Lennox-Gastaut Research Articles

How Can an Na+ Channel Inhibitor Ameliorate Seizures in Lennox-Gastaut Syndrome?

Lennox-Gastaut syndrome (LGS) is an epileptic encephalopathy frequently associated with multiple types of seizures. The classical Na+ channel inhibitors are in general ineffective against the seizures in LGS. Rufinamide is a new Na+ channel inhibitor, but approved for the treatment of LGS. This is not consistent with a choice of antiseizure drugs (ASDs) according to simplistic categorical grouping. The effect of rufinamide on the Na+ channel, cellular discharges, and seizure behaviors was quantitatively characterized in native neurons and mammalian models of epilepsy, and compared with the other Na+ channel inhibitors. With a much faster binding rate to the inactivated Na+ channel than phenytoin, rufinamide is distinctively effective if the seizure discharges chiefly involve short bursts interspersed with hyperpolarized interburst intervals, exemplified by spike and wave discharges (SWDs) on electroencephalograms. Consistently, rufinamide, but not phenytoin, suppresses SWD-associated seizures in pentylenetetrazol or AY-9944 models, which recapitulate the major electrophysiological and behavioral manifestations in typical and atypical absence seizures, including LGS. Na+ channel inhibitors shall have sufficiently fast binding to exert an action during the short bursts and then suppress SWDs, in which cases rufinamide is superior. For the epileptiform discharges where the interburst intervals are not so hyperpolarized, phenytoin could be better because of the higher affinity. Na+ channel inhibitors with different binding kinetics and affinity to the inactivated channels may have different antiseizure scope. A rational choice of ASDs according to in-depth molecular pharmacology and the attributes of ictal discharges is advisable. ANN NEUROL 2021;89:1099-1113.

Seizures in Sotos syndrome: Phenotyping in 49 patients.

We aimed to describe the phenotypic spectrum of seizures in Sotos syndrome, a genetic condition involving overgrowth, macrocephaly, dysmorphic features, and learning disability, in which 60%‐90% have NSD1 pathogenic variants. Patients were recruited from clinics and referral from support groups. Those with seizures and a clinical diagnosis of Sotos syndrome were included. Phenotyping data were collected via structured clinical interview and chart review. Forty‐nine patients were included. Twenty had NSD1 testing results available; of these, 15 (75%) had NSD1 pathogenic variants. Seizure onset age ranged from 3 months to 12 years. Staring spells (absence or focal impaired awareness seizure) were the most frequently reported semiology (33/49; 67%), followed by febrile seizures (25/49; 51%) and afebrile bilateral tonic‐clonic seizures (25/49; 51%). Most patients (33/49; 67%) had multiple seizure types. The majority (33/49; 67%) had seizures controlled on a single antiseizure medication or no medication. Nine (18%) had drug‐resistant epilepsy. Epilepsy syndromes included febrile seizures plus, Lennox‐Gastaut syndrome, childhood absence epilepsy, and generalized tonic‐clonic seizures alone. The seizure phenotype in Sotos syndrome most commonly involves staring spells, afebrile tonic‐clonic seizures or febrile convulsions; however, other seizure types may occur. Seizures are typically well‐controlled with medication, but drug‐resistant epilepsy occurs in a minority.

Anti-seizure medications for Lennox-Gastaut syndrome.

Anti-seizure medications for Lennox-Gastaut syndrome.

Long-term epilepsy control, motor function, cognition, sleep and quality of life in children with West syndrome

