Encephalocraniocutaneous lipomatosis phenotype associated with mosaic biallelic pathogenic variants in the NF1 gene.

Encephalocraniocutaneous lipomatosis (ECCL) is a sporadic congenital condition characterised by ocular, cutaneous and central nervous system involvement. Mosaic activating variants in FGFR1 and KRAS have been reported in several individuals with this syndrome. We report on a patient with neurofibromatosis type 1 (NF1) with a germline pathogenic variant in the NF1 gene and an ECCL phenotype, suggesting ECCL to be part of a spectrum of malformations associated with NF1 pathogenic variants. An anatomical hemispherectomy was performed for intractable epilepsy. Through genetic analysis of blood, cerebral tissue and giant cell lesions in both jaws, we identified the germline NF1 pathogenic variant in all samples and a second-hit pathogenic NF1 variant in cerebral tissue and both giant cell lesions. Both NF1 variants were located on different alleles resulting in somatic mosaicism for a biallelic NF1 inactivation originating in early embryogenesis (second-hit mosaicism or Happle type 2 mosaicism). The biallelic deficit in NF1 in the left hemicranium explains the severe localised, congenital abnormality in this patient. Identical first and second-hit variants in a giant cell lesion of both upper and lower jaws provide confirmatory evidence for an early embryonic second hit involving at least the neural crest. We suggest that the ECCL phenotype may be part of a spectrum of congenital problems associated with mosaic NF1 nullisomy originating during early embryogenesis. The biallelic NF1 inactivation during early embryogenesis mimics the severe activation of the RAS-MAPK pathway seen in ECCL caused by embryonic mosaic activating FGFR1 and KRAS variants in the cranial region. We propose that distinct mechanisms of mosaicism can cause the ECCL phenotype through convergence on the RAS-MAPK pathway.

Call for the use of the ILAE terminology for seizures and epilepsies by health care professionals and regulatory agencies to benefit patients and caregivers.

The International League Against Epilepsy (ILAE) introduced a classification for seizure types in 2017 and updated the classification for epilepsy syndromes in 2022. These classifications aim to improve communication among healthcare professionals and help patients better describe their condition. So far, regulatory agencies have used different terminology. This paper stresses the crucial need for consistently adopting ILAE terminology in both regulatory processes and clinical practice. It highlights how language plays a significant role in healthcare communication and how standardized terminology can enhance patient comprehension. The ongoing review of guidelines by regulatory bodies offers a timely opportunity. Aligning regulatory terminologies holds the potential to facilitate discussions on future drug development and harmonize practices across diverse regions, ultimately fostering improved care and research outcomes in epilepsy treatment.

Comprehensive scoping review of fenfluramine's role in managing generalized tonic-clonic seizures in developmental and epileptic encephalopathies.

Developmental and epileptic encephalopathies (DEEs) are characterized by pharmacoresistant seizures and developmental delay. Patients with DEEs experience multiple seizure types, including tonic-clonic seizures (TCS) that can be generalized tonic-clonic (GTCS) or focal evolving to bilateral tonic-clonic (FBTCS). Fenfluramine (FFA) has demonstrated efficacy in reduction of TCS in patients with Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS), and other DEEs. Using the PRISMA-ScR (Preferred Reporting Items for Systematic Review and Meta-Analyses extension for Scoping Review) guidelines, we performed a scoping review to describe changes in TCS in patients treated with FFA. A comprehensive search of five literature databases was conducted up to February 14, 2023. Studies were included if they reported change in GTCS or TCS (but not FBTCS) after treatment with FFA in patients with DEEs. Duplicate patients and studies with unclear efficacy data were excluded. Fourteen of 422 studies met the eligibility criteria. Data extracted and evaluated by expert clinicians identified 421 unique patients with DS (in nine studies), CDKL5 deficiency disorder, SCN8A-related disorder, LGS, SCN1B-related disorder, and other DEEs. The median percent reduction in GTCS or TCS from baseline was available in 10 studies (n = 328) and ranged from 47.2% to 100%. Following FFA treatment, 10 studies (n = 144) reported ≥50% reduction in GTCS or TCS from baseline in 72% of patients; in nine of those (n = 112), 54% and 29% of patients achieved ≥75% and 100% reduction in GTCS or TCS from baseline, respectively. Overall, this analysis highlighted improvements in GTCS or TCS frequency when patients were treated with FFA regardless of the DEE evaluated. Future studies may confirm the impact of FFA on TCS reduction and on decreased premature mortality risk (including sudden unexpected death in epilepsy), improvement in comorbidities and everyday executive function, decreased health care costs, and improvement in quality of life.

