ABSTRACT
Lennox-Gastaut syndrome (LGS) is a severe form of childhood onset epileptic encephalopathy characterized by multiple drug-resistant seizures, cognitive impairment, and diffuse slow spike and wave (SSW), and generalized paroxysmal fast activity (GPFA) on electroencephalogram (EEG). Systematic review following the Preferred Reporting Items for Systematic Reviews and Meta Analysis (PRISMA) guidelines was done to investigate EEG findings in LGS. PubMed and MEDLINE were systematically searched for English-language studies published until15th may 2023. Original articles and research with patients between age group 1-30 years, and studies with description of EEG findings were included. Search identified 20 studies with 1167 patients. In this analysis 62.6â¯% of patients were male. The median age was 9.6 years. Etiology was structural abnormality in 42.6â¯%, genetic in 8.7â¯% but was unknown in 48.7%. Tonic seizures (74.5â¯%) were most frequent followed by atypical absences (44.3â¯%), myoclonic (39.2â¯%), generalized (38.5â¯%), atonic (34.8â¯%), epileptic spasm (15.9â¯%), focal (11.4â¯%) and non-convulsive status epilepticus (7.0â¯%). Out of 20 studies, only 15 studies mentioned GPFA in 46.6â¯% patients and SSW in 91.7â¯% patients. Unilateral and focal discharges were more common in patients with unilateral structural abnormalities. Seizure discharges on EEG longer than 10â¯second duration correlated with seizure diary counts. Combination of atonic, tonic, and atypical absence seizures correlated with SSW, and myoclonic seizures correlated with GPFA. EEG helps in diagnosis and prognosis of LGS. SSW is present in almost all EEG, and GPFA in 46.6â¯% patients. Longer duration of SSW discharges and disorganized background are associated with poor outcome.
Subject(s)
Electroencephalography , Lennox Gastaut Syndrome , Child , Female , Humans , Male , Electroencephalography/methods , Lennox Gastaut Syndrome/diagnosis , Lennox Gastaut Syndrome/physiopathology , Seizures/physiopathology , Seizures/diagnosisABSTRACT
OBJECTIVE: To evaluate the Refractory Epilepsy Screening Tool for Lennox-Gastaut Syndrome (REST-LGS) for real-world identification of LGS in adults and to develop a scoring system for the tool. METHODS: A retrospective chart review of adults with drug resistant epilepsy (DRE) and intellectual development disorder (IDD) was conducted by 2 primary care providers blinded to diagnosis. The REST-LGS was designed via the Modified Delphi Consensus and was previously validated. This tool consists of 8 criteria (4 major, 4 minor) considered indicative of LGS. To account for missing data in the earlier validation study and to evaluate applicability in a real-world setting, the REST-LGS was refined to include a scoring system in which major criteria were more heavily weighted than minor criteria, producing categories of "likely" (>11 points), "possible" (8-11 points), and "unlikely" (<8 points) LGS. Statistical analyses were descriptive. RESULTS: Of the 100 patients included in the analysis, data for slow spike-waves in electroencephalography and seizure onset age - both major REST-LGS criteria - were missing for 46% and 42% of patients, respectively. The majority of patients met 4 of the 8 REST-LGS criteria (cognitive impairment since childhood, 71%; persistent seizures despite a trial of ≥2 antiseizure medications, 65%; seizure onset before the age of 12 years, 57%; ≥2 seizure types, 56%). All 4 major criteria were met in 22 patients (22%). The percentages of patients considered "likely," "possible," or "unlikely" to have LGS were 26%, 30%, and 44%, respectively. Of the 74 patients without a previous LGS diagnosis, 42 (57%) were identified as "possible" or "likely" to have LGS using REST-LGS. SIGNIFICANCE: In this analysis, the validated REST-LGS was evaluated in a real-world setting. The majority of previously undiagnosed patients were identified via REST-LGS as "possible" or "likely" to have LGS. Extensive missing data highlights challenges of LGS diagnosis in adults. PLAIN LANGUAGE SUMMARY: There is a need to identify adult patients with Lennox-Gastaut syndrome (LGS) so they can receive appropriate treatment. The Refractory Epilepsy Screening Tool for LGS (REST-LGS) questionnaire was designed by experts to identify whether patients with seizures that are not controlled by medications may have LGS. In this study, 2 physicians completed the REST-LGS using charts for 100 patients who experience seizures not controlled by medications. Of the patients who were previously diagnosed as not having LGS, the majority were "likely" or "possible" to have LGS based on the REST-LGS; therefore, the REST-LGS can identify patients for further evaluation.
