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OBJECTIVES: Hemimegalencephaly (HME) is a rare congenital brain malformation presenting predominantly with drug-resistant epilepsy. Hemispheric disconnective surgery is the mainstay of treatment; however, little is known about how postoperative outcomes compare across techniques. Thus we present the largest single-center cohort of patients with HME who underwent epilepsy surgery and characterize outcomes. METHODS: This observational study included patients with HME at University of California Los Angeles (UCLA) from 1984 to 2021. Patients were stratified by surgical intervention: anatomic hemispherectomy (AH), functional hemispherectomy (FH), or less-than-hemispheric resection (LTH). Seizure freedom, functional outcomes, and operative complications were compared across surgical approaches. Regression analysis identified clinical and intraoperative variables that predict seizure outcomes. RESULTS: Of 56 patients, 43 (77%) underwent FH, 8 (14%) underwent AH, 2 (4%) underwent LTH, 1 (2%) underwent unknown hemispherectomy type, and 2 (4%) were managed non-operatively. At median last follow-up of 55 months (interquartile range [IQR] 20-92 months), 24 patients (49%) were seizure-free, 17 (30%) required cerebrospinal fluid (CSF) shunting for hydrocephalus, 9 of 43 (21%) had severe developmental delay, 8 of 38 (21%) were non-verbal, and 15 of 38 (39%) were non-ambulatory. There was one (2%) intraoperative mortality due to exsanguination earlier in this cohort. Of 12 patients (29%) requiring revision surgery, 6 (50%) were seizure-free postoperatively. AH, compared to FH, was not associated with statistically significant improved seizure freedom (hazard ratio [HR] = .48, p = .328), although initial AH trended toward greater odds of seizure freedom (75% vs 46%, p = .272). Younger age at seizure onset (HR = .29, p = .029), lack of epilepsia partialis continua (EPC) (HR = .30, p = .022), and no contralateral seizures on electroencephalography (EEG) (HR = .33, p = .039) independently predicted longer duration of seizure freedom. SIGNIFICANCE: This study helps inform physicians and parents of children who are undergoing surgery for HME by demonstrating that earlier age at seizure onset, absence of EPC, and no contralateral EEG seizures were associated with longer postoperative seizure freedom. At our center, initial AH for HME may provide greater odds of seizure freedom with complications and functional outcomes comparable to those of FH.
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Epilepsia , Hemimegalencefalia , Hemisferectomía , Niño , Humanos , Hemimegalencefalia/complicaciones , Hemimegalencefalia/cirugía , Resultado del Tratamiento , Epilepsia/tratamiento farmacológico , Hemisferectomía/métodos , Convulsiones/complicaciones , Electroencefalografía/efectos adversosRESUMEN
In 1994, the use of interfacet spacer placement was for joint distraction, reduction, and fusion to supplement atlantoaxial or occipitocervical fixation. Here, we present a unique case of bilateral atlantoaxial interfacet fixation using cervical facet cages (CFC) in a pediatric patient with basilar invagination. In addition, we review the literature on atlantoaxial facet fixation. We present a 12-year-old boy with Wiedemann-Steiner syndrome who presented with multiple episodes of sudden neck jerking, described as in response to a sensation of being shocked, and guarding against neck motion, found to have basilar invagination with cervicomedullary compression. He underwent an occiput to C3 fusion with C1-C2 CFC fixation. We also conducted a literature review identifying all publications using the following keywords: "C1" AND "C2" OR "atlantoaxial" AND "facet spacer" OR "DTRAX." The patient demonstrated postoperative radiographic reduction of his basilar invagination from 6.4 to 4.1 mm of superior displacement above the McRae line. There was a 4.5 mm decrease in the atlantodental interval secondary to decreased dens retroflexion. His postoperative course was complicated by worsening of his existing dysphagia but was otherwise unremarkable. His neck symptoms completely resolved. We illustrate the safe use of CFC for atlantoaxial facet distraction, reduction, and instrumented fixation in a pediatric patient with basilar invagination. Review of the literature demonstrates that numerous materials can be safely placed as a C1-C2 interfacet spacer including bone grafts, titanium spacers, and anterior cervical discectomy and fusion cages. We argue that CFC may be included in this arsenal even in pediatric patients.
