Expert Opinion On The Management Of Lennox-gastaut Syndrome: Treatment Algorithms And Practical Consideration

Lennox-Gastaut syndrome (LGS) is a severe epileptic and developmental encephalopathy that is associated with a high rate of morbidity and mortality. It is characterized by multiple seizure types, abnormal electroencephalographic features, and intellectual disability. Although intellectual disability and associated behavioral problems are characteristic of LGS, they are not necessarily present at its outset and are therefore not part of its diagnostic criteria. LGS is typically treated with a variety of pharmacological and non-pharmacological therapies, often in combination. Management and treatment decisions can be challenging, due to the multiple seizure types and comorbidities associated with the condition. A panel of five epileptologists met to discuss consensus recommendations for LGS management, based on the latest available evidence from literature review and clinical experience. Treatment algorithms were formulated. Current evidence favors the continued use of sodium valproate (VPA) as the first-line treatment for patients with newly diagnosed de novo LGS. If VPA is ineffective alone, evidence supports lamotrigine, or subsequently rufinamide, as adjunctive therapy. If seizure control remains inadequate, the choice of next adjunctive antiepileptic drug (AED) should be discussed with the patient/parent/caregiver/clinical team, as current evidence is limited. Non-pharmacological therapies, including resective surgery, the ketogenic diet, vagus nerve stimulation, and callosotomy, should be considered for use alongside AED therapy from the outset of treatment. For patients with LGS that has evolved from another type of epilepsy who are already being treated with an AED other than VPA, VPA therapy should be considered if not trialed previously. Thereafter, the approach for a de novo patient should be followed. Where possible, no more than two AEDs should be used concomitantly. Patients with established LGS should undergo review by a neurologist specialized in epilepsy on at least an annual basis, including a thorough reassessment of their diagnosis and treatment plan. Clinicians should always be vigilant to the possibility of treatable etiologies and alert to the possibility that a patient's diagnosis may change, since the seizure types and electroencephalographic features that characterize LGS evolve over time. To date, available treatments are unlikely to lead to seizure remission in the majority of patients and therefore the primary focus of treatment should always be optimization of learning, behavioral management, and overall quality of life

Are we failing to provide adequate rescue medication to children at risk of prolonged convulsive seizures in schools?

Objective: This paper explores the issues that arise from the discussion of administering rescue medication to children who experience prolonged convulsive seizures in mainstream schools in the UK. Situation analysis: Current guidelines recommend immediate treatment of children with such seizures (defined as seizures lasting more than 5 min) to prevent progression to status epilepticus and neurological morbidity. As children are unconscious during prolonged convulsive seizures, whether or not they receive their treatment in time depends on the presence of a teacher or other member of staff trained and able to administer rescue medication. However, it is thought that the situation varies between schools and depends mainly on the goodwill and resources available locally. Recommendations: A more systematic response is needed to ensure that children receive rescue medication regardless of where their seizure occurs. Possible ways forward include: greater use of training resources for schools available from epilepsy voluntary sector organisations; consistent, practical information to schools; transparent guidance outlining a clear care pathway from the hospital to the school; and implementation and adherence to each child’s individual healthcare plan. Implications: Children requiring emergency treatment for prolonged convulsive seizures during school hours test the goals of integrated, person-centred care as well as joined-up working to which the National Health Service (NHS) aspires. As changes to the NHS come into play and local services become reconfigured, every effort should be made to take account of the particular needs of this vulnerable group of children within broader efforts to improve the quality of paediatric epilepsy services overall.peer-reviewe

Medical treatment in infants and young children with epilepsy: Off-label use of antiseizure medications Survey Report of ILAE Task Force Medical Therapies in Children

OBJECTIVE: Antiseizure medications (ASMs) remain the mainstay of epilepsy treatment. These ASMs have mainly been tested in trials in adults with epilepsy, which subsequently led to the market authorization (MA). For treatment of -especially young- children with epilepsy, several ASMs do not have a MA and guidelines are lacking, subsequently leading to "off-label" use of ASMs. Even though "off-label" ASM prescriptions for children could lead to more adverse events, it can be clinically appropriate and rational if the benefits outweigh the risks. This could be the case if "on-label" ASM, in mono- or polytherapy, fail to achieve adequate seizure control. METHODS: The Medical Therapies Task Force of the International League Against Epilepsy (ILAE) Commission for Pediatrics performed a survey to study the current treatment practices in six classic, early life epilepsy scenarios. Our aim was not only to study first- and second-line treatment preferences, but also to illustrate the use of "off-label" drugs in childhood epilepsies. RESULTS: Our results reveal that several ASMs (e.g. topiramate, oxcarbazepine, benzodiazepines) are prescribed "off-label" in distinct scenarios of young children with epilepsy. In addition, recent scientific guidelines were not always adopted by several survey respondents, suggesting a potential knowledge gap. SIGNIFICANCE: We report the relatively common use of "off-label" prescriptions that underlines the need for targeted and appropriately designed clinical trials, including younger patients, which will also result in the ability to generate evidence-based guidelines

