Predictors of genetic diagnosis in individuals with developmental and epileptic encephalopathies.

OBJECTIVE: To evaluate the clinical predictors of positive genetic investigation in developmental and epileptic encephalopathies, beyond the influence of Dravet Syndrome. METHODS: The study included 98 patients diagnosed with developmental and epileptic encephalopathies. The patients underwent Sanger sequencing of SCN1A, Chromosomal Microarray Analysis, and Whole Exome Sequencing. The association of clinical variables with a positive genetic test was investigated using univariate and multivariate analysis. RESULTS: Genetic diagnosis was identified in 47 (48 %) patients with developmental and epileptic encephalopathies. Beyond Dravet Syndrome influence, first seizure in the context of fever (p < 0.01), seizures precipitated by temperature (p = 0.04), cognitive regression (p = 0.04), hypotonia (p < 0.01), and focal seizures (p = 0.03) increased the chances of a positive genetic investigation. In contrast, atonic seizures (p = 0.01) and generalized discharges on electroencephalogram (p = 0.02) decreased the chances. Dravet Syndrome was positively associated with a genetic developmental and epileptic encephalopathies etiology (p < 0.01), whereas epilepsy with myoclonic-atonic seizures (p = 0.01), developmental and epileptic encephalopathies with spike-wave activation in sleep (p = 0.04), and Lennox-Gastaut syndrome (p = 0.03) were negatively associated. In multivariate analysis, the first seizure in the context of fever (p < 0.01) and hypotonia (p = 0.02) were positively, and atonic seizures (p = 0.01) were negatively and independently associated with a genetic etiology. CONCLUSION: The predictive variables of genetic investigation in developmental and epileptic encephalopathies are first seizure in the context of fever and hypotonia, whereas atonic seizures decrease the chances of finding a genetic cause for developmental and epileptic encephalopathies. Regarding epileptic syndromes, Dravet Syndrome is highly associated with a positive genetic test, whereas epilepsy with myoclonic-atonic seizures, developmental and epileptic encephalopathies with spike-wave activation in sleep, and Lennox-Gastaut syndrome are rarely associated with a positive genetic investigation.

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.

Efficacy analysis of oral dexamethasone in the treatment of infantile spasms and infantile spasms related Lennox-Gastaut syndrome.

OBJECTIVE: Treatment with adrenocorticotropic hormone (ACTH) or a corticosteroid is the first choice for infantile spasms (IS), and vigabatrin is the first choice for children with tuberous sclerosis. Although corticosteroids may be also effective against IS and IS-related Lennox-Gastaut syndrome (LGS), the use of dexamethasone (DEX), a kind of corticosteroid, for these diseases has been rarely reported. This retrospective study aimed to evaluate the efficacy and tolerability of DEX for the treatment of IS and IS-related LGS. METHODS: Patients diagnosed as having IS (including patients whose condition evolved to LGS after the failure of early treatment) in our hospital between May 2009 and June 2019 were treated with dexamethasone after failure of prednisone treatment. The oral dose of DEX was 0.15-0.3 mg/kg/d. Thereafter, the clinical efficacy, electroencephalogram (EEG) findings, and adverse effects were observed every 4-12 weeks depending on the individual patient's response. Then, the efficacy and safety of DEX in the treatment of IS and IS-related LGS were retrospectively evaluated. RESULTS: Among 51 patients (35 cases of IS; 16 cases of IS-related LGS), 35 cases (68.63%) were identified as responders to DEX treatment, comprising 20 cases (39.22%) and 15 cases (29.41%) with complete control and obvious control, respectively. To discuss the syndromes individually, complete control and obvious control were achieved in 14/35 and 9/35 IS cases and in 6/16 and 6/16 IS-related LGS cases, respectively. During DEX withdrawal, 11 of the 20 patients with complete control relapsed (9/14 IS; 2/6 LGS). The duration of dexamethasone treatment (including weaning) in most of the 35 responders was less than 1 year. However, 5 patients were treated with prolonged, low-dose maintenance therapy, which continued for more than 1.5 years. These 5 patients showed complete control, and 3 patients had no recurrence. Except for one child who died of recurrent asthma and epileptic status 3 months after stopping DEX, there were no serious or life-threatening adverse effects during DEX treatment. CONCLUSION: Oral DEX is effective and tolerable for IS and IS-related LGS. all LGS patients were evolved from IS in this study. The conclusion may not apply to patients with other etiology and courses of LGS. Even when prednisone or ACTH is failed, DEX may still be considered as a treatment option. For children who respond to DEX but do not show complete control after 6 months of treatment, prolonged treatment with low-dose DEX administered in the morning might be considered.