Subject(s)
Drug Resistant Epilepsy , Electroencephalography , Lennox Gastaut Syndrome , Humans , Lennox Gastaut Syndrome/diagnosis , Male , Female , Adult , Retrospective Studies , Drug Resistant Epilepsy/diagnosis , Drug Resistant Epilepsy/drug therapy , Young Adult , Intellectual Disability/diagnosis , Adolescent , Middle AgedABSTRACT
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.
Subject(s)
Epilepsies, Myoclonic , NAV1.1 Voltage-Gated Sodium Channel , Humans , Male , Female , Child , Child, Preschool , Epilepsies, Myoclonic/genetics , Epilepsies, Myoclonic/diagnosis , NAV1.1 Voltage-Gated Sodium Channel/genetics , Infant , Adolescent , Electroencephalography , Genetic Testing , Adult , Epilepsy/genetics , Epilepsy/diagnosis , Epilepsy/physiopathology , Young Adult , Exome Sequencing , Lennox Gastaut Syndrome/genetics , Lennox Gastaut Syndrome/diagnosisABSTRACT
BACKGROUND: Dravet Syndrome (DS) is a rare and severe form of childhood epilepsy that is often refractory to conventional antiepileptic drugs. Emerging evidence suggests that Cannabidiol (CBD) offer therapeutic benefits for DS. This review aims to evaluate the efficacy and safety of CBD in pediatric patients with DS based on data from ten clinical trials. METHODS: A review was conducted to identify clinical trials assessing the efficacy and safety of CBD in pediatric patients diagnosed with DS. PubMed, MEDLINE, Scopus, Web of Science, and relevant grey literature were systematically searched for relevant articles up to October 2023, and clinical trials within the last 10 years were included. The search strategy incorporated controlled vocabulary terms and keywords related to "Cannabidiol," "Dravet Syndrome," and "pediatric patients." RESULTS: The analysis revealed promising efficacy outcomes. Notably, CBD demonstrated substantial reductions in seizure frequency, with some patients achieving seizure freedom. The findings emphasised the consistency of CBD's efficacy across different patient subgroups. The safety profile of CBD was generally acceptable, with adverse events often being manageable. CONCLUSION: This review consolidates evidence from multiple clinical trials, affirming the potential of CBD as a promising treatment option for pediatric patients with DS. While further research is needed to address existing knowledge gaps, CBD's efficacy and acceptable safety profile make it a valuable addition to the therapeutic tools for DS.
Subject(s)
Cannabidiol , Epilepsies, Myoclonic , Lennox Gastaut Syndrome , Child , Humans , Anticonvulsants , Cannabidiol/therapeutic use , Epilepsies, Myoclonic/diagnosis , Epilepsies, Myoclonic/drug therapy , Lennox Gastaut Syndrome/drug therapy , Lennox Gastaut Syndrome/diagnosis , Seizures/drug therapyABSTRACT
INTRODUCTION: Lennox Gastaut syndrome (LGS) as an electroclinical diagnosis has been utilized as a clinical entity for more than 70 years. However, with the recognition of other distinct electroclinical epilepsy syndromes, no consistent single etiology, and the variability of criteria used in clinical trials, the clinical utility of such a diagnosis has been questioned. Recently, the International League Against Epilepsy for the first time defined diagnostic criteria for epilepsy syndromes, thereby allowing consistent language and inclusion criteria to be utilized. AREAS COVERED: Recent diagnostic criteria for syndrome diagnosis are explored as defined by the International League Against Epilepsy, with further literature reviewed to highlight relevant features, and differential diagnosis explored. EXPERT OPINION: Developmental and Epileptic Encephalopathy (DEE) is an overall term that may be descriptive of many different epilepsies, most of early onset, whether electroclinically or etiologically defined, of which LGS is one. Although we have moved forward in defining an increasing number of etiologically specific syndromes, this to date remains a minority of the DEEs. Although there is progress with precision medicine targeted at specific causes, the term LGS still remains useful as a diagnosis in defining treatment options, as well as overall prognosis.