PurposeTo assess epilepsy, motor function, cognitive, sleep, and quality of life outcomes and their predictors in a follow-up cohort with West syndrome (WS) at ≥5 years of age. MethodsCross-sectional evaluation in a follow-up cohort of WS (aged 5–14 years), between July 2018 and December 2019, was performed at a tertiary-care referral center in Northern India. 164 children were assessed in-person for epilepsy severity, functional status (gross motor and hand function), social quotient, behavioral comorbidities, sleep problems, and quality of life (QoL) using Early Childhood Epilepsy Severity Scale, Gross Motor Function Classification System, Manual Ability Classification System, Vineland Social Maturity Scale, Diagnostic and Statistical Manual of Mental disorders-5 criteria, Children’s Sleep Habits Questionnaire, and PedsQL-Epilepsy module respectively. Furthermore, 238 children with the inability to visit the hospital were assessed through telephonic interview along with retrospective case record review for epilepsy control, gross and fine motor measures. Results402 children with WS (75 % boys) with regular follow-up were studied and the majority (80 %) had underlying structural etiology. The median age (interquartile range) of the cohort was 92 (78–107) months. Of these, 60 % had evolved to Lennox-Gastaut syndrome (LGS). The following long-term outcomes were observed: ongoing epilepsy (261/402), unfavorable motor status (130/402), moderate to profound intellectual disability (111/164), autistic spectrum disorder (42/164), attention-deficit hyperactivity disorder (18/164), poor sleep (135/164), and impaired QoL (115/164). Non-structural etiology (odds ratio [OR] = 3.8, 95 % confidence interval [CI]: 2.1−5.5, p=<0·0001) and older age (>5 months) at the onset of epileptic spasms (OR = 2·9, 95 % CI: 1.5−5.0, p=<0·0001) were associated with enduring seizure freedom for more than two years. ConclusionThe present study revealed a preponderance of structural etiology and a high rate of transition to LGS. Early age at onset of spasms (before five months) and structural etiology were the predictors of unfavorable long-term epilepsy outcome. QoL was impaired in more than two-thirds of patients and it correlated significantly with cognitive, sleep, motor, and behavioral outcomes. However, the results of our study should be interpreted in the context of significant attrition of the original cohort.

Closed-loop vagal nerve stimulation for intractable epilepsy: A single-center experience

PurposeA new class of heart-rate sensing, closed-loop vagal nerve stimulator (VNS) devices for refractory epilepsy may improve seizure control by using pre-ictal autonomic changes as an indicator for stimulation. We compared our experience with closed- versus open-loop stimulator implantation at a single institution. MethodsWe conducted a retrospective chart review of consecutive VNS implantations performed from 2004 to 2018. Bivariate and multivariable analyses were performed to compare changes in seizure frequency and clinical outcomes (Engel score) with closed- versus open-loop devices. Covariates included age, duration of seizure history, prior epilepsy surgery, depression, Lennox Gastaut Syndrome (LGS), tonic seizures, multiple seizure types, genetic etiology, and VNS settings. We examined early (9-month) and late (24-month) outcomes. ResultsSeventy subjects received open-loop devices, and thirty-one received closed-loop devices. At a median of 8.5 months, there was a greater reduction of seizure frequency after use of closed-loop devices (median 75% [IQR 10–89%]) versus open-loop (50% [0–78%], p < 0.05), confirmed in multivariable analysis (odds ratio 2.72 [95% CI 1.02 – 7.4]). Similarly, Engel outcomes were better after closed-loop compared to open-loop confirmed in the multivariable analysis at the early timepoint (OR 0.26 [95% CI 0.09 – 0.69]). These differences did not persist at a median of 24.5 months. ConclusionsThis retrospective single-center study suggests the use of closed-loop VNS devices is associated with greater seizure reduction and more favorable clinical outcomes than open-loop devices at 9-months though not at 24-months. Expansion of this study to other centers is warranted to increase the generalizability of our study.

Brain cooling reduces the risk of postneonatal epilepsy in newborns affected by moderate to severe hypoxic-ischemic encephalopathy.