GABAA Receptor ß3 Subunit Mutation N328D Heterozygous Knock-in Mice Have Lennox-Gastaut Syndrome.

Lennox-Gastaut Syndrome (LGS) is a developmental and epileptic encephalopathy (DEE) characterized by multiple seizure types, electroencephalogram (EEG) patterns, and cognitive decline. Its etiology has a prominent genetic component, including variants in GABRB3 that encodes the GABAA receptor (GABAAR) ß3 subunit. LGS has an unknown pathophysiology, and few animal models are available for studying LGS. The objective of this study was to evaluate Gabrb3+/N328D knock-in mice as a model for LGS. We generated a heterozygous knock-in mouse expressing Gabrb3 (c.A982G, p.N238D), a de novo mutation identified in a patient with LGS. We investigated Gabrb3+/N328D mice for features of LGS. In 2-4-month-old male and female C57BL/J6 wild-type and Gabrb3+/N328D mice, we investigated seizure severity using video-monitored EEG, cognitive impairment using a suite of behavioral tests, and profiled GABAAR subunit expression by Western blot. Gabrb3+/N328D mice showed spontaneous seizures and signs of cognitive impairment, including deficits in spatial learning, memory, and locomotion. Moreover, Gabrb3+/N328D mice showed reduced ß3 subunit expression in the cerebellum, hippocampus, and thalamus. This phenotype of epilepsy and neurological impairment resembles the LGS patient phenotype. We conclude that Gabrb3+/N328D mice provide a good model for investigating the pathophysiology and therapeutic intervention of LGS and DEEs.

Long-term outcome of developmental and epileptic encephalopathies.

Developmental and epileptic encephalopathies are conditions where there is developmental impairment related to both the underlying etiology independent of epileptiform activity and the epileptic encephalopathy. Usually they have multiple etiologies. Therefore, long-term outcome is related to both etiology-related factors and epilepsy-related factors-age at onset of epilepsy, type(s) of seizure(s), type of electroencephalographic abnormalities, duration of the epileptic disorder. This paper focuses on long-term outcome of six developmental and epileptic encephalopathies with onset from the neonatal period to childhood: early epileptic encephalopathy with suppression bursts, West syndrome, Dravet syndrome, Lennox-Gastaut syndrome, epilepsy with myoclonic atonic seizures and epileptic encephalopathy with continuous spike and waves during slow-wave sleep including Landau-Kleffner syndrome. For each syndrome, definition, main etiologies if multiple, and long-term outcome are discussed.

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.

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.

Expert opinion: Proposed diagnostic and treatment algorithms for Lennox-Gastaut syndrome in adult patients.

Lennox-Gastaut syndrome (LGS) is a severe developmental epileptic encephalopathy diagnosed in childhood that persists through adolescence and into adulthood. While the characteristics of LGS in pediatric patients are well defined, including "drop attacks", interictal slow spike and wave electroencephalogram (EEG) activity, and intellectual disability, these features can evolve over time, and different EEG activities may be present in adult patients with LGS. This may result in missed diagnoses in these patients and subsequent challenges for the adequate treatment of their seizures. Based on discussions held during the LGS Transition of Care advisory board meeting and thereafter, we developed proposed diagnostic and treatment algorithms for LGS in adult patients. We highlight readily available assessments to facilitate diagnosis of LGS, based on past medical history and physical examination. The LGS diagnostic algorithm recommends that clinicians consider the occurrence of wider seizure types and abnormal EEG activities to be potentially indicative of LGS. Seizure types may include atypical absence seizures, myoclonic seizures, focal seizures, and tonic-clonic seizures, and EEG may demonstrate background slowing, focal or multifocal epileptiform discharges, and diffuse fast rhythms during sleep, among other activities. Extended EEG during sleep and video-EEG should be used in equivocal cases. Treatment of LGS in adult patients should incorporate both antiseizure drug (ASD) therapy and nonpharmacologic approaches. Frequent reassessment of patients is considered a central aspect. ASDs were categorized based on order of preference for use in the treatment of LGS; Tier 1 comprises recommended first-line ASDs, and includes valproate, clobazam, lamotrigine, rufinamide, topiramate, and cannabidiol. Other treatment options include diet, neurostimulation, and surgical approaches. Developments with the potential to improve diagnosis in the future include genetic screening, while novel ASDs and advances in neurostimulation techniques may provide valuable treatment options. These algorithms should be frequently revisited to incorporate improved techniques and therapies.