Subject(s)
Epilepsy, Generalized , Epilepsy , Epileptic Syndromes , Lennox Gastaut Syndrome , Status Epilepticus , Humans , Lennox Gastaut Syndrome/diagnosis , Electroencephalography , Epilepsy/diagnosis , Epileptic Syndromes/diagnosis , Diagnosis, Differential , Status Epilepticus/diagnosisABSTRACT
OBJECTIVE: Identification of EEG waveforms is critical for diagnosing Lennox-Gastaut Syndrome (LGS) but is complicated by the progressive nature of the disease. Here, we assess the interrater reliability (IRR) among pediatric epileptologists for classifying EEG waveforms associated with LGS. METHODS: A novel automated algorithm was used to objectively identify epochs of EEG with transient high power, which were termed events of interest (EOIs). The algorithm was applied to EEG from 20 LGS subjects and 20 healthy controls during NREM sleep, and 1350 EOIs were identified. Three raters independently reviewed the EOIs within isolated 15-second EEG segments in a randomized, blinded fashion. For each EOI, the raters assigned a waveform label (spike and slow wave, generalized paroxysmal fast activity, seizure, spindle, vertex, muscle, artifact, nothing, or other) and indicated the perceived subject type (LGS or control). RESULTS: Labeling of subject type had 85% accuracy across all EOIs and an IRR of κ =0.790, suggesting that brief segments of EEG containing high-power waveforms can be reliably classified as pathological or normal. Waveform labels were less consistent, with κ =0.558, and the results were highly variable for different categories of waveforms. Label mismatches typically occurred when one reviewer selected "nothing," suggesting that reviewers had different thresholds for applying named labels. SIGNIFICANCE: Classification of EEG waveforms associated with LGS has weak IRR, due in part to varying thresholds applied during visual review. Computational methods to objectively define EEG biomarkers of LGS may improve IRR and aid clinical decision-making.
Subject(s)
Lennox Gastaut Syndrome , Humans , Child , Lennox Gastaut Syndrome/diagnosis , Reproducibility of Results , Electroencephalography/methods , Seizures , HeadABSTRACT
OBJECTIVE: Lennox-Gastaut syndrome (LGS) is an archetypal developmental and epileptic encephalopathy, for which novel treatments are emerging. Diagnostic criteria for LGS have recently been defined by the International League Against Epilepsy (ILAE). We aimed to apply these criteria in a real-world setting. METHODS: We applied ILAE diagnostic criteria to a cohort of patients diagnosed with LGS by epileptologists following inpatient video-EEG monitoring (VEM) at tertiary comprehensive epilepsy centers between 1995 and 2015. We also assessed mortality in this cohort. RESULTS: Sixty patients diagnosed with LGS and had complete records available for review were identified. Among them, 29 (48%) patients met ILAE diagnostic criteria for LGS (ILAE-DC group). Thirty-one did not meet criteria (non-ILAE-DC) due to the absence of documented tonic seizures (n = 7), EEG features (n = 12), or both tonic seizures and EEG features (n = 10), intellectual disability (n = 1), or drug resistance (n = 1). The ILAE-DC group had a shorter duration of epilepsy at VEM than the non-ILAE-DC group (median = 12.0 years vs. 23.7 years, respectively; p = 0.015). The proportions of patients with multiple seizure types (100% vs. 96.7%), ≤2.5 Hz slow spike-and-wave EEG activity (100% vs. 90%), seizure-related injuries (27.6% vs. 25.8%), and mortality (standardized mortality ratio 4.60 vs. 5.12) were similar between the groups. SIGNIFICANCE: Up to 52% of patients diagnosed with LGS following VEM may not meet recently accepted ILAE criteria for LGS diagnosis. This may reflect both the limitations of retrospective medical record review and a historical tendency of applying the LGS diagnosis to a broad spectrum of severe, early-onset drug-resistant epilepsies with drop attacks. The ILAE criteria allow the delineation of LGS based on distinct electroclinical features, potentiating accurate diagnosis, prognostication, and management formulation. Nonetheless, mortality outcomes between those who did and did not meet ILAE diagnostic criteria for LGS were similarly poor, and both groups suffered high rates of seizure-related injury. PLAIN LANGUAGE SUMMARY: More than half of patients diagnosed with Lennox-Gastaut Syndrome (LGS) at three Australian epilepsy monitoring units between 1995 and 2015 did not meet the recently devised International League Against Epilepsy (ILAE) diagnostic criteria for LGS. Mortality was equally high in those who did and did not meet the ILAE diagnostic criteria, and seizure-related injury was common. The ILAE diagnostic criteria will guide accurate diagnosis, management, prognostication, and research in patients with LGS, however may be limited in their practical application to patients with a longer duration of epilepsy, or to those for whom detailed assessment is difficult.
