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Objective new-onset refractory status epilepticus (NORSE) is defined as de novo refractory seizures occurring in previously healthy adults, without a clear underlying etiology. Due to refractory seizures and insufficient understanding of pathophysiology, management of these patients remains challenging and often leads to poor clinical outcomes. Various infectious and autoimmune mechanisms have been proposed but have not been validated and a large number of patients are thus labeled ‘cryptogenic’. Moreover, histopathological findings have rarely been described in NORSE and are usually autopsy evaluations. In this paper, we describe the clinical correlates and histopathological findings in patients presenting with NORSE. Methods A case series of five patients with NORSE who underwent neurosurgical intervention and had histopathological examination during their acute clinical course. Results In all patients,status epileptics was refractory to treatment with antiseizure drugs (ASDs) and anesthetic agents. Autoimmune work-up revealed elevated titer of anti-GAD antibody in one patient but was unremarkable in others. Empiric use of immunomodulation therapy in three patients did not lead to cessation of status epilepticus (SE). Due to failure of prolonged medical management, three patients underwent palliative surgery for resection of epileptogenic tissue whereas the other two had diagnostic brain biopsy. Histopathology obtained during biopsy revealed evidence of vasculitis in one and necrotizing vasculopathy in another. The patient with anti-GAD antibodies had evidence of lymphocytic infiltration in limbic structures. The remaining two had nonspecific histopathological findings. Significance Although our findings are limited by a small number of patients, it adds to the growing premise of NORSE being related to an underlying autoimmune process. Additional studies, especially with histopathological data are needed to better understand this devastating disorder.

Objective To assess the long-term safety and efficacy of eslicarbazepine acetate (ESL) monotherapy in adults with focal seizures (FS). Methods Study 050 was a long-term, multicenter, open-label (OL) safety extension of two conversion-to-ESL monotherapy studies in adults with refractory FS. After participating in Study 045 or 046, patients started on ESL 1600 mg once daily (QD) (or 1200 mg if they previously had a dose reduction), and could adjust the dose 400 mg/week to a dose between 800–2400 mg QD. Patients could add up to two additional antiepileptic drugs (AEDs). This post-hoc analysis focuses on the actual monotherapy subgroup, which included patients in Studies 045/046/050 who did not add additional AEDs. Study endpoints included treatment retention time, time on ESL monotherapy, change in standardized seizure frequency (SSF), change in quality of life (QoL) in epilepsy (QOLIE-31) and Montgomery-Asberg Depression Rating Scale (MADRS) scores, and incidence of treatment-emergent adverse events (TEAEs); serious adverse events (SAEs), TEAEs leading to discontinuation, and TEAEs related to allergic reaction, hyponatremia and thyroid function were also evaluated. Results There were 274 patients in the Study 050 full intent-to-treat (ITT) population and 140 patients in the actual monotherapy subgroup. Median treatment retention time and time on ESL monotherapy were both >5 years. Median reduction in SSF from baseline was 66.4% in the full ITT population and 78.3% in the actual monotherapy subgroup; responder (≥50% reduction in SSF) rates were 62.4% and 74.3%, respectively. QOLIE-31 scores increased from baseline in the full ITT population and the actual monotherapy subgroup (4.1- and 7.5-point increases, respectively). MADRS scores decreased from baseline in both the full ITT population and the actual monotherapy subgroup (0.7- and 2.9-point decreases, respectively). TEAEs occurred in 85.4% of patients in the full ITT population and 81.4% of patients in the actual monotherapy subgroup. Incidences of SAEs and TEAEs leading to discontinuation, as well as dizziness, depression, fall, partial seizures with secondary generalization, and complex partial seizures, were higher in the full ITT population than in the actual monotherapy subgroup. Allergic reactions, hyponatremia, and hypothyroidism were infrequent, particularly in the actual monotherapy subgroup. Conclusions The results of this post-hoc analysis suggest that long-term treatment with ESL was effective and well tolerated, both as a monotherapy and in combination with other AEDs for FS. QoL and tolerability appeared to be better, and incidence of depression lower, in the patient population taking ESL as a monotherapy, compared with the population that included patients taking ESL as an adjunctive therapy.

Objective Abnormalities of brain structures and neuronal networks have been identified in MRI studies of patients with Sudden Unexpected Death in Epilepsy (SUDEP) as well as in those at elevated risk. The goal of this study was to identify common patterns of objectively detected brain glucose metabolic abnormalities associated with SUDEP patients and those at high SUDEP risk. Methods Patients with refractory epilepsy (n = 78, age: 16–61 years, 44 females), who underwent comprehensive presurgical evaluation, were assessed for their risk of SUDEP using the revised SUDEP-7 inventory. From the 57 patients with low SUDEP risk, 35 were selected to match their demographic and clinical characteristics to those with high SUDEP risk (n = 21). [18F]fluoro-deoxy-glucose positron emission tomography (FDG-PET) abnormalities were evaluated in the high- and low-SUDEP risk subgroups compared to FDG-PET scans of a healthy adult control group using statistical parametric mapping (SPM). Individual FDG-PET scans of 4 additional patients, who died from SUDEP, were also analyzed by SPM. Results Mean SUDEP-7 score was 6.1 in the high and 2.7 in the low SUDEP risk group. MRI showed no lesion in 36 patients (64%). Statistical parametric mapping analysis of the high SUDEP risk subgroup showed bilateral medial frontal and inferior frontal hypometabolism as a common pattern. The low-risk group showed no specific common metabolic abnormalities on SPM group analysis. Individual PET scans of all 4 patients who died from SUDEP also showed bilateral frontal lobe hypometabolism. Conclusions These data show that bilateral frontal lobe involvement on FDG-PET, especially the medial and inferior frontal cortex, may be a common metabolic pattern associated with high SUDEP risk and SUDEP itself, in patients with refractory focal epilepsy.

Prior studies have used functional neuroimaging to demonstrate that the organization of the autistic brain is different from that of the non-autistic brain. Similarly, patients with epilepsy have also shown cortical reorganization. We present a case study that provides direct confirmation of disorganized sensorimotor distribution in a patient with autism spectrum disorder and epilepsy. To our knowledge, this is the first time cortical mapping directly showing abnormal cortical organization in a patient with autism spectrum disorder and epilepsy has been reported in the literature.

Objective To evaluate and compare the effects of concomitant lamotrigine (LTG) or carbamazepine (CBZ) on the incidence of treatment-emergent adverse events (TEAEs) in patients taking adjunctive eslicarbazepine acetate (ESL) for focal (partial-onset) seizures (FS). Methods These post-hoc analyses of data pooled from three randomized, double-blind, placebo-controlled studies of adjunctive ESL (BIA-2093-301, −302 and −304) included adults (≥16 years) with FS refractory to 1–3 antiepileptic drugs (AEDs). Patients were randomized equally to placebo, ESL 400 mg (Studies 301 and 302 only), 800 mg, or 1200 mg once daily (8-week baseline, 2-week titration, and 12-week maintenance periods). TEAEs, TEAEs leading to discontinuation, and serious AEs (SAEs) were evaluated in patients taking, or not taking, LTG (excluding those taking CBZ or phenytoin [PHT]; i.e., the +LTG and −LTG/–CBZ subgroups), or CBZ (excluding those taking LTG or PHT; i.e., the +CBZ and −LTG/–CBZ subgroups) at baseline. Results LTG was used concomitantly by 248 patients (+LTG; placebo, n = 81; ESL, n = 167) and CBZ by 613 patients (+CBZ; placebo, n = 172; ESL, n = 441); 361 patients were taking neither LTG nor CBZ (−LTG/–CBZ; placebo, n = 109; ESL, n = 252). The overall incidence of TEAEs with ESL (any dose) was numerically higher for +CBZ (77%) than for +LTG (73%) or –LTG/–CBZ (68%; statistical significance not tested). Among patients taking ESL, dizziness, diplopia, and vomiting were reported more frequently in the +CBZ subgroup (30%, 14%, and 10%, respectively) than in the +LTG (16%, 8%, 5%) or –LTG/–CBZ (11%, 3%, 5%) subgroups. The overall incidence of TEAEs leading to discontinuation with ESL was higher for +CBZ (21%) than for +LTG (13%) or –LTG/–CBZ (15%). Dizziness leading to discontinuation with ESL was reported more frequently in the +CBZ subgroup than in the +LTG or –LTG/–CBZ subgroups (9%, 3%, and 3%, respectively). The overall incidence of SAEs in patients taking ESL was comparable across subgroups (+LTG, 5%; +CBZ, 6%; –LTG/–CBZ, 5%). The results were similar when evaluating placebo-adjusted incidences. Conclusion There was a potential pharmacodynamic interaction between AEDs with a putatively similar mechanism of action, with a seemingly lesser interaction between ESL and LTG versus ESL and CBZ. If combining ESL with LTG or CBZ, clinicians should be aware of the potential risk for an increased incidence of TEAEs typically associated with voltage-gated sodium channel inhibitors (e.g., dizziness, blurred vision, vertigo, diplopia, headache, or vomiting).