EEF1A2 mutations in epileptic encephalopathy/intellectual disability: Understanding the potential mechanism of phenotypic variation.

EEF1A2 encodes protein elongation factor 1-alpha 2, which is involved in Guanosine triphosphate (GTP)-dependent binding of aminoacyl-transfer RNA (tRNA) to the A-site of ribosomes during protein biosynthesis and is highly expressed in the central nervous system. De novo mutations in EEF1A2 have been identified in patients with extensive neurological deficits, including intractable epilepsy, globe developmental delay, and severe intellectual disability. However, the mechanism underlying phenotype variation is unknown. Using next-generation sequencing, we identified a novel and a recurrent de novo mutation, c.294C>A; p.(Phe98Leu) and c.208G>A; p.(Gly70Ser), in patients with Lennox-Gastaut syndrome. The further systematic analysis revealed that all EEF1A2 mutations were associated with epilepsy and intellectual disability, suggesting its critical role in neurodevelopment. Missense mutations with severe molecular alteration in the t-RNA binding sites or GTP hydrolysis domain were associated with early-onset severe epilepsy, indicating that the clinical expression was potentially determined by the location of mutations and alteration of molecular effects. This study highlights the potential genotype-phenotype relationship in EEF1A2 and facilitates the evaluation of the pathogenicity of EEF1A2 mutations in clinical practice.

Nonseizure consequences of Dravet syndrome, KCNQ2-DEE, KCNB1-DEE, Lennox-Gastaut syndrome, ESES: A functional framework.

RATIONALE: Developmental epilepsies and encephalopathies (DEEs) are characterized by many severe developmental impairments, which are not well-described. A functional framework could facilitate understanding of their nature and severity and guide the selection instruments to measure improvements in therapeutic trials. METHODS: An online survey administered through several parent-organized foundations utilized accepted functional classifications and questionnaires derived from common instruments to determine levels of mobility, fine motor, communication, and feeding functions. Statistical analyses focused on overall levels of function and across-group comparisons adjusted for age. RESULTS: From 6/2018 to 2/2020, 252 parents provided information for one or more functional domains. Median age was 7.2 years (interquartile range (IQR): 3.9 to 11.8), and 128 (51%) were females. DEE groups were Dravet syndrome (N = 72), KCNQ2-DEE (N = 80), KCNB1-DEE, (N = 33), Lennox-Gastaut syndrome (LGS; N = 26), electrographic status epilepticus in sleep (ESES; N = 15), and others (N = 26). Overall, functional hand grasp was absent in 48 (20%). Of children ≥2 years old, 60/214 (28%) could not walk independently, 85 (40%) were dependent on someone else for feeding, and 153 (73%) did not effectively communicate with unfamiliar people. Impairments entailing absence or near absence of independent function (profound impairment) were observed in 0, 1, 2, 3, and 4 domains for 58 (25%), 78 (34%), 40 (17%), 33 (14%), and 22 (10%) children, respectively. After adjustment for age, impairment levels varied substantially across DEE group for mobility (p < 0.0001), feeding (p < 0.0001), communication (p < 0.0001), hand grasp (p < 0.0001), and number of profoundly impaired domains (p < 0.0001). Three or four profoundly affected domains were reported in 44% of KCNQ2-DEE participants, followed by LGS (29%), KCNB1-DEE (27%), ESES (7%), and Dravet syndrome (6%). CONCLUSIONS: Many children with DEEs experience severe functional impairments, and few children have typical function. As precision therapies will emphasize nonseizures consequences of DEEs, understanding the nature of abilities and impairments will be critical to selecting appropriate outcome measures in therapeutic trials.

Asymmetric Slow-Spike-Wave Patterns with Maximal Discharges Contralateral to MRI Lesions Predict Better Surgical Prognosis in Symptomatic Lennox-Gastaut Syndrome or Lennox-Gastaut Phenotypes.