Subject(s)
Epilepsy , Lennox Gastaut Syndrome , Humans , Lennox Gastaut Syndrome/diagnosis , Lennox Gastaut Syndrome/therapy , Retrospective Studies , Australia , SeizuresABSTRACT
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.
Subject(s)
Deep Learning , Lennox Gastaut Syndrome , Humans , Lennox Gastaut Syndrome/diagnosis , Brain , ElectroencephalographyABSTRACT
PURPOSE: There are three major changes in the new definition of Lennox-Gastaut syndrome (LGS) compared with the traditional definition: (1) onset prior to 18 years, (2) must include tonic seizure, (3) generalized slow spike-waves (SSW) and (instead of or) generalized paroxysmal fast activity (GPFA) on electroencephalography (EEG). We investigated the practical implications and potential limitations of the new LGS definition based on a large cohort of patients in an exploratory study. METHODS: This was a retrospective database study. All patients with an electro-clinical diagnosis of LGS (based on its traditional definition) at the outpatient epilepsy clinic at Shiraz University of Medical Sciences, Shiraz, Iran were included (from 2008 until 2020). Patients were reclassified based on the new definition of LGS. RESULTS: In total, 3737 patients were registered. Based on its traditional definition, 300 patients were diagnosed as having LGS. According to the new definition of LGS, only 96 patients (32% of the traditional cohort) had LGS. One patient, who had other criteria, had and age at onset of 21 years; 29 patients (9.7%) did not have SSW in their EEGs; 139 people (46.3%) did not have GPFA in their EEGs; and, 111 patients (37%) did not report having tonic seizures. CONCLUSION: The new International League Against Epilepsy (ILAE) definition of LGS has some important practical implications and limitations. Before reinforcing and making this new definition compulsory in future research and clinical practice, more work is needed to enlighten various aspects of such changes in the definition of this epilepsy syndrome.
Subject(s)
Epilepsy , Lennox Gastaut Syndrome , Humans , Young Adult , Electroencephalography , Epilepsy/diagnosis , Lennox Gastaut Syndrome/diagnosis , Retrospective Studies , SeizuresABSTRACT
Lennox-Gastaut syndrome is a severe drug-resistant developmental and epileptic encephalopathy with slow spike and wave on EEG (DEE-SSW) composing about 1-2% of epilepsy patients. Seizures in DEE-SSW are caused by a variety of etiologies, and there is a large unmet treatment need as seizures are usually treatment-resistant and individuals are often unable to function independently. The updated definition by the International League Against Epilepsy has established formal diagnostic criteria allowing for more uniform diagnosis. This article provides a review of typical medication management and treatment strategies, including new and developing surgical approaches. Future directions in treatment include expanding genetic testing with the potential for gene therapy and continuously improving surgical options with the goal to prevent progression to DEE-SSW.
Subject(s)
Lennox Gastaut Syndrome , Humans , Lennox Gastaut Syndrome/diagnosis , Lennox Gastaut Syndrome/therapy , Seizures , Electroencephalography , Genetic Testing , Genetic TherapyABSTRACT
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.