In Australia, about 40% of patients undergo mastectomy to treat breast cancer, with negative impacts on body image, sexual function and quality of life. Whilst breast reconstruction is associated with increased patient self-esteem and a greater sense of wholeness and well-being, the national reconstruction rate is low at 18%. This study aimed to compare demographics, treatment factors and information provision about breast reconstruction in women who had and did not have breast reconstruction following mastectomy treatment and identify goals and concerns underpinning women’s reconstruction decisions. Female patients who had a mastectomy to treat breast cancer between 2010 and 2014 in a culturally and linguistically diverse (CALD) and socially disadvantaged region participated in a cross-sectional study, completing a questionnaire in their language of choice (English, Vietnamese, Chinese or Arabic). Completed surveys were returned by 168 women (42% response rate; 77% English-speaking), of whom only 19.0% (n = 32) reported having had breast reconstruction. Reconstruction rates were significantly lower in women who reported speaking a language other than English at home versus only English (37.5% vs 62.5%, p = 0.03). However, all women expressed a desire for more information about breast reconstruction and more support to make their decision about breast reconstruction. Patients identified a need for greater information provision on breast reconstruction, highlighting an urgent need for resources specifically about breast reconstruction, particularly for non-English-speaking patients. Greater provision of information prior to mastectomy is critical to underpin breast cancer patients’ decisions about breast reconstruction, especially for non-English speaking patients.

Status epilepticus (SE) is defined as ongoing seizures lasting longer than five minutes or multiple seizures without recovery. Benzodiazepines (BZDs) are first-line agents for the management of SE. Our objective was to evaluate BZD dosing in SE patients and its effects on clinical/electrographic outcomes. A retrospective analysis was conducted from a prospective database of SE patients admitted to a university-based neurocritical care unit. The initial presentation and progression to refractory SE (RSE) and non-convulsive SE (NCSE) with coma was evaluated. Outcome measures included length of stay (LOS), rates of intubation, ventilator-dependent days, and Glasgow outcome scale (GOS). The lorazepam equivalent (LE) dosage of BZDs administered was calculated and we analysed variations in progression if 4 mg or more of LE (adequate BZDs) was administered. Among 100 patients, the median dose of LE was 3 mg (IQR: 2-5 mg). Only 31% of patients received adequate BZDs. Only 18.9% of patients with NCSE without coma received adequate BZDs (p=0.04). Among patients progressing to RSE, 75.4% had not received adequate BZDs (p=0.04) and among patients developing NCSE with coma, 80.6% did not receive adequate BZDs (p=0.07). Escalating doses of BZDs were associated with a decrease in cumulative incidences of RSE (correlation coefficient r=-0.6; p=0.04) and NCSE with coma (correlation coefficient r=-0.7; p=0.003). Outcome measures were not influenced by BZD dosing. The majority of our patients were not adequately dosed with BZDs. Inadequate BZD dosing progressed to RSE and had a tendency to lead to NCSE with coma. Our study demonstrates the need to develop a hospital-wide protocol to guide first responders in the management of SE.

Objective Relationship between electrographic seizures on hippocampal electrocorticography (IH-ECoG) and presence/type of hippocampal pathology remains unclear. Methods IH-ECoG was recorded for 10–20 min from the ventricular surface of the hippocampus following removal of the temporal neocortex in 40 consecutive patients. Correlation between intraoperative hippocampal seizures and preoperative MRI, hippocampal histopathology, and EEG from invasive monitoring was determined. Results IH-ECoG captured electrographic seizures in 15/40 patients (in 8/23 with abnormal hippocampal signal on MRI and 7/17 patients without MRI abnormality). Hippocampal neuronal loss was observed in 22/40 (Group 1), while 18/40 had no significant neuronal loss (Group 2). In Group 1, 4/22 had seizures on IH-ECoG, while 11/18 had electrographic seizures in Group 2. In 24/40 patients who underwent prolonged extraoperative intracranial EEG (IC-EEG) recording, hippocampal seizures were captured in 14. Of these, 7 also had seizures during IH-ECoG. In 10/24 IC-EEG patients without seizures, 3 had seizures on IH-ECoG. Conclusions IH-ECoG frequently captures spontaneous electrographic seizures. These are more likely to occur in patients with pathologic processes that do not disrupt/infiltrate hippocampus compared to patients with intractable epilepsy associated with disrupted hippocampal architecture. Significance Intraoperative hippocampal seizures may result from deafferentation from the temporal neocortex and disinhibition of the perforant pathway.

Intrathecal administration of gadolinium may result in catastrophic neurologic injury. Policies that prevent accidental injection of high-dose intrathecal gadolinium should be advocated.

A 32-year-old man presents with intractable right temporal lobe epilepsy of currently unknown etiology described as focal unaware seizures with teeth grinding and rhythmic left leg movements with and without spread to bilateral tonic-clonic (video 1). The patient and caregivers report episodes of bruxism during wakefulness and sleep. MRI shows an incidental left frontal developmental venous anomaly, and the temporal lobes are symmetrical with normal architecture and without signal abnormalities. Fluorodeoxyglucose-PET shows hypometabolism in the lateral right temporal lobe, right medial prefrontal cortex, and adjacent lateral/inferior frontal cortex and insula. Video EEG captured 6 right temporal lobe seizures (figure).

To identify the role of acute surgical intervention in the treatment of refractory status epilepticus (RSE). Retrospective review of consecutive patients who underwent epilepsy surgery from 2006 to 2015 was done to identify cases where acute surgical intervention was employed for the treatment of RSE. In addition, the adult and pediatric RSE literature was reviewed for reports of surgical treatment of RSE. Nine patients, aged 20–68 years, with various etiologies were identified to have undergone acute surgical resection for the treatment of RSE, aided by electrocorticography. Patients required aggressive medical therapy with antiepileptic drugs and intravenous anesthetic drugs for 10–54 days and underwent extensive neurodiagnostic testing prior to resective surgery. Eight out of nine patients survived and five patients were seizure-free at the last follow-up. The literature revealed 13 adult and 48 pediatric cases where adequate historical detail was available for review and comparison. We present the largest cohort of consecutive adult patients who underwent resective surgery in the setting of RSE. We also reveal that surgery can be efficacious in aborting status and in some can lead to long-term seizure freedom. Acute surgical intervention is a viable option in prolonged RSE and proper evaluation for such intervention should be conducted, although the timing and type of surgical intervention remain poorly defined.