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Articulación Atlantoaxoidea , Fusión Vertebral , Humanos , Masculino , Niño , Articulación Atlantoaxoidea/cirugía , Articulación Atlantoaxoidea/diagnóstico por imagen , Fusión Vertebral/métodos , Vértebras Cervicales/cirugía , Vértebras Cervicales/diagnóstico por imagen , Fijadores Internos , Articulación Cigapofisaria/cirugía , Articulación Cigapofisaria/diagnóstico por imagenRESUMEN
Choline is usually supplemented as ruminally protected choline chloride to prevent its degradation in the rumen, but the effects of unprotected choline on ruminal fermentation are unclear. Some research indicates a possible role of dietary fiber on microbial degradation of choline; therefore we aimed to evaluate the effects of unprotected choline chloride on ruminal fermentation and to investigate whether those effects depend on dietary neutral detergent fiber (NDF) concentration. Our hypothesis was that dietary NDF concentration would influence choline chloride effects on microbial ruminal fermentation. We used 8 fermentors in a duplicated 4 × 4 Latin square with a 2 × 2 factorial arrangement, combining 2 factors: (1) dietary NDF concentration and (2) unprotected choline chloride supplementation. Resulting treatments are (1) 30%NDF/Ctrl [30% NDF control diet without supplemental choline (Cho)]; (2) 30%NDF/Cho [30% NDF diet plus 1.9 g of choline ion per kg of dry matter (DM)]; (3) 40%NDF/Ctrl (40% NDF control diet without supplemental choline); and (4) 40%NDF/Cho (40% NDF diet plus 1.9 g of choline ion per kg of DM). Four 10-d periods were completed, each consisting of 7 d for adaptation and 3 d for collection of samples for estimation of nutrient disappearance and daily average concentrations of volatile fatty acids and NH3-N. In addition, kinetics of pH, acetate, and propionate were evaluated at 0, 1, 2, 4, 6, and 8 h after morning feeding. On the last day of each period, bacteria pellets were harvested for 15N analysis and N metabolism. Fixed effects of dietary NDF concentration, unprotected choline chloride supplementation, and their interaction (NDF × Cho) were tested using the MIXED procedure of SAS version 9.4 (SAS Institute Inc., Cary, NC). Choline tended to increase total volatile fatty acid concentrations and decreased acetate molar proportion regardless of dietary NDF concentration, but it increased propionate molar proportion and decreased acetate to propionate ratio only with the 30% NDF diet. Supplementing choline decreased NDF disappearance regardless of dietary NDF; however, organic matter disappearance tended to be reduced only when choline was added to 40% NDF. Our data indicate that unprotected choline chloride effects on ruminal fermentation depend on dietary NDF concentration, allowing for a greater propionate synthesis without decreasing organic matter disappearance when fed with a 30% NDF diet.
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Detergentes , Rumen , Alimentación Animal/análisis , Animales , Colina/metabolismo , Detergentes/metabolismo , Dieta/veterinaria , Fibras de la Dieta/metabolismo , Digestión , Fermentación , Rumen/metabolismoRESUMEN
Ectoparasitic stable flies (Stomoxys calcitrans [L.]), horn flies (Haematobia irritans [L.]), and face flies (Musca autumnalis De Geer) negatively affect dry matter intake, milk production, and health of pastured dairy cows. These flies cause fly avoidance behaviors and are a major welfare concern for dairy producers. The objective of this study was to evaluate the effects of mesh Shoofly Leggins (Stone Manufacturing & Supply, Kansas City, MO) on fly avoidance behaviors and numbers of flies attacking pastured dairy cows. In a crossover design, lactating dairy cows (n = 80) were randomly assigned to groups with and without leggings (Shoofly Leggins worn on all legs). All cows were managed in one group. Cows were observed for 2-wk periods, and then treatments were reversed in the next 2-wk interval. Counts of stable flies, horn flies, and face flies on all cows were recorded twice daily (once in morning per cow: 0930 to 1230 h; and once in the afternoon per cow: 1330 to 1630 h), 3 times per wk on Tuesday, Wednesday, and Thursday of each week during the study period. The total number of flies per cow was greater on cows with leggings than cows without leggings. The number of horn flies per cow was greater on cows in with leggings (26.4 flies/side) compared with cows without leggings (24.1 flies/side). Stable fly numbers were similar for cows with and without leggings (12.8 flies/leg). A random subset of 20 focal cows per group was observed during 5-min intervals to record frequencies of 4 behaviors: leg stomps, head tosses, skin twitches, and tail swishes. Counts of head tosses (2.6 vs. 3.1), skin twitches (20.9 vs. 19.6), and tail swishes (21.3 vs. 19.3) were similar for cows without leggings versus cows with leggings, respectively. However, foot stomps were 39% lower for cows with leggings compared with cows without leggings, and leg stomps were 26% higher in the afternoon than in the morning (2.9 vs. 2.4, respectively). A positive correlation was observed between stable and horn flies and all insect avoidance behaviors. Numbers of stable flies were 1.5 times greater in the afternoon than in the morning. The results of this study indicated that flies were associated with cow fly avoidance behaviors regardless of the use of leggings, but leggings effectively reduced foot stomps by 39%, so their use may provide some relief from stable fly injury to pastured dairy cows.