Subject(s)
Epilepsy , Lennox Gastaut Syndrome , Male , Female , Mice , Animals , Lennox Gastaut Syndrome/diagnosis , Receptors, GABA-A/genetics , Mice, Inbred C57BL , Epilepsy/genetics , Seizures , Mutation , Electroencephalography , gamma-Aminobutyric Acid/geneticsABSTRACT
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.
Subject(s)
Lennox Gastaut Syndrome , Spasms, Infantile , Child , Humans , Spasms, Infantile/drug therapy , Spasms, Infantile/diagnosis , Lennox Gastaut Syndrome/drug therapy , Lennox Gastaut Syndrome/diagnosis , Retrospective Studies , Prednisone/therapeutic use , Adrenocorticotropic Hormone/therapeutic use , Adrenal Cortex Hormones/therapeutic use , Electroencephalography , Dexamethasone/adverse effects , Anticonvulsants/therapeutic useABSTRACT
SUMMARY: Quantitative analysis of continuous electroencephalography (QEEG) is increasingly being used to augment seizure detection in critically ill patients. Typically, seizures manifest on QEEG as abrupt increases in power and frequency, a visual pattern often called "flames." Here, we present a case of a 16-year-old patient with intractable Lennox-Gastaut syndrome secondary to a pathogenic variant in the SCN2A gene who had tonic seizures that manifest as abrupt decreases in power on QEEG, a visual pattern we term "icicles." Recognition of QEEG patterns representative of different seizure types is important as QEEG use becomes more widespread including in pediatric populations.
Subject(s)
Lennox Gastaut Syndrome , Child , Humans , Adolescent , Lennox Gastaut Syndrome/diagnosis , Lennox Gastaut Syndrome/complications , Seizures/diagnosis , Seizures/complications , ElectroencephalographyABSTRACT
INTRODUCTION: The aim of this study was to extend our knowledge of the genetic background of Argentinean pediatric patients with developmental and epileptic encephalopathy (DEE) applying a next generation sequencing (NGS) panel. METHODS: Thirty one patients with DEE were studied, including these phenotypes: Dravet syndrome (n:7), Dravet like syndrome (n:3), West syndrome (WS) (n:6), WS that evolved to Lennox-Gastaut syndrome (LGS) (n:4), epilepsy of infancy with migrating focal seizures (n:2), continuous spikes and waves during slow sleep evolving to LGS (n:1), LGS (n:1), myoclonic status in non-progressive encephalopathy (n:1), myoclonic atonic epilepsy (n:1), epileptic encephalopathy with multifocal spikes (n:1) and unclassified epileptic encephalopathy (n:4). Fifty-two genes frequently associated with DEE were studied by NGS in genomic DNA from peripheral blood. RESULTS: Relevant variants were detected in 12 cases; 6 novel pathogenic or likely pathogenic variants, 6 previously reported as pathogenic and 1 variant of unknown significance. Single-nucleotide heterozygous variants were identified in the SCN1A (5), GABRG2 (1), STXBP1 (2) genes, a mosaic variant in SCN2A (1) and a homozygous variant in SCN1B (1). Additionally, a heterozygous deletion involving the SCN1A, SCN2A and SCN3A genes (1), and the most frequent triplet repeat expansion in the ARX gene (1) were detected. DISCUSSION: Genetic diagnosis was made in 39% of patients. We emphasize the importance of considering mosaic variants, copy number variants and hereditary forms when designing and interpreting molecular studies, to optimize diagnosis and management of patients. Approximately 42% of the detected variants were novel, expanding the knowledge of the molecular basis of DEEs in Latin-American patients.
