Syntaxin-5's flexibility in SNARE pairing supports Golgi functions.

Deficiency in the conserved oligomeric Golgi (COG) complex that orchestrates SNARE-mediated tethering/fusion of vesicles that recycle the Golgi's glycosylation machinery results in severe glycosylation defects. Although two major Golgi v-SNAREs, GS28/GOSR1, and GS15/BET1L, are depleted in COG-deficient cells, the complete knockout of GS28 and GS15 only modestly affects Golgi glycosylation, indicating the existence of an adaptation mechanism in Golgi SNARE. Indeed, quantitative mass-spectrometry analysis of STX5-interacting proteins revealed two novel Golgi SNARE complexes-STX5/SNAP29/VAMP7 and STX5/VTI1B/STX8/YKT6. These complexes are present in wild-type cells, but their usage is significantly increased in both GS28- and COG-deficient cells. Upon GS28 deletion, SNAP29 increased its Golgi residency in a STX5-dependent manner. While STX5 depletion and Retro2-induced diversion from the Golgi severely affect protein glycosylation, GS28/SNAP29 and GS28/VTI1B double knockouts alter glycosylation similarly to GS28 KO, indicating that a single STX5-based SNARE complex is sufficient to support Golgi glycosylation. Importantly, co-depletion of three Golgi SNARE complexes in GS28/SNAP29/VTI1B TKO cells resulted in severe glycosylation defects and a reduced capacity for glycosylation enzyme retention at the Golgi. This study demonstrates the remarkable plasticity in SXT5-mediated membrane trafficking, uncovering a novel adaptive response to the failure of canonical intra-Golgi vesicle tethering/fusion machinery.

Seizure-free days as a novel outcome in patients with Lennox-Gastaut syndrome: Post hoc analysis of patients receiving cannabidiol in two randomized controlled trials.

OBJECTIVE: In this post hoc analysis, we aimed to assess seizure-free days as a potential new outcome measure to use in randomized placebo-controlled trials (RCTs) of patients with Lennox-Gastaut syndrome (LGS). METHODS: In two phase 3 RCTs (GWPCARE3, GWPCARE4), eligible patients were randomized to receive plant-derived highly purified cannabidiol (CBD; Epidiolex® in the USA; 100 mg/mL oral solution) at 10 mg/kg/day (CBD10; GWPCARE3 only), at 20 mg/kg/day (CBD20), or matched placebo. The treatment period comprised a 2-week dose titration and a 12-week maintenance period. This post hoc analysis evaluated the least-squares (LS) mean changes from baseline and difference versus placebo in the number of drop or total seizure-free days per 28 days during the treatment period or maintenance period alone. LS mean changes were estimated using an analysis of covariance model, with categorical age and baseline number of drop or total seizure-free days as covariates, and treatment group as a fixed factor. RESULTS: A total of 396 patients were included in this post hoc analysis. During the 14-week treatment period, LS mean changes from baseline in number of drop seizure-free days per 28 days for patients receiving placebo (n = 161), CBD10 (n = 73), and CBD20 (n = 162) were 2.81 (95% confidence interval [CI] = 1.75-3.88), 5.64 (95% CI = 4.08-7.20), and 6.45 (95% CI = 5.39-7.52), respectively. The LS mean differences in number of drop seizure-free days versus placebo were 2.83 (95% CI = .98-4.68) for CBD10 and 3.64 (95% CI = 2.18-5.10) for CBD20. For total seizure-free days, LS mean differences versus placebo were 2.63 (95% CI = .92-4.34) for CBD10 and 3.50 (95% CI = 2.16-4.85) for CBD20. The improvements from baseline in seizure-free days during the maintenance period alone were similar to the entire treatment period. SIGNIFICANCE: Drop and total seizure-free days represent potential new and clinically meaningful endpoints for future RCTs in patients with LGS.

Long-term effectiveness of add-on perampanel in patients with Lennox-Gastaut syndrome: A multicenter retrospective study.

