RESUMO
OBJECTIVES: Although hemispheric surgeries are among the most effective procedures for drug-resistant epilepsy (DRE) in the pediatric population, there is a large variability in seizure outcomes at the group level. A recently developed HOPS score provides individualized estimation of likelihood of seizure freedom to complement clinical judgement. The objective of this study was to develop a freely accessible online calculator that accurately predicts the probability of seizure freedom for any patient at 1-, 2-, and 5-years post-hemispherectomy. METHODS: Retrospective data of all pediatric patients with DRE and seizure outcome data from the original Hemispherectomy Outcome Prediction Scale (HOPS) study were included. The primary outcome of interest was time-to-seizure recurrence. A multivariate Cox proportional-hazards regression model was developed to predict the likelihood of post-hemispheric surgery seizure freedom at three time points (1-, 2- and 5- years) based on a combination of variables identified by clinical judgment and inferential statistics predictive of the primary outcome. The final model from this study was encoded in a publicly accessible online calculator on the International Network for Epilepsy Surgery and Treatment (iNEST) website (https://hops-calculator.com/). RESULTS: The selected variables for inclusion in the final model included the five original HOPS variables (age at seizure onset, etiologic substrate, seizure semiology, prior non-hemispheric resective surgery, and contralateral fluorodeoxyglucose-positron emission tomography [FDG-PET] hypometabolism) and three additional variables (age at surgery, history of infantile spasms, and magnetic resonance imaging [MRI] lesion). Predictors of shorter time-to-seizure recurrence included younger age at seizure onset, prior resective surgery, generalized seizure semiology, FDG-PET hypometabolism contralateral to the side of surgery, contralateral MRI lesion, non-lesional MRI, non-stroke etiologies, and a history of infantile spasms. The area under the curve (AUC) of the final model was 73.0%. SIGNIFICANCE: Online calculators are useful, cost-free tools that can assist physicians in risk estimation and inform joint decision-making processes with patients and families, potentially leading to greater satisfaction. Although the HOPS data was validated in the original analysis, the authors encourage external validation of this new calculator.
Assuntos
Epilepsia Resistente a Medicamentos , Epilepsia , Hemisferectomia , Espasmos Infantis , Criança , Humanos , Hemisferectomia/métodos , Espasmos Infantis/cirurgia , Estudos Retrospectivos , Fluordesoxiglucose F18 , Resultado do Tratamento , Epilepsia/diagnóstico por imagem , Epilepsia/cirurgia , Convulsões/diagnóstico , Convulsões/etiologia , Convulsões/cirurgia , Epilepsia Resistente a Medicamentos/diagnóstico por imagem , Epilepsia Resistente a Medicamentos/cirurgia , Imageamento por Ressonância Magnética , EletroencefalografiaRESUMO
New neurons continue to be generated in the subgranular zone of the dentate gyrus of the adult mammalian hippocampus. This process has been linked to learning and memory, stress and exercise, and is thought to be altered in neurological disease. In humans, some studies have suggested that hundreds of new neurons are added to the adult dentate gyrus every day, whereas other studies find many fewer putative new neurons. Despite these discrepancies, it is generally believed that the adult human hippocampus continues to generate new neurons. Here we show that a defined population of progenitor cells does not coalesce in the subgranular zone during human fetal or postnatal development. We also find that the number of proliferating progenitors and young neurons in the dentate gyrus declines sharply during the first year of life and only a few isolated young neurons are observed by 7 and 13 years of age. In adult patients with epilepsy and healthy adults (18-77 years; n = 17 post-mortem samples from controls; n = 12 surgical resection samples from patients with epilepsy), young neurons were not detected in the dentate gyrus. In the monkey (Macaca mulatta) hippocampus, proliferation of neurons in the subgranular zone was found in early postnatal life, but this diminished during juvenile development as neurogenesis decreased. We conclude that recruitment of young neurons to the primate hippocampus decreases rapidly during the first years of life, and that neurogenesis in the dentate gyrus does not continue, or is extremely rare, in adult humans. The early decline in hippocampal neurogenesis raises questions about how the function of the dentate gyrus differs between humans and other species in which adult hippocampal neurogenesis is preserved.