Functional brain maps were first delineated in two dimensions 80 years ago. By analysing stimulation and intracranial EEG data from 100 patients with epilepsy, Nakai et al. generate 3D and 4D language maps incorporating space, time and causality. These whole-brain maps allow prediction of language areas for patients undergoing neurosurgery., We have provided 3-D and 4D mapping of speech and language function based upon the results of direct cortical stimulation and event-related modulation of electrocorticography signals. Patients estimated to have right-hemispheric language dominance were excluded. Thus, 100 patients who underwent two-stage epilepsy surgery with chronic electrocorticography recording were studied. An older group consisted of 84 patients at least 10 years of age (7367 artefact-free non-epileptic electrodes), whereas a younger group included 16 children younger than age 10 (1438 electrodes). The probability of symptoms transiently induced by electrical stimulation was delineated on a 3D average surface image. The electrocorticography amplitude changes of high-gamma (70–110 Hz) and beta (15–30 Hz) activities during an auditory-naming task were animated on the average surface image in a 4D manner. Thereby, high-gamma augmentation and beta attenuation were treated as summary measures of cortical activation. Stimulation data indicated the causal relationship between (i) superior-temporal gyrus of either hemisphere and auditory hallucination; (ii) left superior-/middle-temporal gyri and receptive aphasia; (iii) widespread temporal/frontal lobe regions of the left hemisphere and expressive aphasia; and (iv) bilateral precentral/left posterior superior-frontal regions and speech arrest. On electrocorticography analysis, high-gamma augmentation involved the bilateral superior-temporal and precentral gyri immediately following question onset; at the same time, high-gamma activity was attenuated in the left orbitofrontal gyrus. High-gamma activity was augmented in the left temporal/frontal lobe regions, as well as left inferior-parietal and cingulate regions, maximally around question offset, with high-gamma augmentation in the left pars orbitalis inferior-frontal, middle-frontal, and inferior-parietal regions preceded by high-gamma attenuation in the contralateral homotopic regions. Immediately before verbal response, high-gamma augmentation involved the posterior superior-frontal and pre/postcentral regions, bilaterally. Beta-attenuation was spatially and temporally correlated with high-gamma augmentation in general but with exceptions. The younger and older groups shared similar spatial-temporal profiles of high-gamma and beta modulation; except, the younger group failed to show left-dominant activation in the rostral middle-frontal and pars orbitalis inferior-frontal regions around stimulus offset. The human brain may rapidly and alternately activate and deactivate cortical areas advantageous or obtrusive to function directed toward speech and language at a given moment. Increased left-dominant activation in the anterior frontal structures in the older age group may reflect developmental consolidation of the language system. The results of our functional mapping may be useful in predicting, across not only space but also time and patient age, sites specific to language function for presurgical evaluation of focal epilepsy.

Marijuana-based treatment for refractory epilepsy shows promise in surveys, case series, and clinical trials. However, literature on their EEG effects is sparse. Our objective is to analyze the effect of marijuana on EEG in a 24-year-old patient with idiopathic generalized epilepsy treated with cannabis. We blindly reviewed 3 long-term EEGs-a 24-hour study while only on antiepileptic drugs, a 72-hour EEG with Cannabis indica smoked on days 1 and 3 in addition to antiepileptic drugs, and a 48-hour EEG with combination C indica/sativa smoked on day 1 plus antiepileptic drugs. Generalized spike-wave discharges and diffuse paroxysmal fast activity were categorized as interictal and ictal, based on duration of less than 10 seconds or greater, respectively. Data from three studies concatenated into contiguous time series, with usage of marijuana modeled as time-dependent discrete variable while interictal and ictal events constituted dependent variables. Analysis of variance as initial test for significance followed by time series analysis using Generalized Autoregressive Conditional Heteroscedasticity model was performed. Statistical significance for lower interictal events (analysis of variance P = 0.001) was seen during C indica use, but not for C indica/sativa mixture (P = 0.629) or ictal events (P = 0.087). However, time series analysis revealed a significant inverse correlation between marijuana use, with interictal (P < 0.0004) and ictal (P = 0.002) event rates. Using a novel approach to EEG data, we demonstrate a decrease in interictal and ictal electrographic events during marijuana use. Larger samples of patients and EEG, with standardized cannabinoid formulation and dosing, are needed to validate our findings.

Lacosamide (LCM) is a third-generation anti-epileptic drug (AED) for partial-onset epilepsy with minimal hepatic metabolism and drug-drug interactions. The impact of individual patient variables such as race on drug metabolism have been under-reported in AEDs and LCM has not been specifically investigated. Our aim was to assess the role race plays on serum LCM levels in the management of epilepsy. Thus, we retrospectively reviewed patients with focal seizures who received LCM and had LCM levels as part of their routine clinical care in our Level IV Epilepsy Center. Variables including age, race, gender, LCM serum levels, LCM daily dose, and concomitant AEDs were collected and analyzed. A total of 93 patients with 1–3 clinic visits yielded 122 LCM serum levels. African Americans (AA) comprised 62.3% of our serum samples. Daily LCM doses averaged 350 mg/day (range 50–1000 mg/day). Eighty-nine percent of patients took 1–2 other AEDs. Overall, AA patients had lower LCM levels (mean 6.8 μg/mL) compared to White patients (mean of 7.1 μg/mL) (p = .017) even when considering for the daily dose effect (p = .007). Analysis of co-variables did not have significant effect on LCM levels. Overall, AA patients had a weaker relationship between LCM daily dose (adjusted for weight) and serum levels as compared to White patients and require a higher LCM dose per weight to achieve similar levels. Differences in pharmacogenetics may play an important role in these findings and focus on how these variations impact seizure burden.

Breast cancer is a heterogeneous disease displaying different histopathological characteristics, molecular profiling and clinical behavior. This study describes the expression patterns of senescence markers P53, DEC1 and DCR2 and assesses their significance on patient survival as a single or combined marker with P16 or P14 using breast cancer progression series. One thousand and eighty (1080) patients with primary invasive ductal carcinoma, no special type, were recruited through an 11-year retrospective study period. We constructed tissue microarrays of normal, benign hyperplasia, ductal carcinoma in situ and invasive ductal carcinoma from each patient and performed immunohistochemical staining to study the protein expression. Statistical analysis includes Pearson chi-square, Kaplan-Meier log ran test and Cox proportional hazard regression were undertaken to determine the associations and predict the survival outcomes. P53, DEC1 and DCR2 expression correlated significantly with normal, benign, premalignant and malignant tissues with (p

Refractory status epilepticus is defined as persistent seizures despite appropriate use of two intravenous medications, one of which is a benzodiazepine. It can be seen in up to 40% of cases of status epilepticus with an acute symptomatic etiology as the most likely cause. New-onset refractory status epilepticus (NORSE) is a recently coined term for refractory status epilepticus where no apparent cause is found after initial testing. A large proportion of NORSE cases are eventually found to have an autoimmune etiology needing immunomodulatory treatment. Management of refractory status epilepticus involves treatment of an underlying etiology in addition to intravenous anesthetics and antiepileptic drugs. Alternative treatment options including diet therapies, electroconvulsive therapy, and surgical resection in case of a focal lesion should be considered. Short-term and long-term outcomes tend to be poor with significant morbidity and mortality with only one-third of patients reaching baseline neurological status.

Summary Background We previously reported the 5-year results of the phase 3 IBCSG 23-01 trial comparing disease-free survival in patients with breast cancer with one or more micrometastatic (≤2 mm) sentinel nodes randomly assigned to either axillary dissection or no axillary dissection. The results showed no difference in disease-free survival between the groups and showed non-inferiority of no axillary dissection relative to axillary dissection. The current analysis presents the results of the study after a median follow-up of 9·7 years (IQR 7·8–12·7). Methods In this multicentre, randomised, controlled, open-label, non-inferiority, phase 3 trial, participants were recruited from 27 hospitals and cancer centres in nine countries. Eligible women could be of any age with clinical, mammographic, ultrasonographic, or pathological diagnosis of breast cancer with largest lesion diameter of 5 cm or smaller, and one or more metastatic sentinel nodes, all of which were 2 mm or smaller and with no extracapsular extension. Patients were randomly assigned (1:1) before surgery (mastectomy or breast-conserving surgery) to no axillary dissection or axillary dissection using permuted blocks generated by a web-based congruence algorithm, with stratification by centre and menopausal status. The protocol-specified primary endpoint was disease-free survival, analysed in the intention-to-treat population (as randomly assigned). Safety was assessed in all randomly assigned patients who received their allocated treatment (as treated). We did a one-sided test for non-inferiority of no axillary dissection by comparing the observed hazard ratios (HRs) for disease-free survival with a margin of 1·25. This 10-year follow-up analysis was not prespecified in the trial's protocol and thus was not adjusted for multiple, sequential testing. This trial is registered with ClinicalTrials.gov, number NCT00072293. Findings Between April 1, 2001, and Feb 8, 2010, 6681 patients were screened and 934 randomly assigned to no axillary dissection (n=469) or axillary dissection (n=465). Three patients were ineligible and were excluded from the trial after randomisation. Disease-free survival at 10 years was 76·8% (95% CI 72·5–81·0) in the no axillary dissection group, compared with 74·9% (70·5–79·3) in the axillary dissection group (HR 0·85, 95% CI 0·65–1·11; log-rank p=0·24; p=0·0024 for non-inferiority). Long-term surgical complications included lymphoedema of any grade in 16 (4%) of 453 patients in the no axillary dissection group and 60 (13%) of 447 in the axillary dissection group, sensory neuropathy of any grade in 57 (13%) in the no axillary dissection group versus 85 (19%) in the axillary dissection group, and motor neuropathy of any grade (14 [3%] in the no axillary dissection group vs 40 [9%] in the axillary dissection group). One serious adverse event (postoperative infection and inflamed axilla requiring hospital admission) was attributed to axillary dissection; the event resolved without sequelae. Interpretation The findings of the IBCSG 23-01 trial after a median follow-up of 9·7 years (IQR 7·8–12·7) corroborate those obtained at 5 years and are consistent with those of the 10-year follow-up analysis of the Z0011 trial. Together, these findings support the current practice of not doing an axillary dissection when the tumour burden in the sentinel nodes is minimal or moderate in patients with early breast cancer. Funding International Breast Cancer Study Group.