This retrospective study assessed long-term effectiveness of add-on perampanel (PER) in patients with Lennox-Gastaut syndrome (LGS). Outcomes included time to PER failure and time to seizure relapse in responders. PER failure was defined as either discontinuation of PER or initiation of another treatment. Seizure relapse in responders was defined as occurrence of a seizure in seizure-free patients and increase of at least 50% in average monthly seizure frequency for those who were responders. Eighty-seven patients were included. Treatment failure occurred in 52 (59.8%) subjects at a median time of 12 months. Treatment failure was due to lack of efficacy in 27 (52.0%) patients, lack of tolerability in 14 (27.0%), and both reasons in 11 (21.0%). A slower titration was associated with a lower risk of PER failure compared to faster titration schedules, and the occurrence of adverse events increased the risk of treatment failure. Thirty-six patients (41.4%) were responders during a median follow-up of 11 months. Seizure relapse occurred in 13 of 36 (36.1%) patients after a median time of 21 months. The overall rate of seizure responders was 23 of 87 (26.4%) at the end of follow-up. This study provides real-world evidence on the effectiveness of PER as adjunctive treatment in LGS patients.

Deep learning for automated detection of generalized paroxysmal fast activity in Lennox-Gastaut syndrome.

OBJECTIVES: Generalized paroxysmal fast activity (GPFA) is a key electroencephalographic (EEG) feature of Lennox-Gastaut Syndrome (LGS). Automated analysis of scalp EEG has been successful in detecting more typical abnormalities. Automatic detection of GPFA has been more challenging, due to its variability from patient to patient and similarity to normal brain rhythms. In this work, a deep learning model is investigated for detection of GPFA events and estimating their overall burden from scalp EEG. METHODS: Data from 10 patients recorded during four ambulatory EEG monitoring sessions are used to generate and validate the model. All patients had confirmed LGS and were recruited into a trial for thalamic deep-brain stimulation therapy (ESTEL Trial). RESULTS: The correlation coefficient between manual and model estimates of event counts was r2 = 0.87, and for total burden was r2 = 0.91. The average GPFA detection sensitivity was 0.876, with an average false-positive rate of 3.35 per minute. There was no significant difference found between patients with early or delayed deep brain stimulation (DBS) treatment, or those with active vagal nerve stimulation (VNS). CONCLUSIONS: Overall, the deep learning model was able to accurately detect GPFA and provide accurate estimates of the overall GPFA burden and electrographic event counts, albeit with a high false-positive rate. SIGNIFICANCE: Automated GPFA detection may enable automated calculation of EEG biomarkers of burden of disease in LGS.

Paroxysmal fast activity is a biomarker of treatment response in deep brain stimulation for Lennox-Gastaut syndrome.

OBJECTIVE: Epilepsy treatment trials typically rely on seizure diaries to determine seizure frequency, but these are time-consuming and difficult to maintain accurately. Fast, reliable, and objective biomarkers of treatment response are needed, particularly in Lennox-Gastaut syndrome (LGS), where high seizure frequency and comorbid cognitive and behavioral issues are additional obstacles to accurate diary-keeping. Here, we measured generalized paroxysmal fast activity (GPFA), a key interictal electrographic feature of LGS, and correlated GPFA burden with seizure diaries during a thalamic deep brain stimulation (DBS) treatment trial (Electrical Stimulation of the Thalamus in Epilepsy of Lennox-Gastaut Phenotype [ESTEL]). METHODS: GPFA and electrographic seizure counts from intermittent, 24-h electroencephalograms (EEGs) were compared to 3-month diary-recorded seizure counts in 17 young adults with LGS (mean age ± SD = 24.9 ± 6.6) in the ESTEL study, a randomized clinical trial of DBS lasting 12 months (comprising a 3-month baseline and 9 months of postimplantation follow-up). RESULTS: Baseline median seizures measured by diaries numbered 2.6 (interquartile range [IQR] = 1.4-5) per day, compared to 284 (IQR = 120.5-360) electrographic seizures per day, confirming that diaries capture only a small fraction of seizure burden. Across all patient EEGs, the average number of GPFA discharges per hour of sleep was 138 (IQR =72-258). GPFA duration and frequency, quantified over 2-h windows of sleep EEG, were significantly associated with diary-recorded seizure counts over 3-month intervals (p < .001, η2 p  = .30-.48). For every GPFA discharge, there were 20-25 diary seizures witnessed over 3 months. There was high between-patient variability in the ratio between diary seizure burden and GPFA burden; however, within individual patients, the ratio was similar over time, such that the percentage change from pre-DBS baseline in seizure diaries strongly correlated with the percentage change in GPFA. SIGNIFICANCE: When seeking to optimize treatment in patients with LGS, monitoring changes in GPFA may allow rapid titration of treatment parameters, rather than waiting for feedback from seizure diaries.