BACKGROUND Neonatal hypoxic-ischemic encephalopathy is still a significant cause of neonatal death and neurodevelopmental disabilities, such as cerebral palsy, mental delay, and epilepsy. After the introduction of therapeutic hypothermia, the prognosis of hypoxic-ischemic encephalopathy has improved, with reduction of death and disabilities. However, few studies evaluated whether hypothermia affects rate and severity of postneonatal epilepsy. We evaluated rates, characteristics and prognostic markers of postneonatal epilepsy in infants with moderate to severe hypoxic-ischemic encephalopathy treated or not with therapeutic hypothermia. METHODS We analyzed clinical data, EEG recordings, cerebral Magnetic Resonance Imaging (MRI) and outcome in 23 cooled and 26 non-cooled asphyxiated neonates (≥36 weeks' gestation), admitted from 2004 to 2012. RESULTS Among 49 neonates 11 (22%) had postneonatal epilepsy, of which 9 (18%) were non-cooled and 2 (4%) were cooled (P=0.05). Six of 11 infants (55%) had West syndrome, 4 (36%) had focal epilepsy and 1 (9%) had Lennox-Gastaut Syndrome. At multiple logistic regression analysis MRI pattern significantly correlated with postneonatal epilepsy (OR 0.19, 95% CI 0.04-0.88, P=0.03). Extensive lesions in basal ganglia and thalami plus cortical and white matter were associated with postneonatal epilepsy. CONCLUSIONS Only perinatal asphyxia with extensive lesions in basal ganglia and thalami plus cortical and white matter lesion conveys a high risk for early and severe postneonatal epilepsy. Moreover, therapeutic hypothermia is associated with a decrease of the risk of developing postneonatal epilepsy.

CLB add-on treatment in patients with epileptic encephalopathy: a single center experience with long-term follow-up

Clobazam (CLB) is an effective anticonvulsant used as an adjunctive treatment for several seizures and epilepsy syndromes. Data are limited on efficacy and safety of CLB as add-on therapy for epileptic encephalopaties (EEs) other than Lennox-Gastaut syndrome (LGS). This retrospective study aimed to assess efficacy and safety of long-term CLB add-on therapy for various EE syndromes. Data on CLB add-on therapy were assessed in 74 children (60.8% male) after 3months (early) and 12months (late) follow-up as well as in 57 (77%) patients who had been on CLB therapy longer than 12months (mean:39.11 ± 30.29; range:12-129months) (very late) were reported.Data on CLB add-on therapy were assessed in 74 children (60.8% male) after 3months (early) and 12months (late) follow-up as well as in 57 (77%) patients who had been on CLB therapy longer than 12months (mean:39.11 ± 30.29; range:12-129months) (very late) were reported. Good response rate (> 50%) for seizures was achieved in 24% at early follow-up, 30% at late follow-up, and 35% during very late follow-up. Complete seizure remission was achieved for 15% seizures; 72.7% occurred at very late follow-up. Myoclonic seizures were the most responsive (35%); this response increased during late follow-up (46%), whereas 27.3% of myoclonic-atonic/atonic seizures had good response at early and very late follow-up. At late follow-up, comparison of mean effective doses of CLB did not show significant difference among types of seizures with good response. Adverse effects reported in 15% of patients did not require stopping CLB therapy. Generalized epileptogenic potentials significantly decreased while focal epileptogenic potentials significantly increased at first year of treatment in comparison to basal EEG findings (p < 0.001). CLB should be considered as an optional antiepileptic that is well tolerated, particularly in EEs with myoclonic and myoclonic-atonic/atonic seizures.

Evolution of Infantile Spasms to Lennox-Gastaut Syndrome: What Is There to Know?

