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Background Non-convulsive seizures (NCS) or non-convulsive status epilepticus (NCSE) has been reported in 8–20 % of critically ill patient populations, and delayed diagnosis and treatment of NCSE may lead to increased mortality. This study seeks to better understand the risk factors, characteristics, and outcome of NCS/NCSE in the neurological ICU. Methods This is a prospective observational study, recruiting consecutive patients admitted to the adult neurological ICU with altered mental status. Patients with anoxic brain injury were excluded from the study. Data were collected and analyzed for prevalence of NCSE/NCS, EEG patterns, associated risk factors, treatment response, and final outcome. Results NCSE/NCS was detected in 21 % of 170 subjects. Clinical seizures preceded EEG diagnosis of NCSE/NCS in 25 % of cases. Significant risk factors for NCSE/NCS were a past medical history of intracranial tumor, epilepsy, or meningitis/encephalitis, or MRI evidence of encephalomalacia. Subtle clinical findings such as twitching of oral or ocular muscles and eye deviations were found on exam in 50 % of the NCSE/NCS group. Mortality was increased in NCSE cases as 31 % of NCSE/NCS patients died compared to 14 % in non-NCSE/NCS group. Conclusions Specific clinical features along with history and imaging findings may be used to identify patients at high risk of NCSE/NCS in the neurological ICU.

Abstract BACKGROUND Focal seizures in temporal lobe epilepsy (TLE) are associated with widespread brain network perturbations and neurocognitive problems. OBJECTIVE To determine whether brainstem connectivity disturbances improve with successful epilepsy surgery, as recent work has demonstrated decreased brainstem connectivity in TLE that is related to disease severity and neurocognitive profile. METHODS We evaluated 15 adult TLE patients before and after (>1 yr; mean, 3.4 yr) surgery, and 15 matched control subjects using magnetic resonance imaging to measure functional and structural connectivity of ascending reticular activating system (ARAS) structures, including cuneiform/subcuneiform nuclei (CSC), pedunculopontine nucleus (PPN), and ventral tegmental area (VTA). RESULTS TLE patients who achieved long-term postoperative seizure freedom (10 of 15) demonstrated increases in functional connectivity between ARAS structures and fronto-parietal-insular neocortex compared to preoperative baseline (P = .01, Kruskal–Wallis), with postoperative connectivity patterns resembling controls’ connectivity. No functional connectivity changes were detected in 5 patients with persistent seizures after surgery (P = .9, Kruskal–Wallis). Among seizure-free postoperative patients, larger increases in CSC, PPN, and VTA functional connectivity were observed in individuals with more frequent seizures before surgery (P < .05 for each, Spearman's rho). Larger postoperative increases in PPN functional connectivity were seen in patients with lower baseline verbal IQ (P = .03, Spearman's rho) or verbal memory (P = .04, Mann–Whitney U). No changes in ARAS structural connectivity were detected after successful surgery. CONCLUSION ARAS functional connectivity disturbances are present in TLE but may recover after successful epilepsy surgery. Larger increases in postoperative connectivity may be seen in individuals with more severe disease at baseline.