To evaluate the nature and incidence of psychiatric and cognitive adverse events (AEs) reported with eslicarbazepine acetate (ESL) used as adjunctive treatment for refractory partial-onset seizures (POS) in adults.This was a post-hoc analysis of data pooled from three randomized double-blind, placebo-controlled trials (BIA-2093-301, -302, -304). After an 8-week baseline period, patients received placebo or adjunctive ESL 400mg (studies 301 and 302 only), 800mg, or 1200mg once daily (QD) for 14weeks (2-week titration period, 12-week maintenance period). Psychiatric and cognitive AEs were identified from individual patient data. Suicidality was also evaluated using the Columbia-Classification Algorithm of Suicide Assessment (C-CASA), or the Columbia-Suicide Severity Rating Scale (C-SSRS). P-values were obtained using the chi-square test of independence or Fisher's exact test, without correcting for multiplicity.The analysis population included 1447 patients (ESL, n=1021; placebo, n = 426). Psychiatric treatment-emergent AEs (TEAEs) occurred in 10.8% of patients receiving ESL, and in a comparable proportion (10.3%) of patients receiving placebo (p=0.802). The incidence of depression and suicidality-related TEAEs was higher for ESL (7.4%) vs. placebo (3.8%) (p=0.009). The occurrence of these TEAEs differed between treatment groups (p = 0.010), but there was no notable trend between increasing ESL dose and increasing incidence of depression and suicidality-related TEAEs. Aggression/hostility-related TEAEs occurred in0.1% of patients taking ESL vs. 0.9% taking placebo. The incidence of cognitive TEAEs was higher for ESL (7.1%) vs. placebo (4.0%) (p=0.023); incidences of memory impairment, attention disturbance, apathy, and aphasia were higher for ESL 1200mg than for other treatment groups. Incidences of psychiatric and cognitive serious AEs (SAEs) were 0.6% and 0.2% with ESL, and 0.5% and 0% with placebo, respectively. Psychiatric and cognitive TEAEs leading to discontinuation occurred in 1.9% and 1.4% of patients taking ESL, and 0.7% and 0.5% taking placebo, respectively.In phase III clinical trials of adjunctive ESL for treatment-refractory POS, psychiatric and cognitive TEAEs were reported infrequently with ESL and placebo. The incidences of depression and suicidality-related TEAEs and of cognitive TEAEs were higher for patients taking ESL vs. placebo. Incidences of psychiatric and cognitive SAEs, and TEAEs leading to discontinuation, were low with ESL and placebo.

Objective In the general population, injury related to seizures often involves falls, head trauma, soft tissue injuries, burns and fractures. Additionally, postictal deleterious behavior changes can by experienced by patients. We seek to identify the risk for seizure-related injury (SRI) and postictal aggression (PIA) in patients with refractory epilepsy. Methods Self-reported SRI and PIA were gathered through a seizure questionnaire as part of the epilepsy center’s seizure safety protocol. Retrospective review of questionnaire, clinical course, and demographic data was completed. Statistical analysis of variables of interest was done using nonparametric methods. Results 126 patient questionnaires were completed over a one-year duration. Most patients reported seizure related injury (56.3 %) and postictal aggression (52.4 %). Increased disease duration was associated with seizure related injury and its severity (Kwallis p = 0.025), with number of antiepileptic drugs (AEDs) as significant factors (p = 0.012). Postictal aggression was also associated with a longer duration of epilepsy (Ranksum p = 0.037, t-test p = 0.04) and higher seizure frequency (p = 0.017). Patients who reported seizure related injury and postictal aggression were on more AEDs (p = 0.0003, p = 0.01, respectively), with first-generation AEDs being most contributory. Conclusion The majority of patients with seizures report seizure-related injuries and postictal aggression. Duration and AED regimen are significant risk factors and screening practices can potentially guide safety measures and recommendations.

Our recent electrocorticography (ECoG) study suggested reverse speech, a widely used control task, to be a poor control for non-language-related auditory activity. We hypothesized that this may be due to retained perception as a human voice. We report a follow-up ECoG study in which we contrast forward and reverse speech with a signal-correlated noise (SCN) control task that cannot be perceived as a human voice.Ten patients were presented 90 audible stimuli, including 30 each of corresponding forward speech, reverse speech, and SCN trials, during ECoG recording with evaluation of gamma activity between 50 and 150 Hz.Sites of the lateral temporal gyri activated throughout speech stimuli were generally less activated by SCN, while some temporal sites seemed to process both human and non-human sounds. Reverse speech trials were associated with activities across the temporal lobe similar to those associated with forward speech.Findings herein externally validate functional neuroimaging studies utilizing SCN as a control for non-language-specific auditory function. Our findings are consistent with the notion that stimuli perceived as originating from a human voice are poor controls for non-language auditory function.Our findings have implications in functional neuroimaging research as well as improved clinical mapping of auditory functions.

Epilepsy is a disease of recurrent seizures that can be associated with a wide variety of acquired and developmental brain lesions. Current medications for patients with epilepsy can suppress seizures; they do not cure or modify the underlying disease process. On the other hand, surgical removal of focal brain regions that produce seizures can be curative. This surgical procedure can be more precise with the placement of intracranial recording electrodes to identify brain regions that generate seizure activity as well as those that are critical for normal brain function. The detail that goes into these surgeries includes extensive neuroimaging, electrophysiology, and clinical data. Combined with precisely localized tissues removed, these data provide an unparalleled opportunity to learn about the interrelationships of many "systems" in the human brain not possible in just about any other human brain disorder. Herein, we describe a systems biology approach developed to study patients who undergo brain surgery for epilepsy and how we have begun to apply these methods to patients whose seizures are associated with brain tumors. A central goal of this clinical and translational research program is to improve our understanding of epilepsy and brain tumors and to improve diagnosis and treatment outcomes of both.

We measured the spatial, temporal and developmental patterns of gamma activity augmented by picture- and auditory-naming tasks and determined the clinical significance of naming-related gamma-augmentation.We studied 56 epileptic patients (age: 4-56 years) who underwent extraoperative electrocorticography. The picture-naming task consisted of naming of a visually-presented object; the auditory-naming task consisted of answering an auditorily-presented sentence question.Naming-related gamma-augmentation at 50-120 Hz involved the modality-specific sensory cortices during stimulus presentation and inferior-Rolandic regions during responses. Gamma-augmentation in the bilateral occipital and inferior/medial-temporal regions was more intense in the picture-naming than auditory-naming task, whereas that in the bilateral superior-temporal, left middle-temporal, left inferior-parietal, and left frontal regions was more intense in the auditory-naming task. Patients above 10 years old, compared to those younger, showed more extensive gamma-augmentation in the left dorsolateral-premotor region. Resection of sites showing naming-related gamma-augmentation in the left hemisphere assumed to contain essential language function was associated with increased risk of post-operative language deficits requiring speech therapy (p0.05).Measurement of gamma-augmentation elicited by either naming task was useful to predict postoperative language deficits.A smaller degree of frontal engagement in the picture-naming task can be explained by no requirement of syntactic processing or less working memory load. More extensive gamma-augmentation in the left dorsolateral-premotor region in older individuals may suggest more proficient processing by the mature brain.

