Ketone Body Rescued Seizure Behavior Of LRP1 Deficiency By Modulating Glutamate Transport

LRP1, the low-density lipoprotein receptor 1, would be a novel candidate epilepsy gene according to our bioinformatic results and the animal study. In this study, we explored the role of LRP1 in Epilepsy and whether Beta-hydroxybutyrate, the principal ketone body of the ketogenic diet can treat epilepsy caused by LRP1 deficiency. UAS/GAL4 system was used to establish different genotype models. Flies were given Standard, High-sucrose, and ketone body food randomly. The bang-sensitive test was performed on flies and seizure-like behavior was assessed. Morphologic alteration of LRP1 defect in the brain was detected under GPF expression flies. We established global, astrocytic, and neuronal LRP1 knockdown flies. Whole body and glia LRP1 defect flies had a higher seizure rate compared to the control group in the behavior test. Ketone body decreased the seizure rate in behavior test in all LRP1 defect flies, compared to Standard and High sucrose diet. In morphologic experiments, we found that LRP1 deficiency caused partial loss of the ellipsoidal body and partial destruction of the fan-shaped body. Overexpression of glutamate transporter gene Eaat1 could mimic the ketone body effect on LRP1 deficiency flies. This study demonstrated that LRP1 defect globally or in astrocytes or neurons could induce epilepsy. The ketone body efficaciously rescued epilepsy caused by LRP1 knockdown. The results support screening for LRP1 mutations as discriminating conduct for individuals who require clinical attention and further clarify the mechanism of the ketogenic diet in Epilepsy, which could help Epilepsy patients making a precise treatment case by case.

The relative effectiveness of law enforcement policies aimed at reducing illegal trade: Evidence from laboratory markets

Despite recent emphasis and implementation of national and international anti-money laundering policies, illegal product markets, and their associated illicit profit remain a global problem. In addition to law enforcement aimed at reducing money-laundering, enforcement also takes place during (1) the production (e.g. crop eradication) and (2) sale (e.g. seizure of products during transportation that interrupts buyer and seller transactions) of the illegal product. Since funds for enforcement come from limited budgets, understanding where in this production-trade-laundering cycle law enforcement is most impactful becomes a global question. Using laboratory experimental markets and a seizure rate of 20%, we find that law enforcement focused on seizing laundered profits does little to reduce illegal market activity when compared to no law enforcement, suggesting that focusing law enforcement on money laundering will likely be ineffective at reducing crime. Results further show the amount of illicit trade is nearly 32% lower when law enforcement is focused at the point of sale, and there may be additional economic incentives that reduce illicit trade in the long run when compared to no law enforcement. Enforcement at the point of production also reduces market activity, but not as effectively as enforcement at the point of sale. Lastly, the empirical findings deviate from equilibrium predictions, suggesting law enforcement policy based on theory alone may lead to inefficient allocation of limited law enforcement resources.

GP.5 Entropy on routine EEG: an interictal marker of seizure frequency?

Background: Sample entropy (SampEn) can quantify the unpredictability of a physiological signal. We sought to assess if SampEn on EEG could reflect recent seizure activity. Methods: Charts of all patients undergoing an outpatient EEG between January and March 2018 were reviewed to assess seizure occurrences in the follow-up period between the two clinical visits surrounding the EEG. 9s-EEG segments were extracted at pre-specified time points. SampEn was calculated for all segments and values aggregated at the 25thpercentile. We performed a multivariate zero-inflated analysis to test the association between SampEn and seizure rate around the EEG, after controlling for age, presence of IED, presence of abnormal slowing, and presence of a focal brain lesion. Results: 269 EEGs were screened and 133 met inclusion criteria (112 patients). 80 EEGs (60%) were from patients with epilepsy, of which 47 had at least one seizure within the year preceding the EEG. Remaining EEGs were from patients who were deemed not to have epilepsy at last follow-up. Each 1SD decrease in SampEn was associated with a 3.93-fold increase in the rate of daily seizures (95% CI: 1.19–12.99, p = 0.02). Conclusions: Sample entropy of EEG is a potential objective method to assess contemporary seizure occurrence.