Assuntos
Hipocampo/citologia , Neurogênese , Neurônios/citologia , Adolescente , Adulto , Idoso , Animais , Animais Recém-Nascidos , Contagem de Células , Proliferação de Células , Criança , Pré-Escolar , Giro Denteado/citologia , Giro Denteado/embriologia , Epilepsia/patologia , Feminino , Desenvolvimento Fetal , Voluntários Saudáveis , Hipocampo/anatomia & histologia , Hipocampo/embriologia , Humanos , Lactente , Macaca mulatta , Masculino , Pessoa de Meia-Idade , Células-Tronco Neurais/citologia , Adulto JovemRESUMO
Astrocytes are critical for the development and function of synapses. There are notable species differences between human astrocytes and commonly used animal models. Yet, it is unclear whether astrocytic genes involved in synaptic function are stable or exhibit dynamic changes associated with disease states and age in humans, which is a barrier in understanding human astrocyte biology and its potential involvement in neurologic diseases. To better understand the properties of human astrocytes, we acutely purified astrocytes from the cerebral cortices of over 40 humans across various ages, sexes, and disease states. We performed RNA sequencing to generate transcriptomic profiles of these astrocytes and identified genes associated with these biological variables. We found that human astrocytes in tumor-surrounding regions downregulate genes involved in synaptic function and sensing of signals in the microenvironment, suggesting involvement of peritumor astrocytes in tumor-associated neural circuit dysfunction. In aging, we also found downregulation of synaptic regulators and upregulation of markers of cytokine signaling, while in maturation we identified changes in ionic transport with implications for calcium signaling. In addition, we identified subtle sexual dimorphism in human cortical astrocytes, which has implications for observed sex differences across many neurologic disorders. Overall, genes involved in synaptic function exhibit dynamic changes in the peritumor microenvironment and aging. These data provide powerful new insights into human astrocyte biology in several biologically relevant states that will aid in generating novel testable hypotheses about homeostatic and reactive astrocytes in humans.SIGNIFICANCE STATEMENT Astrocytes are an abundant class of cells playing integral roles at synapses. Astrocyte dysfunction is implicated in a variety of human neurologic diseases. Yet our knowledge of astrocytes is largely based on mouse studies. Direct knowledge of human astrocyte biology remains limited. Here, we present transcriptomic profiles of human cortical astrocytes, and we identified molecular differences associated with age, sex, and disease state. We found that peritumor and aging astrocytes downregulate genes involved in astrocyte-synapse interactions. These data provide necessary insight into human astrocyte biology that will improve our understanding of human disease.
Assuntos
Astrócitos , Transcriptoma , Envelhecimento/patologia , Animais , Astrócitos/fisiologia , Feminino , Humanos , Masculino , Camundongos , Sinapses/fisiologia , Microambiente TumoralRESUMO
OBJECTIVE: This study was undertaken to identify molecular mechanisms in brain tissue of Rasmussen encephalitis (RE) when compared to people with non-RE epilepsy (PWE) and control cases using whole exome sequencing (WES), RNAseq, and proteomics. METHODS: Frozen brain tissue (ages = 2-19 years) was obtained from control autopsy (n = 14), surgical PWE (n = 10), and surgical RE cases (n = 27). We evaluated WES variants in RE associated with epilepsy, seizures, RE, and human leukocyte antigens (HLAs). Differential expression was evaluated by RNAseq (adjusted p < .05) and label-free quantitative mass spectrometry (false discovery rate < 5%) in the three groups. RESULTS: WES revealed no common pathogenic variants in RE, but several rare and likely deleterious variants of unknown significance (VUS; ANGPTL7/MTOR, SCN1A, FCGR3B, MTOR) and more common HLA VUS in >25% of RE cases (HLA-DRB1, HLA-DQA2), all with allele frequency < 5% in the general population. RNAseq in RE versus PWE (1516 altered transcripts) revealed significant activation of crosstalk between dendritic and natural killer cells (p = 7.94 × 10-6 , z = 2.65), in RE versus control (7466 transcripts) neuroinflammation signaling activation (p = 6.31 × 10-13 , z = 5.07), and in PWE versus control (945 transcripts) phagosome formation activation (p = 2.00 × 10-13 , z = 5.61). Proteomics detected fewer altered targets. SIGNIFICANCE: In RE, we identified activated immune signaling pathways and immune cell type annotation enrichment that suggest roles of the innate and adaptive immune responses, as well as HLA variants that may increase vulnerability to RE. Follow-up studies could evaluate cell type density and subregional localization associated with top targets, clinical history (neuropathology, disease duration), and whether modulating crosstalk between dendritic and natural killer cells may limit disease progression.
Assuntos
Encefalite , Epilepsia , Humanos , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Encefalite/patologia , Encéfalo/patologia , Epilepsia/patologia , Serina-Treonina Quinases TOR , Proteínas Semelhantes a Angiopoietina , Proteína 7 Semelhante a AngiopoietinaRESUMO
PURPOSE: It remains controversial whether neuronal damage and synaptic reorganization found in some forms of epilepsy are the result of an initial injury and potentially contributory to the epileptic condition or are the cumulative affect of repeated seizures. A number of reports of human and animal pathology suggest that at least some neuronal loss precedes the onset of seizures, but there is debate over whether there is further damage over time from intermittent seizures. In support of this latter hypothesis are MRI studies in people that show reduced hippocampal volumes and cortical thickness with longer durations of the disease. In this study we addressed the question of neuronal loss from intermittent seizures using kindled rats (no initial injury) and rats with limbic epilepsy (initial injury). METHODS: Supragranular mossy fiber sprouting, hippocampal neuronal densities, and subfield area measurements were determined in rats with chronic limbic epilepsy (CLE) that developed following an episode of limbic status epilepticus (n = 25), in kindled rats (n = 15), and in age matched controls (n = 20). To determine whether age or seizure frequency played a role in the changes, CLE and kindled rats were further classified by seizure frequency (low/high) and the duration of the seizure disorder (young/old). RESULTS: Overall there was no evidence for progressive neuronal loss from recurrent seizures. Compared with control and kindled rats, CLE animals showed increased mossy fiber sprouting, decreased neuronal numbers in multiple regions and regional atrophy. In CLE, but not kindled rats: 1) Higher seizure frequency was associated with greater mossy fiber sprouting and granule cell dispersion; and 2) greater age with seizures was associated with decreased hilar densities, and increased hilar areas. There was no evidence for progressive neuronal loss, even with more than 1000 seizures. CONCLUSION: These findings suggest that the neuronal loss associated with limbic epilepsy precedes the onset of the seizures and is not a consequence of recurrent seizures. However, intermittent seizures do cause other structural changes in the brain, the functional consequences of which are unclear.
