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Summary Objective To present the baseline data of the international TuberOus SClerosis registry to increase disease Awareness (TOSCA) with emphasis on the characteristics of epilepsies associated with tuberous sclerosis complex (TSC). Methods Retrospective and prospective patients’ data on all aspects of TSC were collected from multiple countries worldwide. Epilepsy variables included seizure type, age at onset, type of treatment, and treatment outcomes and association with genotype, seizures control, and intellectual disability. As for noninterventional registries, the study protocol did not specify any particular clinical instruments, laboratory investigations, or intervention. Evaluations included those required for diagnosis and management following local best practice. Results Epilepsy was reported in 83.6% of patients (1852/2216) at baseline; 38.9% presented with infantile spasms and 67.5% with focal seizures. The mean age at diagnosis of infantile spasms was 0.4 year (median <1 year; range <1‐30 years) and at diagnosis of focal seizures was 2.7 years (median 1 year; range <1‐66 years). A total of 1469 patients (79.3%) were diagnosed with epilepsy <2 years. The rate of infantile spasms was higher in patients with a TSC2 mutation than in patients with a TSC1 mutation (47.3% vs 23%). ɣ‐aminobutyric acid (GABA)ergic drugs were the most common treatment modality for both infantile spasms (78.7%) and focal seizures (65.5%). Infantile spasms and focal seizures were controlled in 76.3% and 58.2% of patients, respectively. Control of seizures was associated with lower rates of intellectual disability in both groups. Significance This registry reports the largest international cohort of patients with TSC. Findings confirmed the typical onset pattern of infantile spasms and other focal seizures in the first 2 years of life, and the high rates of infantile spasms in patients with TSC2 mutation. Our results underscored the occurrence of focal seizures at all ages, including an onset that preceded emergence of infantile spasms. Seizure control was shown to be associated with lower rates of intellectual disability but did not preclude the presence of intellectual disability.

Objective Molecular genetic etiologies in epilepsy have become better understood in recent years, creating important opportunities for precision medicine. Building on these advances, detailed studies of the complexities and outcomes of genetic testing for epilepsy can provide useful insights that inform and refine diagnostic approaches and illuminate the potential for precision medicine in epilepsy. Methods We used a multi‐gene next‐generation sequencing (NGS) panel with simultaneous sequence and exonic copy number variant detection to investigate up to 183 epilepsy‐related genes in 9769 individuals. Clinical variant interpretation was performed using a semi‐quantitative scoring system based on existing professional practice guidelines. Results Molecular genetic testing provided a diagnosis in 14.9%‐24.4% of individuals with epilepsy, depending on the NGS panel used. More than half of these diagnoses were in children younger than 5 years. Notably, the testing had possible precision medicine implications in 33% of individuals who received definitive diagnostic results. Only 30 genes provided 80% of molecular diagnoses. While most clinically significant findings were single‐nucleotide variants, ~15% were other types that are often challenging to detect with traditional methods. In addition to clinically significant variants, there were many others that initially had uncertain significance; reclassification of 1612 such variants with parental testing or other evidence contributed to 18.5% of diagnostic results overall and 6.1% of results with precision medicine implications. Significance Using an NGS gene panel with key high‐yield genes and robust analytic sensitivity as a first‐tier test early in the diagnostic process, especially for children younger than 5 years, can possibly enable precision medicine approaches in a significant number of individuals with epilepsy.

Electroencephalography (EEG) can identify biomarkers of epileptogenesis and ictogenesis. However, few studies have used EEG in the prediction of poststroke seizures. Our primary aim was to evaluate whether early EEG abnormalities can predict poststroke epilepsy. A prospective study of consecutive acute anterior circulation ischemic stroke patients, without previous epileptic seizures, who were admitted to a stroke unit over 24 months and followed for 1 year. All patients underwent standardized clinical and diagnostic assessment during the hospital stay and after discharge. Video-EEG was performed in the first 72 h (first EEG), daily for the first 7 days, in case of neurological deterioration, at discharge, and at 12 months after stroke. The occurrence of epileptic seizures in the first year after stroke (primary outcome) was evaluated clinically and neurophysiologically during the hospital stay and at 12 months. A telephone interview was also performed at 6 months. The primary outcome was the occurrence of at least one unprovoked seizure (poststroke epilepsy). Secondary outcomes were the occurrence of at least one acute symptomatic seizure and (interictal and/or ictal) epileptiform activity on at least one EEG during the hospital stay for acute stroke. The first EEG variables were defined using international criteria/terminology. Bivariate and multivariate analyses with adjustment for age, admission National Institutes of Health Stroke Scale (NIHSS) score, and Alberta Stroke Program Early CT Score (ASPECTS) were performed. A total of 151 patients were included; 38 patients (25.2%) had an acute symptomatic seizure and 23 (16%) had an unprovoked seizure.The first EEG background activity asymmetry and first EEG with interictal epileptiform activity were independent predictors of poststroke epilepsy during the first year after stroke ( = 0.043 and = 0.043, respectively). No EEG abnormality independently predicted acute symptomatic seizures. However, the presence of periodic discharges on the first EEG was an independent predictor of epileptiform activity (p = 0.009) during the hospital stay. An early poststroke EEG can predict epilepsy in the first year after stroke, independently from clinical and imaging-based infarct severity.