Objective We determined the clinical impact and developmental changes of auditory-language-related augmentation of gamma activity at 50–120Hz recorded on electrocorticography (ECoG). Methods We analyzed data from 77 epileptic patients ranging 4–56years in age. We determined the effects of seizure-onset zone, electrode location, and patient-age upon gamma-augmentation elicited by an auditory-naming task. Results Gamma-augmentation was less frequently elicited within seizure-onset sites compared to other sites. Regardless of age, gamma-augmentation most often involved the 80–100Hz frequency band. Gamma-augmentation initially involved bilateral superior-temporal regions, followed by left-side dominant involvement in the middle-temporal, medial-temporal, inferior-frontal, dorsolateral-premotor, and medial-frontal regions and concluded with bilateral inferior-Rolandic involvement. Compared to younger patients, those older than 10years had a larger proportion of left dorsolateral-premotor and right inferior-frontal sites showing gamma-augmentation. The incidence of a post-operative language deficit requiring speech therapy was predicted by the number of resected sites with gamma-augmentation in the superior-temporal, inferior-frontal, dorsolateral-premotor, and inferior-Rolandic regions of the left hemisphere assumed to contain essential language function ( r 2 =0.59; p =0.001; odds ratio=6.04 [95% confidence-interval: 2.26–16.15]). Conclusions Auditory-language-related gamma-augmentation can provide additional information useful to localize the primary language areas. Significance These results derived from a large sample of patients support the utility of auditory-language-related gamma-augmentation in presurgical evaluation.

We determined the utility of electrocorticography (ECoG) and stimulation for detecting language-related sites in patients with left-hemispheric language-dominance on Wada test.We studied 13 epileptic patients who underwent language mapping using event-related gamma-oscillations on ECoG and stimulation via subdural electrodes. Sites showing significant gamma-augmentation during an auditory-naming task were defined as language-related ECoG sites. Sites at which stimulation resulted in auditory perceptual changes, failure to verbalize a correct answer, or sensorimotor symptoms involving the mouth were defined as language-related stimulation sites. We determined how frequently these methods revealed language-related sites in the superior-temporal, inferior-frontal, dorsolateral-premotor, and inferior-Rolandic regions.Language-related sites in the superior-temporal and inferior-frontal gyri were detected by ECoG more frequently than stimulation (p0.05), while those in the dorsolateral-premotor and inferior-Rolandic regions were detected by both methods equally. Stimulation of language-related ECoG sites, compared to the others, more frequently elicited language symptoms (p0.00001). One patient developed dysphasia requiring in-patient speech therapy following resection of the dorsolateral-premotor and inferior-Rolandic regions containing language-related ECoG sites not otherwise detected by stimulation.Language-related gamma-oscillations may serve as an alternative biomarker of underlying language function in patients with left-hemispheric language-dominance.Measurement of language-related gamma-oscillations is warranted in presurgical evaluation of epileptic patients.

Injury occurs in epilepsy monitoring units (EMUs) to patients with epileptic seizures (ES); however, there are limited data regarding the safety concerns of patients with psychogenic nonepileptic seizures (PNES) being monitored in EMUs. We reviewed EMU records from 116 PNES and compared them to 170 ES. Three falls (2.6%) occurred in PNES without injury compared to 6 falls (3.5%) in ES with 1 injury, a facial hematoma. Of the 9 total falls, 8 patients were ambulatory during their events. Several adverse incidents occurred for both groups. Of the PNES without staff response, 30 of 39 were due to PNES being less than 60s in duration, and 16 of 39 involved lack of push-button activation to alert the staff. For the ES group, 57 of 101 were due to electrographic seizures without seizure detection software or push-button activation. Similar safety protocols should be administered while monitoring these patients regardless of seizure type.

Long term video electroencephalography (EEG) in epilepsy monitoring units (EMU) is used to diagnose and treat patients with epilepsy. Injury occurs in the EMU, including reports of death. No standardized patient safety protocols exist. Our objective is to determine the frequency and contributing factors to injury in the EMU.We reviewed medical records and video EEG of patients with epilepsy admitted to our EMU from December 1, 2008 to June 1, 2009. Data was collected on seizure type, onset, length, and frequency. Seizure related falls, injury, and adverse events were recorded. Data regarding the physical environment and treatment during seizures were analyzed too.20 patients with 170 seizures were collected. Of the 170 total seizures captured, only 1 injury (0.6%) and 6 falls occurred (3.5%). 5 of the 6 falls were related to patients being ambulatory. No seizures resulted in prolonged stay. Of the 170 seizures captured, other adverse events included 1 status epilepticus (0.6%), 2 postictal aggression (1.2%), 4 objects in mouth (2.4%), 14 ambulatory at seizure onset (8.2%) and 5 postictal ambulation from bed (2.9%). Staff responded to 69 out of 170 seizures (40.6%). Of the 101 seizures without staff response, 57 seizures were electrographic without seizure detection software or push button activation.Falls and adverse events that can lead to injury occur in the EMU, yet the degree of actual injury is minimal. To improve safety outcomes, standardized protocols with appropriate outlined nursing care and procedures for continuous monitoring of patients by staff need to be employed.

Objective We measured cortical gamma-oscillations in response to visual–language tasks consisting of picture naming and word reading in an effort to better understand human visual–language pathways. Methods We studied six patients with focal epilepsy who underwent extraoperative electrocorticography (ECoG) recording. Patients were asked to overtly name images presented sequentially in the picture naming task and to overtly read written words in the reading task. Results Both tasks commonly elicited gamma-augmentation (maximally at 80–100Hz) on ECoG in the occipital, inferior–occipital–temporal and inferior-Rolandic areas, bilaterally. Picture naming, compared to reading task, elicited greater gamma-augmentation in portions of pre-motor areas as well as occipital and inferior–occipital–temporal areas, bilaterally. In contrast, word reading elicited greater gamma-augmentation in portions of bilateral occipital, left occipital–temporal and left superior–posterior-parietal areas. Gamma-attenuation was elicited by both tasks in portions of posterior cingulate and ventral premotor–prefrontal areas bilaterally. The number of letters in a presented word was positively correlated to the degree of gamma-augmentation in the medial occipital areas. Conclusions Gamma-augmentation measured on ECoG identified cortical areas commonly and differentially involved in picture naming and reading tasks. Longer words may activate the primary visual cortex for the more peripheral field. Significance The present study increases our understanding of the visual–language pathways.

Summary Purpose: Some patients with pharmacoresistant epilepsy undergoing the Wada test experience transient shivering. The purpose of this study was to investigate various clinical and radiographic characteristics of these individuals to delineate underlying mechanisms of this phenomenon. Methods: A systematic review of prospectively collected information on patients undergoing the Wada test was performed. All demographic, clinical, and radiographic information was obtained and reviewed by the appropriate expert in the field; statistical analysis was performed to determine the predictors of transient shivering. Results: A total of 120 consecutive carotid artery injections in 59 patients were included in the study. Shivering was observed in 46% of the patients, and it was not significantly affected by gender, age, location of epileptogenic zone, brain lesion on magnetic resonance imaging (MRI), side of the first injection, duration of the hemiparesis, or excess slow wave activity on electroencephalography (EEG). However, shivering was more likely to follow sodium amobarbital injection if there was no filling of the posterior circulation on cerebral angiogram. Discussion: Transient shivering during the Wada test is common. A transient but selective functional lesion of the anterior hypothalamus produced by the effects of sodium amobarbital may result in disinhibition of the posterior hypothalamus and other brainstem thermoregulatory centers, thereby inducing transient shivering.