The severity of seizures and epileptiform activity index in the assessment of antiepileptic treatment efficacy in patients with generalized tonic-clonic awakening seizures

Objective: to evaluate the role of seizure severity and epileptiform activity index (IEA) assessment in newly-diagnosed idiopathic generalized epilepsy with generalized tonic-clonic awakening seizures (GTCS).Material and methods. The study included 31 patients with newly-diagnosed generalized epilepsy with GTCS aged 14–52 years (mean age 25.06±9.3 years), which were divided into two groups depending on seizure severity: Group 1 (n=9, 29%) with <18 points, and Group 2 (n=22, 71%) with ≥18 points. Seizure severity was analysed by using National Hospital Seizure Severity Scale (NHS3). All patients underwent video-electroencephalography monitoring (8–24 hours) with IEA assessment at baseline and at 1, 3, 6 and 12 months after the beginning of treatment. Therapeutic efficacy was assessed using the criteria of seizure absence (medically induced remission), seizure rate decrease by >50% (responders), seizure rate decrease by <50% (insufficient efficacy), seizure rate increase and retention in treatment.Results. Total EAI at baseline was significantly higher in patients from Group 2 (p=0.019). Despite markedly reduced EAI level in both groups, in Group 1 (less than 18 points by NHS3) EAI was significantly lower compared to Group 2 (≥18 points) at all subsequent visits: visit 2 (p=0.038), visit 3 (p=0.035), visit 4 (p=0.047), and visit 5 (p=0.022).Conclusions. Assessing seizure severity may become an additional objective criterion while evaluating treatment efficacy.

Efficacy and safety of using vagus nerve stimulation in patients with pharmacoresistant epilepsy in the Russian Federation: a multi-center retrospective observational program

Objective: to assess efficacy and safety of vagus nerve stimulation (VNS) in patients with pharmacoresistant epilepsy.Material and methods. A multi-center retrospective observational program was applied in patients with pharmacoresistant epilepsy by using vagus nerve stimulation for at least 2 years. There were enrolled 151 subjects, patient age on stimulator implantation varied from 5 to 65 years (24.4±13.1 years). Among them, subjects under 18 or at least 18 years of age comprised 58 (38.4%) and 93 (61.6%), respectively. Changes in rate and severity of major group epileptic seizures (highly disabling type) 24 months after VNS-therapy vs. baseline state as well as during 3-, 6-, 9-, 12-month follow-up were compared. There were assessed stimulator-related effects on VNS-therapy as well as patient quality of life 2 years after therapy. The dynamics of the frequency of all types of epileptic seizures was evaluated according to McHugh Outcome scale.Results. Mean epilepsy duration on stimulator implantation was 170.9±126.8 months, with maximum up to 666 months (55 years). Number of patients with dominant (disabling) seizures on implantation procedure comprised 136 (90.1%). Decline in dominant epileptic seizure rate by 50–99% was recorded in 91 patients (66.9%) 24 months after VNStherapy. Among such subjects were 41 patients (30.15%) featured with disabling seizures including 24 fully seizure free subjects (17.65%). Decreased rate of all group epileptic seizures by more than 50% (responders) was found in 52.9% cases, including subjects under 18 and adults in 63.9% and as few as 46.3% (p<0.05), respectively. While assessing dynamic rate for all groups of epileptic seizures applied with VNS-therapy by using McHugh Outcome scale it was found that class I (lowered seizure rate by 80–100%) was observed in 44 cases (29.1%), including 18 patients under 18 (31%) and 26 subjects above 18 (28%) (insignificant difference). Mean dominant group epileptic seizure rate was also significantly decreased in both age groups from 20 down to 5.7 per month. Severity of epileptic seizures and postseizure condition upon VNS-therapy was decreased in 38.6% and 43.9% patients 24 months after therapy and on final follow-up visit, respectively (more than 24 months after implantation). No serious adverse events as well as adverse effects resulting in therapy cancel were noted. Conclusion. Vagus nerve stimulation is an effective and safe auxiliary treatment method for therapy of pharmacoresistant epilepsy both in children and adults.><0.05) , respectively. While assessing dynamic rate for all groups of epileptic seizures applied with VNS-therapy by using McHugh Outcome scale it was found that class I (lowered seizure rate by 80–100%) was observed in 44 cases (29.1%), including 18 patients under 18 (31%) and 26 subjects above 18 (28%) (insignificant difference). Mean dominant group epileptic seizure rate was also significantly decreased in both age groups from 20 down to 5.7 per month. Severity of epileptic seizures and postseizure condition upon VNS-therapy was decreased in 38.6% and 43.9% patients 24 months after therapy and on final follow-up visit, respectively (more than 24 months after implantation). No serious adverse events as well as adverse effects resulting in therapy cancel were noted.Conclusion. Vagus nerve stimulation is an effective and safe auxiliary treatment method for therapy of pharmacoresistant epilepsy both in children and adults.