Children with infantile spasms may develop Lennox-Gastaut syndrome. The diagnostic criteria for Lennox-Gastaut syndrome are vague, and many experts use varying combinations of the following criteria for diagnosis: paroxysmal fast activity on electroencephalography (EEG), slow spike and wave on EEG, developmental delay, multiple seizure types, and nocturnal tonic seizures. Our objective was to determine the prevalence of Lennox-Gastaut syndrome in a high-risk cohort of children with a history of infantile spasms and the characteristics of infantile spasms that were associated with the diagnosis of Lennox-Gastaut syndrome. Children with infantile spasms who were diagnosed and treated at Children's Hospital Colorado between 2012 and 2018 were included. Lennox-Gastaut syndrome was defined as having 3 of 5 of the following characteristics: paroxysmal fast activity, slow spike and wave, current developmental delay, multiple seizure types, or tonic seizures. Descriptive statistics were performed using median and interquartile range. Univariable analysis was performed with Pearson chi-square, Fisher exact, or the Kruskal-Wallis test. Ninety-seven children met inclusion criteria, and 36% (35/97) met criteria for Lennox-Gastaut syndrome. Developmental delay and history of seizures prior to the onset of infantile spasms were identified as risk factors for the development of Lennox-Gastaut syndrome (P = .003) as was poor response to first treatment for spasms (P = .004). Children with an unknown etiology of infantile spasms were less likely to develop Lennox-Gastaut syndrome (P = .019). Eighty percent (28/35) of the children who met Lennox-Gastaut syndrome criteria lacked a documented diagnosis. Thirty-six percent of children with infantile spasms met criteria for Lennox-Gastaut syndrome. Risk factors for development of Lennox-Gastaut syndrome were developmental delay and seizures prior to the onset of infantile spasms and poor response to first treatment for infantile spasms. Children with an unknown etiology of infantile spasms were less likely to develop Lennox-Gastaut syndrome. Eighty percent of the children who met our criteria were not given a documented diagnosis of Lennox-Gastaut syndrome, which highlights the fact that many children may not be receiving a diagnosis of Lennox-Gastaut syndrome. We recommend establishing clear guidelines for the diagnosis of Lennox-Gastaut syndrome to ensure that the diagnosis is being made accurately.

Transition from pediatric to adult care in a Japanese cohort of childhood-onset epilepsy: prevalence of epileptic syndromes and complexity in the transition

AimWe retrospectively examined patients with childhood-onset epilepsy who transitioned from pediatric to adult care to reveal the clinical characteristics and evaluate the complexity of transitioning. MethodsThe subjects were 220 patients (89 males, 131 females) who had been treated at our pediatric epilepsy clinic and had transferred to adult care between 2014 and 2018 without attending a transition clinic or program. The demographic data of the patients were retrospectively analyzed. ResultsThe ages at transition ranged from 15 to 54 years (median: 27 years old). There were 91 patients with focal epilepsies (FEs) and 129 patients with generalized epilepsies [genetic generalized epilepsy (GGE) n = 30, generalized epilepsy of various etiologies (GEv) n = 99]. A most frequent epileptic syndrome was temporal lobe epilepsy followed by frontal lobe epilepsy in FEs, GTCS only followed by juvenile myoclonic epilepsy in GGE and Lennox-Gastaut syndrome followed by Dravet syndrome in GEv. At the age of transition, a total of 77 of the 96 patients with developmental and epileptic encephalopathies (DEE) had pharmacoresistant seizures, which was positively correlated with a late transition age (P≤0.05). More than monthly seizures and greater than moderate disabilities were noted in 45% and 55% of the patients, respectively. ConclusionThe patients with childhood-onset epilepsy transitioned to adult care from the hospital-based pediatric epilepsy clinic were characterized by generalized>focal epilepsy, a frequent complication of DEE, more than monthly seizures, and worse than moderate intellectual disabilities. The complication of DEE made a smooth transition difficult and delayed the transition age.

Phenotypic Spectrum of Seizure Disorders in MBD5-Associated Neurodevelopmental Disorder.

ObjectiveTo describe the phenotypic spectrum in patients with MBD5-associated neurodevelopmental disorder (MAND) and seizures; features of MAND include intellectual disability, epilepsy, psychiatric features of aggression and hyperactivity, and dysmorphic features including short stature and microcephaly, sleep disturbance, and ataxia.MethodsWe performed phenotyping on patients with MBD5 deletions, duplications, or point mutations and a history of seizures.ResultsTwenty-three patients with MAND and seizures were included. Median seizure onset age was 2.9 years (range 3 days–13 years). The most common seizure type was generalized tonic-clonic; focal, atypical absence, tonic, drop attacks, and myoclonic seizures occurred frequently. Seven children had convulsive status epilepticus and 3 nonconvulsive status epilepticus. Fever, viral illnesses, and hot weather provoked seizures. EEG studies in 17/21 patients were abnormal, typically showing slow generalized spike-wave and background slowing. Nine had drug-resistant epilepsy, although 3 eventually became seizure-free. All but one had moderate-to-severe developmental impairment. Epilepsy syndromes included Lennox-Gastaut syndrome, myoclonic-atonic epilepsy, and infantile spasms syndrome. Behavioral problems in 20/23 included aggression, self-injurious behavior, and sleep disturbance.ConclusionsMBD5 disruption may be associated with severe early childhood-onset developmental and epileptic encephalopathy. Because neuropsychiatric dysfunction is common and severe, it should be an important focus of clinical management.