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Enfermedades de los Bovinos/parasitología , Infestaciones Ectoparasitarias/veterinaria , Muscidae , Ropa de Protección/veterinaria , Animales , Reacción de Prevención , Conducta Animal , Bovinos , Enfermedades de los Bovinos/prevención & control , Estudios Cruzados , Infestaciones Ectoparasitarias/prevención & control , Femenino , LactanciaRESUMEN
BACKGROUND: Vestibular schwannomas (VSs) are benign neoplasms of the Schwann cells of cranial nerve VIII, and treatment of VS typically involves surgical resection. However, tumor recurrence may necessitate reintervention, and secondary treatment modalities include repeat surgical resection or adjuvant radiosurgery. The purpose of this study is to examine the scientific literature in order to determine whether surgical resection or radiosurgery for recurrent VS results in better tumor control, hearing preservation, and preservation of facial nerve function. METHODS: The PubMed, Scopus, Embase, Cochrane, and Web of Science databases were searched for studies reporting on patients undergoing either radiosurgery or repeat surgical resection after primary surgical resection for recurrent VS. Statistical analyses were performed on the compiled data, primarily outcome data involving tumor control, hearing preservation, and preservation of facial nerve function. RESULTS: We analyzed the data of 15 individual studies involving 359 total patients, and our results reveal that tumor control rates are comparable between adjuvant radiosurgery (91%, CI: 88-94%) and secondary resection (92%, CI 75-98%). However, adjuvant radiosurgery was shown to preserve good facial nerve function better (94%, CI 84-98%) compared to secondary surgical resection (56%, CI 41-69%). CONCLUSION: With comparable tumor control rates and better preservation of good facial nerve function, this study suggests that secondary radiosurgery for recurrent VS is associated with both optimal tumor control and preservation of good facial nerve function.
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Nervio Facial/cirugía , Pérdida Auditiva/epidemiología , Neuroma Acústico/radioterapia , Complicaciones Posoperatorias/epidemiología , Radiocirugia/métodos , Humanos , Neuroma Acústico/cirugía , Radiocirugia/efectos adversos , Nervio Vestibulococlear/cirugíaRESUMEN
Monitoring of radiocarbon (C14) in carbon dioxide is demonstrated using mid-infrared spectroscopy and a quantum cascade laser. The measurement is based on cavity ring-down spectroscopy, and a high sensitivity is achieved with a simple setup. The instrument was tested using a standardized sample containing elevated levels of radiocarbon. Radiocarbon dioxide could be detected from samples with an isotopic ratio C14/C as low as 50 parts-per-trillion, corresponding to an activity of 5 kBq/m(3) in pure CO(2), or 2 Bq/m(3) in air after extraction of the CO(2) from an air sample. The instrument is simple, compact, and robust, making it the ideal tool for on-site measurements. It is aimed for monitoring radioactive gaseous emissions in a nuclear power environment, during the operation and decommissioning of nuclear power plants. Its high sensitivity also makes it the ideal tool for the detection of leaks in radioactive waste repositories.
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Dexamethasone treatment of F0 pregnant rodents alters F1 placental function and adult cardiometabolic phenotype. The adult phenotype is transmitted to the F2 generation without further intervention, but whether F2 placental function is altered by F0 dexamethasone treatment remains unknown. In the present study, F0 mice were untreated or received dexamethasone (0.2µgg(-1)day(-1), s.c.) over Days 11-15 or 14-18 of pregnancy (term Day 21). Depending on the period of F0 dexamethasone treatment, F1 offspring were lighter at birth or grew more slowly until weaning (P<0.05). Glucose tolerance (1gkg(-1), i.p.) of adult F1 males was abnormal. Mating F1 males exposed prenatally to dexamethasone with untreated females had no effect on F2 placental function on Day 19 of pregnancy. In contrast, when F1 females were mated with untreated males, F2 placental clearance of the amino acid analogue (14)C-methylaminoisobutyric acid was increased by 75% on Day 19 specifically in dams prenatally exposed to dexamethasone on Days 14-18 (P<0.05). Maternal plasma corticosterone was also increased, but F2 placental Slc38a4 expression was decreased in these dams (P<0.05). F0 dexamethasone treatment had no effect on F2 fetal or placental weights, regardless of lineage. Therefore, the effects of F0 dexamethasone exposure are transmitted intergenerationally to the F2 placenta via the maternal, but not paternal, line.
