RESUMO
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.
Assuntos
Fumar Cigarros , Epilepsia , Anticonvulsivantes/uso terapêutico , Café , Interações Medicamentosas , Epilepsia/tratamento farmacológico , Humanos , Lamotrigina/uso terapêutico , Estudos Prospectivos , Triazinas/uso terapêuticoRESUMO
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.
Assuntos
Epilepsia Resistente a Medicamentos/terapia , Terapia por Estimulação Elétrica/métodos , Epilepsias Parciais/terapia , Neuroestimuladores Implantáveis , Qualidade de Vida , Adolescente , Adulto , Idoso , Transtorno Depressivo/epidemiologia , Epilepsia Resistente a Medicamentos/fisiopatologia , Epilepsia Resistente a Medicamentos/psicologia , Epilepsias Parciais/fisiopatologia , Epilepsias Parciais/psicologia , Feminino , Seguimentos , Humanos , Hemorragias Intracranianas/epidemiologia , Masculino , Transtornos da Memória/epidemiologia , Pessoa de Meia-Idade , Estudos Prospectivos , Infecções Relacionadas à Prótese/epidemiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Estado Epiléptico/epidemiologia , Morte Súbita Inesperada na Epilepsia/epidemiologia , Suicídio/estatística & dados numéricos , Resultado do Tratamento , Adulto JovemRESUMO
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.
Assuntos
Córtex Cerebral/fisiopatologia , Estimulação Encefálica Profunda/métodos , Epilepsia Resistente a Medicamentos/fisiopatologia , Epilepsia Resistente a Medicamentos/terapia , Terapia por Estimulação Elétrica/métodos , Eletroencefalografia , Neocórtex/fisiopatologia , Adolescente , Adulto , Mapeamento Encefálico , Estimulação Encefálica Profunda/instrumentação , Terapia por Estimulação Elétrica/instrumentação , Eletrodos Implantados , Epilepsias Parciais/fisiopatologia , Epilepsias Parciais/terapia , Epilepsia Parcial Complexa/fisiopatologia , Epilepsia Parcial Complexa/terapia , Epilepsia Motora Parcial/fisiopatologia , Epilepsia Motora Parcial/terapia , Epilepsia Tônico-Clônica/fisiopatologia , Epilepsia Tônico-Clônica/terapia , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
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.
Assuntos
Encéfalo/diagnóstico por imagem , Epilepsia Resistente a Medicamentos/diagnóstico por imagem , Imageamento por Ressonância Magnética , Adulto , Encéfalo/fisiopatologia , Encéfalo/cirurgia , Mapeamento Encefálico , Epilepsia Resistente a Medicamentos/fisiopatologia , Epilepsia Resistente a Medicamentos/cirurgia , Eletroencefalografia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Projetos Piloto , Estudos Prospectivos , Adulto JovemRESUMO
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.
Assuntos
Ondas Encefálicas/fisiologia , Eletrocardiografia Ambulatorial , Epilepsia do Lobo Temporal/patologia , Epilepsia do Lobo Temporal/fisiopatologia , Lateralidade Funcional/fisiologia , Adolescente , Adulto , Eletrodos Implantados , Feminino , Hipocampo/patologia , Hipocampo/fisiopatologia , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
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.
Assuntos
Proteínas Reguladoras de Apoptose/genética , Proteínas de Transporte/genética , Neoplasias do Sistema Nervoso Central/genética , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Proteínas de Membrana/genética , Proteínas Associadas aos Microtúbulos/genética , Mutação , Proteínas Proto-Oncogênicas/genética , Neoplasias do Sistema Nervoso Central/patologia , Células Endoteliais/metabolismo , Hemangioma Cavernoso do Sistema Nervoso Central/patologia , Humanos , Proteína KRIT1 , Quinases Associadas a rho/metabolismoRESUMO
Due to concern and debate in the epilepsy medical community and to the current interest of the US Food and Drug Administration (FDA) in revising approaches to the approval of generic drugs, the FDA is currently supporting ongoing bioequivalence studies of antiepileptic drugs, the EQUIGEN studies. During the design of these crossover studies, the researchers could not find commercial or non-commercial statistical software that quickly allowed computation of sample sizes for their designs, particularly software implementing the FDA requirement of using random-effects linear models for the analyses of bioequivalence studies. This article presents tables for sample-size evaluations of average bioequivalence studies based on the two crossover designs used in the EQUIGEN studies: the four-period, two-sequence, two-formulation design, and the six-period, three-sequence, three-formulation design. Sample-size computations assume that random-effects linear models are used in bioequivalence analyses with crossover designs. Random-effects linear models have been traditionally viewed by many pharmacologists and clinical researchers as just mathematical devices to analyze repeated-measures data. In contrast, a modern view of these models attributes an important mathematical role in theoretical formulations in personalized medicine to them, because these models not only have parameters that represent average patients, but also have parameters that represent individual patients. Moreover, the notation and language of random-effects linear models have evolved over the years. Thus, another goal of this article is to provide a presentation of the statistical modeling of data from bioequivalence studies that highlights the modern view of these models, with special emphasis on power analyses and sample-size computations.