UNC13B variants associated with partial epilepsy with favourable outcome

The unc-13 homolog B (UNC13B) gene encodes a presynaptic protein, mammalian uncoordinated 13–2 (Munc13-2), that is highly expressed in the brain—predominantly in the cerebral cortex—and plays an essential role in synaptic vesicle priming and fusion, potentially affecting neuronal excitability. However, the functional significance of UNC13B mutation in human disease is not known. In this study we screened for novel genetic variants in a cohort of 446 unrelated cases (families) with partial epilepsy without acquired causes by trio-based whole-exome sequencing. UNC13B variants were identified in 12 individuals affected by partial epilepsy and/or febrile seizures from eight unrelated families. The eight probands all had focal seizures and focal discharges in EEG recordings, including two patients who experienced frequent daily seizures and one who showed abnormalities in the hippocampus by brain MRI; however, all of the patients showed favorable outcome without intellectual or developmental abnormalities. The identified UNC13B variants included one nonsense variant, two variants at or around a splice site, one compound heterozygous missense variant, and four missense variants that cosegregated in the families. The frequency of UNC13B variants identified in the present study was significantly higher than that in a control cohort of Han Chinese and controls of the East Asian and all populations in the Genome Aggregation Database. Computational modeling, including hydrogen bond and docking analyses, suggested that the variants lead to functional impairment. In Drosophila, seizure rate and duration were increased by Unc13b knockdown compared to wild-type flies, but these effects were less pronounced than in sodium voltage-gated channel alpha subunit 1 (Scn1a) knockdown Drosophila. Electrophysiologic recordings showed that excitatory neurons in Unc13b-deficient flies exhibited increased excitability. These results suggest that UNC13B is potentially associated with epilepsy. The frequent daily seizures and hippocampal abnormalities but ultimately favorable outcome under antiepileptic therapy in our patients indicate that partial epilepsy caused by UNC13B variant is a clinically manageable condition.

Analysis for use coastguard Offshore Platforms or SWATH Patrol Vessels in the Colombian Pacific Ocean

The average cocaine seizure rate of coast guard operations in the Colombian Pacific can be improved. To enhance this indicator, detection and interdiction must be improved. Therefore, the option of using an offshore platform with better detection means, and several Rapid Reasponse Units (RRUs) stationed offshore, is being analyzed. As a result, offshore platforms are neither feasible nor viable due to the depth of the sea floor (> 2 km), but SWATH platforms can be used. The parametric design of two SWATHs is performed and an operational evaluation is made of the different current units and SWATHs. The operational evaluation of the different current units and the proposed SWATHs is carried out and contrasted with their acquisition and life cycle cost, showing that the SWATHs have a better efficiency/cost ratio. Therefore, they can be considered as an alternative to improve the efficiency of cocaine seizures and other coast guard operations.

Amygdala Low-Frequency Stimulation Reduces Pathological Phase-Amplitude Coupling in the Pilocarpine Model of Epilepsy

Temporal-lobe epilepsy (TLE) is the most common type of drug-resistant epilepsy and warrants the development of new therapies, such as deep-brain stimulation (DBS). DBS was applied to different brain regions for patients with epilepsy; however, the mechanisms of action are not fully understood. Therefore, we tried to characterize the effect of amygdala DBS on hippocampal electrical activity in the lithium-pilocarpine model in male Wistar rats. After status epilepticus (SE) induction, seizure patterns were determined based on continuous video recordings. Recording electrodes were inserted in the left and right hippocampus and a stimulating electrode in the left basolateral amygdala of both Pilo and age-matched control rats 10 weeks after SE. Daily stimulation protocol consisted of 4 × 50 s stimulation trains (4-Hz, regular interpulse interval) for 10 days. The hippocampal electroencephalogram was analyzed offline: interictal epileptiform discharge (IED) frequency, spectral analysis, and phase-amplitude coupling (PAC) between delta band and higher frequencies were measured. We found that the seizure rate and duration decreased (by 23% and 26.5%) and the decrease in seizure rate correlated negatively with the IED frequency. PAC was elevated in epileptic animals and DBS reduced the pathologically increased PAC and increased the average theta power (25.9% ± 1.1 vs. 30.3% ± 1.1; p < 0.01). Increasing theta power and reducing the PAC could be two possible mechanisms by which DBS may exhibit its antiepileptic effect in TLE; moreover, they could be used to monitor effectiveness of stimulation.