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Dexametasona/farmacología , Glucocorticoides/farmacología , Placenta/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal/metabolismo , Reproducción/efectos de los fármacos , Animales , Femenino , Ratones , Placenta/metabolismo , EmbarazoRESUMEN
OBJECTIVES: To determine the ability of foramen ovale electrodes (FOEs) to localize epileptogenic foci after inconclusive noninvasive investigations in patients with suspected mesial temporal lobe epilepsy (MTLE). METHODS: We identified patients with medically intractable epilepsy who had undergone FOE investigation for initial invasive monitoring at our institution between 2005 and 2012. Indications for initiating FOE investigation were grouped into four categories: (1) bilateral anterior temporal ictal activity on scalp electroencephalography (EEG), (2) unclear laterality of scalp EEG onset due to muscle artifact or significant delay following clinical manifestation, (3) discordance between ictal and interictal discharges, and (4) investigation of a specific anatomic abnormality or competing putative focus. The FOE investigation was classified as informative if it provided sufficient evidence to make a treatment decision. RESULTS: Forty-two consecutive patients underwent FOE investigation, which was informative in 38 patients (90.5%). Of these 38 patients, 24 were determined to be appropriate candidates for resective surgery. Five were localized sufficiently for surgery, but were considered high risk for verbal memory deficit, and nine were deemed poor surgical candidates because of bilateral ictal origins. The remaining 4 of 42 patients had inconclusive FOE studies and were referred for further invasive investigation. Of the 18 patients who underwent resective surgery, 13 (72%) were seizure-free (Engel class I) at last follow-up (mean 22.5 months). SIGNIFICANCE: More than 90% of our 42 FOE studies provided sufficient evidence to render treatment decisions. When undertaken with an appropriate hypothesis, FOE investigations are a minimally invasive and efficacious means for evaluating patients with suspected MTLE after an inconclusive noninvasive investigation.
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Electroencefalografía/métodos , Epilepsia del Lóbulo Temporal/diagnóstico , Epilepsia del Lóbulo Temporal/fisiopatología , Foramen Oval/fisiopatología , Procesamiento de Señales Asistido por Computador , Adolescente , Adulto , Dominancia Cerebral/fisiología , Electrodos Implantados , Epilepsia del Lóbulo Temporal/cirugía , Femenino , Humanos , Masculino , Recuerdo Mental/fisiología , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Aprendizaje Verbal/fisiologíaRESUMEN
AIM: Socioeconomic deprivation is associated with poorer survival from colorectal cancer. We examined the association of deprivation with access to treatment, disease stage at presentation and choice of treatment for colorectal cancer within a regional managed clinical network. METHOD: We performed a retrospective analysis of data from the Southeast Scotland Cancer Network colorectal database for the period 2003-2009. Socioeconomic status was assigned into five categories using postcode of residence and the Scottish Index of Multiple Deprivation score. Outcomes were access to consultation and treatment, stage of disease at presentation and treatment factors (type of surgery, adjuvant radiotherapy and adjuvant chemotherapy). RESULTS: Of 4960 colorectal cancer patients, 4016 patients (81%) underwent operative treatment. Deprivation was not associated with age, gender, tumour site, disease stage, delay in treatment pathway or permanent stoma rate. Primary tumour resection (P = 0.006) and chemotherapy treatment (P = 0.018) were higher in the least deprived compared with the most deprived quintile. Socioeconomic status was associated with both primary tumour resection [odds ratio for the most affluent compared with the most deprived quintiles (OR) 1.34, 95% confidence interval (CI) 1.05-1.72, P = 0.018] and chemotherapy treatment (OR 1.44, 95% CI 1.15-1.80, P = 0.001). However, when health board of treatment was added to the model, only chemotherapy treatment was independently associated with deprivation (OR 1.46, 95% CI 1.16-1.83, P = 0.001). CONCLUSION: Deprivation is not associated with treatment delay or more advanced disease stage at presentation. An apparent association between deprivation and treatment choice may be explained by other differences between patients treated in different areas.