Activation of Mast-Cell-Derived Chymase in the Lacrimal Glands of Patients with IgG4-Related Ophthalmic Disease.

The purpose of this present study was to investigate the distribution and expression of chymase in the lacrimal glands (LGs) of patients afflicted with IgG4-related ophthalmic disease (IgG4-ROD). LGs from patients with severe canalicular obstruction were considered the control group. Toluidine blue staining confirmed a significant increase in the number of mast cells in the LGs obtained from the IgG4-ROD patients. In addition, immunostaining of serial sections from the LGs showed a significant increase in the number of chymase-positive cells and tryptase-positive cells in the IgG4-ROD LGs compared to the normal control LGs. The mRNA expression of chymase, tryptase, TGF-ß1, and collagen-I tended to increase in the IgG4-ROD LGs. Immunostaining of vimentin and α-smooth muscle actin (α-SMA) showed that myofibroblasts were the main cellular components in severely fibrotic regions of LGs in patients with IgG4-ROD. Linear regression analyses on the number of mast cells, chymase-positive cells, and tryptase-positive cells revealed significant positive correlations between those respective cells. Our findings suggest that chymase may play a role in the fibrotic disorder of IgG4-ROD LGs through the regulation of TGF-ß1 activation and collagen-I deposition, and that it may be a therapeutic target for patients afflicted with IgG4-ROD.

Management of Lennox-Gastaut syndrome beyond childhood: A comprehensive review.

Lennox-Gastaut syndrome (LGS) is a childhood-onset epileptic encephalopathy characterized by multiple types of medically intractable seizures, cognitive impairment, and generalized slow spike-wave discharges in electroencephalography (EEG). Although the onset of this epileptic syndrome occurs typically before eight years of age with a peak age between 3 and 5 years, lifelong persistence of the syndrome is usual. The evolution of clinical features, EEG findings, and paucity of knowledge about LGS among adult health care providers can make LGS significantly underdiagnosed in the adult population. Management of LGS remains problematic beyond childhood due to intractable seizures, the difficult transition from pediatric to adult neurologists, challenging behaviors, impaired cognition, poor quality of life, and disabled social life. In focusing on the management of LGS beyond childhood, this narrative review describes medical and surgical management of epilepsy, the transition from pediatric to adult care, and management of other common comorbidities associated with LGS. Several antiepileptic drugs (AEDs) such as lamotrigine, topiramate, felbamate, rufinamide, clobazam, and Epidiolex (pure pharmaceutical grade cannabidiol (CBD) oil) have been noted to be effective in well-designed, randomized controlled trials. Other non-pharmacological therapies, such as vagus nerve stimulation, ketogenic diet, and epilepsy surgery, have been frequently utilized in the management of intractable seizures associated with LGS. However, effective management of LGS requires a broader perspective to not only control seizures but improve the quality of life by addressing cognitive and behavioral problems, sleep disturbances, physical disability, social disability, and educational and employment challenges.

Cognitive and functional status in late-onset Lennox-Gastaut syndrome: Variation on a classic phenotype.