The persistence of HIV-1 associated neurocognitive disorders (HAND) in the post-cART era, afflicting between 40 and 70% of HIV-1 seropositive individuals, supports a critical need for the development of adjunctive therapeutic treatments. Selective estrogen receptor β agonists, including S-Equol (SE), have been implicated as potential therapeutic targets for the treatment of neurocognitive disorders. In the present study, the therapeutic efficacy of 0.2 mg SE for the treatment of HAND was assessed to address two key questions in the HIV-1 transgenic (Tg) rat. First, does SE exhibit robust therapeutic efficacy when treatment is initiated relatively early (i.e., between 2 and 3 months of age) in the course of viral protein exposure? Second, does the therapeutic utility of SE generalize across multiple neurocognitive domains? Treatment with SE enhanced preattentive processes and stimulus-response learning to the level of controls in all (i.e., 100%) HIV-1 Tg animals. For sustained and selective attention, statistically significant effects were not observed in the overall analyses (Control: Placebo, n  = 10, SE, n  = 10; HIV-1 Tg: Placebo, n  = 10, SE, n  = 10). However, given our a priori hypothesis, subsequent analyses were conducted, revealing enhanced sustained and selective attention, approximating controls, in a subset (i.e., 50%, n  = 5 and 80%, n  = 8, respectively) of HIV-1 Tg animals treated with SE. Thus, the therapeutic efficacy of SE is greater when treatment is initiated relatively early in the course of viral protein exposure and generalizes across neurocognitive domains, supporting an adjunctive therapeutic for HAND in the post-cART era. Graphical Abstract HIV-1 transgenic (Tg) and control animals were treated with either 0.2 mg S-Equol (SE) or placebo between 2 and 3 months of age (Control: Placebo, n  = 10, SE, n  = 10; HIV-1 Tg: Placebo, n  = 10, SE, n  = 10). Neurocognitive assessments, tapping preattentive processes, stimulus response learning, sustained attention and selective attention, were conducted to evaluate the utility of SE as a therapeutic for HIV-1 associated neurocognitive disorders (HAND). Planned comparisons between HIV-1 Tg and control animals treated with placebo were utilized to establish a genotype effect, revealing prominent neurocognitive impairments (NCI) in the HIV-1 Tg rat across all domains. Furthermore, to establish the utility of SE, HIV-1 Tg animals treated with SE were compared to control animals treated with placebo. Treatment with 0.2 mg SE ameliorated NCI, to levels that were indistinguishable from controls, in at least a subset (i.e., 50–100%) of HIV-1 Tg animals. Thus, SE supports an efficacious, adjunctive therapeutic for HAND.

Summary Objectives The Psychology Task Force of the Medical Therapies Commission of the International League Against Epilepsy (ILAE) has been charged with taking steps to improve global mental health care for people with epilepsy. This study aimed to inform the direction and priorities of the Task Force by examining epilepsy healthcare providers’ current practical experiences, barriers, and unmet needs around addressing depression and anxiety in their patients. Methods A voluntary 27‐item online survey was distributed via ILAE chapters and networks. It assessed practices in the areas of screening, referral, management, and psychological care for depression and anxiety. A total of 445 participants, from 67 countries (68% high income), commenced the survey, with 87% completing all components. Most respondents (80%) were either neurologists or epileptologists. Results Less than half of respondents felt adequately resourced to manage depression and anxiety. There was a lack of consensus about which health professionals were responsible for screening and management of these comorbidities. About a third only assessed for depression and anxiety following spontaneous report and lack of time was a common barrier (>50%). Routine referrals to psychiatrists (>55%) and psychologists (>41%) were common, but approximately one third relied on watchful waiting. A lack of both trained mental health specialists (>55%) and standardized procedures (>38%) was common barriers to referral practices. The majority (>75%) of respondents’ patients identified with depression or anxiety had previously accessed psychotropic medications or psychological treatments. However, multiple barriers to psychological treatments were endorsed, including accessibility difficulties (52%). Significance The findings suggest that while the importance of managing depression and anxiety in patients with epilepsy is being recognized, there are ongoing barriers to effective mental health care. Key future directions include the need for updated protocols in this area and the integration of mental health professionals within epilepsy settings.