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Carcinoma/terapia , Quimioterapia Adyuvante/estadística & datos numéricos , Neoplasias Colorrectales/terapia , Procedimientos Quirúrgicos del Sistema Digestivo/estadística & datos numéricos , Accesibilidad a los Servicios de Salud/estadística & datos numéricos , Disparidades en Atención de Salud/estadística & datos numéricos , Pobreza/estadística & datos numéricos , Anciano , Anciano de 80 o más Años , Carcinoma/diagnóstico , Estudios de Cohortes , Neoplasias Colorrectales/diagnóstico , Diagnóstico Tardío/estadística & datos numéricos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Escocia , Factores Socioeconómicos , Tiempo de Tratamiento/estadística & datos numéricosRESUMEN
OBJECTIVE: Corpus callosotomy (CC) is an important treatment for atonic seizures in patients with generalized or multifocal drug-resistant epilepsy (DRE). Traditionally, CC is performed via an open microsurgical approach, but more recently, MR-guided stereotactic laser interstitial thermal therapy (LITT) corpus callosum ablation (CCA) has been developed to leverage the safety and minimally invasive nature of LITT. Given the recent adoption of CCA at select centers, how CCA compares to CC is unknown. We aim to compare the clinical seizure outcomes of CCA and CC after extended follow-up. METHODS: We performed a retrospective cohort study to compare the effectiveness and safety of CC to CCA from 1994 to 2022. The primary outcome was a 50% reduction in target seizure. Secondary outcome measures were postoperative length of stay, adverse events, and other effectiveness metrics. Comparative statistics were executed using Stata. Normality for continuous variables was assessed, and parametric statistics were utilized as needed. Frequency was compared with chi-squared or Fischer's exact tests, when applicable. RESULTS: Data from 47 operations performed on 36 patients were included in this study, of which 13 (36%) patients underwent 17 CCA. Patients who received CCA had similar rates of meaningful reduction (>50%) of atonic seizures as their CC counterparts (55% vs 70% P = 0.15). Patients undergoing CCA had significantly shorter hospitalizations than those receiving CC (2.5 vs 6.0 days P < 0.001). There was no significant difference in rates of postoperative complications between the groups, although the magnitude of the complication rates was lower in the CCA cohort (12% vs 28%). SIGNIFICANCE: This early experience suggests CCA has similar outcomes to traditional CC, albeit with a shorter hospital stay. However, future studies are necessary to investigate the noninferiority between these two approaches. Large multicenter studies are necessary to investigate differences in adverse events and whether these findings generalize across other centers.
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Cuerpo Calloso , Terapia por Láser , Humanos , Estudios Retrospectivos , Cuerpo Calloso/cirugía , Resultado del Tratamiento , Convulsiones , Espectroscopía de Resonancia Magnética , Rayos LáserRESUMEN
BACKGROUND: Focal epilepsy caused by a posterior fossa lesion is a rare phenomenon. In these cases, seizure onset typically occurs during the first few months of life, with episodes of epileptic hemifacial spasms and abnormal eye movements. Patients often present with drug-resistant epilepsy and often require resection for the best chance of seizure freedom. OBSERVATIONS: The authors present the case of a 19-month-old male with intractable epileptic hemifacial spasms and a dorsally exophytic right brainstem and middle cerebellar peduncle hamartoma, following 2 prior subtotal resections. The authors recommended a third suboccipital craniotomy with intraoperative electrocorticography, which revealed interictal spiking from an intralesional depth electrode. Near-total resection led to durable seizure freedom. LESSONS: Although posterior fossa lesions are rarely associated with epileptiform activity, this case demonstrates that pediatric patients with epileptic hemifacial spasms associated with a posterior fossa lesion may respond favorably to resection. Furthermore, this case demonstrates that intralesional electrocorticography can detect epileptic activity in posterior fossa lesions, which may predict postoperative seizure outcomes. https://thejns.org/doi/10.3171/CASE2452.
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Low-grade epilepsy-associated tumors (LEATs) are a common cause of drug-resistant epilepsy in children. Herein, we demonstrate the feasibility of using tumor tissue derived from stereoelectroencephalography (sEEG) electrodes upon removal to molecularly characterize tumors and aid in diagnosis. An 18-year-old male with focal epilepsy and MRI suggestive of a dysembryoplastic neuroepithelial tumor (DNET) in the left posterior temporal lobe underwent implantation of seven peri-tumoral sEEG electrodes for peri-operative language mapping and demarcation of the peri-tumoral ictal zone prior to DNET resection. Using electrodes that passed through tumor tissue, we show successful isolation of tumor DNA and subsequent analysis using standard methods for tumor classification by DNA, including Glioseq targeted sequencing and DNA methylation array analysis. This study provides preliminary evidence for the feasibility of molecular diagnosis of LEATs or other lesions using a minimally invasive method with microscopic tissue volumes. The implications of sEEG electrodes in tumor characterization are broad but would aid in diagnosis and subsequent targeted therapeutic strategies.