Efficacy assessment of levetiracetam monotherapy in newly-diagnosed epilepsy in adults using epileptiform activity index

Levetiracetam (LEV) is one of the most commonly prescribed antiepileptic drugs (AED). However, there were no studies on its efficacy and safety in terms of the correlation with epileptiform activity index (EAI) performed among the Russian population.Aim. To evaluate the efficacy and tolerability of LEV monotherapy in patients with newly-diagnosed epilepsy using epileptiform activity index (EAI) assessment.Materials and methods. The study included 107 patients (46 (43.0%) male and 61 (57.0%) female) with focal epilepsy (FE) (39.3%; n=42) or idiopathic generalized epilepsy (IGE) (60.7%; n=65). At each visit, video-electroencephalographic (video-EEG) monitoring was performed (baseline and in 1, 3, 6, and 12 months of the therapy). Therapeutic drug monitoring was performed at dose titration in 1 month of the therapy or in case of therapy correction. Treatment efficacy was assessed using the criteria of seizure absence (medically induced remission), seizure rate decrease by >50% (responders), seizure rate decrease by <50% – insufficient efficacy, a composite index of efficacy/tolerability (retention on treatment), and seizure rate increase compared to baseline and/or development of a new type of seizures (aggravation). Adverse events (AE) were assessed using the scale for side effects in AED treatment (SIDAED).Results. Total EAI at baseline was 5.2-fold higher in patients with IGE compared to FE patients (23.4±3.0 and 4.5±0.97, respectively). After 1 month of LEV therapy, EAI decreased to 3.4±1.1 and 1.9±0.4 in patients with IGE and FE, respectively (p<0.01). The decrease continued during the whole follow-up period. Retention on monotherapy was achieved in 82.2% (n=88/107) patients; in 87.6% (n=57/65) patients with IGE and in 73.8% (n=31/42) with FE. The rate of serious AEs during the follow-up period was 8.4% (n=9).Conclusions. LEV is an effective drug of choice for the initial treatment of newly-diagnosed FE and IGE in monotherapy along with a significant decrease in EAI. EAI is an objective measure of LEV treatment efficacy.

Efficacy and Tolerability of Lacosamide for Focal Epileptic Patients: Study from Epilepsy Clinic in Makkah

Background: Lacosamide characterized by a novel dual mode of action in its components, in which it has a func-tionalized amino acid that selectively pro, motes inactivation of voltage-gated sodium channels slowly among patients. Objective: To assess the effectiveness and tolerability of Lacosamide in the treatment of focal epileptic patients. Methods: This retrospective cohort study obtains data from the clinic notes or diaries of all patients during 2014 to 2019 from King Abdullah Medical City. The multivariate generalized estimating equation (GEE) repeated measure Logistic Re-gression Analysis was used to assess the change in patients’ odds of having an improvised seizure rate. Results: Majority of the focal epileptic patients were diagnosed with temporal epilepsy (57.9%), while 26.3% had frontal epileptic lesion/diagnoses. Majority of the patients (54.4%) had received a combination of old and new treatment. 57.14% of the seven patients had dizziness and headache, tremors (n = 1), loss of balance (n = 1) and increased seizure with abnormal vision acuity and psychosis (n = 1). 84.2% of the patients had reduction of their median seizure frequency at the 12-month period. However, there were no significant difference on the seizure control rate based on clinical characteristics. There were no statistically significant differences between male and female patients on their improvement rate across the four times on average. Conclusion: Lacosamide is an effective well tolerate drug for patients with focal epilepsy.