Summary The spatial relationship between an intracranial EEG-defined epileptic focus and cortical hypometabolism on glucose PET has not been precisely described. In order to quantitatively evaluate the hypothesis that ictal seizure onset and/or rapid seizure propagation, detected by subdural EEG monitoring, commonly involves normometabolic cortex adjacent to hypometabolic cortical regions, we applied a novel, landmark-constrained conformal mapping approach in 14 children with refractory neocortical epilepsy. The 3D brain surface was parcellated into finite cortical elements (FCEs), and hypometabolism was defined using lobe- and side-specific asymmetry indices derived from normal adult controls. The severity and location of hypometabolic areas vs. ictal intracranial EEG abnormalities were compared on the 3D brain surface. Hypometabolism was more severe in the seizure onset zone than in cortical areas covered by non-onset electrodes. However, similar proportions of the onset electrodes were located over and adjacent to (within 2cm) hypometabolic regions (46% vs. 41%, respectively), whereas rapid seizure spread electrodes preferred these "adjacent areas" rather than the hypometabolic area itself (51% vs. 22%). On average, 58% of the hypometabolic regions had no early seizure involvement. These findings strongly support that the seizure onset zone often extends from hypometabolic to adjacent normometabolic cortex, while large portions of hypometabolic cortex are not involved in seizure onset or early propagation. The clinical utility of FDG PET in guiding subdural electrode placement in neocortical epilepsy could be greatly enhanced by extending grid coverage to at least 2cm beyond hypometabolic cortex, when feasible.

Since prediction of long-term seizure outcome using preoperative diagnostic modalities remains suboptimal in epilepsy surgery, we evaluated whether interictal spike frequency measures obtained from extraoperative subdural electrocorticography (ECoG) recording could predict long-term seizure outcome. This study included 61 young patients (age 0.4-23.0 years), who underwent extraoperative ECoG recording prior to cortical resection for alleviation of uncontrolled focal seizures. Patient age, frequency of preoperative seizures, neuroimaging findings, ictal and interictal ECoG measures were preoperatively obtained. The seizure outcome was prospectively measured [follow-up period: 2.5-6.4 years (mean 4.6 years)]. Univariate and multivariate logistic regression analyses determined how well preoperative demographic and diagnostic measures predicted long-term seizure outcome. Following the initial cortical resection, Engel Class I, II, III and IV outcomes were noted in 35, 6, 12 and 7 patients, respectively. One child died due to disseminated intravascular coagulation associated with pseudomonas sepsis 2 days after surgery. Univariate regression analyses revealed that incomplete removal of seizure onset zone, higher interictal spike-frequency in the preserved cortex and incomplete removal of cortical abnormalities on neuroimaging were associated with a greater risk of failing to obtain Class I outcome. Multivariate logistic regression analysis revealed that incomplete removal of seizure onset zone was the only independent predictor of failure to obtain Class I outcome. The goodness of regression model fit and the predictive ability of regression model were greatest in the full regression model incorporating both ictal and interictal measures [R(2) 0.44; Area under the receiver operating characteristic (ROC) curve: 0.81], slightly smaller in the reduced model incorporating ictal but not interictal measures (R(2) 0.40; Area under the ROC curve: 0.79) and slightly smaller again in the reduced model incorporating interictal but not ictal measures (R(2) 0.27; Area under the ROC curve: 0.77). Seizure onset zone and interictal spike frequency measures on subdural ECoG recording may both be useful in predicting the long-term seizure outcome of epilepsy surgery. Yet, the additive clinical impact of interictal spike frequency measures to predict long-term surgical outcome may be modest in the presence of ictal ECoG and neuroimaging data.

Summary Purpose: To determine the electroclinical significance and histopathological correlates of cortical γ-aminobutyric acidA(GABAA) receptor abnormalities detected in and remote from human neocortical epileptic foci. Methods: Cortical areas with decreased11C-flumazenil (FMZ) binding were objectively identified on positron emission tomography (PET) images and correlated to intracranial electroencephalography (EEG) findings, clinical seizure variables, histology findings, and surgical outcome in 20 patients (mean age, 9.9 years) with intractable partial epilepsy of neocortical origin and nonlocalizing magnetic resonance imaging (MRI). Results: Focal decrease of cortical FMZ binding was detected in the lobe of seizure onset in 17 (85%) patients. Eleven patients (55%) had 17 remote cortical areas with decreased FMZ binding outside the lobe of seizure onset. Thirteen of those 16 (81%) of the 17 remote cortical regions that were covered by subdural EEG were around cortex showing rapid seizure spread on intracranial EEG. Remote FMZ PET abnormalities were associated with high seizure frequency and, when resected, showed gliosis in all six cases where material was available. Higher number of unresected cortical regions with decreased FMZ binding was associated with poorer surgical outcome. Conclusions: Focal decreases of cortical GABAA receptor binding on PET may include cortical regions remote from the primary focus, particularly in patients with high seizure frequency, and these regions are commonly involved in rapid seizure propagation. Although these regions may not always need to be resected to achieve seizure freedom, a careful evaluation of cortex with decreased GABAA receptor binding prior to resection using intracranial EEG may facilitate optimal surgical outcome in patients with intractable neocortical epilepsy.

Summary Objective We determined whether the primary motor hand area was most frequently located in the precentral gyrus in young patients with intractable focal seizures. Methods Sixty-five patients with focal seizures aged between 5 months and 20 years who underwent a two-stage epilepsy surgery using chronic subdural-EEG monitoring were studied. Pairs of subdural electrodes were electrically stimulated, and the brain region with contralateral hand movement induced by the lowest-intense stimulus was defined as the primary motor hand area. Results Contralateral hand movement was induced without afterdischarges in 50 children but not in the remaining 15 children. The unpaired t -test revealed that failure to induce contralateral hand motor movement was associated with younger age of subjects. Among the 50 patients with a positive motor response, the primary motor hand area was confined to the precentral gyrus in 9 patients, confined to the postcentral gyrus in 24, and located in both the pre- and post-central gyri in the remaining 17. The McNemar's test revealed that the observed frequency of 24 patients showing the primary motor hand area confined to the postcentral gyrus was larger than chance frequency. Logistic regression analysis failed to demonstrate that the observation of the primary motor hand area confined to the postcentral gyrus was associated with the age, the presence of dysplastic lesion or the seizure onset involving the frontal lobe. Conclusion Our study failed to support the traditionally-accepted notion that the primary motor hand area is most frequently located in the precentral gyrus but rather demonstrated that a substantial proportion of young patients had the primary motor hand area in the postcentral gyrus.

Interictal spikes are hallmarks of epileptic neocortex that are used commonly in both EEG and electrocorticography (ECoG) to localize epileptic brain regions. Despite their prevalence, the exact relationship between interictal spiking and the molecular pathways that drive the production and propagation of seizures is not known. We have recently identified a common group of genes induced in human epileptic foci, including EGR1, EGR2, c-fos, and MKP-3. We found that the expression levels of these genes correlate precisely with the frequency of interictal activity and can thus serve as markers of epileptic activity. Here, we explore this further by comparing the expression of these genes within human epileptic neocortex to both ictal and specific electrical parameters of interictal spiking from subdural recordings prior to surgical resection in order to determine the electrical properties of the human neocortex that correlate best to the expression of these genes. Seizure frequency as well as quantitative electrophysiological parameters of interictal spikes including frequency, amplitude, duration, and area were calculated at each electrode channel and compared to quantitative real-time RT-PCR measurements of four activity-dependent genes (c-fos, EGR1, EGR2, and MKP-3) in the underlying neocortical tissue. Local neocortical regions of seizure onset had consistently higher spike firing frequencies and higher spike amplitudes compared to nearby "control" cortex. In contrast, spike duration was not significantly different between these two areas. There was no relationship observed between seizure frequency and the expression levels of activity-dependent genes for the patients examined in this study. However, within each patient, there were highly significant correlations between the expression of three of these genes (c-fos, EGR1, EGR2) and the frequency, amplitude, and total area of the interictal spikes at individual electrodes. We conclude that interictal spiking is closely associated with the expression of a group of activity-dependent transcription factors in neocortical human epilepsy. Since there was little correlation between gene expression and seizure frequency, our results suggest that interictal spiking is a stronger driving force behind these activity-dependent gene changes and may thus participate in the development and maintenance of the abnormal neuronal hyperactivity seen in human epileptic neocortex.