Lennox-Gastaut syndrome (LGS) denotes a refractory epileptic encephalopathy of childhood onset with the triad of generalized slow spike-wave (GSSW) on interictal scalp electroencephalogram (EEG), multiple seizure types, and intellectual impairment. The neurobiology of LGS is said to sustain abnormal patterns of brain activity and connectivity that ultimately impair normal cerebral developmental mechanisms. However, we describe eight patients from our combined practice who presented with electroclinical findings consistent with LGS but without significant cognitive impairment. All patients fulfilled the other criteria of LGS with multiple seizure types (three or more of generalized tonic-clonic, atonic, tonic, myoclonic, and atypical absence) and GSSW activity on EEG. Four subjects completed high school, two completed some college, two acquired college degrees, and all performed basic and instrumental activities of daily living (ADL) independently. Magnetic resonance imaging (MRI) was normal in all patients. We speculate that a variation of the classic phenotype of LGS can present with preserved cognitive and functional status, often with onset in the second decade of life, and associated with normal brain imaging.

Optimization of SAW Devices with LGS/Pt Structure for Sensing Temperature.

Research has shown that SAW (surface acoustic wave) devices with an LGS/Pt (langasite La3Ga5SiO14/platinum) structure are useful in high-temperature sensor applications. Extreme high temperature brings great acoustic attenuation because of the thermal radiation loss, which requires that the sensing device offer a sufficiently high quality factor (Q) and a low loss. Therefore, it is necessary to improve the performance of the quality factor as much as possible so as to better meet the application of high-temperature sensors. Based on these reasons, the main work of this paper was to extract accurate simulation parameters to optimize the Pt/LGS device and obtain Q-value device parameters. Optimization of SAW devices with LGS/Pt structure for sensing extreme high temperature was addressed by employing a typical coupling of modes (COM) model in this work. Using the short pulse method, the reflection coefficient of Pt electrodes on LGS substrate was extracted accurately by characterizing the prepared SAW device with strategic design. Other relevant parameters for COM simulation were determined by finite element analysis. To determine the optimal design parameters, the COM simulation was conducted on the SAW sensing device with a one-port resonator pattern for sensing extreme temperature, which allows for a larger Q-value and low insertion loss. Experimental results validate the theoretical simulation. In addition, the corresponding high-temperature characteristics of the prepared sensing device were investigated.

The refractory epilepsy screening tool for Lennox-Gastaut syndrome (REST-LGS).

BACKGROUND: The complex clinical presentation and progression of Lennox-Gastaut syndrome (LGS) can complicate the accurate diagnosis of this severe, lifelong, childhood-onset epilepsy, often resulting in suboptimal treatment. The Refractory Epilepsy Screening Tool for LGS (REST-LGS) was developed to improve the identification of patients with LGS. METHODS: Using the Modified Delphi Consensus, a group of experts developed and tested the REST-LGS Case Report Form (CRF) comprising 8 criteria (4 major, 4 minor) considered potentially indicative of LGS. Diagnosis-blinded specialist and nonspecialist raters at 2 epilepsy centers applied the CRF to deidentified patient records, including 1:1 records of patients with drug-resistant epilepsy or confirmed LGS. Interrater reliability was measured by Cohen's κ. Diagnosis was then unblinded to reveal common criteria for LGS or drug-resistant epilepsy. Cronbach's α was used to measure internal consistency between raters for all criteria combined. RESULTS: Of 200 patients, 81% to 85% met 1 to 3 major criteria. At both sites, moderate (κ, 0.41-0.60) to good (κ, 0.61-0.80) agreement on most criteria was reached between expert and nonexpert raters. Unblinding revealed that most patients with LGS met 3 major and 2 to 3 minor criteria, while patients with drug-resistant epilepsy met ≤1 major and only 1 to 2 minor criteria. Cronbach's α of raters at both sites was 0.64. CONCLUSIONS: The combined number of major/minor criteria on the CRF may be particularly indicative of LGS. Therefore, the REST-LGS may be a valuable clinical tool in identifying patients requiring further diagnostic evaluation for LGS.