Retrospective chart review study of use of cannabidiol (CBD) independent of concomitant clobazam use in patients with Lennox-Gastaut syndrome or Dravet syndrome

PURPOSE: This retrospective chart review study (GWEP20052) evaluated plant-derived highly purified cannabidiol (CBD; Epidyolex®; 100 mg/mL oral solution) use without clobazam as add-on therapy in patients aged ≥2 years with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) enrolled in a European Early Access Program. METHODS: Data were extracted from patient charts covering a period starting 3 months before CBD treatment and concluding after 12 months of CBD treatment, or sooner if a patient discontinued CBD or started clobazam. RESULTS: Of 114 enrolled patients, data were available for 107 (92 LGS, 15 DS) who received CBD without clobazam for ≥3 months. Mean age: 14.5 (LGS) and 10.5 (DS) years; female: 44% (LGS) and 67% (DS). Mean time-averaged CBD dose: 13.54 (LGS) and 11.56 (DS) mg/kg/day. Median change from baseline in seizure frequency per 28 days over 3-month intervals varied from -6.2% to -20.9% for LGS and 0% to -16.7% for DS. Achievement of ≥50% reduction in drop (LGS) or convulsive (DS) seizures at 3 and 12 months: LGS, 19% (n = 69) and 30% (n = 53); DS, 21% (n = 14) and 13% (n = 8). Retention on CBD without clobazam (enrolled set): 94%, 80%, 69%, and 63% at 3, 6, 9, and 12 months. Adverse event (AE) incidence was 31%, most commonly somnolence, seizure, diarrhea, and decreased appetite. Two patients discontinued CBD owing to AEs, and four patients with LGS experienced elevated liver enzymes. CONCLUSION: Results support favorable effectiveness and retention of CBD without concomitant clobazam for up to 12 months in clinical practice

Methodology of a Natural History Study of a Rare Neurodevelopmental Disorder: Alternating Hemiplegia of Childhood as a Prototype Disease

Here, we describe the process of development of the methodology for an international multicenter natural history study of alternating hemiplegia of childhood as a prototype disease for rare neurodevelopmental disorders. We describe a systematic multistep approach in which we first identified the relevant questions about alternating hemiplegia of childhood natural history and expected challenges. Then, based on our experience with alternating hemiplegia of childhood and on pragmatic literature searches, we identified solutions to determine appropriate methods to address these questions. Specifically, these solutions included development and standardization of alternating hemiplegia of childhood-specific spell video-library, spell calendars, adoption of tailored methodologies for prospective measurement of nonparoxysmal and paroxysmal manifestations, unified data collection protocols, centralized data platform, adoption of specialized analysis methods including, among others, Cohen kappa, interclass correlation coefficient, linear mixed effects models, principal component, propensity score, and ambidirectional analyses. Similar approaches can, potentially, benefit in the study of other rare pediatric neurodevelopmental disorders

A structured, blended learning program towards proficiency in epileptology: the launch of the ILAE Academy Level 2 Program

The ILAE Academy is the online learning platform of the International League Against Epilepsy (ILAE) and offers a structured educational program addressing the competency-based ILAE curriculum in epileptology. The platform was launched in July 2020 with a self-paced course portfolio of interactive e-learning modules addressing ILAE Level 1 learning objectives, defined as the entry level in epileptology. Using feedback questionnaires from completed Level 1 courses as well as sociodemographic and learning-related data obtained from 47 participants, we show that over 50% of learners have an entry level in epileptology and do not have access to on-site training and over 40% do not have access to on-site training. Most respondents found the case-based e-learning modules relevant to their practice needs, and the time for completion was regarded as viable for most, reiterating the value of an online self-paced training in the field. Participants who have successfully completed all compulsory e-learning material of the Level 1 program and received their final certificate will now be eligible to subscribe to the Level 2 program. The Level 2 program addressing the proficiency level of the ILAE curriculum of epileptology was launched on the ILAE Academy platform in May 2022. The Level 2 program will offer an evolving series of self-paced, interactive, case-based e-learning modules on diagnosis, treatment, and counseling of common as well as rare epilepsies at a higher level of care. An interactive online EEG and MRI reader was developed and is embedded into the course content to satisfy the demands of the learners. The hallmark of this level will be the blended learning with tutored online courses, e.g., the established VIREPA courses on EEG and the newly introduced VIREPA MRI program. Our distinguished faculty will hold live tutored online courses in small groups in various languages and continental time zones. Finally, the ILAE face-to-face curricular teaching courses at summer schools and congresses will represent another pillar of this advanced teaching level. The ILAE Academy will also provide Continuing Medical Education (CME) credits to support career planning in epileptology