Assuntos
Epilepsias Parciais/patologia , Hipocampo/patologia , Sistema Límbico/fisiopatologia , Neurônios/patologia , Convulsões/patologia , Estado Epiléptico/patologia , Animais , Progressão da Doença , Epilepsias Parciais/fisiopatologia , Excitação Neurológica , Fibras Musgosas Hipocampais/patologia , Neurópilo/patologia , Ratos , Recidiva , Convulsões/fisiopatologia , Estado Epiléptico/fisiopatologiaRESUMO
OBJECTIVE: Hemispheric surgeries are an effective treatment option to control seizures for children with hemimegalencephaly (HME); however, not enough is known about their cognitive outcomes. This study aimed to delineate the cognitive and language outcomes after hemispherectomy for HME and identify the clinical characteristics associated with cognition and language. METHODS: Data came from the Global Pediatric Epilepsy Surgery Registry, a patient-driven web-based registry for epilepsy surgery. We focused on children's functional status, assessed through parent-reports of cognitive and language skills. Parents also reported on their satisfaction with surgery, their child's quality of life, and various demographic, clinical, and surgery characteristics. RESULTS: Parents of 45 children (40% female) participated. Children were aged 2.6 (SD 6.5) months at seizure onset, 10.8 (SD 12.7) months at hemispherectomy, and 8.7 (SD 4.8) years at follow-up, at which point 68% were seizure-free. We found that at follow-up, 43% had average or mildly impaired cognition, 26% could speak age appropriately, and 21% had satisfactory reading skills. A total of 55%, 43%, and 17% of children first babbled, spoke their first words, and started speaking in sentences at an age-appropriate period, respectively. Children who had undergone a right hemisphere resection and those who were older at epilepsy onset were more likely to have better cognitive and language outcomes. SIGNIFICANCE: Children with HME have delayed language milestones and continue to require significant language and literacy support long-term after cerebral hemispherectomy.
Assuntos
Epilepsia , Hemimegalencefalia , Hemisferectomia , Criança , Cognição , Epilepsia/tratamento farmacológico , Epilepsia/cirurgia , Feminino , Hemimegalencefalia/cirurgia , Humanos , Idioma , Masculino , Qualidade de Vida , Convulsões/cirurgia , Resultado do TratamentoRESUMO
OBJECTIVE: This study was undertaken to determine whether the vertical parasagittal approach or the lateral peri-insular/peri-Sylvian approach to hemispheric surgery is the superior technique in achieving long-term seizure freedom. METHODS: We conducted a post hoc subgroup analysis of the HOPS (Hemispheric Surgery Outcome Prediction Scale) study, an international, multicenter, retrospective cohort study that identified predictors of seizure freedom through logistic regression modeling. Only patients undergoing vertical parasagittal, lateral peri-insular/peri-Sylvian, or lateral trans-Sylvian hemispherotomy were included in this post hoc analysis. Differences in seizure freedom rates were assessed using a time-to-event method and calculated using the Kaplan-Meier survival method. RESULTS: Data for 672 participants across 23 centers were collected on the specific hemispherotomy approach. Of these, 72 (10.7%) underwent vertical parasagittal hemispherotomy and 600 (89.3%) underwent lateral peri-insular/peri-Sylvian or trans-Sylvian hemispherotomy. Seizure freedom was obtained in 62.4% (95% confidence interval [CI] = 53.5%-70.2%) of the entire cohort at 10-year follow-up. Seizure freedom was 88.8% (95% CI = 78.9%-94.3%) at 1-year follow-up and persisted at 85.5% (95% CI = 74.7%-92.0%) across 5- and 10-year follow-up in the vertical subgroup. In contrast, seizure freedom decreased from 89.2% (95% CI = 86.3%-91.5%) at 1-year to 72.1% (95% CI = 66.9%-76.7%) at 5-year to 57.2% (95% CI = 46.6%-66.4%) at 10-year follow-up for the lateral subgroup. Log-rank test found that vertical hemispherotomy was associated with durable seizure-free progression compared to the lateral approach (p = .01). Patients undergoing the lateral hemispherotomy technique had a shorter time-to-seizure recurrence (hazard ratio = 2.56, 95% CI = 1.08-6.04, p = .03) and increased seizure recurrence odds (odds ratio = 3.67, 95% CI = 1.05-12.86, p = .04) compared to those undergoing the vertical hemispherotomy technique. SIGNIFICANCE: This pilot study demonstrated more durable seizure freedom of the vertical technique compared to lateral hemispherotomy techniques. Further studies, such as prospective expertise-based observational studies or a randomized clinical trial, are required to determine whether a vertical approach to hemispheric surgery provides superior long-term seizure outcomes.