Novel Local Coding Algorithm for Finger Multimodal Feature Description and Recognition.

Recently, finger-based biometrics, including fingerprint (FP), finger-vein (FV) and finger-knuckle-print (FKP) with high convenience and user friendliness, have attracted much attention for personal identification. The features expression which is insensitive to illumination and pose variation are beneficial for finger trimodal recognition performance improvement. Therefore, exploring suitable method of reliable feature description is of great significance for developing finger-based biometric recognition system. In this paper, we first propose a correction approach for dealing with the pose inconsistency among the finger trimodal images, and then introduce a novel local coding-based feature expression method to further implement feature fusion of FP, FV, and FKP traits. First, for the coding scheme a bank of oriented Gabor filters is used for direction feature enhancement in finger images. Then, a generalized symmetric local graph structure (GSLGS) is developed to fully express the position and orientation relationships among neighborhood pixels. Experimental results on our own-built finger trimodal database show that the proposed coding-based approach achieves excellent performance in improving the matching accuracy and recognition efficiency.

Optimizing clobazam treatment in patients with Lennox-Gastaut syndrome.

Given the complexities managing Lennox-Gastaut syndrome (LGS)-comorbid conditions, multiple associated seizure types that tend to be refractory to treatment-dosage optimization of antiepileptic drug (AED) treatment is a challenge. In the absence of clinical trial data on optimization of AED dosage in patients with LGS, dose titration is guided by personal experience, anecdotal evidence, and specific patient factors (age, comorbid conditions and medications, seizure types, etc.). The goal of this study was to determine whether a 20% increase in adjunctive clobazam was a reasonable benchmark for improved seizure response in patients with LGS who had responded to adjunctive clobazam treatment during a 12-week lead-in trial. This was a post hoc analysis of data from a long-term, open-label extension (OLE) study, which comprised patients who completed 1 of 2 pivotal clobazam lead-in studies. During the lead-in studies, patients received either placebo or clobazam (0.25, 0.50, or 1.0mg/kg/d) (maximum 40mg/d); during OLE, patients received clobazam up to 2.0mg/kg/d (maximum 80mg/d). The post hoc analysis population comprised patients who had ≥25%, ≥50%, or ≥75% seizure reduction from baseline during lead-in clobazam treatment and ≥12months of follow-up data during OLE. Successful dosage increase (i.e., dosage optimization) was defined as ≥20% clobazam dosage increase from OLE baseline, and improved seizure control from OLE baseline (improvement in seizure responder status, or >50% reduction in total seizure frequency). Patients were stratified by responder status after lead-in treatment (OLE baseline) and by lead-in clobazam dosage received. The findings of the analysis indicated that clobazam dosage increases of ≥20% during long-term treatment improved seizure control >80% of patients with LGS who responded to clobazam during lead-in treatment. Rates of successful dosage increase during OLE were high regardless of lead-in dosage received, with the highest rate of successful dosage increase among patients who received low-dosage clobazam during lead-in. Similarly, rates of successful dose increase were high regardless of lead-in seizure responder category, with the highest rates occurring in patients with the highest (≥75%) lead-in response.

Assessment of treatment patterns and healthcare costs associated with probable Lennox-Gastaut syndrome.