Electro-clinical features in epileptic children with chromosome 15q duplication syndrome

ObjectiveWe aimed to describe epilepsy and EEG patterns related to vigilance states and age, in chromosome15-long-arm-duplication-syndrome (dup15q) children with epilepsy, in both duplication types: interstitial (intdup15) and isodicentric (idic15). MethodsClinical data and 70 EEGs of 12 patients (5 intdup15, 7 idic15), followed from 4.5 m.o to 17y4m (median follow-up 8y3m), were retrospectively reviewed. EEGs were analyzed visually and using power spectrum analysis. ResultsSeventy video-EEGs were analyzed (1–16 per patient, median 6), follow-up lasting up to 8y10m (median 4y2m): 25 EEGs in intdup15 (8 m.o to 12y.o, median 4y6m) and 45 EEGs in idic15 (7 m.o to 12 y.o, median 15 m). Epilepsy: 6 West syndrome (WS) (2intdup15, 4idic15); 4 Lennox-Gastaut syndromes (LGS) (1 intdup15, 3 idic15), 2 evolving from WS; focal epilepsy (3 intdup15). In idic15, WS displayed additional myoclonic seizures (3), atypical (4) or no hypsarrhythmia (2) and posterior predominant spike and polyspike bursts (4). Beta-band rapid-rhythms (RR): present in 11 patients, power decreased during non-REM-sleep, localization shifted from diffuse to anterior, peak frequency increased with age. ConclusionWS with peculiar electro-clinical features and LGS, along with beta-band RR decreasing in non-REM-sleep and shifting from diffuse to anterior localization with age are recognizable features pointing towards dup15q diagnosis in children with autism spectrum disorder and developmental delay. SignificanceThis study describes electroclinical features in both interstitial and isodicentric duplications of chromosome 15q, in epileptic children, including some recent extensions regarding sleep features; and illustrates how the temporo-spatial organization of beta oscillations can be of significant help in directing towards dup15q diagnosis hypothesis.

Consciousness among delta waves: a paradox?

A common observation in EEG research is that consciousness vanishes with the appearance of delta (1-4 Hz) waves, particularly when those waves are high amplitude. High amplitude delta oscillations are frequently observed in states of diminished consciousness, including slow wave sleep, anaesthesia, generalized epileptic seizures, and disorders of consciousness, such as coma and the vegetative state. This strong correlation between loss of consciousness and high amplitude delta oscillations is thought to stem from the widespread cortical deactivation that occurs during the 'down states' or troughs of these slow oscillations. Recently, however, many studies have reported the presence of prominent delta activity during conscious states, which casts doubt on the hypothesis that high amplitude delta oscillations are an indicator of unconsciousness. These studies include work in Angelman syndrome, epilepsy, behavioural responsiveness during propofol anaesthesia, postoperative delirium, and states of dissociation from the environment such as dreaming and powerful psychedelic states. The foregoing studies complement an older, yet largely unacknowledged, body of literature that has documented awake, conscious patients with high amplitude delta oscillations in clinical reports from Rett syndrome, Lennox-Gastaut syndrome, schizophrenia, mitochondrial diseases, hepatic encephalopathy, and non-convulsive status epilepticus. At the same time, a largely parallel body of recent work has reported convincing evidence that the complexity or entropy of EEG and magnetoencephalographic signals strongly relates to an individual's level of consciousness. Having reviewed this literature, we discuss plausible mechanisms that would resolve the seeming contradiction between high amplitude delta oscillations and consciousness. We also consider implications concerning theories of consciousness, such as integrated information theory and the entropic brain hypothesis. Finally, we conclude that false inferences of unconscious states can be best avoided by examining measures of electrophysiological complexity in addition to spectral power.