Functional seizures (formerly psychogenic nonepileptic seizures), paroxysmal episodes that are often similar to epileptic seizures in their clinical presentation and display no aberrant brain electrical patterns, are understudied. Patients experience a long diagnostic delay, few treatment modalities, a high rate of comorbidities, and significant stigma due to the lack of knowledge about functional seizures. To characterize the clinical epidemiology of a population of patients with functional seizures observed at Vanderbilt University Medical Center (VUMC). This case-control study included patients with functional seizures identified in the VUMC electronic health record (VUMC-EHR) system from October 1989 to October 2018. Patients with epilepsy were excluded from the study and all remaining patients in the VUMC medical center system were used as controls. In total, the study included 1431 patients diagnosed with functional seizures, 2251 with epilepsy and functional seizures, 4715 with epilepsy without functional seizures, and 502 200 control patients who received treatment at VUMC for a minimum of a 3 years. Data were analyzed from November 2018 to March 2020. Diagnosis of functional seizures, as identified from the VUMC-EHR system by an automated phenotyping algorithm that incorporated International Classification of Diseases, Ninth Revision (ICD-9) codes, International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes, Current Procedural Terminology codes, and natural language processing. Associations of functional seizures with comorbidities and risk factors, measured in odds ratios (ORs). Of 2 346 808 total patients in the VUMC-EHR aged 18 years or older, 3341 patients with functional seizures were identified (period prevalence, 0.14%), 1062 (74.2%) of whom were women and for which the median (interquartile range) age was 49.3 (39.4-59.9) years. This assessment replicated previously reported associations with psychiatric disorders including posttraumatic stress disorder (PTSD) (OR, 1.22; 95% CI, 1.21-1.24; P < 3.02 × 10-5), anxiety (OR, 1.14; 95% CI, 1.13-1.15; P < 3.02 × 10-5), and depression (OR, 1.14; 95% CI, 1.13-1.15; P < 3.02 × 10-5), and identified novel associations with cerebrovascular disease (OR, 1.08; 95% CI, 1.06-1.09; P < 3.02 × 10-5). An association was found between functional seizures and the known risk factor sexual assault trauma (OR, 10.26; 95% CI, 10.09-10.44; P < 3.02 × 10-5), and sexual assault trauma was found to mediate nearly a quarter of the association between female sex and functional seizures in the VUMC-EHR. This case-control study found evidence to support previously reported associations, discovered new associations between functional seizures and PTSD, anxiety, and depression. An association between cerebrovascular disease and functional seizures was also found. Results suggested that sexual trauma may be a mediating factor in the association between female sex and functional seizures.

Abstract BACKGROUND Selective amygdalohippocampectomy (SelAH) is designed to treat medically refractory mesial temporal lobe epilepsy with reduced morbidity compared to standard anterior temporal lobectomy. At our institution, we perform SelAH via a transcortical approach via small corticectomy in the middle temporal gyrus. OBJECTIVE To discuss the surgical anatomy and nuances of SelAH, share our institutional experience, and perform a review of literature. METHODS Institutional experience was recorded by collecting demographic and outcome data from 1999 to 2017 under an Institutional Review Board protocol in a prospective manner using a REDCap database. RESULTS A total of 211 SelAH procedures were performed at our institution between 1999 and 2017. Of these patients, 54% (113/211) were females. The average age at surgery was 39.4 yr. Two-year Engel outcome data were available for 168 patients, of which 73% (123/168) had Engel I outcomes. Engel II outcomes were reported in 16.6% (28/168), III in 4.7% (8/168), and IV in 5.3% (9/168). Our review of literature showed that this is comparable to the seizure freedom rates reported by other groups. We then reviewed our surgical methodology based on operative reports and created illustrations of the surgical anatomy of temporal lobe approach. These illustrations were compared with postoperative magnetic resonance imaging to provide a better 3D understanding of the complex architecture of mesial temporal structures. CONCLUSION SelAH is a minimally invasive, safe, and effective approach for the treatment of medically refractory epilepsy with good surgical outcomes and low morbidity. We feel that mastering the complex anatomy of this approach helps achieve successful outcomes. Graphical Abstract Graphical Abstract

•Patients were more likely to continue LCM with titration rate >4 weeks.•Patients reported fewer AEs when LCM was titrated over >4 weeks.•AEs were more common when LCM added to Na-channel blocking AEDs.•Discontinuation was more common when LCM added to Na-channel blocking AEDs.•LCM achieved greater seizure freedom rate in clinical practice compared to pivotal trials. Post marketing analysis of anti-epileptic drug (AED) efficacy and tolerability is of great value to the clinician since it is more representative of clinical practice than clinical trial data. We analyzed our experience with lacosamide (LCM) in patients treated after marketing. We identified all patients who were treated with LCM during the four year period after marketing, excluding patients who were in clinical trials. We recorded demographic data and analyzed efficacy and tolerability in patients who had at least one follow up visit or telephone call 3 months after the initiation of LCM. A total of 165 patients met our inclusion criteria. The mean age was 41 years. The majority of the cohort had focal epilepsy (146 patients) (88.4%). The mean duration of treatment was 31.2 months. Eighty one patients (49.1%) were continuing LCM at last follow up. Adverse effects (AEs) and discontinuation were significantly more common when LCM was added to one or more Na-channel blocking agents (NCB) (p = 0.0003 and 0.17). The 50% responder rate was 26% at 3 months and increased to 49% at 36 months. Patients were more likely to continue the drug and less likely to have AEs with slower titration over >4 weeks (p = 0.02 for each). Four or more previously failed AEDs predicted poorer response rate compared to three or less AEDs (p = 0.001). LCM use in clinical practice was associated with greater rate of seizure freedom than in clinical trials. Discontinuation and occurrence of AEs were significantly more likely with faster titration and adding LCM to NCB agents.