北陸地方における工業都市発達の要因についての一考察

OBJECTIVE: We aimed to investigate the current practices guiding surgical resection strategies involving epileptogenic zones (EZs) near or in eloquent cortex (EC) at pediatric epilepsy surgery centers worldwide. METHODS: A survey was conducted among 40 respondents from 33 pediatric epilepsy surgery centers worldwide on the weight assigned to diagnostic tests used to define the EZ and EC, how EC is viewed, and how surgeries are planned for foci near or in eloquent cortex. RESULTS: A descriptive analysis was performed that revealed considerable variation in the use of diagnostic tests and resective strategies toward EZ and EC. SIGNIFICANCE: The wide variation in strategies may contribute to undesirable outcomes characterized by poor seizure control with added deficits and underscores the need to establish best practices in pediatric epilepsy surgery. The survey data were used to formulate a set of recommendations to help minimize deficits and to report them consistently

Sex-based electroclinical differences and prognostic factors in epilepsy with eyelid myoclonia

Although a striking female preponderance has been consistently reported in epilepsy with eyelid myoclonia (EEM), no study has specifically explored the variability of clinical presentation according to sex in this syndrome. Here, we aimed to investigate sex-specific electroclinical differences and prognostic determinants in EEM. Data from 267 EEM patients were retrospectively analyzed by the EEM Study Group, and a dedicated multivariable logistic regression analysis was developed separately for each sex. We found that females with EEM showed a significantly higher rate of persistence of photosensitivity and eye closure sensitivity at the last visit, along with a higher prevalence of migraine with/without aura, whereas males with EEM presented a higher rate of borderline intellectual functioning/intellectual disability. In female patients, multivariable logistic regression analysis revealed age at epilepsy onset, eyelid myoclonia status epilepticus, psychiatric comorbidities, and catamenial seizures as significant predictors of drug resistance. In male patients, a history of febrile seizures was the only predictor of drug resistance. Hence, our study reveals sex-specific differences in terms of both electroclinical features and prognostic factors. Our findings support the importance of a sex-based personalized approach in epilepsy care and research, especially in genetic generalized epilepsies

The spectrum of epilepsy with eyelid myoclonia: delineation of disease subtypes from a large multicenter study

Objective Epilepsy with eyelid myoclonia (EEM) has been associated with marked clinical heterogeneity. Early epilepsy onset has been recently linked to lower chances of achieving sustained remission and to a less favorable neuropsychiatric outcome. However, much work is still needed to better delineate this epilepsy syndrome. Methods In this multicenter retrospective cohort study, we included 267 EEM patients from nine countries. Data on electroclinical and demographic features, intellectual functioning, migraine with or without aura, family history of epilepsy, and epilepsy syndromes in relatives were collected in each patient. The impact of age at epilepsy onset (AEO) on EEM clinical features was investigated, along with the distinctive clinical characteristics of patients showing sporadic myoclonia involving body regions other than eyelids (body-MYO). Results Kernel density estimation revealed a trimodal distribution of AEO, and Fisher-Jenks optimization disclosed three EEM subgroups: early onset (EO-EEM), intermediate onset (IO-EEM), and late onset (LO-EEM). EO-EEM was associated with the highest rate of intellectual disability, antiseizure medication refractoriness, and psychiatric comorbidities and with the lowest rate of family history of epilepsy. LO-EEM was associated with the highest proportion of body-MYO and generalized tonic-clonic seizures (GTCS), whereas IO-EEM had the lowest observed rate of additional findings. A family history of EEM was significantly more frequent in IO-EEM and LO-EEM compared with EO-EEM. In the subset of patients with body-MYO (58/267), we observed a significantly higher rate of migraine and GTCS but no relevant differences in other electroclinical features and seizure outcome. Significance Based on AEO, we identified consistent EEM subtypes characterized by distinct electroclinical and familial features. Our observations shed new light on the spectrum of clinical features of this generalized epilepsy syndrome and may help clinicians toward a more accurate classification and prognostic profiling of EEM patients