Assuntos
Epilepsia Resistente a Medicamentos , Epilepsia , Hemisferectomia , Criança , Epilepsia Resistente a Medicamentos/cirurgia , Epilepsia/cirurgia , Hemisferectomia/métodos , Humanos , Projetos Piloto , Estudos Prospectivos , Estudos Retrospectivos , Convulsões/cirurgia , Resultado do TratamentoRESUMO
OBJECTIVE: To develop and validate a model to predict seizure freedom in children undergoing cerebral hemispheric surgery for the treatment of drug-resistant epilepsy. METHODS: We analyzed 1267 hemispheric surgeries performed in pediatric participants across 32 centers and 12 countries to identify predictors of seizure freedom at 3 months after surgery. A multivariate logistic regression model was developed based on 70% of the dataset (training set) and validated on 30% of the dataset (validation set). Missing data were handled using multiple imputation techniques. RESULTS: Overall, 817 of 1237 (66%) hemispheric surgeries led to seizure freedom (median follow-up = 24 months), and 1050 of 1237 (85%) were seizure-free at 12 months after surgery. A simple regression model containing age at seizure onset, presence of generalized seizure semiology, presence of contralateral 18-fluoro-2-deoxyglucose-positron emission tomography hypometabolism, etiologic substrate, and previous nonhemispheric resective surgery is predictive of seizure freedom (area under the curve = .72). A Hemispheric Surgery Outcome Prediction Scale (HOPS) score was devised that can be used to predict seizure freedom. SIGNIFICANCE: Children most likely to benefit from hemispheric surgery can be selected and counseled through the implementation of a scale derived from a multiple regression model. Importantly, children who are unlikely to experience seizure control can be spared from the complications and deficits associated with this surgery. The HOPS score is likely to help physicians in clinical decision-making.
Assuntos
Epilepsia Resistente a Medicamentos/cirurgia , Hemisferectomia , Resultado do Tratamento , Idade de Início , Criança , Pré-Escolar , Estudos de Coortes , Epilepsia Resistente a Medicamentos/patologia , Epilepsia Resistente a Medicamentos/fisiopatologia , Feminino , Humanos , Lactente , Modelos Logísticos , Masculino , Prognóstico , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: Tuberous sclerosis complex (TSC) is a rare genetic disorder that commonly leads to drug-resistant epilepsy in affected patients. This study aimed to determine whether the underlying genetic mutation (TSC1 vs. TSC2) predicts seizure outcomes following surgical treatments for epilepsy. METHODS: We retrospectively assessed TSC patients using the TSC Natural History Database core registry. Data review focused on outcomes in patients treated with surgical resection or vagus nerve stimulation. RESULTS: A total of 42 patients with a TSC1 mutation, and 145 patients with a TSC2 mutation, were identified. We observed a distinct clinical phenotype: children with TSC2 mutations tended to be diagnosed with TSC at a younger age than those with a TSC1 mutation (p < 0.001), were more likely to have infantile spasms (p < 0.001), and to get to surgery at a later age (p = 0.003). Among this TSC2 cohort, seizure control following resective epilepsy surgery was achieved in less than half (47%) the study sample. In contrast, patients with TSC1 mutations tended to have more favorable postsurgical outcomes; seizure control was achieved in 66% of this group. CONCLUSION: TSC2 mutations result in a more severe epilepsy phenotype that is also less responsive to resective surgery. It is important to consider this distinct clinical disposition when counseling families preoperatively with respect to seizure freedom. Larger samples are required to better characterize the independent effects of genetic mutation, infantile spasms, and duration of epilepsy as they relate to seizure control following resective or neuromodulatory epilepsy surgery.
Assuntos
Esclerose Tuberosa , Humanos , Mutação , Estudos Retrospectivos , Convulsões/genética , Convulsões/cirurgia , Esclerose Tuberosa/complicações , Esclerose Tuberosa/genética , Esclerose Tuberosa/cirurgia , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/genéticaRESUMO
BACKGROUND: In cases of intractable epilepsy resistant to drug therapy, hemispherectomy is often the only treatment option to mitigate seizures; however, the true long-term subjective visual outcomes are relatively unexplored. In this study, we sought to determine and characterize patient-reported visual function years after hemispherectomy. METHODS: This was an observational study conducted on a large cohort of children with seizure disorder treated with cerebral hemispherectomy. An online survey was sent to parents with questions to assess subjective visual function with a variety of questions from presence of visual field defects after hemispherectomy, to improvement over time, compensatory mechanisms used, and development of strabismus. RESULTS: This survey was emailed to 248 parents of previously evaluated children who agreed to be re-surveyed, 48 (20%) of which responded. The average age at hemispherectomy was approximately 5 (±4) years, and the average time after hemispherectomy was 7 (±5) years. Thirty-nine patients (81%) were seizure-free after 1 surgery and 85% (n = 41) were seizure-free after ≥1 surgeries. Thirty-four (71%) experienced a visual field defect after surgery, but 25 (52%) experienced subjective improvement over time. Thirty-eight (79%) used compensatory mechanisms, such as head tilting, with 16 (33%) patients experiencing subjective improvement over time. Twenty-seven (56%) patients experienced a decrease in visual acuity after surgery with 12 (25%) experiencing subjective improvement over time. CONCLUSION: In a large cohort examining patient-reported visual outcomes years after hemispherectomy, most patients experienced strabismus and/or visual field defects. However, more than half reported improvements and compensatory mechanisms (exotropic strabismus and ipsilateral esotropic strabismus) over time, presumably to enhance visual field function. By exploring subjective visual and cognitive function, this paper uniquely characterizes patient-reported improvements over time, and provides motivation for larger longitudinal studies using more quantitative measures of visual function and improvement after hemispherectomy.