Developmental epileptic encephalopathy in DLG4-related synaptopathy.

OBJECTIVE: The postsynaptic density protein of excitatory neurons PSD-95 is encoded by discs large MAGUK scaffold protein 4 (DLG4), de novo pathogenic variants of which lead to DLG4-related synaptopathy. The major clinical features are developmental delay, intellectual disability (ID), hypotonia, sleep disturbances, movement disorders, and epilepsy. Even though epilepsy is present in 50% of the individuals, it has not been investigated in detail. We describe here the phenotypic spectrum of epilepsy and associated comorbidities in patients with DLG4-related synaptopathy. METHODS: We included 35 individuals with a DLG4 variant and epilepsy as part of a multicenter study. The DLG4 variants were detected by the referring laboratories. The degree of ID, hypotonia, developmental delay, and motor disturbances were evaluated by the referring clinician. Data on awake and sleep electroencephalography (EEG) and/or video-polygraphy and brain magnetic resonance imaging were collected. Antiseizure medication response was retrospectively assessed by the referring clinician. RESULTS: A large variety of seizure types was reported, although focal seizures were the most common. Encephalopathy related to status epilepticus during slow-wave sleep (ESES)/developmental epileptic encephalopathy with spike-wave activation during sleep (DEE-SWAS) was diagnosed in >25% of the individuals. All but one individual presented with neurodevelopmental delay. Regression in verbal and/or motor domains was observed in all individuals who suffered from ESES/DEE-SWAS, as well as some who did not. We could not identify a clear genotype-phenotype relationship even between individuals with the same DLG4 variants. SIGNIFICANCE: Our study shows that a subgroup of individuals with DLG4-related synaptopathy have DEE, and approximately one fourth of them have ESES/DEE-SWAS. Our study confirms DEE as part of the DLG4-related phenotypic spectrum. Occurrence of ESES/DEE-SWAS in DLG4-related synaptopathy requires proper investigation with sleep EEG.

A tool for Dravet syndrome-associated neuropsychiatric comorbidities evaluation (DANCE).

BACKGROUND: Dravet syndrome (DS) is a rare and severe form of epilepsy that begins in infancy, which is primarily caused by pathogenic variants in the SCN1A gene. DS is characterized by prolonged and frequent drug-resistant seizures, as well as developmental delays and behavioral problems. The identification of these comorbidities is based on clinical interview and relies on healthcare professionals (HCPs) experience. METHODS: We assembled a group of expert HCPs and caregivers to create a screening checklist for assessing DS-Associated Neuropsychiatric Comorbidities (DANC). The checklist includes questions related to cognitive and psychiatric domains, motor skills, and the impact of DS on families' daily lives. We administered the checklist to 24 caregivers of DS patients from Belgium, France, and Spain. After piloting, we obtained feedback from expert HCPs and caregivers to refine the checklist. RESULTS: DS patients showed a wide array of neuropsychiatric symptoms related to DS. The most common cognitive domains reported were attention difficulties and multitasking problems (18/24 caregivers), and impulsivity (17/24), while the most common psychiatric symptoms were temper tantrums (14/24), mood swings (13/24) and autism spectrum disorder (12/24). Balance and coordination problem have been reported in almost all patients with a statement of only 4/23 with complete mobility. Most patients were dependent on others for self-care and eating, and presented sleeping disturbances. Caregivers reported high levels of stress in the family unit, both between siblings and parents. Results show that the main concerns of parents were the behavior and the cognition of the person with DS. The quantitative feedback results showed good-to-very good scores on usefulness, ease of completion, clarity and comprehensiveness of the checklist. CONCLUSIONS: This pilot study suggests that the DANCE checklist could be a useful screening tool in daily practice for neuropsychiatric comorbidities facilitating their diagnosis and treatment, and empowering both caregivers and patients.