Automatic detection of generalized paroxysmal fast activity in interictal EEG using time-frequency analysis

ObjectiveMarkup of generalized interictal epileptiform discharges (IEDs) on EEG is an important step in the diagnosis and characterization of epilepsy. However, manual EEG markup is a time-consuming, subjective, and the specialized task where the human reviewer needs to visually inspect a large amount of data to facilitate accurate clinical decisions. In this study, we aimed to develop a framework for automated detection of generalized paroxysmal fast activity (GPFA), a generalized IED seen in scalp EEG recordings of patients with the severe epilepsy of Lennox-Gastaut syndrome (LGS). MethodsWe studied 13 children with LGS who had GPFA events in their interictal EEG recordings. Time-frequency information derived from manually marked IEDs across multiple EEG channels was used to automatically detect similar events in each patient's interictal EEG. We validated true positives and false positives of the proposed spike detection approach using both standalone scalp EEG and simultaneous EEG-functional MRI (EEG-fMRI) recordings. ResultsGPFA events displayed a consistent low-high frequency arrangement in the time-frequency domain. This ‘bimodal’ spectral feature was most prominent over frontal EEG channels. Our automatic detection approach using this feature identified EEG events with similar time-frequency properties to the manually marked GPFAs. Brain maps of EEG-fMRI signal change during these automatically detected IEDs were comparable to the EEG-fMRI brain maps derived from manual IED markup. ConclusionGPFA events have a characteristic bimodal time-frequency feature that can be automatically detected from scalp EEG recordings in patients with LGS. The validity of this time-frequency feature is demonstrated by EEG-fMRI analysis of automatically detected events, which recapitulates the brain maps we have previously shown to underlie generalized IEDs in LGS. SignificanceThis study provides a novel methodology that enables a fast, automated, and objective inspection of generalized IEDs in LGS. The proposed framework may be extendable to a wider range of epilepsy syndromes in which monitoring the burden of epileptic activity can aid clinical decision-making and faster assessment of treatment response and estimation of future seizure risk.

Cannabidiol in Pharmacoresistant Epilepsy: Clinical Pharmacokinetic Data From an Expanded Access Program.

Background and Aim: Data on the clinical pharmacokinetics of cannabidiol (CBD) are scanty. We explored the effect of demographic and clinical variables on plasma concentrations of purified CBD in patients with Dravet (DS) and Lennox–Gastaut syndrome (LGS). Methods: The study design was an open, prospective, multicenter expanded access program (EAP). Venous blood samples were drawn from patients between 8 and 9 am, before the CBD morning dose, 12 h apart from the last evening dose, and then 2.5 h after their usual morning dose. Results: We collected 127 plasma samples (67-morning pre-dosing and 60 post-dosing) from 43 patients (24 females, 19 males), 27 with LGS and 16 with DS. Mean ± standard deviation age was 26 ± 15 years. Duration of CBD treatment averaged 4.2 ± 2.9 months at 13.2 ± 4.6 mg/kg/day. CBD median trough plasma concentration was 91 ng/ml; it doubled to 190 ng/ml 2.5 h post-dosing (p < 0.001). Cannabidiol trough plasma concentrations were linearly related to daily doses (r = 0.564, p < 0.001). Median trough CBD plasma concentration-to-weight-adjusted dose ratio (C/D) was 32% higher (p < 0.02) in plasma samples from subjects aged 18 and over than in those under 18. Sex and concomitant antiseizure medications (ASMs) were not associated with significant variations in CBD C/D, but caution is required due to the potential influence of confounders. Conclusion: These are the first data on CBD pharmacokinetics in children and adults with LGS or DS in a real-world setting. The most relevant finding was the higher CBD C/D in adults. In practice, reduced weight-normalized doses might be required with aging to achieve the same CBD plasma levels.

The role of new medical treatments for the management of developmental and epileptic encephalopathies: Novel concepts and results.

