefalografía , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Variaciones Dependientes del Observador , Proyectos Piloto , Estudios Prospectivos , Adulto Joven
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