Practical considerations for the use of fenfluramine to manage patients with Dravet syndrome or Lennox-Gastaut syndrome in clinical practice.

Fenfluramine (FFA), an antiseizure medication (ASM) with serotonergic and sigma-1 receptor activity, is used to manage patients with developmental and epileptic encephalopathies (DEEs). It is approved in the US for treating seizures associated with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) in patients ≥2 years old and as add-on therapy for seizures associated with DS and LGS in the EU, UK, and Japan in similarly aged patients. Consensus guidelines for treatment of DS have recommended FFA to be an early-line ASM, and it has also shown efficacy in managing seizures associated with LGS. DS and LGS are DEEs associated with a range of seizure types, developmental impairments, and multiple comorbidities. Here we provide case vignettes describing 4 patients (3 DS and 1 LGS) aged 4-29 years old in whom up to 14 ASMs had previously failed, to illustrate real-world practice issues encountered by neurologists. This review provides guidance on the use of FFA in the context of ASM polytherapy and drug-drug interactions (DDIs), behavioral issues, dose titration, and adverse events. Along with data from the clinical trial program, these case vignettes emphasize the low risk of DDIs, a generally well-tolerated safety profile, and other seizure and nonseizure benefits (eg, improved cognition and sleep) associated with the use of FFA in DS or LGS. PLAIN LANGUAGE SUMMARY: Fenfluramine is used to treat seizures in individuals with Dravet syndrome and Lennox-Gastaut syndrome, but there are a range of issues that clinicians may face when treating patients. This review highlights four patients from the authors' everyday clinical work and offers guidance and practical considerations by neurologists with expertise in managing these complex conditions related to drug interactions, dosing, and side effects associated with fenfluramine.

Automated sleep staging on reduced channels in children with epilepsy.

Objectives: This study aimed to validate a sleep staging algorithm using in-hospital video-electroencephalogram (EEG) in children without epilepsy, with well-controlled epilepsy (WCE), and with drug-resistant epilepsy (DRE). Methods: Overnight video-EEG, along with electrooculogram (EOG) and chin electromyogram (EMG), was recorded in children between 4 and 18 years of age. Classical sleep staging was performed manually as a ground truth. An end-to-end hierarchical recurrent neural network for sequence-to-sequence automatic sleep staging (SeqSleepNet) was used to perform automated sleep staging using three channels: C4-A1, EOG, and chin EMG. Results: In 176 children sleep stages were manually scored: 47 children without epilepsy, 74 with WCE, and 55 with DRE. The 5-class sleep staging accuracy of the automatic sleep staging algorithm was 84.7% for the children without epilepsy, 83.5% for those with WCE, and 80.8% for those with DRE (Kappa of 0.79, 0.77, and 0.73 respectively). Performance per sleep stage was assessed with an F1 score of 0.91 for wake, 0.50 for N1, 0.83 for N2, 0.84 for N3, and 0.86 for rapid eye movement (REM) sleep. Conclusion: We concluded that the tested algorithm has a high accuracy in children without epilepsy and with WCE. Performance in children with DRE was acceptable, but significantly lower, which could be explained by a tendency of more time spent in N1, and by abundant interictal epileptiform discharges and intellectual disability leading to less recognizable sleep stages. REM sleep time, however, significantly affected in children with DRE, can be detected reliably by the algorithm.Clinical trial registration: ClinicalTrials.gov, identifier NCT04584385.

Outpatient management of prolonged seizures and seizure clusters to prevent progression to a higher-level emergency: Consensus recommendations of an expert working group.