Assuntos
Hemisferectomia/efeitos adversos , Medidas de Resultados Relatados pelo Paciente , Complicações Pós-Operatórias/etiologia , Escotoma/etiologia , Convulsões/cirurgia , Acuidade Visual , Campos Visuais/fisiologia , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Masculino , Complicações Pós-Operatórias/fisiopatologia , Escotoma/fisiopatologia , Fatores de Tempo , Testes de Campo VisualRESUMO
Pathological high-frequency oscillations (HFOs), specifically fast ripples (FRs, >250â¯Hz), are pathognomonic of an active epileptogenic zone. However, the origin of FRs remains unknown. Here we explored the correlation between FRs recorded with intraoperative pre-resection electrocorticography (ECoG) and spontaneous synaptic activity recorded ex vivo from cortical tissue samples resected for the treatment of pharmacoresistant epilepsy. The cohort included 47 children (ages 0.22-9.99â¯yr) with focal cortical dysplasias (CD types I and II), tuberous sclerosis complex (TSC) and non-CD pathologies. Whole-cell patch clamp recordings were obtained from pyramidal neurons and interneurons in cortical regions that were positive or negative for pathological HFOs, defined as FR band oscillations (250-500â¯Hz) at ECoG. The frequency of spontaneous excitatory and inhibitory postsynaptic currents (sEPSCs and IPSCs, respectively) was compared between HFO+ and HFO- regions. Regardless of pathological substrate, regions positive for FRs displayed significantly increased frequencies of sIPSCs compared with regions negative for FRs. In contrast, the frequency of sEPSCs was similar in both regions. In about one third of cases (nâ¯=â¯17), pacemaker GABA synaptic activity (PGA) was observed. In the vast majority (nâ¯=â¯15), PGA occurred in HFO+ areas. Further, fast-spiking interneurons displayed signs of hyperexcitability exclusively in HFO+ areas. These results indicate that, in pediatric epilepsy patients, increased GABA synaptic activity is associated with interictal FRs in the epileptogenic zone and suggest an active role of GABAergic interneurons in the generation of pathological HFOs. Increased GABA synaptic activity could serve to dampen excessive excitability of cortical pyramidal neurons in the epileptogenic zone, but it could also promote neuronal network synchrony.
Assuntos
Epilepsia/fisiopatologia , Neurônios GABAérgicos/patologia , Interneurônios/patologia , Ondas Encefálicas/fisiologia , Criança , Pré-Escolar , Eletrocorticografia , Epilepsia/cirurgia , Feminino , Humanos , Lactente , Masculino , Sinapses/patologia , Ácido gama-Aminobutírico/metabolismoRESUMO
The increased focus on stakeholder engagement in determining the aims, design, conduct of research and dissemination of results is substantially changing the biomedical research paradigm. In this era of patient-centered care, incorporating participatory action research methodology into large-scale multi-center studies is essential. The adoption of community engagement facilitates meaningful contribution to the design and implementation of clinical studies. Consequently, encouraging citizen participation and involving key organizations may guide the effective development of future clinical research protocols. Here, we discuss our experience in engaging individuals, their caregivers, as well as scientific and consumer organizations in public outreach and knowledge transfer to assist in the development of effective strategies for recruitment and retention in a future post-traumatic epilepsy prevention randomized controlled trial within the National Institute of Neurologic Disorders and Stroke Center Without Walls, Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx). The study includes a Public Engagement Core with a diverse consortium of stakeholder partners. Based on the Core's ongoing experience, it is recommended that multicenter studies integrate a participatory action research based approach to harness the benefits of a collective inquiry. The blueprint created by the EpiBioS4Rx Public Engagement Core is a resource that could be applied in other areas of biomedical research.
Assuntos
Lesões Encefálicas Traumáticas/prevenção & controle , Pesquisa Participativa Baseada na Comunidade , Epilepsia Pós-Traumática/prevenção & controle , Participação do Paciente , Animais , Lesões Encefálicas Traumáticas/complicações , Cuidadores , Biologia Computacional , Epilepsia Pós-Traumática/etiologia , Humanos , Participação dos InteressadosRESUMO
PURPOSE: The purpose of this study was to examine the cognitive function and depressive traits most frequently associated with the clinical assessment of patients with epilepsy and if these clinical parameters are linked to glycolipid levels and inflammatory and apoptotic markers. METHODS: Patients with epilepsy (nâ¯=â¯32) and healthy subjects (nâ¯=â¯41) were recruited to participate in this study. Neuropsychological evaluation was performed in both groups through a battery of cognitive tests. Inflammatory markers, apoptotic factors, and deoxyribonucleic acid (DNA) damage were measured in blood samples. Additionally, the metabolic markers total cholesterol (CHO), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglyceride (TG), and glucose (GLU) levels were analyzed. RESULTS: Statistical analyses showed that patients with epilepsy presented decreased