INTRODUCTION: Lennox-Gastaut syndrome (LGS) is a severe subtype of childhood-onset epileptic encephalopathy with drug-resistant and poor surgical prognosis. However, electroencephalogram (EEG) patterns of symptomatic LGS or LG phenotypes with structural brain lesions including focal abnormalities or asymmetric slow-spike-wave (SSW) patterns remain largely unknown. Due to the contradictory lateralization difference between MRI lesions and EEG pattern in symptomatic LGS or LG phenotypes, it is difficult to determine the precise lateralization of epileptic lesions, which is crucial to better surgical prognosis. This study is aim to ascertain the clinical characteristics of the EEG patterns, and its relationship with MRI lesions and to evaluate its prognostic value of surgical treatment in symptomatic LGS or LG phenotypes. METHODS: Twenty-four symptomatic LGS cases with asymmetric EEG SSW patterns and contralaterally independent or contralaterally dominant MRI lesions were collected, and their clinical features were analyzed retrospectively. RESULTS: In this cohort, most of lesions were perinatal or acquired during the first 6 months of life. The most common etiology was intracerebral hemorrhage. The LGS patients with both asymmetric SSW and focal sporadic epileptic waves (SEW) patterns showed the best surgical outcome with Engel class I level. Asymmetric SSW patterns with maximal discharges contralateral to MRI lesions were frequently observed in most of symptomatic LGS or LG phenotypes. Predominantly diffuse destructive lesions led to an attenuated voltage of ipsilateral scalp EEG producing an asymmetric SSW pattern in those patients with symptomatic LGS or LG phenotypes. CONCLUSIONS: Our study reveals a special SEW EEG pattern in symptomatic LG patients with asymmetric SSW and MRI lesions contralateral to the dominant EEG patterns. Contradictory lateralization difference between MRI and EEG probably arises from the relative voltage attenuation presenting in EEG ipsilateral to huge destructive lesions from early life. Our study suggests that the independent focal SEW activity remaining ipsilateral to the MRI lesion can potentially predict better surgical prognosis in symptomatic LGS or LG phenotypes.

Personalized medicine: Vinpocetine to reverse effects of GABRB3 mutation.

OBJECTIVE: To screen a library of potential therapeutic compounds for a woman with Lennox-Gastaut syndrome due to a Y302C GABRB3 (c.905A>G) mutation. METHODS: We compared the electrophysiological properties of cells with wild-type or the pathogenic GABRB3 mutation. RESULTS: Among 1320 compounds, multiple candidates enhanced GABRB3 channel conductance in cell models. Vinpocetine, an alkaloid derived from the periwinkle plant with anti-inflammatory properties and the ability to modulate sodium and channel channels, was the lead candidate based on efficacy and safety profile. Vinpocetine was administered as a dietary supplement over 6 months, reaching a dosage of 20 mg three times per day, and resulted in a sustained, dose-dependent reduction in spike-wave discharge frequency on electroencephalograms. Improved language and behavior were reported by family, and improvements in global impression of change surveys were observed by therapists blinded to intervention. SIGNIFICANCE: Vinpocetine has potential efficacy in treating patients with this mutation and possibly other GABRB3 mutations or other forms of epilepsy. Additional studies on pharmacokinetics, potential drug interactions, and safety are needed.

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.

Panayiotopoulos syndrome and Gastaut syndrome are distinct entities in terms of neuropsychological findings.

BACKGROUND: Although the courses of self-limited focal epilepsies of childhood are considered as benign, a handful of studies suggested that these children may suffer from cognitive problems. Implementing tailor-made educational strategies would aid these children to reach their full potentials. Therefore, it is crucial to understand and differentiate the complete neuropsychological and behavioral profiles of these rather common syndromes. We aimed to examine the distinct cognitive and behavioral profiles of the Panayiotopoulos syndrome (PS) and the Gastaut syndrome (GS), comparatively. METHOD: Twenty patients with PS, 20 patients with GS, and 20 healthy controls have been recruited. The testing protocol included Wechsler Intelligence Scale for Children-Revised, Conner's Continuous Performance Test, Verbal Fluency Test, Stroop Color and Word Test, Color Trails Test, Tower of London Test, Symbol Digit Modalities Test, California Verbal Learning Test-Children's Version, Rey Complex Figure Test, Benton Face Recognition Test, Benton Judgment of Line Orientation, Peabody Picture Vocabulary Test, Reading and Writing Test, Child Behavior Checklist, Conner's Parent Rating Scale-48, and Behavior Rating Inventory of Executive Function. Demographical, clinical, electrophysiological data, and imaging findings have also been evaluated. RESULTS: With regard to intelligence, the patients with PS scored less in all scales compared to the healthy controls. However, only the performance IQ (intelligence quotient) scores differed significantly between the patient groups, with the patients with PS scoring lower than the patients with GS. Verbal memory problems were eminent in both of the patient groups; whereas, visual memory was impaired only in the group with PS. Psychomotor speed was affected in both groups. Reading problems were prominent only in the patients with PS. Writing and arithmetic skills were defective in both patient groups. There were no noteworthy behavioral problems in comparison to healthy subjects. CONCLUSION: Using neuropsychological profiles, this study demonstrated that the GS and the PS are two distinct entities. Cognitive dysfunction is a more prominent and widespread feature of the patients with PS; whereas, the patients with GS suffer only from milder and isolated cognitive problems.