Lennox-Gastaut syndrome (LGS) is a chronic and severe form of epilepsy characterized by intractable seizures, cognitive impairment, and abnormal electroencephalogram findings with slow spike-wave complexes. It typically presents before age 8, but symptoms continue into adulthood and require lifelong treatment associated with significant clinical burden. Data on LGS-associated healthcare utilization and costs are limited. In this study we use a claims-based LGS classifier based on random forest methodology to identify patients with probable LGS from the a Medicaid multi-state database and assess its prevalence across the age spectrum, healthcare utilization, treatment patterns, costs, and comorbid conditions. The classifier identified patients with probable LGS across all ages, with up to 8% of 10-year-old patients with epilepsy identified as having probable LGS. The prevalence of probable LGS was lower in older age cohorts, indicating that it may be under-recognized in older patients. Our analysis showed that probable LGS is associated with considerably higher total healthcare and medical costs than non-LGS patients. The costs were generally consistent between age cohorts, suggesting that the cost burden extends beyond childhood and has a lifelong impact. Analysis of treatment patterns suggest that while the majority of probable LGS patients in this study received widest-spectrum AEDs, a considerable proportion did not and therefore may have been inadequately treated. Further, usage of clobazam and rufinamide was decreased in older compared to younger patient cohorts, indicating that older patient cohorts are less likely to be receiving optimum treatment for LGS. These findings indicate the need for increased clinical attention to LGS beyond pediatric years, with a focus on optimization of treatment for LGS patients of all ages with widest-spectrum AEDs. Timely recognition and adequate treatment of LGS are likely to result in improved outcomes and less costly management of this condition.

Effectiveness of the low-glucose suspend feature of insulin pump during fasting during Ramadan in type 1 diabetes mellitus.

BACKGROUND: Severe hypoglycaemia during the daytime of Ramadan fasting is a highly feared complication. In a prospective study, we investigated the effect of the low-glucose suspend (LGS) algorithm on the frequency of hypoglycaemia in adolescents with T1DM who wished to fast during Ramadan. SUBJECTS AND METHODS: Sixty patients (19 males and 41 females, 15.6 ± 2.7 years, duration of diabetes 5.8 ± 2.9 years, pump therapy for 1.73 ± 0.99 years, used the Paradigm(®) Veo(™) System (Medtronic) and were divided into two groups: first (n=25), those who used the sensor with low-glucose suspend (LGS) feature and second (n = 35), those who used the sensor but turned off low-glucose suspend (LGS) feature. RESULTS: A total of 2716 LGS alerts occurred, and 48.6% began in the afternoon between 4pm and 7pm. The mean duration of LGS events was 26.5 min, 38% lasted for <5 min and 5.3% lasted for 120 min. Among these episodes, the mean sensor glucose was 62.3 ± 5.96 mg/dL at LGS activation, rose to 129.8 ± 11.6 mg/dL by the end of the LGS episode (when insulin delivery was automatically resumed) and was 155.6 ± 11.1 mg/dL at 240 min. LGS usage significantly reduced area under the curve (AUC) <70, AUC <60 mg/dL (p = 0.0001) and >240 mg/dL (p = 0.006). None of the LGS-on group broke their fast versus 15 in the second group (p = 0.001). No episodes of severe hyperglycaemia or DKA were noticed in either groups. CONCLUSIONS: Usage of low-glucose suspend (LGS) significantly reduced exposure to hypoglycaemia without compromising safety. Copyright © 2016 John Wiley & Sons, Ltd.

Human iPSC-derived photoreceptor transplantation in the cone dominant 13-lined ground squirrel.

Several retinal degenerations affect the human central retina, which is primarily comprised of cones and is essential for high acuity and color vision. Transplanting cone photoreceptors is a promising strategy to replace degenerated cones in this region. Although this approach has been investigated in a handful of animal models, commonly used rodent models lack a cone-rich region and larger models can be expensive and inaccessible, impeding the translation of therapies. Here, we transplanted dissociated GFP-expressing photoreceptors from retinal organoids differentiated from human induced pluripotent stem cells into the subretinal space of damaged and undamaged cone-dominant 13-lined ground squirrel eyes. Transplanted cell survival was documented via noninvasive high-resolution imaging and immunohistochemistry to confirm the presence of human donor photoreceptors for up to 4 months posttransplantation. These results demonstrate the utility of a cone-dominant rodent model for advancing the clinical translation of cell replacement therapies.

Therapeutic outcome of patients with Lennox-Gastaut syndrome with mitochondrial respiratory chain complex I deficiency.