OBJECTIVE: The management of prolonged seizures (PS) and seizure clusters (SC) is impeded by the lack of international, evidence-based guidance. We aimed to develop expert recommendations regarding consensus definitions of PS, SC, and treatment goals to prevent progression to higher-level emergencies such as status epilepticus (SE). METHODS: An expert working group, comprising 12 epileptologists, neurologists, and pharmacologists from Europe and North America, used a modified Delphi consensus methodology to develop and anonymously vote on statements. Consensus was defined as ≥75% voting "Agree"/"Strongly agree." RESULTS: All group members strongly agreed that termination of an ongoing seizure in as short a time as possible is the primary goal of rapid and early seizure termination (REST) and that an ideal medication for REST would start to act within 2 min of administration to terminate ongoing seizure activity. Consensus was reached on the terminology defining PS (with proposed thresholds of 5 min for prolonged focal seizures and 2 min for prolonged absence seizures and the convulsive phase of bilateral tonic-clonic seizures) and SC (an abnormal increase in seizure frequency compared with the individual patient's usual seizure pattern). All group members strongly agreed or agreed that patients who have experienced a PS should be offered a REST medication, and all patients who have experienced a SC should be offered an acute cluster treatment (ACT). Further, when prescribing a REST medication or ACT, a seizure action plan should be agreed upon in consultation with the patient and caregiver. SIGNIFICANCE: The expert working group had a high level of agreement on the recommendations for defining and managing PS and SC. These recommendations will complement the existing guidance for the management of acute seizures, with the possibility of treating them earlier to potentially avoid progression to more severe seizures, including SE.

Long-term neurocognitive, psychosocial, and physical outcomes after prenatal exposure to radiotherapy: a multicentre cohort study of the International Network on Cancer, Infertility, and Pregnancy.

BACKGROUND: The main data available on the safety of radiation during pregnancy originate from animal studies and from studies of survivors of atomic or nuclear disasters. The effect of radiotherapy to treat maternal cancer on fetal development is uncertain. This report presents a unique cohort and aims to determine the long-term neurocognitive, psychosocial and physical outcomes of offspring of mothers treated with radiotherapy during pregnancy. METHODS: In this international, multicentre, mixed retrospective-prospective cohort study, we recruited participants between Aug 5, 2006, and Aug 24, 2023, aged between 1·5 and 46 years, at three referral centres in Belgium, the Netherlands, and the USA. Participants were eligible if they were born from mothers treated with radiotherapy during pregnancy. Fetal radiation doses were obtained from medical records and participants were followed up at predefined ages (1·5, 3, 6, 9, 12, 15, and 18 years) and 5-yearly in adulthood, based on age at enrolment, using a neurocognitive test battery (measuring intelligence, attention, and memory), parent-reported executive function and psychosocial questionnaires, and a medical assessment. Results were compared with test-specific normative data. Linear regression models investigated associations between radiotherapy factors (fetal radiation dose, gestational age at the start and end of radiotherapy, and radiotherapy duration) and outcomes. FINDINGS: 68 maternal cases of radiotherapy during pregnancy were registered by the three participating centres, of which 61 resulted in a livebirth and were therefore eligible to participate in the child follow-up study. After excluding those who did not give consent, 43 participants born from 42 mothers treated with radiotherapy during pregnancy were included in the study (median age at first assessment 3 years [IQR 2-11]; median age at last assessment 12 years [9-18]; median number of assessments two [1-4]). 18 (42%) of the included participants were female and 25 (58%) male, and 37 (86%) were of White ethnicity. Mean neurocognitive outcomes of the entire cohort were within normal ranges. No associations were found with fetal radiation dose or timing of radiotherapy during pregnancy. Six (16%) of 38 participants with neurocognitive outcomes scored lower than one SD on at least one neurocognitive outcome, three (7%) reported chronic medical conditions (spasmophilia, spastic diplegia, and IgG deficiency), and three (7%) were diagnosed with attention-deficit hyperactivity disorder (of whom two scored lower on attention). Of ten (23%) participants with lower neurocognitive score(s), a chronic medical condition, or attention-deficit hyperactivity disorder, eight were born preterm. The remaining 33 (77%) participants showed no neurocognitive, psychosocial, or chronic physical problems. INTERPRETATION: We show on average normal neurocognitive, psychosocial, and physical outcomes after prenatal exposure to radiotherapy. Differences in outcomes could not be explained by exposure to radiotherapy during pregnancy. These results suggest that extra-abdomino-pelvic radiotherapy exposure during pregnancy in general does not adversely affect outcomes of liveborn children. Further research with a larger sample is necessary to confirm these findings. FUNDING: Kom Op Tegen Kanker, KWF Kankerbestrijding, Stichting Tegen Kanker, Research Foundation Flanders.