Cannabis for the Treatment of Epilepsy: an Update.

PURPOSE OF REVIEW: For millennia, there has been interest in the use of cannabis for the treatment of epilepsy. However, it is only recently that appropriately powered controlled studies have been completed. In this review, we present an update on the research investigating the use of cannabidiol (CBD), a non-psychoactive component of cannabis, in the treatment of epilepsy. RECENT FINDINGS: While the anticonvulsant mechanism of action of CBD has not been entirely elucidated, we discuss the most recent data available including its low affinity for the endocannabinoid receptors and possible indirect modulation of these receptors via blocking the breakdown of anandamide. Additional targets include activation of the transient receptor potential of vanilloid type-1 (TRPV1), antagonist action at GPR55, targeting of abnormal sodium channels, blocking of T-type calcium channels, modulation of adenosine receptors, modulation of voltage-dependent anion selective channel protein (VDAC1), and modulation of tumor necrosis factor alpha release. We also discuss the most recent studies on various artisanal CBD products conducted in patients with epilepsy in the USA and internationally. While a high percentage of patients in these studies reported improvement in seizures, these studies were either retrospective or conducted via survey. Dosage/preparation of CBD was either unknown or not controlled in the majority of these studies. Finally, we present data from both open-label expanded access programs (EAPs) and randomized placebo-controlled trials (RCTs) of a highly purified oral preparation of CBD, which was recently approved by the FDA in the treatment of epilepsy. In the EAPs, there was a significant improvement in seizure frequency seen in a large number of patients with various types of treatment-refractory epilepsy. The RCTs have shown significant seizure reduction compared to placebo in patients with Dravet syndrome and Lennox-Gastaut syndrome. Finally, we describe the available data on adverse effects and drug-drug interactions with highly purified CBD. While this product is overall well tolerated, the most common side effects are diarrhea and sedation, with sedation being much more common in patients taking concomitant clobazam. There was also an increased incidence of aspartate aminotransferase and alanine aminotransferase elevations while taking CBD, with many of the patients with these abnormalities also taking concomitant valproate. CBD has a clear interaction with clobazam, significantly increasing the levels of its active metabolite N-desmethylclobazam in several studies; this is felt to be due to CBD's inhibition of CYP2C19. EAP data demonstrate other possible interactions with rufinamide, zonisamide, topiramate, and eslicarbazepine. Additionally, there is one case report demonstrating need for warfarin dose adjustment with concomitant CBD. Understanding of CBD's efficacy and safety in the treatment of TRE has expanded significantly in the last few years. Future controlled studies of various ratios of CBD and THC are needed as there could be further therapeutic potential of these compounds for patients with epilepsy.

Lennox-Gastaut syndrome: a comprehensive review.

Lennox-Gastaut syndrome (LGS) is considered an epileptic encephalopathy and is defined by a triad of multiple drug-resistant seizure types, a specific EEG pattern showing bursts of slow spike-wave complexes or generalized paroxysmal fast activity, and intellectual disability. The prevalence of LGS is estimated between 1 and 2% of all patients with epilepsy. The etiology of LGS is often divided into two groups: identifiable (genetic-structural-metabolic) in 65 to 75% of the patients and LGS of unknown cause in others. Lennox-Gastaut syndrome may be considered as secondary network epilepsy. The seizures in LGS are usually drug-resistant, and complete seizure control with resolution of intellectual and psychosocial dysfunction is often not achievable. Reduction in frequency of the most incapacitating seizures (e.g., drop attacks and tonic-clonic seizures) should be the major objective. Valproate, lamotrigine, and topiramate are considered to be the first-line drugs by many experts. Other effective antiepileptic drugs include levetiracetam, clobazam, rufinamide, and zonisamide. The ketogenic diet is an effective and well-tolerated treatment option. For patients with drug resistance, a further therapeutic option is surgical intervention. Corpus callosotomy is a palliative surgical procedure that aims at controlling the most injurious seizures. Finally, vagus nerve stimulation offers reasonable seizure improvement. The long-term outcome for patients with LGS is generally poor. This syndrome is often associated with long-term adverse effects on intellectual development, social functioning, and independent living.