Introducción: El objetivo del estudio fue ampliar el conocimiento de las bases moleculares de las encefalopatías epilépticas y del desarrollo (EED) en pacientes pediátricos argentinos aplicando un panel de secuenciación de nueva generación (NGS). Métodos: Se analizaron 31 pacientes con los fenotipos clínicos de síndrome de Dravet (n:7), síndrome símil Dravet (n:3), síndrome de West (SW) (n:6), SW que evoluciona a síndrome de Lennox Gastaut (SLG)(N:4), epilepsia de la infancia con crisis focales migratorias (n:2), actividad de punta onda continua durante el sueño que evolucionan a SLG (n:1), SLG (n:1), encefalopatía no progresiva con estatus mioclónico (n:1), epilepsia mioclónica atónica (n:1), encefalopatía epiléptica con espigas multifocales (n:1) y encefalopatía epiléptica indeterminada (n:4). Se estudiaron los 52 genes más frecuentemente asociados a EED a través de NGS, en ADN extraído de sangre periférica. Resultados: Se identificaron variantes relevantes en 12 casos, de las cuales 5 fueron nuevas y 6 previamente reportadas como patogénicas o posiblemente patogénicas, mientras que una variante fue clasificada como de significado incierto. Variantes heterocigotas, de nucleótido único, se identificaron en los genes SCN1A (5), GABRG2 (1), STXBP1 (2), una variante en mosaico en SCN2A (1) y otra homocigota en SCN1B (1). Además, se detectó una deleción que involucra a los genes SCN1A, SCN2A y SCN3A (1) y la expansión de repeticiones de tripletes más frecuente en el gen ARX (1). Discusión: Se alcanzó el diagnóstico molecular en el 39% de los pacientes. Remarcamos la importancia de considerar variantes en mosaico, variantes en el número de copias y formas heredadas al momento de diseñar e interpretar los estudios moleculares, de tal forma de optimizar el diagnóstico y seguimiento de los pacientes con EED. Cabe destacar, que el 42% de las variantes detectadas fueron nuevas, ampliando nuestro conocimiento sobre las bases moleculares de las EED en población latino americana.
Subject(s)
Brain Diseases , Epilepsies, Myoclonic , Epilepsy , Lennox Gastaut Syndrome , Spasms, Infantile , Humans , Epilepsy/diagnosis , Epilepsies, Myoclonic/diagnosis , Brain Diseases/genetics , Lennox Gastaut Syndrome/diagnosis , Lennox Gastaut Syndrome/genetics , Spasms, Infantile/diagnosis , Spasms, Infantile/genetics , Phenotype , SeizuresABSTRACT
BACKGROUND: Lennox Gastaut Syndrome (LGS) is an epilepsy syndrome presenting in childhood, classically characterised by a triad of cognitive or developmental impairment, multiple seizure types and EEG features of slow-spike waves (SWW), with or without paroxysmal fast activity (PFA) in sleep. There is increasing scientific opinion in favour of a less rigid approach to LGS diagnosis and this clinical audit attempts to shed light on how the LGS diagnostic criteria used may have changed over time, in a large tertiary paediatric neurology unit (Great Ormond Street Hospital (GOSH), London, UK). METHODS: Electronic patient records were reviewed for patients with a diagnosis of LGS made at GOSH within two time periods, 2014-2017 and 2018-2021. Patient demographics, aetiology, clinical features, EEG features, investigation results and medications were reviewed. Findings were compared against the International League Against Epilepsy (ILAE) Diagnostic Manual criteria for LGS diagnosis (the classical triad plus PFA in sleep). Existing GOSH data regarding total number of new epilepsy referrals to GOSH and ICD10 codes (including all epilepsy and epilepsy syndromes) per year were also used to review LGS diagnoses as proportions of new epilepsy referrals and total number of epilepsy diagnoses. RESULTS: 5 LGS diagnoses were made in 2014-2017 compared to 40 diagnoses made in 2018-2021. There was a steep increase in the number of LGS diagnoses and LGS diagnoses as a proportion of total epilepsy diagnoses in the last 4 years, coinciding with the licensing of cannabidiol for management of LGS in the UK in 2018. There was a much less marked increase in LGS diagnoses as a proportion of epilepsy referrals from 2018 (and an as yet unexplained high proportion in 2014). The 2014-17 cohort fit a more classical LGS diagnostic criteria of the triad plus presence of PFA on sleep EEG (100% in 2014-17 vs 68% in 2018-21), with a more classical preceding history of infantile spasms (80% in 2014-17 vs 23% in 2018-21). Common seizure types were similar in both groups and a male preponderance was also noted in both groups. Cannabidiol use in LGS patients has also increased over time, all prescribed after 2018. CONCLUSIONS: Despite the limitations of the small numbers of patients in each group, the results of this clinical audit are in keeping with changing clinical trends in favour of a broader LGS diagnostic criteria. The combination of this less rigid diagnostic criteria, the steep increase in diagnosis seen from 2018 onwards (coinciding with UK cannabidiol licencing for LGS in 2018) and the fact that most of the LGS patients in both groups are currently prescribed cannabidiol, may reflect a strategic shift in attitude towards LGS diagnosis or an increase in referrals for LGS, possibly to help facilitate access to novel treatments.