SummaryObjective The site of action for antiepileptic drugs (AEDs) is within the brain; however, cerebrospinal fluid (CSF) concentration is highly variable. Lacosamide (LCM) is approved by the U.S. Food and Drug Administration (FDA) for treatment of partial-onset seizures in adults, and has linear pharmacokinetics in serum. Penetration across the blood–brain barrier (BBB) is unknown. This study aims to provide additional insights into the pharmacokinetics of LCM. Methods Thirty adults undergoing craniotomy for treatment of intractable epilepsy or brain tumor were recruited and were either taking LCM long term (group 1, n = 15), or were LCM naive, receiving LCM as prophylaxis for surgery (group 2, n = 15). All patients received one intravenous (IV) dose (15 min infusion) immediately prior to craniotomy. CSF and arterial blood were collected simultaneously following craniotomy. LCM concentrations were measured in serum and CSF. Results LCM concentration differences between groups 1 and 2 for both CSF and serum were statistically significant (p ≤ 0.0005), but there was no statistically significant difference in CSF/serum ratios (group 1 = 0.726 ± 0.231; group 2 = 0.556 ±0.241; p = 0.0585). LCM concentration in serum correlated positively with CSF concentration in group 1 (Pearson r = 0.8527, p

Objective In patients with tumor-related epilepsy (TRE), surgery traditionally focuses on tumor resection; but identification and removal of associated epileptogenic zone may improve seizure outcome. Here, we study spatial relationship of tumor and seizure onset and early spread zone (SOSz). We also perform quantitative analysis of interictal epileptiform activities in patients with both TRE and non-lesional epilepsy in order to better understand the electrophysiological basis of epileptogenesis. Methods Twenty-five patients (11 with TRE and 14 with non-lesional epilepsy) underwent staged surgery using intracranial electrodes. Tumors were outlined on MRI and images were coregistered with post-implantation CT images. For each electrode, distance to the nearest tumor margin was measured. Electrodes were categorized based on distance from tumor and involvement in seizure. Quantitative EEG analysis studying frequency, amplitude, power, duration and slope of interictal spikes was performed. Results At least part of the SOSz was located beyond 1.5 cm from the tumor margin in 10/11 patients. Interictally, spike frequency and power were higher in the SOSz and spikes near tumor were smaller and less sharp. Interestingly, peritumoral electrodes had the highest spike frequencies and sharpest spikes, indicating greatest degree of epileptic synchrony. A complete resection of the SOSz resulted in excellent seizure outcome. Conclusions Seizure onset and early spread often involves brain areas distant from the tumor. Significance Utilization of epilepsy surgery approach for TRE may provide better seizure outcome and study of the intracranial EEG may provide insight into pathophysiology of TRE.

Bromethalin is a neurotoxin found in some rodenticides. A delusional 21-year-old male presented to a hospital with altered mental status the day after ingesting a bromethalin-based rodenticide. He died 7 days after his self-reported exposure to c. 17 mg bromethalin (equivalent to 0.33 mg bromethalin/kg). His clinicopathologic course was characterized by altered mental status, obtundation, increased cerebrospinal fluid pressure, cerebral edema, death, and diffuse histologic vacuolization of the white matter in the central nervous system seen on microscopic examination at autopsy. The presence of a demethylated form of bromethalin in the patient's liver and brain was confirmed by gas chromatography with mass spectrometry. Clinical signs and lesions observed in this patient are similar to those seen in animals poisoned with bromethalin. This case illustrates the potential for bromethalin ingestion to result in fatal human poisoning.

Recent advances in continuous electroencephalogram (EEG) monitoring with digital EEG acquisition, storage, and quantitative analysis allow uninterrupted assessment of cerebral cortical activity in critically ill neurological-neurosurgical patients. Early recognition of worsening brain function can prove of vital importance as one can initiate measures aimed to prevent further brain damage. Although continuous EEG monitoring provides adequate spatial and temporal resolution and is able to continuously assess brain function in these critically ill patients, it requires a trained electroencephalographer to interpret the massive amounts of data generated. This limitation impedes the widespread use of EEG in assessing real-time brain function in critically ill patients. Here, we demonstrate the utility of a novel method of automated EEG analysis that segments and extracts EEG features, classifies and groups them according to various patterns, and then presents them in a compressed fashion. This permits real-time viewing of several hours of EEG on a single page. Examples are presented from three patients, two with recurrent seizures and one with diagnosis of subarachnoid hemorrhage. These patients illustrate the ability of this novel method to detect important real-time physiological changes in brain function that could enable early interventions aimed to prevent irreversible brain damage.

Abnormal metabolism of tryptophan has been implicated in modulation of tumor cell proliferation and immunoresistance. α-[11C]Methyl-l-tryptophan (AMT) is a PET tracer to measure cerebral tryptophan metabolism in vivo. In the present study, we have measured tumor tryptophan uptake in 40 patients with primary brain tumors using AMT PET and standard uptake values (SUV). Tryptophan metabolism was further quantified in 23 patients using blood input data. Estimates of the volume of distribution ( VD') and the metabolic rate constant ( k'3) were calculated and related to magnetic resonance imaging (MRI) and histology findings. All grade II to IV gliomas and glioneuronal tumors showed increased AMT SUV, including all recurrent/residual tumors. Gadolinium enhancement on MRI was associated with high VD' values, suggesting impaired blood–brain barrier, while k'3values were not related to contrast enhancement. Low-grade astrocytic gliomas showed increased tryptophan metabolism, as measured by k'3. In contrast, oligodendrogliomas showed high VD' values but lower k'3as compared with normal cortex. In astrocytic tumors, low grade was associated with high k'3and lower VD', while high-grade tumors showed the reverse pattern. The findings show high AMT uptake in primary and residual/recurrent gliomas and glioneuronal tumors. Increased AMT uptake can be due to increased metabolism of tryptophan and/or high volume of distribution, depending on tumor type and grade. High tryptophan metabolic rates in low-grade tumors may indicate activation of the kynurenine pathway, a mechanism regulating tumor cell growth. AMT PET might be a useful molecular imaging method to guide therapeutic approaches aimed at controlling tumor cell proliferation by acting on tryptophan metabolism.

To study the relation between the spike frequency during intraoperative electrocorticography (ECoG) under general anesthesia with isoflurane and that during extraoperative ECoG monitoring in children with intractable neocortical epilepsy.Twenty-one children (age, 1-16 years; 15 boys and six girls) who underwent intraoperative and extraoperative ECoG monitoring with subdural electrode arrays were studied. The spike frequency and the spatial pattern of spike frequency were compared between intraoperative and extraoperative ECoGs for each patient (by using Wilcoxon signed-ranks and Spearman's rank correlation, respectively).In 15 of 21 patients, the spike frequency was significantly lower during intraoperative than during extraoperative ECoG (mean z = -6.3; p0.001). In four of 21 patients, no significant difference was found in the spike frequency between intraoperative and extraoperative recordings. In two of 21 patients, spike frequency reached one spike/min neither during intraoperative nor extraoperative recording; therefore appropriate comparison of spike frequency was not possible. A significant positive correlation in the spike-frequency pattern was seen between intraoperative and extraoperative recordings in nine of nine cases who hador = 10 spikes/min during intraoperative ECoG (mean rho = 0.62; p0.01), in five of six cases with one to nine spikes/min (mean rho = 0.50; p0.01), and in none of five cases with less than one spike/min (mean rho = 0.13).General anesthesia often decreases the spike frequency in children with neocortical epilepsy, yet intraoperative ECoG can reliably reflect the awake interictal spiking pattern when spike frequency exceeds one spike/min during intraoperative ECoG recording.