[Transional syndrome: from West to Lennox-Gastaut syndromes]. / Síndrome transicional: del síndrome de West al síndrome de Lennox-Gastaut.

West syndrome or infantile spasms is an epileptic encephalopathy, classified as generalized epilepsies and syndromes. There are multiple reports of the evolution from West to Lennox-Gastaut syndrome of 25 up to 60%, without a specific cause is determined. It has been reported that they may be only an epileptic entity age dependent that it would be in relation to the degree of brain immaturity. In this retrospective review of 130 cases of West syndrome, only 14 (10.7%) evolved to Lennox-Gastaut. Having received in all cases vigabatrin as a treatment, makes us suppose that the low incidence could be related to the use of this drug. Given that vigabatrin has a gabaergic action and increased levels of ACTH, may explain this relationship but this must be confirmed with the best knowledge of the intimate mechanisms of these serious epileptic encephalopathies.

Deficient activity of alanyl-tRNA synthetase underlies an autosomal recessive syndrome of progressive microcephaly, hypomyelination, and epileptic encephalopathy.

Aminoacyl-transfer RNA (tRNA) synthetases ligate amino acids to specific tRNAs and are essential for protein synthesis. Although alanyl-tRNA synthetase (AARS) is a synthetase implicated in a wide range of neurological disorders from Charcot-Marie-Tooth disease to infantile epileptic encephalopathy, there have been limited data on their pathogenesis. Here, we report loss-of-function mutations in AARS in two siblings with progressive microcephaly with hypomyelination, intractable epilepsy, and spasticity. Whole-exome sequencing identified that the affected individuals were compound heterozygous for mutations in AARS gene, c.2067dupC (p.Tyr690Leufs*3) and c.2738G>A (p.Gly913Asp). A lymphoblastoid cell line developed from one of the affected individuals showed a strong reduction in AARS abundance. The mutations decrease aminoacylation efficiency by 70%-90%. The p.Tyr690Leufs*3 mutation also abolished editing activity required for hydrolyzing misacylated tRNAs, thereby increasing errors during aminoacylation. Our study has extended potential mechanisms underlying AARS-related disorders to include destabilization of the protein, aminoacylation dysfunction, and defective editing activity.

Adult motor phenotype differentiates Dravet syndrome from Lennox-Gastaut syndrome and links SCN1A to early onset parkinsonian features.

Distinguishing adult patients with Lennox-Gastaut syndrome from those with Dravet syndrome is challenging. We have previously reported that patients with Dravet syndrome present a very peculiar motor phenotype. Here we sought to confirm that this association was not linked to the chronic use of antiepileptic drugs or the many lifetime seizures. To this aim, we studied 14 adult patients with Lennox-Gastaut syndrome and 14 adults with Dravet syndrome because both conditions share similar seizure severity. We found that antecollis and parkinsonian gait were significantly more common in the Dravet group, thus suggesting that these features are part of the Dravet syndrome adult phenotype.

Lennox-Gastaut Syndrome: A State of the Art Review.

Lennox-Gastaut syndrome (LGS) is a severe age-dependent epileptic encephalopathy usually with onset between 1 and 8 years of age. Functional neuroimaging studies recently introduced the concept of Lennox-Gastaut as "secondary network epilepsy" resulting from dysfunctions of a complex system involving both cortical and subcortical structures (default-mode network, corticoreticular connections, and thalamus). These dysfunctions are produced by different disorders including hypoxic-ischemic encephalopathies, meningoencephalitis, cortical malformations, neurocutaneous disorders, or tumors. The list of etiologies was expanded to pathogenic copy number variants at whole-genome array comparative genomic hybridization associated with late-onset cases or pathogenic mutations involving genes, such as GABRB3, ALG13, SCN8A, STXBP1, DNM1, FOXG1, or CHD2. Various clinical trials demonstrated the usefulness of different drugs (including rufinamide, clobazam, lamotrigine, topiramate, or felbamate), ketogenic diet, resective surgery, corpus callosotomy, and vagus nerve stimulation in the treatment of epileptic manifestations. The outcome of LGS often remains disappointing regarding seizure control or cognitive functioning. The realization of animal models, which are still lacking, and the full comprehension of molecular mechanisms involved in epileptogenesis and cognitive impairment would give a relevant support to further improvements in therapeutic strategies for LGS patients.