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Neoplasias Encefálicas , Epilepsia , Masculino , Humanos , Niño , Adolescente , Electroencefalografía/métodos , Neoplasias Encefálicas/cirugía , Electrodos Implantados , ADNRESUMEN
BACKGROUND AND OBJECTIVES: Hemimegalencephaly (HME) is a rare diffuse malformation of cortical development characterized by unihemispheric hypertrophy, drug-resistant epilepsy (DRE), hemiparesis, and developmental delay. Definitive treatment for HME-related DRE is hemispheric surgery through either anatomic (AH) or functional hemispherectomy (FH). This individual patient data meta-analysis assessed seizure outcomes of AH and FH for HME with pharmacoresistant epilepsy, predictors of Engel I, and efficacy of different FH approaches. METHODS: PubMed, Web of Science, and Cumulative Index to Nursing and Allied Health Literature were searched from inception to Jan 13th, 2023, for primary literature reporting seizure outcomes in >3 patients with HME receiving AH or FH. Demographics, neurophysiology findings, and Engel outcome at the last follow-up were extracted. Postsurgical seizure outcomes were compared through 2-tailed t -test and Fisher exact test. Univariate and multivariate Cox regression analyses were performed to identify independent predictors of Engel I outcome. RESULTS: Data from 145 patients were extracted from 26 studies, of which 89 underwent FH (22 vertical, 33 lateral), 47 underwent AH, and 9 received an unspecified hemispherectomy with a median last follow-up of 44.0 months (FH cohort) and 45.0 months (AH cohort). Cohorts were similar in preoperative characteristics and at the last follow-up; 77% (n = 66) of the FH cohort and 81% (n = 38) and of the AH cohort were Engel I. On multivariate analysis, only the presence of bilateral ictal electroencephalography abnormalities (hazard ratio = 11.5; P = .002) was significantly associated with faster time-to-seizure recurrence. A number-needed-to-treat analysis to prevent 1 additional case of posthemispherectomy hydrocephalus reveals that FH, compared with AH, was 3. There was no statistical significance for any differences in time-to-seizure recurrence between lateral and vertical FH approaches (hazard ratio = 2.59; P = .101). CONCLUSION: We show that hemispheric surgery is a highly effective treatment for HME-related DRE. Unilateral ictal electroencephalography changes and using the FH approach as initial surgical management may result in better outcomes due to significantly lower posthemispherectomy hydrocephalus probability. However, larger HME registries are needed to further delineate the predictors of seizure outcomes.
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Epilepsia Refractaria , Epilepsia , Hemimegalencefalia , Hemisferectomía , Hidrocefalia , Humanos , Hemisferectomía/efectos adversos , Hemimegalencefalia/etiología , Hemimegalencefalia/cirugía , Epilepsia Refractaria/cirugía , Epilepsia/cirugía , Epilepsia/etiología , Convulsiones/etiología , Resultado del Tratamiento , Electroencefalografía , Hidrocefalia/cirugíaRESUMEN
Somatic mosaic variants contribute to focal epilepsy, but genetic analysis has been limited to patients with drug-resistant epilepsy (DRE) who undergo surgical resection, as the variants are mainly brain-limited. Stereoelectroencephalography (sEEG) has become part of the evaluation for many patients with focal DRE, and sEEG electrodes provide a potential source of small amounts of brain-derived DNA. We aimed to identify, validate, and assess the distribution of potentially clinically relevant mosaic variants in DNA extracted from trace brain tissue on individual sEEG electrodes. We enrolled a prospective cohort of eleven pediatric patients with DRE who had sEEG electrodes implanted for invasive monitoring, one of whom was previously reported. We extracted unamplified DNA from the trace brain tissue on each sEEG electrode and also performed whole-genome amplification for each sample. We extracted DNA from resected brain tissue and blood/saliva samples where available. We performed deep panel and exome sequencing on a subset of samples from each case and analysis for potentially clinically relevant candidate germline and mosaic variants. We validated candidate mosaic variants using amplicon sequencing and assessed the variant allele fraction (VAF) in amplified and unamplified electrode-derived DNA and across electrodes. We extracted DNA from >150 individual electrodes from 11 individuals and obtained higher concentrations of whole-genome amplified vs unamplified DNA. Immunohistochemistry confirmed the presence of neurons in the brain tissue on electrodes. Deep sequencing and analysis demonstrated similar depth of coverage between amplified and unamplified samples but significantly more called mosaic variants in amplified samples. In addition to the mosaic PIK3CA variant detected in a previously reported case from our group, we identified and validated four potentially clinically relevant mosaic variants in electrode-derived DNA in three patients who underwent laser ablation and did not have resected brain tissue samples available. The variants were detected in both amplified and unamplified electrode-derived DNA, with higher VAFs observed in DNA from electrodes in closest proximity to the electrical seizure focus in some cases. This study demonstrates that mosaic variants can be identified and validated from DNA extracted from trace brain tissue on individual sEEG electrodes in patients with drug-resistant focal epilepsy and in both amplified and unamplified electrode-derived DNA samples. Our findings support a relationship between the extent of regional genetic abnormality and electrophysiology, and suggest that with further optimization, this minimally invasive diagnostic approach holds promise for advancing precision medicine for patients with DRE as part of the surgical evaluation.