Developmental and epileptic encephalopathies (DEEs) are among the most challenging of all epilepsies to manage, given the exceedingly frequent and often severe seizure types, pharmacoresistance to conventional antiseizure medications, and numerous comorbidities. During the past decade, efforts have focused on development of new treatment options for DEEs, with several recently approved in the United States or Europe, including cannabidiol as an orphan drug in Dravet and Lennox-Gastaut syndromes and everolimus as a possible antiepileptogenic and precision drug for tuberous sclerosis complex, with its impact on the mammalian target of rapamycin pathway. Furthermore, fenfluramine, an old drug, was repurposed as a novel therapy in the treatment of Dravet syndrome. The evolution of new insights into pathophysiological processes of various DEEs provides possibilities to investigate novel and repurposed drugs and to place them into the context of their role in future management of these patients. The purpose of this review is to provide an overview of these new medical treatment options for the DEEs and to discuss the clinical implications of these results for improved treatment.

The role of surgery in the management of Lennox-Gastaut syndrome: A systematic review and meta-analysis of the clinical evidence.

Lennox-Gastaut syndrome (LGS) is a severe form of childhood onset epilepsy in which patients require multiple medications and may be candidates for palliative surgical intervention. In this meta-analysis, we sought to evaluate the impact of palliative vagus nerve stimulation (VNS), corpus callosotomy (CC), and resective surgery (RS) by analyzing their impact on seizure control, antiepileptic drug (AED) usage, quality of life (QOL), behavior, cognition, prognostic factors, and complications. A systematic search of PubMed MEDLINE, Scopus, and Cochrane Database of Systematic Reviews was performed to find articles that met the following criteria: (1) prospective/retrospective study with original data, (2) at least one LGS surgery patient aged less than 18 years, and (3) information on seizure frequency reduction (measured as percentage, Engel class, or qualitative comment). Seizures were analyzed quantitatively in a meta-analysis of proportions and a random-effects model, whereas other outcomes were analyzed qualitatively. Forty studies with 892 LGS patients met the selection criteria, with 19 reporting on CC, 17 on VNS, four on RS, two on RS + CC, one on CC + VNS, and one on deep brain stimulation. CC seizure reduction rate was 74.1% (95% confidence interval [CI] = 64.5%-83.7%), and VNS was 54.6% (95% CI = 42.9%-66.3%), which was significantly different (p<.001). RS seizure reduction was 88.9% (95% CI = 66.1%-99.7%). Many VNS patients reported alertness improvements, and most had no major complications. VNS was most effective for atonic/tonic seizures; higher stimulation settings correlated with better outcomes. CC patients reported moderate cognitive and QOL improvements; disconnection syndrome, transient weakness, and respiratory complications were noted. Greater callosotomy extent correlated with better outcomes. AED usage most often did not change after surgery. RS showed considerable QOL improvements for patients with localized seizure foci. In the reported literature, CC appeared to be more effective than VNS for seizure reduction. VNS may provide a similar or higher level of QOL improvement with lower aggregate risk of complications. Patient selection, anatomy, and seizure type will inform decision-making.

Is sulthiame effective and tolerated as add-on therapy for infants with epilepsy? A Cochrane Review summary with commentary.

Is sulthiame effective and tolerated as add-on therapy for infants with epilepsy? A Cochrane Review summary with commentary.

The efficacy and tolerability of auto-stimulation-VNS in children with Lennox-Gastaut syndrome