Assuntos
Modelos Lineares , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Projetos de Pesquisa , Anticonvulsivantes/farmacocinética , Disponibilidade Biológica , Estudos Cross-Over , Epilepsia/metabolismo , Humanos , Lamotrigina , Equivalência Terapêutica , Triazinas/farmacocinéticaRESUMO
Otherwise benign MRI findings (so-called "incidentalomas") are a frequent cause of worry on the part of both clinician and patient. Knowledge of the imaging characteristics of incidentalomas, their (typically slight) pathologic significance, and how to distinguish these from less benign pathologic mimics can help avoid unnecessary worry, expense, and workup.
Assuntos
Hemorragia Cerebral/etiologia , Hemorragia Cerebral/patologia , Embolia Intracraniana/etiologia , Embolia Intracraniana/patologia , Imageamento por Ressonância Magnética , Mucormicose/complicações , Sepse/complicações , Idoso , Evolução Fatal , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Síndromes Mielodisplásicas/complicações , Sepse/microbiologiaRESUMO
Cerebral cavernous malformations are common vascular lesions of the central nervous system that predispose to seizures, focal neurologic deficits and potentially fatal hemorrhagic stroke. Human genetic studies have identified three genes associated with the disease and biochemical studies of these proteins have identified interaction partners and possible signaling pathways. A variety of animal models of CCM have been described to help translate the cellular and biochemical insights into a better understanding of disease mechanism. In this minireview, we discuss the contributions of animal models to our growing understanding of the biology of cavernous malformations, including the elucidation of the cellular context of CCM protein actions and the in vivo confirmation of abnormal endothelial cell-cell interactions. Challenges and progress towards developing a faithful model of CCM biology are reviewed.
Assuntos
Hemangioma Cavernoso do Sistema Nervoso Central , Proteínas Associadas aos Microtúbulos/genética , Fenótipo , Proteínas Proto-Oncogênicas/genética , Animais , Modelos Animais de Doenças , Predisposição Genética para Doença , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Hemangioma Cavernoso do Sistema Nervoso Central/fisiopatologia , Humanos , Proteína KRIT1 , Proteínas dos Microfilamentos/genética , Peixe-ZebraRESUMO
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.
Assuntos
Antineoplásicos/toxicidade , Barreira Hematoencefálica , Giro Denteado/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/farmacologia , Animais , Antineoplásicos/metabolismo , Bromodesoxiuridina/metabolismo , Proliferação de Células/efeitos dos fármacos , Ciclofosfamida/toxicidade , Doxorrubicina/toxicidade , Fluoruracila/toxicidade , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Paclitaxel/toxicidade , Redução de PesoAssuntos
Cérebro/patologia , Epilepsia/etiologia , Hemangioma Cavernoso do Sistema Nervoso Central/complicações , Hemangioma Cavernoso do Sistema Nervoso Central/patologia , Adulto , Anticonvulsivantes/uso terapêutico , Neoplasias Encefálicas/patologia , Artérias Cerebrais/anormalidades , Artérias Cerebrais/patologia , Artérias Cerebrais/fisiopatologia , Hemorragia Cerebral/etiologia , Hemorragia Cerebral/patologia , Hemorragia Cerebral/fisiopatologia , Cérebro/fisiopatologia , Diagnóstico Diferencial , Células Endoteliais/patologia , Predisposição Genética para Doença/genética , Gliose/etiologia , Gliose/patologia , Gliose/fisiopatologia , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Hemossiderina/metabolismo , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Monitorização FisiológicaRESUMO
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.
Assuntos
Hemorragia Cerebral/etiologia , Ensaios Clínicos como Assunto/normas , Malformações Arteriovenosas Intracranianas/complicações , Algoritmos , Biomarcadores , Hemorragia Cerebral/classificação , Hemorragia Cerebral/diagnóstico , Hemorragia Cerebral/epidemiologia , Transtornos da Consciência/etiologia , Diagnóstico por Imagem/métodos , Diagnóstico por Imagem/normas , Humanos , Malformações Arteriovenosas Intracranianas/diagnóstico , Imageamento por Ressonância Magnética , Transtornos dos Movimentos/etiologia , Convulsões/etiologia , Transtornos de Sensação/etiologia , Tomografia Computadorizada por Raios XRESUMO
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.