Subject(s)
Cannabidiol , Epilepsy , Epileptic Syndromes , Lennox Gastaut Syndrome , Spasms, Infantile , Child , Humans , Male , Lennox Gastaut Syndrome/diagnosis , Spasms, Infantile/diagnosis , Electroencephalography , Epilepsy/diagnosis , SeizuresABSTRACT
PURPOSE: Although international guidelines exist, the clinical heterogeneity of Lennox-Gastaut syndrome (LGS) and the increasing availability of new and repurposed drugs (e.g., fenfluramine and cannabidiol) requires a practical guide to patient management in the clinical context. We report the results of a consensus survey among 42 Italian experts in the diagnosis and treatment of LGS. METHODS: The consensus procedure followed a modified Delphi approach. Statements were formulated, based on the most recent published evidence and the clinicians' personal experience, then discussed, and agreed upon by the experts through a two-round voting procedure. Approval of a statement was reached with an average score ≥7. RESULTS: Thirteen statements dealing with three main topics (i.e., clinical diagnosis and prognosis, impact on the Quality of Life (QoL), and treatment strategies) were generated. Six statements achieved a level of agreement sufficient for approval on the first voting round. Following the discussion and a few consequent amendments, most of the statements increased their level of agreement and all 13 were approved. CONCLUSIONS: Overall, the statements draw a slightly more benign picture of this rare and severe disease, highlighting the possibility of remission - albeit modest -, an apparent trend towards lower mortality, and the availability of several effective drugs, to which greater accessibility would be hoped for. Valproate remains a major therapeutic option in LGS patients although lamotrigine, rufinamide, topiramate, cannabidiol, and clobazam are popular therapeutic options in Italy, allowing for a tailor-made antiseizure therapy.
Subject(s)
Cannabidiol , Lennox Gastaut Syndrome , Anticonvulsants/therapeutic use , Cannabidiol/therapeutic use , Clobazam/therapeutic use , Consensus , Fenfluramine/therapeutic use , Humans , Lamotrigine , Lennox Gastaut Syndrome/diagnosis , Lennox Gastaut Syndrome/drug therapy , Quality of Life , Topiramate/therapeutic use , Valproic Acid/therapeutic useSubject(s)
Epilepsy , Lennox Gastaut Syndrome , Adult , Electroencephalography , Epilepsy/diagnosis , Humans , Lennox Gastaut Syndrome/diagnosisABSTRACT
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.
Subject(s)
Epilepsies, Myoclonic , Epilepsy , Lennox Gastaut Syndrome , Spasms, Infantile , Child , Electroencephalography , Epilepsies, Myoclonic/diagnosis , Epilepsies, Myoclonic/etiology , Epilepsy/diagnosis , Epilepsy/epidemiology , Epilepsy/etiology , Humans , Infant, Newborn , Lennox Gastaut Syndrome/diagnosis , Seizures/complications , Spasms, Infantile/complications , Spasms, Infantile/etiologyABSTRACT
The aim of the current study was to investigate the age at onset in patients with Lennox-Gastaut Syndrome (LGS). We also investigated the clinical and EEG characteristics of these patients in different age groups. This was a retrospective study. All patients with a diagnosis of LGS were recruited at the outpatient epilepsy clinic at Shiraz University of Medical Sciences, Shiraz, Iran, from 2008 through 2020. 300 patients had LGS. Age at onset was 3.3 ± 4.1 years (minimum = 0 and maximum = 21 years). In 10 patients (3%) LGS started at age 14 years or above. Epileptic spasms were more often observed in those with an age at onset below one year (8%) compared with those with an age at onset of 1 to 8 years (0.7%) [Odds Ratio (OR) = 10.32]. Intellectual disability was less frequently observed in those with an age at onset of 8 years and above (68%) compared with those with an age at onset of 1 to 8 years (90%) (OR = 0.33). Tonic-clonic seizures were more often observed in those with an age at onset of 8 years and above (83%) compared with those with an age at onset of 1 to 8 years (55%) (OR = 2.87). While age at onset of LGS in the majority of patients is below 8 years, in some patients the syndrome begins in their late childhood or even during adolescence. Age at onset of LGS has significant correlations with the clinical manifestations of the syndrome.