Objectives Seizure burden is typically measured by seizure frequency yet it entails more than seizure counts, especially for people with severe epilepsies and their caregivers. We aimed to characterize the multi‐faceted nature of seizure burden in young people and their parents who are living with severe early‐life epilepsies. Methods A one‐day workshop and a series of teleconferences were held with parents of children with severe, refractory epilepsy of early‐life origin and providers for children with epilepsy. The workshop sessions were structured as focus groups and aimed to identify components of seizure burden and their impact from the perspective of parents and providers. Data were gathered, organized, and refined during the workshop using an iterative 4‐step process that drew upon grounded theory. Results Three primary components of seizure burden were identified: frequency, severity, and unpredictability, which was as important if not more important at times than frequency and severity. Caregivers noted that the impacts of seizures were experienced as acute‐immediate consequences, longer‐term consequences, and as chronic effects that develop and evolve over time. The severity of the child's neurological and medical status as well as where in the disease journey a family was represented additional contextual factors that influenced the experience of seizure burden. Significance Patient‐reported and patient‐centered outcomes are increasingly incorporated into the evaluation of treatment effectiveness. Without understanding how the disease creates burden for the patient (or family), it is difficult to know how to assess the impact of treatment. Our preliminary findings indicate seizure burden is a complex construct and unpredictability can be as important as frequency and severity.

Objective Our study assessed perampanel monotherapy in patients (aged ≥12 years) with focal‐onset seizures (FOS) with or without focal to bilateral tonic‐clonic seizures (FBTCS) in Japan and South Korea. Methods Study 342 (NCT03201900; FREEDOM) is a single‐arm, open‐label, Phase III study. Patients initially received perampanel in a 32‐week 4‐mg/d Treatment Phase (6‐week Titration; 26‐week Maintenance Periods). If they experienced a seizure during the 4‐mg/d Maintenance Period, they could be up‐titrated to 8 mg/d across an additional 30‐week Treatment Phase (4‐week Titration; 26‐week Maintenance Periods). Primary endpoint was the seizure‐freedom rate during the Maintenance Period (4 mg/d and last evaluated dose [4 or 8 mg/d]). Secondary endpoints included time to first seizure onset and to withdrawal during Maintenance. Treatment‐emergent adverse events (TEAEs) were monitored. Results At data cutoff (February 28, 2019), 89 patients with FOS (84 [94.4%] with newly diagnosed epilepsy and 5 [5.6%] with recurrence of epilepsy after a period of remission) had received ≥1 perampanel dose; 16 patients discontinued during the 4‐mg/d Titration Period, meaning 73 patients entered the 4‐mg/d Maintenance Period and were included in the primary analysis set for efficacy. Seizure‐freedom rate in the 26‐week Maintenance Period was 46/73 (63.0%; 95% confidence interval [CI]: 50.9‐74.0) at 4 mg/d and 54/73 (74.0%; 95% CI: 62.4‐83.5) at 4 or 8 mg/d. Cumulative probability of seizure‐onset and withdrawal rates during Maintenance was 30.8% (95% CI: 21.5‐43.0) and 23.7% (95% CI: 15.4‐35.3) at 4 mg/d, and 18.2% (95% CI: 11.0‐29.3) and 23.3% (95% CI: 15.2‐34.8) at 4 or 8 mg/d. Perampanel was generally well tolerated, and the most common TEAE was dizziness. Significance Perampanel monotherapy (4 to 8 mg/d) was efficacious and consistent with the known safety profile up to 26 weeks in patients (≥12 years) with primarily newly diagnosed FOS with or without FBTCS.