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Objectives: Brain-limited pathogenic somatic variants are associated with focal pediatric epilepsy, but reliance on resected brain tissue samples has limited our ability to correlate epileptiform activity with abnormal molecular pathology. We aimed to identify the pathogenic variant and map variant allele fractions (VAFs) across an abnormal region of epileptogenic brain in a patient who underwent stereoelectroencephalography (sEEG) and subsequent motor-sparing left frontal disconnection. Methods: We extracted genomic DNA from peripheral blood, brain tissue resected from peri-sEEG electrode regions, and microbulk brain tissue adherent to sEEG electrodes. Samples were mapped based on an anatomic relationship with the presumed seizure onset zone (SOZ). We performed deep panel sequencing of amplified and unamplified DNA to identify pathogenic variants with subsequent orthogonal validation. Results: We detect a pathogenic somatic PIK3CA variant, c.1624G>A (p.E542K), in the brain tissue samples, with VAF inversely correlated with distance from the SOZ. In addition, we identify this variant in amplified electrode-derived samples, albeit with lower VAFs. Discussion: We demonstrate regional mosaicism across epileptogenic tissue, suggesting a correlation between variant burden and SOZ. We also validate a pathogenic variant from individual amplified sEEG electrode-derived brain specimens, although further optimization of techniques is required.
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BACKGROUND: A positive circumferential resection margin (CRM) has been associated with a poorer prognosis in oesophageal and oesophagogastric junctional (OGJ) cancer. The College of American Pathologists defines the CRM as positive if tumour cells are present at the margin, whereas the Royal College of Pathologists also include tumour cells within 1 mm of this margin. The relevance of these differences is not clear and no study has investigated the impact of adjuvant therapy. The aim was to identify the optimal definition of an involved CRM in patients undergoing resection for oesophageal or OGJ cancer, and to determine whether adjuvant radiotherapy improved survival in patients with an involved CRM. METHODS: This was a single-centre retrospective study of patients who had undergone attempted curative resection for a pathological T3 oesophageal or OGJ cancer. Clinicopathological variables and distance from the tumour to the CRM, measured to ± 0.1 mm, were correlated with survival. RESULTS: A total of 226 patients were included. Sex (P = 0·018), tumour differentiation (P = 0·019), lymph node status (P < 0·001), number of positive nodes (P < 0·001), and CRM distance (P = 0·042) were independently predictive of prognosis. No significant survival difference was observed between positive CRM 0-mm and 0·1-0·9-mm groups after controlling for other prognostic variables. Both groups had poorer survival than matched patients with a CRM at least 1 mm clear of tumour cells. Among patients with a positive CRM of less than 1 mm, those undergoing observation alone had a median survival of 18·6 months, whereas survival was a median of 10 months longer in patients undergoing adjuvant radiotherapy, but otherwise matched for prognostic variables (P = 0·009). CONCLUSION: A positive CRM of 1 mm or less should be regarded as involved. Adjuvant radiotherapy confers a significant survival benefit in selected patients with an involved CRM.
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Adenocarcinoma/cirugía , Carcinoma de Células Escamosas/cirugía , Neoplasias Esofágicas/cirugía , Unión Esofagogástrica/cirugía , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Quimioterapia Adyuvante/mortalidad , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Unión Esofagogástrica/patología , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Pronóstico , Radioterapia Adyuvante/mortalidad , Estudios RetrospectivosRESUMEN
Epilepsy affects at least 2% of the population at some time in their lives. The epilepsies are a heterogeneous group of disorders, many with an inherited component. Although specific genes have been identified in a few rare diseases causing seizures as part of a more diffuse brain disorder, the molecular pathology of the common idiopathic epilepsies is still unknown. Linkage has been reported for some generalised epilepsy syndromes, but only very recently for familial partial epilepsy syndromes. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a partial epilepsy causing frequent, violent, brief seizures at night, usually beginning in childhood. The gene for ADNFLE maps to chromosome 20q13.2-q13.3 in one large Australian kindred. The neuronal nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4) maps to the same region of 20q (ref. 12) and the gene is expressed in all layers of the frontal cortex. We screened affected family members for mutations within CHRNA4 and found a missense mutation that replaces serine with phenylalanine at codon 248, a strongly conserved amino acid residue in the second transmembrane domain. The mutation is present in all 21 available affected family members and in four obligate carriers, but not in 333 healthy control subjects.