scores in memory, attention, language, and executive function tests compared with the control group. Analysis revealed that there was negative correlation in epilepsy for seizure duration vs. oral language (Râ¯=â¯-0.4484, pâ¯<â¯0.05) and seizure duration vs. problem solving (executive functions) (Râ¯=â¯-0.3995, pâ¯<â¯0.05). This was also observed when comparing depression with temporal-spatial orientation (TSO) (Râ¯=â¯-0.39, pâ¯<â¯0.05). Furthermore, we observed a higher depression score in patients with epilepsy than in the healthy ones. Statistical analyses showed higher acetylcholinesterase (AChE) (pâ¯<â¯0.05), interleukin 1ß (IL-1ß, pâ¯<â¯0.001), and tumor necrosis factor-alpha (TNF-α) (pâ¯<â¯0.001) levels compared with those in the control group. Moreover, patients with epilepsy had significantly higher serum levels of caspase 3 (CASP 3) (pâ¯<â¯0.001) and Picogreen (pâ¯<â¯0.001) compared with the control subjects. Regarding the metabolic markers, higher glycolipid levels were observed in the patients with epilepsy (CHOâ¯<â¯0.05*, LDLâ¯<â¯0.0001*, TGâ¯<â¯0.05*, GLU pâ¯<â¯0.05). High-density lipoprotein levels were not significant. The patients with epilepsy had significant correlation when comparing total language with TNF-α (Râ¯=â¯-0.4, pâ¯<â¯0.05), praxes with CASP 3 (Râ¯=â¯-0.52, pâ¯<â¯0.01), total CHO with total language (Râ¯=â¯-0.48, pâ¯<â¯0.05), TG with semantic memory (Râ¯=â¯-0.54, pâ¯<â¯0.05), TG with prospective memory (Râ¯=â¯-0.2165, pâ¯<â¯0.02), TG with total memory (Râ¯=â¯-0.53, pâ¯<â¯0.02), and GLU with total attention (Râ¯=â¯-0.62, pâ¯<â¯0.002). CONCLUSION: This study supports the evidence of a distinct neuropsychological profile between patients with epilepsy and healthy subjects. Furthermore, our findings suggest that inflammatory pathway, glycolipid profile, and depressive factors may be associated with cognitive dysfunction in patients with epilepsy.
Assuntos
Cognição/fisiologia , Depressão/epidemiologia , Epilepsia , Inflamação/metabolismo , Adulto , Idoso , Apoptose/fisiologia , Atenção/fisiologia , Biomarcadores/metabolismo , Estudos de Casos e Controles , Caspase 3 , Disfunção Cognitiva , Citocinas/sangue , Dano ao DNA/fisiologia , Epilepsia/metabolismo , Epilepsia/patologia , Epilepsia/psicologia , Função Executiva/fisiologia , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Lipoproteínas/sangue , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Compostos Orgânicos , Triglicerídeos/sangue , Fator de Necrose Tumoral alfa/sangue , Adulto JovemRESUMO
The International League Against Epilepsy (ILAE) Classification of the Epilepsies has been updated to reflect our gain in understanding of the epilepsies and their underlying mechanisms following the major scientific advances that have taken place since the last ratified classification in 1989. As a critical tool for the practicing clinician, epilepsy classification must be relevant and dynamic to changes in thinking, yet robust and translatable to all areas of the globe. Its primary purpose is for diagnosis of patients, but it is also critical for epilepsy research, development of antiepileptic therapies, and communication around the world. The new classification originates from a draft document submitted for public comments in 2013, which was revised to incorporate extensive feedback from the international epilepsy community over several rounds of consultation. It presents three levels, starting with seizure type, where it assumes that the patient is having epileptic seizures as defined by the new 2017 ILAE Seizure Classification. After diagnosis of the seizure type, the next step is diagnosis of epilepsy type, including focal epilepsy, generalized epilepsy, combined generalized, and focal epilepsy, and also an unknown epilepsy group. The third level is that of epilepsy syndrome, where a specific syndromic diagnosis can be made. The new classification incorporates etiology along each stage, emphasizing the need to consider etiology at each step of diagnosis, as it often carries significant treatment implications. Etiology is broken into six subgroups, selected because of their potential therapeutic consequences. New terminology is introduced such as developmental and epileptic encephalopathy. The term benign is replaced by the terms self-limited and pharmacoresponsive, to be used where appropriate. It is hoped that this new framework will assist in improving epilepsy care and research in the 21st century.
Assuntos
Epilepsia/classificação , Epilepsia/diagnóstico , Terminologia como Assunto , Epilepsia/etiologia , Humanos , Agências InternacionaisRESUMO
Focal malformations of cortical development, including focal cortical dysplasia (FCD) and hemimegalencephaly (HME), are important causes of intractable childhood epilepsy. Using targeted and exome sequencing on DNA from resected brain samples and nonbrain samples from 53 patients with FCD or HME, we identified pathogenic germline and mosaic mutations in multiple PI3K/AKT pathway genes in 9 patients, and a likely pathogenic variant in 1 additional patient. Our data confirm the association of DEPDC5 with sporadic FCD but also implicate this gene for the first time in HME. Our findings suggest that modulation of the mammalian target of rapamycin pathway may hold promise for malformation-associated epilepsy.