ObjectiveLennox-Gastaut syndrome (LGS) is a severe drug-resistant epilepsy (DRE) of childhood. The Vagus Nerve Stimulator (VNS) is established as a safe and effective treatment for DRE. This study assesses efficacy and tolerability of the auto-stimulation VNS models in pediatric patients with LGS. MethodsThis is a retrospective chart review of a cohort of pediatric patients (Age 1–18 years old) with LGS implanted with an auto-stimulation VNS model at a single level four pediatric epilepsy center. Patient responder’s rate was measured as seizure reduction over baseline and improvements in five quality-of-life measures as reported by the patients and families. Efficacy and tolerability were assessed at 1, 3, 6, 12, 18 and 24 months compared to baseline. ResultsThis cohort includes 71 consecutive children with Lennox-Gastaut syndrome who underwent implantation with one of two models of the auto-stimulation VNS. The average age of the children at implantation was 20.82 months. Of those patients, 55 % of patients achieved greater than 50 % seizure reduction at six months, 67.7 % at 12 months, and 65 % at 24 months. At 12 months 11 % of the patients were completely seizure free and at 24 months 17 % were seizure free. By 24 months post implantation most of the patient families reported at least a 50 % improvement rate in one or more of the quality-of-life measures. The most commonly reported adverse events were dysphonia, paresthesia, and shortness of breath, all of which were tolerated and subsided by 24 months. SignificanceThis study provides evidence that VNS models with the auto-stimulation paradigm based on detection of tachycardia are well tolerated and effective in a pediatric population with LGS. Furthermore, this study shows that for this population, the auto-stimulation models of the VNS may provide additional benefits over the earlier VNS versions.

The unchanging face of Lennox-Gastaut syndrome in adulthood

PurposeLennox-Gastaut syndrome (LGS) is a severe childhood-onset epileptic encephalopathy characterized by the presence of multiple types of intractable seizures, cognitive impairment, and specific electroencephalogram (EEG) patterns. The aim of this study was to investigate the electroclinical features of patients with LGS during adulthood. MethodsWe retrospectively identified the medical records of 20 patients aged over 18 years with a diagnosis of LGS from 3896 patients with epilepsy. ResultsThirteen (65 %) patients were male. The mean age of the patients was 23.4 ± 7.1 (min-max; 18–43) years, and the mean follow-up period was 5.6 ± 4.5 (min-max; 1–14) years. The etiology was identified in 11 (55 %) patients. None of the patients achieved seizure freedom. The most prevalent seizure types were atypical absences in 14 (70 %) patients, tonic seizures in 13 (65 %) patients, and atonic seizures in 11 (55 %) patients. One (5 %) patient was diagnosed as having psychogenic non-epileptic seizures. Mental retardation was reported in all patients and only half of them could walk independently. All patients had drug-resistant seizures and 16 (80 %) patients were on polytherapy. A vagus nerve stimulator was implanted into ten (50 %) patients and five reported 50–80 % seizure reduction. Ketogenic diet was administered to two (10 %) patients and epilepsy surgery was performed in two (10 %) patients with no significant benefit. ConclusionsPaying attention to all factors of seizure outcomes, cognitive impairment, and ambulatory status, all patients were dependent on caregivers for daily living abilities. LGS has life-long persistence with poor outcomes, even during adulthood.

From an Alternative Medicine to a New Treatment for Refractory Epilepsies: Can Cannabidiol Follow the Same Path to Treat Neuropsychiatric Disorders?

Although cannabis has been known for ages as an “alternative medicine” to provide relief from seizures, pain, anxiety, and inflammation, there had always been a limited scientific review to prove and establish its use in clinics. Early studies carried out by Carlini's group in Brazil suggested that cannabidiol (CBD), a non-psychotropic phytocannabinoid present in Cannabis sativa, has anticonvulsant properties in animal models and reduced seizure frequency in limited human trials. Over the past few years, the potential use of cannabis extract in refractory epilepsy, including childhood epilepsies such as Dravet's syndrome and Lennox-Gastaut Syndrome, has opened a new era of treating epileptic patients. Thus, a considerable number of pre-clinical and clinical studies have provided strong evidence that phytocannabinoids has anticonvulsant properties, as well as being promising in the treatment of different neuropsychiatric disorders, such as depression, anxiety, post-traumatic stress disorder (PTSD), addiction, neurodegenerative disorders and autism spectrum disorder (ASD). Given the advances of cannabinoids, especially CBD, in the treatment of epilepsy, would the same expectation regarding the treatment of other neuropsychiatric disorders be possible? The present review highlights some contributions from Brazilian researchers and other studies reported elsewhere on the history, pre-clinical and clinical data underlying the use of cannabinoids for the already widespread treatment of refractory epilepsies and the possibility of use in the treatment of some neuropsychiatric disorders.