The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology. Epilepsies are common brain disorders and are classified based on clinical phenotyping, imaging and genetics. Here, the authors perform genome-wide association studies for 3 broad and 7 subtypes of epilepsy and identify 16 loci - 11 novel - that are further annotated by eQTL and partitioned heritability analyses.

The progress of developing an effective closed-loop neuromodulation system for many neurological pathologies is hindered by the difficulties in accurately capturing a useful representation of a brain’s instantaneous functional state. Existing approaches rely on expert labeling of electroencephalography data to develop biomarkers of neurophysiological pathology. These techniques do not capture the highly complex functional states of the brain that are presumed to exist between labeled states or allow for the likely possibility of variation among identically labeled states. Thus, we propose BrainState, a self-supervised technique to model an arbitrarily complex instantaneous functional state of a brain using neural multivariate timeseries data. Application of BrainState to intracranial electroencephalography data from patients with epilepsy was able to capture diverse pre-seizure states and quantify nuanced effects of neuromodulation. We anticipate that BrainState will enable the development of sophisticated closed-loop neuromodulation systems for a diverse array of neurological pathologies.

Patients who were seen in emergency departments within 7 days after the onset of Covid-19 symptoms and were considered appropriate for discharge were randomly assigned to receive either convalescent plasma or placebo. Convalescent plasma did not prevent disease progression.

Most Australian women access contraception through general practitioners (GPs) but choose oral methods rather than long‐acting reversible contraceptives (LARCS). The Australian Contraceptive ChOice pRoject (ACCORd) successfully tested a complex intervention for LARC uptake. We aimed to explore the critical elements of this intervention to increase LARC uptake. ACCORd was a cluster randomised control trial conducted in 57 GP clinics in Melbourne, Australia. To explore intervention impact, fidelity checks (n=21 GPs) and interviews with 37 GPs and 40 patients were undertaken 12 months after initial consultations. Data were inductively coded, thematically analysed and mapped to Normalization Process Theory constructs. Doctors understood the importance of effectiveness‐based contraceptive counselling (EBCC). GPs demonstrated cognitive engagement in the promotion of LARC and some appreciated the rapid referral pathways. GPs and women valued the effectiveness approach. GPs held varying views about having a rapid referral pathway, with many already having established pathways in place. Some GPs viewed intrauterine device insertion costs or insertion training as barriers to ongoing practice. Most GPs and women saw the ACCORD model as effective and sustainable. GP training in EBCC and the use of rapid referral pathways were critical features of an effective sustainable model for successful uptake of LARCs in primary care. Improving Australian women's access to and use of LARCs is sustainable with EBCC training and support for general practitioners.

The failure of chemoreflexes, arousal, and/or autoresuscitation to asphyxia may underlie some sudden infant death syndrome (SIDS) cases. In Part I, we showed that some SIDS infants had altered 5-hydroxytryptamine (5-HT)2A/C receptor binding in medullary nuclei supporting chemoreflexes, arousal, and autoresuscitation. Here, using the same dataset, we tested the hypotheses that the prevalence of low 5-HT1A and/or 5-HT2A/C receptor binding (defined as levels below the 95% confidence interval of controls—a new approach), and the percentages of nuclei affected are greater in SIDS versus controls, and that the distribution of low binding varied with age of death. The prevalence and percentage of nuclei with low 5-HT1A and 5-HT2A/C binding in SIDS were twice that of controls. The percentage of nuclei with low 5-HT2A/C binding was greater in older SIDS infants. In >80% of older SIDS infants, low 5-HT2A/C binding characterized the hypoglossal nucleus, vagal dorsal nucleus, nucleus of solitary tract, and nuclei of the olivocerebellar subnetwork (important for blood pressure regulation). Together, our findings from SIDS infants and from animal models of serotonergic dysfunction suggest that some SIDS cases represent a serotonopathy. We present new hypotheses, yet to be tested, about how defects within serotonergic subnetworks may lead to SIDS.