Summary: Purpose: Reoperation after failed cortical resection can alleviate seizures in patients with intractable neocortical epilepsy, provided that previously nonresected epileptic regions are accurately defined and removed. Most imaging modalities have limited value in identifying such regions after a previous surgery. Positron emission tomography (PET) using α−[11C]methyl-l-tryptophan (AMT) can detect epileptogenic cortical areas as regions with increased tracer uptake. This study analyzed whether increased cortical AMT uptake can detect nonresected epileptic foci in patients with previously failed neocortical resection. Methods: Thirty-three young patients (age 3–26 years; mean age, 10.8 years) with intractable epilepsy of neocortical origin, and a previously failed cortical resection performed at various epilepsy centers, underwent further presurgical evaluation for reoperation. AMT-PET scans were performed 6 days to 7 years after the first surgery. Focal cortical areas with increased AMT uptake were objectively identified and correlated to ictal EEG data as well as clinical variables (age, postsurgical time, etiology). Results: Cortical increases of AMT uptake were detected on the side of the previous resections in 12 cases. In two patients scanned shortly (within a week) after surgery, diffuse hemispheric increases were observed, without any further localization value. In contrast, in 10 (43%) of 23 patients scanned >2 months but within 2.3 years after surgery, focal cortical increases occurred, concordant with seizure onset on ictal EEG. Age, etiology (lesional vs. cryptogenic), epileptiform EEG activity during PET, or time of the last seizure were not significantly related to the presence of increased AMT uptake. All patients with localizing AMT-PET, who underwent reoperation, became seizure free (n = 5) or showed considerable improvement of seizure frequency (n = 2). Conclusions: AMT-PET can identify nonresected epileptic cortex in patients with a previously failed neocortical epilepsy surgery and, with proper timing for the scan, can assist in planning reoperation.

Long-term video-EEG monitoring in the epilepsy monitor-ing unit (EMU), while generally a safe procedure (1, 2), can be associated with adverse events. The majority of EMUs have experienced falls, status epilepticus, and postictal psychosis during monitoring (3); although rare, fatalities and near-fatalities have also occurred in the EMU (2, 4). Even patients with psychogenic nonepileptic seizures are prone to adverse events, usually falls, at a significant rate (5). Provocative proce-dures such as antiepileptic drug (AED) withdrawal and sleep deprivation increase the risk for adverse events, particularly if there is a history of generalized tonic-clonic seizures (GTCs) as a proportion of them will inevitably experience difficult to control seizures that may require intubation and treatment in the intensive care unit (ICU). Such risks should be understood, prior to monitoring, by both the treating physician as well as the patient. Nonetheless, because video-EEG monitoring is an elective procedure for which possible morbidities are predict-able and potentially systematically preventable, safety in the EMU must always be the primary goal of any admission plan.Despite potential hazards and acknowledged importance of safety measures, there is a wide variation in practice with regard to drug withdrawal, seizure observation, and rescue protocols (6) in the EMU and a clear lack of consensus between epilepsy centers. Implementation of the safety measures may be costly, especially when additional personnel are involved. Automated safety alerts may miss critical events owing to the high false-positive rate that are ignored and can lead to delay in responding to seizures (7).Because of the importance of this issue, the American Epilepsy Society formed a workgroup to search for evidence and best practices regarding safety measures for patients ad-mitted to the EMU. The first product of this effort was a survey published by Shafer et al. in 2011, identifying the extent to which adverse events occurred in the EMU, including falls, sta-tus epilepticus, postictal psychosis, and pulling of implanted electrodes (3).In their most recent article, “A consensus-based approach to patient safety in epilepsy monitoring units: Recommenda-tions for preferred practices” (8), Shafer et al. build upon these findings to establish a set of consensus practice recommenda-tions for enhancing patient safety in the EMU. First, a set of statements regarding safety were developed by four work-groups in the key areas: seizure observation, seizure provoca-tion, management of acute seizures, and activity/environment. Because the authors found that literature searches revealed lack of evidence, expert consensus was sought using the Delphi methodology. This methodology consists of a series of iterative questionnaires and anonymous feedback (9). A set of statements from the workgroups were consolidated by a screening committee, evaluated by a small group of indepen-dent experts, and then further revised. The resulting state-ments were then submitted to the Delphi process; they were sent in an e-mailed survey to a select group of American Epi-lepsy Society (AES) members, an expert group, and workgroup members. Respondents rated each of the safety statements on a scale between one (completely agree) and nine (completely disagree). A second survey was sent, with each item’s mean and spread; the participants were asked to reevaluate them. Items where rating showed a strong agreement (at least eight) were accepted. These exhaustive efforts generated a set of 30 safety recommendations with strong consensus.Some of the seemingly more important recommenda-tions did not reach sufficient consensus to be included. For example, the question of whether continuous observation is needed for all patients all the time did not reach consensus. Given the relatively stringent criteria needed for a recommen-dation to reach acceptable consensus, a lack of consensus on a particular recommendation should not necessarily indicate that the safety measures need not be implemented. For example, the use of a pulse oximeter did not reach consensus, but it may nevertheless be considered because of ease of implementation, low cost, and effectiveness as an adjunctive alarm device.Will adherence to these safety measures translate to improvement in safety outcomes? There is some encouraging data to suggest that it will. After instituting EMU safety process improvements that included staff education, expanded EMU staffing, fall prevention protocols, and enhanced communica-tion hand-offs, one large EMU was able to achieve significant decrease in missed seizures and a small, though statistically insignificant, decrease in rate of falls (10). Further studies are definitely warranted to determine the extent of improved outcomes as a result of these recommendations.

Hippocampal sclerosis (HS) is the most common neuropathologic finding in patients with medically refractory temporal lobe epilepsy (TLE). The mechanisms resulting in neuronal injury and cell loss in HS are incompletely understood, but inhibition of protein synthesis may play a pivotal role in these processes. This study examined the relationships between two molecules known to be involved in reduced protein synthesis in animals subjected to traumatic brain injury. Translational initiation of protein synthesis is inhibited when 2alpha (eIF2alpha) is phosphorylated. Recently, nitric oxide (NO) has been shown to reduce protein synthesis by inducing phosphorylation of eIF2alpha. We performed immunocytochemistry for eIF2alpha(P) and histochemistry (NADPH-D reaction) for nitric oxide synthase (NOS) to determine the distribution of these molecules in hippocampi removed from patients undergoing anterior temporal lobectomy (ATL) for medically intractable TLE due to HS. The greatest number of eIF2alpha(P) positive cells was in the CA1 sector of the hippocampus, followed by the hilus of the dentate gyrus. NADPH-D positive neurons were observed most often in the hilus. Labeling in both instances involved neuronal cell body cytoplasm and varicose processes. Combination of both staining procedures revealed close relationships between differentially labeled neurons within the hilus. The results suggest that NO participates in the phosphorylation of eIF2alpha since we demonstrated that nNOS processes are closely related to eIF2alpha(P) positive cells. This may occur through activation of kinases such as PERK, which was recently revealed. In human, TLE protein synthesis inhibition may occur at the translational level since the eIF2alpha (P) labeling is cytoplasmic. Protein synthesis inhibition may contribute to neuronal cell injury and death in HS.

Summary: Purpose: We studied the relation between quantitative interictal subdural EEG data and visually defined ictal subdural EEG findings in children with intractable neocortical epilepsy, and determined whether interictal EEG data are predictive of ictal EEG onset zones. Methods: Thirteen children (aged 1.2–15.4 years) underwent prolonged intracranial EEG recording, using 48- to 120-channel subdural electrodes. Three distinct 10-min segments of the continuous interictal EEG recording were selected for each patient, and the spike frequency for each channel was determined by using an automatic spike-detection program. Subsequently the average spike frequency of each electrode was compared with ictal assessment (onset, spread, and no early ictal involvement). In addition, 50 distinct interictal spikes were averaged for each patient, and the amplitude and latency after the leading spike (averaged spike showing the earliest peak) were measured for each electrode and analyzed with respect to ictal EEG findings. Results: Reproducibility of the spike-frequency pattern derived from three 10-min segments was high (Kendall's W, 0.85 ± 0.08). Electrodes showing the highest spike frequency, the highest spike amplitude, and the leading spike were found to be a part of the seizure onset in 13 of 13, 12 of 13, and 10 of 13 cases, respectively. There was significant correlation between ictal assessment and spike frequency as well as spike amplitude. A receiver operating characteristics analysis showed that a cutoff threshold at 14% of the maximal spike frequency resulted in a specificity of 0.90 and a sensitivity of 0.77 for the detection of seizure-onset electrodes. Conclusions: Quantitative interictal subdural EEG may predict ictal-onset zones in children with intractable neocortical epilepsy.