Objective Genetic causes are increasingly identified in patients with focal epilepsy. These genetic causes may be related to the effectiveness of epilepsy surgery. We aimed to assess the use and yield of genetic testing in a large cohort of patients who were evaluated for epilepsy surgery. Methods We performed a retrospective single‐center consecutive cohort study of patients who were evaluated for surgery between 1990 and 2016. Within this cohort, we assessed the use of genetic testing—either before or after presurgical decision‐making. We evaluated genetic results as well as the outcome of presurgical decision‐making and surgery, and compared these end points for different subgroups—especially MRI‐positive vs MRI‐negative patients. Patients with tuberous sclerosis (TSC) and KRIT1 mutations were excluded from analysis. Results Of the 2385 epilepsy patients who were evaluated for surgery, 1280 (54%) received surgical treatment in our center. Of the entire cohort, 325 (14%) underwent genetic testing, comprising 156 of 450 MRI‐negative patients (35%) vs 169 of 1935 MRI‐positive patients (9%). A genetic cause of epilepsy was found in 40 of the 325 patients (12%, 2% of the entire cohort), mainly consisting of mutations in ion channel function and synaptic transmission genes, and mTOR pathway gene mutations. Three of the seven patients with mTOR pathway gene mutations underwent surgery; two achieved complete seizure freedom. One of the 17 patients with germline mutations in ion channel function and synaptic transmission genes received resective surgery but was not rendered seizure‐free; two other patients underwent invasive intracranial EEG‐monitoring before being rejected. Significance This study shows that genetic testing is increasingly applied in focal epilepsy patients who are considered for epilepsy surgery. The diagnostic yield of genetic testing is highest in next generation sequencing techniques, and the outcome of genetic testing assists selecting eligible patients for invasive intracranial monitoring and resective surgery.

Objective The objective of this study was to identify the signaling pathway that is immediately triggered by status epilepticus (SE) and in turn contributes to the excessive brain‐derived neurotrophic factor (BDNF)/tropomyosin‐related kinase receptor B (TrkB) signaling within the hippocampus. Methods We used quantitative PCR, enzyme‐linked immunosorbent assay, and Western blot analysis to examine gene expression at both mRNA and protein levels in the hippocampus following prolonged SE in mice and rats. Three classical animal models of SE were utilized in the present study to avoid any model‐ or species‐specific findings. Results We showed that both cyclooxygenase‐2 (COX‐2) and BDNF in the hippocampus were rapidly upregulated after SE onset; however, the induction of COX‐2 temporally preceded that of BDNF. Blocking COX‐2 activity by selective inhibitor SC‐58125 prevented BDNF elevation in the hippocampus following SE; prostaglandin E2 (PGE2), a major product of COX‐2 in the brain, was sufficient to stimulate hippocampal cells to secrete BDNF, suggesting that a PGE2 signaling pathway might be directly involved in hippocampal BDNF production. Inhibiting the Gαs‐coupled PGE2 receptor EP2 by our recently developed selective antagonist TG6‐10‐1 decreased the SE‐triggered phosphorylation of the cAMP response element‐binding protein (CREB) and activation of the BDNF/TrkB signaling in the hippocampus. Significance The molecular mechanisms whereby BDNF/TrkB signaling is upregulated in the hippocampus by SE largely remain unknown. Our findings suggest that COX‐2 via the PGE2/EP2 pathway regulates hippocampal BDNF/TrkB activity following prolonged seizures. EP2 inhibition by our bioavailable and brain‐permeable antagonists such as TG6‐10‐1 might therefore provide a novel strategy to suppress the abnormal TrkB activity, an event that can sufficiently trigger pathogenic processes within the brain including acquired epileptogenesis.

Objective Deep brain stimulation of the ANT is a novel treatment option in refractory epilepsy with an established efficacy at the group level. However, data on the effect of individualized programming are currently lacking. We report the effect of programming changes on outcome in deep brain stimulation of anterior nucleus of thalamus (ANT DBS). Secondly, we investigated whether the effect differs between seizure types. Thirdly, we compared the response status between patients with stimulation contacts verified inside the ANT with patients with contacts located outside of ANT. Methods The participants were 27 consecutive patients with ANT DBS implantation with at least two‐year follow‐up. Seizures were subdivided into focal aware (FAS), focal impaired awareness (FIAS), and focal to bilateral tonic‐clonic seizures (FBTCS). The patients’ seizure diaries were analyzed retrospectively to assess changes in different seizure types. Active contact locations for each patient were verified from preoperative MRI and postoperative CT fusion images using SureTune III (Medtronic Inc, Minneapolis, MN) software. Results A significant reduction in monthly mean seizure frequency occurred in FIAS: 56% at two‐year and 65% at five‐year follow‐up. The effects on FAS and FBTCS were less pronounced. Patients with contacts inside the ANT or on the anterolateral border of ANT experienced a greater reduction in seizure frequency than patients with outside‐ANT contacts. Ultimately, seven patients became responders due to changes in DBS programming or repositioning of contacts, increasing our responder rate from 44% to 70% as measured by a seizure reduction of at least 50%. Significance ANT DBS appears to be especially effective in reducing FIAS, when the appropriately chosen contacts are activated.