Background: Lennox-Gastaut syndrome (LGS), a severe developmental epileptic encephalopathy, has various underlying causes. Mitochondrial respiratory chain complex I (MRC I) deficiency is an important cause of metabolic disorders such as mitochondrial dysfunction that can compromise brain function, thereby causing intractable epilepsy, including LGS. Thus, it can be expected that the presence or absence of MRC I deficiency may affect the treatment outcome of patients with LGS. Objectives: In this retrospective study, we aimed to investigate differences in the epilepsy characteristics and treatment outcomes between patients with LGS with and without MRC I deficiency. Methods: We retrospectively reviewed the medical records of 92 patients with LGS. We divided 68 patients with LGS according to the presence (n = 30) or absence (n = 38) of MRC I deficiency and compared their epilepsy characteristics. Results: Generalized tonic and drop seizures were significantly worse in patients with LGS and MRC I deficiency than in those without MRC I deficiency group at the 1-year follow-up (p < 0.001) and final follow-up 1 (p < 0.001). Patients with LGS and MRC I deficiency had significantly fewer electroencephalogram (EEG) improvements compared to those without MRC I deficiency at the 1-year follow-up (p = 0.031). Additionally, in the final follow-up period, patients with LGS and MRC I deficiency had significantly less improvement in EEG findings compared to patients without MRC I deficiency (p < 0.001). Conclusion: The overall treatment prognosis-in terms of improvement in traumatic generalized tonic seizure, drop seizure, and EEG findings-is worse in patients with LGS and MRC I deficiency than that in patients with LGS but without MRC I deficiency. Additional and targeted treatment is required to treat LGS with MRC I deficiency.

Efficacy and Safety of Vagus Nerve Stimulation in Lennox-Gastaut Syndrome: A Scoping Review.

Lennox-Gastaut syndrome (LGS) is a severe developmental and epileptic encephalopathy characterized by drug-resistant seizures, cognitive impairments, and abnormal electroencephalographic patterns. Vagus nerve stimulation (VNS) is a widely used neuromodulation therapy for LGS, but its effects on seizure outcomes, different seizure types, non-seizure outcomes, and adverse events in this population have not been comprehensively reviewed. To conduct a scoping review on the use of VNS in LGS, a literature search was performed in PubMed, OVID, Web of Science, and Embase from inception to 9 June 2024, using relevant keywords and without restrictions on study design. The search yielded forty eligible studies (twenty-four retrospective cohorts, fourteen prospective cohorts, and two registry analyses) comprising 1400 LGS patients treated with VNS. No randomized controlled trials were identified. Across studies, the median seizure reduction ranged from 20.6% to 65%, with 0% to 100% of patients achieving a ≥50% seizure reduction. No consistent preoperative biomarker of VNS responsiveness was identified in LGS. Although inconsistent among different studies, tonic, atonic, and tonic-clonic seizures responded best, while focal seizures responded worst. Improvements in seizure severity, alertness, and quality of life were reported in some studies, but cognitive and adaptive functioning generally remained unchanged. Adverse events were mostly mild and transient, including hoarseness, cough, and paresthesia. Device-related complications and infections were uncommon. In conclusion, further research is needed to better understand VNS's position in the evolving LGS treatment landscape and its cost effectiveness.

Electroclinical features and long-term outcome of cryptogenic epilepsy in children with Down syndrome.