Assuntos
Hemimegalencefalia/genética , Malformações do Desenvolvimento Cortical/genética , Mutação/genética , Proteínas Repressoras/genética , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/genética , Estudos de Coortes , Proteínas Ativadoras de GTPase , Hemimegalencefalia/diagnóstico , Humanos , Malformações do Desenvolvimento Cortical/diagnóstico , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genéticaRESUMO
OBJECTIVE: Children with medically refractory epilepsy stand to benefit from surgery and live a life free of seizures. However, a large proportion of potentially eligible children do not receive a timely referral for a surgical evaluation. We aimed to describe experiences during the arduous time before the referral and the parent-reported facilitators that helped them move forward through this slow time. METHODS: Individual semi-structured interviews with 37 parents of children who had previously undergone epilepsy surgery at UCLA (2006-2011) were recorded, transcribed, and systematically analyzed by two independent coders using thematic analysis. Clinical data were extracted from medical records. RESULTS: Parents, 41.3years of age on average, were mostly Caucasian, English-speaking, mothers, married, and employed. The mean age at surgery for children was 8.2years with a mean time from epilepsy onset to surgery of 5.4years. Parental decision-making was facilitated when parents eventually received a presurgical referral and navigated to a multidisciplinary team that they trusted to care for their child with medically refractory epilepsy. Four themes described the experiences that parents used to feel a sense of moving forward. The first theme, processing, involved working through feelings and was mostly done alone. The second theme, navigating the complex unknowns of the health-care system, was more active and purposeful. Processing co-occurred with navigating in a fluid intersection, the third theme, which was evidenced by deliberate actions. The fourth theme, facilitators, explained helpful ways of processing and navigating; parents utilized these mechanisms to turn vulnerable times following the distress of their child's diagnosis into an experience of productivity. SIGNIFICANCE: To limit parental distress and remediate the slow and arduous journey to multidisciplinary care at a comprehensive epilepsy center for a surgical evaluation, we suggest multi-pronged interventions to modify barriers associated with parents, providers, and health-care systems. Based on the facilitators that moved parents of our sample forward, we provide practical suggestions such as increased peer support, developing the role of patient navigators and communication strategies with parents before, during, and after referral to a comprehensive epilepsy center and presurgical evaluation.
Assuntos
Encéfalo/cirurgia , Tomada de Decisões , Epilepsia/cirurgia , Procedimentos Neurocirúrgicos , Pais , Encaminhamento e Consulta , Adolescente , Criança , Pré-Escolar , Comunicação , Feminino , Humanos , MasculinoRESUMO
BACKGROUND: The management of drug-resistant epilepsy in children with Tuberous Sclerosis Complex (TSC) is challenging because of the multitude of treatment options, wide range of associated costs, and uncertainty of seizure outcomes. The most cost-effective approach for children whose epilepsy has failed to improve with first-line medical therapy is uncertain. METHODS: A review of MEDLINE from 1990 to 2015 was conducted. A cost-utility analysis, from a third-party payer perspective, was performed for children with drug-resistant epilepsy that had failed to improve with 2 antiseizure drugs (ASDs) and that was amenable to resective epilepsy surgery, across a time-horizon of 5years. Four strategies were included: (1) resective epilepsy surgery, (2) vagus nerve stimulator (VNS) implantation, (3) ketogenic diet, and (4) addition of a third ASD (specifically, carbamazepine). The incremental cost per quality-adjusted life year (QALY) gained was analyzed. RESULTS: Given a willingness-to-pay (WTP) of $100,000 per QALY, the addition of a third ASD ($6600 for a gain of 4.14 QALYs) was the most cost-effective treatment strategy. In a secondary analysis, if the child whose epilepsy had failed to improve with 3 ASDs, ketogenic diet, addition of a fourth ASD, and resective epilepsy surgery were incrementally cost-effective treatment strategies. Vagus nerve stimulator implantation was more expensive yet less effective than alternative strategies and should not be prioritized. CONCLUSIONS: The addition of a third ASD is a universally cost-effective treatment option in the management of children with drug-resistant epilepsy that has failed to improve with 2 ASDs. For children whose epilepsy has failed to improve with 3 ASDs, the most cost-effective treatment depends on the health-care resources available reflected by the WTP.
Assuntos
Dieta Cetogênica/economia , Epilepsia Resistente a Medicamentos/terapia , Custos de Cuidados de Saúde , Esclerose Tuberosa/complicações , Estimulação do Nervo Vago/economia , Anticonvulsivantes/economia , Anticonvulsivantes/uso terapêutico , Carbamazepina/economia , Carbamazepina/uso terapêutico , Criança , Análise Custo-Benefício , Epilepsia Resistente a Medicamentos/economia , Epilepsia Resistente a Medicamentos/etiologia , Epilepsia Resistente a Medicamentos/cirurgia , Humanos , Estudos Retrospectivos , Comportamento Social , Resultado do TratamentoRESUMO
BACKGROUND: Rasmussen encephalitis (RE) is a rare neuroinflammatory disease characterized by intractable seizures and progressive atrophy on one side of the cerebrum. Perivascular cuffing and clusters of T cells in the affected cortical hemisphere are indicative of an active cellular immune response. METHODS: Peripheral blood mononuclear cells (PBMCs) and brain-infiltrating lymphocytes (BILs) were isolated from 20 RE surgery specimens by standard methods, and CD3(+) T cell populations were analyzed by flow cytometry. Gamma delta T cell receptor spectratyping was carried out by nested PCR of reversed transcribed RNA extracted from RE brain tissue, followed by high resolution capillary electrophoresis. A MiSeq DNA sequencing platform was used to sequence the third complementarity determining region (CDR3) of δ1 chains. RESULTS: CD3(+) BILs from all of the RE brain specimens comprised both αß and γδ T cells. The median αß:γδ ratio was 1.9 (range 0.58-5.2) compared with a median ratio of 7.7 (range 2.7-40.8) in peripheral blood from the same patients. The αß T cells isolated from brain tissue were predominantly CD8(+), and the majority of γδ T cells were CD4(-) CD8(-). Staining for the early activation marker CD69 showed that a fraction of the αß and γδ T cells in the BILs were activated (median 42%; range 13-91%, and median 47%; range 14-99%, respectively). Spectratyping T cell receptor (TCR) Vδ1-3 chains from 14 of the RE brain tissue specimens indicated that the γδ T cell repertoire was relatively restricted. Sequencing δ1 chain PCR fragments revealed that the same prevalent CDR3 sequences were found in all of the brain specimens. These CDR3 sequences were also detected in brain tissue from 15 focal cortical dysplasia (FCD) cases. CONCLUSION: Neuroinflammation in RE involves both activated αß and γδ T cells. The presence of γδ T cells with identical TCR δ1 chain CDR3 sequences in all of the brain specimens examined suggests that a non-major histocompatibility complex (MHC)-restricted immune response to the same antigen(s) is involved in the etiology of RE. The presence of the same δ1 clones in CD brain implies the involvement of a common inflammatory pathway in both diseases.