Subject(s)
Intellectual Disability , Lennox Gastaut Syndrome , Spasms, Infantile , Adolescent , Age of Onset , Child , Electroencephalography , Humans , Intellectual Disability/diagnosis , Intellectual Disability/epidemiology , Lennox Gastaut Syndrome/diagnosis , Lennox Gastaut Syndrome/epidemiology , Retrospective Studies , Spasms, Infantile/diagnosis , Spasms, Infantile/epidemiologyABSTRACT
Introducción: El síndrome de Lowe o síndrome oculocerebrorenal es un trastorno multisistémico. Es una enfermedad rara e infrecuente. Objetivo: Exponer un caso clínico típico, con fracaso renal controlado sin método dialítico y que de manera tardía en su adolescencia se diagnostica con síndrome de Lennox-Gastaut. Presentación caso: Adolescente masculino de 18 años nacido de un embarazo sin riesgo y parto por cesárea, macrofeto. Desde el nacimiento, con diagnóstico perinatal de catarata congénita y evolutivamente glaucoma bilateral con tratamiento conservador. A partir del primer año de vida padece de acidosis tubular y síndrome de Fanconi con evolución a una enfermedad renal crónica. Relacionado todo con retraso del desarrollo psicomotor, discapacidad intelectual, estereotipias, síntomas obsesivos compulsivos y depresión. De manera tardía, a los 10 años tuvo inicio de crisis epilépticas de varios tipos con predominio de las tónicas durante el sueño y en vigilia, frecuentes, con electroencefalograma característico de síndrome Lennox-Gastaut. Tuvo atención interdisciplinaria y evolución clínica estable hasta la edad adulta cumplida. El estudio molecular de ADN materno y del niño confirmaron la mutación c2224_2226 del GTA (exón 19), delección de valina en la posición 742 del cromosoma X del OCRL 1, que ratifica el síndrome de Lowe. Conclusiones: El Síndrome de Lowe, es un trastorno multisistémico, ligado al cromosoma X y frecuente en varones. Clínicamente se caracteriza por alteraciones oftalmológicas, renales y neurológicas(AU)
Introduction: Lowe syndrome or oculocerebrorenal syndrome is a multisystemic disorder. It's a rare and uncommon disease. Objective: Show a typical clinical case, with controlled renal failure without dialytic method and that late in the adolescence is diagnosed with Lennox-Gastaut syndrome. Case presentation: 18-year-old male adolescent born of a risk-free pregnancy and cesarean delivery, with macrosomia. From birth, he had a perinatal diagnosis of congenital cataract and evolutionarily bilateral glaucoma with conservative treatment. From the first year of life he suffers from tubular acidosis and Fanconi syndrome with an evolution to chronic kidney disease. All of these were related to delayed psychomotor development, intellectual disability, stereotypies, obsessive-compulsive symptoms and depression. Lately, at 10 years old, epileptic seizures of various types with predominance of tonic ones during sleep and wakefulness began; they were frequent, with characteristic electroencephalogram of Lennox-Gastaut syndrome. He had interdisciplinary care and stable clinical evolution into adulthood. The molecular study of the mother and child DNA confirmed the c2224_2226 mutation of GTA (exon 19), valine deletion at position 742 of the X chromosome of OCRL 1, which ratifies Lowe syndrome. Conclusion: Lowe Syndrome is a multisystemic disorder, linked to the X chromosome and common in males. Clinically, it is characterized by ophthalmological, renal and neurological alterations(AU)