OBJECTIVE: To describe the electroclinical features and the long-term outcomes of epilepsy in a large cohort of males and females with Down syndrome who developed epilepsy in childhood. STUDY DESIGN: Subjects with Down syndrome and cryptogenic epilepsy with onset in childhood were identified retrospectively from the databases of 16 Italian epilepsy centers over a 40-year period. For each subject, age at onset of seizures, seizure semiology and frequency, electroencephalography characteristics, treatment with antiepileptic drugs, and long-term clinical and electroencephalography outcomes were analyzed. RESULTS: A total of 104 subjects (64 males [61.5%], 40 females [38.5%]) were identified. Seizure onset occurred within 1 year of birth in 54 subjects (51.9%), between 1 and 12 years in 42 subjects (40.4%), and after 12 years in 8 subjects (7.7%). Males had a younger age of seizure onset than females. Of the 104 subjects, 51 (49.0%) had infantile spasms (IS), 35 (33.7%) had partial seizures (PS), and 18 (17.3%) had generalized seizures (GS). Febrile seizures were recorded in 5 (4.8%) subjects. Intractable seizures were observed in 23 (22.1%) subjects, including 5 (9.8%) with IS, 8 (44.4%) with PS, and 10 (31.3%) with GS. CONCLUSION: Cryptogenic epilepsy in Down syndrome may develop during the first year of life in the form of IS or, successively, as PS or GS. Electroclinical features of IS resemble those of idiopathic West syndrome, with a favorable response to treatment with adrenocorticotropic hormone seen. Patients experiencing PS and GS may be resistant to therapy with antiepileptic drugs.

Determinants of intelligence in childhood-onset epilepsy: a single-center study.

The purpose of this study was to quantify the intelligence of children with epilepsy and to determine the clinical factors associated with intellectual impairment. The medical records of patients diagnosed with childhood-onset epilepsy at a single tertiary medical center in Korea between 2006 and 2011 were retrospectively reviewed. The Korean Education Development Institute-Wechsler Intelligence Scale for Children or Korean Wechsler Intelligence Scale for adults was used to quantify the level of intelligence. Age at seizure onset, etiology, epilepsy duration, number of seizures in the last year, use of antiepileptic drugs, EEG/MRI findings, and epilepsy classification were recorded. The association between clinical factors and the intelligence was determined using logistic regression. Three hundred and twenty-two patients were included in the analysis. One hundred and seventy-six (54.7%) patients had low intelligence (intelligence quotient [IQ]<80) with 18 (5.6%) defined as borderline mental retardation (IQ 70-79), 47 (14.6%) as mild mental retardation (IQ 60-69), and 111 (34.5%) as moderate-to-severe mental retardation (IQ<60). Epilepsy duration, number of seizures in the last year, and epilepsy classification were significantly associated with low intelligence in multivariate logistic regression (p<0.05). However, when analyzed according to etiology, these factors were not associated with low intelligence in children with idiopathic epilepsy. The most important factors associated with low intelligence in childhood-onset epilepsy are the underlying etiology and, in cryptogenic and symptomatic epilepsy, seizure burden. The results of this study underscore the importance of seizure control to alleviate the harmful impact of epilepsy on cognition.

Real-world data on cannabidiol treatment of various epilepsy subtypes: A retrospective, multicenter study.

OBJECTIVE: Cannabidiol (CBD) is approved for treatment of Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS), and tuberous sclerosis complex (TSC). Several studies suggest antiseizure effects also beyond these three epilepsy syndromes. METHODS: In a retrospective multicenter study, we analyzed the efficacy and tolerability of CBD in patients with epilepsy at 16 epilepsy centers. RESULTS: The study cohort comprised 311 patients with epilepsy with a median age of 11.3 (0-72) years (235 children and adolescents, 76 adults). Therapy with CBD was off-label in 91.3% of cases due to age, epilepsy subtype, lack of adjunct therapy with clobazam, and/or higher dose applied. CBD titration regimens were slower than recommended, with good tolerability of higher doses particularly in children. Of all patients, 36.9% experienced a reduction in seizure frequency of >50%, independent of their epilepsy subtype or clobazam co-medication. The median observation period was 15.8 months. About one third of all patients discontinued therapy within the observation period due to adverse effects or lack of efficacy. Adverse effects were reported frequently (46.9%). SIGNIFICANCE: Our study highlights that CBD has an antiseizure effect comparable to other antiseizure medications with a positive safety profile independent of the epilepsy subtype. Comedication with clobazam was not associated with a better outcome. Higher doses to achieve seizure frequency reduction were safe, particularly in children. These findings call for further trials for an extended approval of CBD for other epilepsy subtypes and for children <2 years of age.