Assuntos
Encefalite/imunologia , Encefalite/fisiopatologia , Imunidade Celular/fisiologia , Receptores de Antígenos de Linfócitos T gama-delta/fisiologia , Linfócitos T/fisiologia , Antígenos CD/imunologia , Antígenos CD/fisiologia , Antígenos de Diferenciação de Linfócitos T/imunologia , Antígenos de Diferenciação de Linfócitos T/fisiologia , Encéfalo/imunologia , Encéfalo/patologia , Encéfalo/fisiopatologia , Criança , Pré-Escolar , Estudos de Coortes , Regiões Determinantes de Complementaridade/imunologia , Regiões Determinantes de Complementaridade/fisiologia , Encefalite/patologia , Epilepsia/imunologia , Epilepsia/patologia , Epilepsia/fisiopatologia , Feminino , Humanos , Imunidade Celular/imunologia , Lactente , Lectinas Tipo C/imunologia , Lectinas Tipo C/fisiologia , Masculino , Malformações do Desenvolvimento Cortical do Grupo I/imunologia , Malformações do Desenvolvimento Cortical do Grupo I/patologia , Malformações do Desenvolvimento Cortical do Grupo I/fisiopatologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/fisiologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Linfócitos T/imunologia , Linfócitos T/patologiaRESUMO
OBJECTIVE: Whether febrile status epilepticus (FSE) produces hippocampal sclerosis (HS) and temporal lobe epilepsy (TLE) has long been debated. Our objective is to determine whether FSE produces acute hippocampal injury that evolves to HS. METHODS: FEBSTAT and 2 affiliated studies prospectively recruited 226 children aged 1 month to 6 years with FSE and controls with simple febrile seizures. All had acute magnetic resonance imaging (MRI), and follow-up MRI was obtained approximately 1 year later in the majority. Visual interpretation by 2 neuroradiologists informed only of subject age was augmented by hippocampal volumetrics, analysis of the intrahippocampal distribution of T2 signal, and apparent diffusion coefficients. RESULTS: Hippocampal T2 hyperintensity, maximum in Sommer's sector, occurred acutely after FSE in 22 of 226 children in association with increased volume. Follow-up MRI obtained on 14 of the 22 with acute T2 hyperintensity showed HS in 10 and reduced hippocampal volume in 12. In contrast, follow-up of 116 children without acute hyperintensity showed abnormal T2 signal in only 1 (following another episode of FSE). Furthermore, compared to controls with simple febrile seizures, FSE subjects with normal acute MRI had abnormally low right to left hippocampal volume ratios, smaller hippocampi initially, and reduced hippocampal growth. INTERPRETATION: Hippocampal T2 hyperintensity after FSE represents acute injury often evolving to a radiological appearance of HS after 1 year. Furthermore, impaired growth of normal-appearing hippocampi after FSE suggests subtle injury even in the absence of T2 hyperintensity. Longer follow-up is needed to determine the relationship of these findings to TLE.
Assuntos
Hipocampo/patologia , Estado Epiléptico/complicações , Estado Epiléptico/patologia , Criança , Pré-Escolar , Imagem de Difusão por Ressonância Magnética , Feminino , Seguimentos , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Estudos Prospectivos , Fatores de Risco , Esclerose/etiologiaRESUMO
OBJECTIVE: From May to September 2014, Epilepsia conducted an online survey seeking opinions on whether consciousness should be used in describing focal and generalized seizures, and what terms should be applied to describe focal seizures with loss of awareness and amnesia. This study reports the findings of that survey. METHODS: Two questions asked if consciousness should be used to classify seizures and what terms should be applied. Another four questions addressed demographic information. RESULTS: Of 209 individuals that started the poll, 147 (70.3%) completing it, and most that completed it were epileptologists (66%) from Europe (41%) and North America (27%). A majority (64%) indicated that the presence or absence of consciousness should be used to describe focal and generalized seizures, whereas 23% said it should not be used. When asked what term should be used to describe focal seizures with altered awareness and amnesia, 36% said focal impaired consciousness seizures (FICS), 30% selected complex partial seizures (CPS), and 16% answered focal dyscognitive seizures. SIGNIFICANCE: This survey indicates that most responders prefer that consciousness be considered in the description of focal and generalized seizures, despite the difficulty in determining awareness clinically. Furthermore, responders could not agree on a single term that could be used to define focal seizures with loss of awareness and amnesia.