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Cromosomas Humanos Par 20 , Epilepsia del Lóbulo Frontal/genética , Genes Dominantes , Mutación Puntual , Receptores Nicotínicos/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Pollos , Mapeo Cromosómico , Cartilla de ADN , Femenino , Lóbulo Frontal/metabolismo , Ligamiento Genético , Humanos , Masculino , Datos de Secuencia Molecular , Linaje , Reacción en Cadena de la Polimerasa , Ratas , Receptores Nicotínicos/química , Homología de Secuencia de AminoácidoRESUMEN
The epilepsies comprise a group of syndromes that are divided into generalized and partial (focal) types. Familial occurrence has long been recognized but progress in mapping epilepsy genes has been slow except for rare cases where the inheritance is easily determined from classical genetic studies. Linkage is established for three generalized syndromes: the EBN1 and EBN2 genes for benign familial neonatal convulsions (BFNC) map to chromosomes 20q and 8q (refs 2-5), the EPM1 gene for Unverricht-Lundborg disease maps to 21q (ref. 6) and the gene for the northern epilepsy syndrome maps to 8p (ref. 7). A claim for linkage of the EJM1 gene for the common generalized syndrome of juvenile myoclonic epilepsy to 6p is currently in dispute. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) was recently described in five families. We now report the chromosomal assignment, to 20q13.2, for the gene for ADNFLE in one large Australian kindred with 27 affected individuals spanning six generations.
Asunto(s)
Cromosomas Humanos Par 20 , Epilepsia del Lóbulo Frontal/genética , Epilepsia Generalizada/genética , Femenino , Ligamiento Genético , Marcadores Genéticos , Humanos , Masculino , Linaje , Receptores Nicotínicos/genéticaRESUMEN
Febrile seizures affect approximately 3% of all children under six years of age and are by far the most common seizure disorder. A small proportion of children with febrile seizures later develop ongoing epilepsy with afebrile seizures. Segregation analysis suggests the majority of cases have complex inheritance but rare families show apparent autosomal dominant inheritance. Two putative loci have been mapped (FEB1 and FEB2), but specific genes have not yet been identified. We recently described a clinical subset, termed generalized epilepsy with febrile seizures plus (GEFS+), in which many family members have seizures with fever that may persist beyond six years of age or be associated with afebrile generalized seizures. We now report linkage, in another large GEFS+ family, to chromosome region 19q13.1 and identification of a mutation in the voltage-gated sodium (Na+)-channel beta1 subunit gene (SCN1B). The mutation changes a conserved cysteine residue disrupting a putative disulfide bridge which normally maintains an extracellular immunoglobulin-like fold. Co-expression of the mutant beta1 subunit with a brain Na+-channel alpha subunit in Xenopus laevis oocytes demonstrates that the mutation interferes with the ability of the subunit to modulate channel-gating kinetics consistent with a loss-of-function allele. This observation develops the theme that idiopathic epilepsies are a family of channelopathies and raises the possibility of involvement of other Na+-channel subunit genes in febrile seizures and generalized epilepsies with complex inheritance patterns.
Asunto(s)
Epilepsia Generalizada/genética , Ligamiento Genético , Mutación Puntual/genética , Convulsiones Febriles/genética , Canales de Sodio/genética , Secuencia de Aminoácidos , Animales , Cromosomas Humanos Par 19/genética , Análisis Mutacional de ADN , Femenino , Humanos , Masculino , Datos de Secuencia Molecular , Oocitos , Técnicas de Placa-Clamp , Linaje , Canales de Sodio/fisiología , Tasmania , Xenopus laevisRESUMEN
Mesial temporal lobe epilepsy (mTLE) is an important cause of drug-resistant epilepsy (DRE) in adults and children. Traditionally, the surgical option of choice for mTLE includes a frontotemporal craniotomy and open resection of the anterior temporal cortex and mesial temporal structures. Although this technique is effective and durable, the neuropsychological morbidity resulting from temporal neocortical resections has resulted in the investigation of alternative approaches to resect the mesial temporal structures to achieve seizure freedom while minimizing postoperative cognitive deficits. Outcomes supporting the use of selective temporal resections have resulted in alternative approaches to directly access the mesial temporal structures via endoscopic approaches whose direct trajectory to the epileptogenic zone minimizes retraction, resection, and manipulation of surrounding cortex. The authors reviewed the utility of the endoscopic transmaxillary, endoscopic endonasal, endoscopic transorbital, and endoscopic supracerebellar transtentorial approaches for the treatment of drug-resistant mesial temporal lobe epilepsy. First, a review of the literature demonstrated the anatomical feasibility of each approach, including the limits of exposure provided by each trajectory. Next, clinical data assessing the safety and effectiveness of these techniques in the treatment of DRE were analyzed. An outline of the surgical techniques is provided to highlight the technical nuances of each approach. The direct access to mesial temporal structures and avoidance of lateral temporal manipulation makes endoscopic approaches promising alternatives to traditional methods for the treatment of DRE arising from the temporal pole and mesial temporal lobe. A dearth of literature outlining clinical outcomes, a need for qualified cosurgeons, and a lack of experience with endoscopic approaches remain major barriers to widespread application of the aforementioned techniques. Future studies are warranted to define the utility of these approaches moving forward.