The expanding field of genetic developmental and epileptic encephalopathies: current understanding and future perspectives.

Recent advances in genetic testing technologies have revolutionised the identification of genetic abnormalities in early onset developmental and epileptic encephalopathies (DEEs). In this Review, we provide an update on the expanding landscape of genetic factors contributing to DEEs, encompassing over 800 reported genes. We focus on the cellular and molecular mechanisms driving epileptogenesis, with an emphasis on emerging therapeutic strategies and effective treatment options. We explore noteworthy, novel genes linked to DEE phenotypes, such as gBRAT-1 and GNAO1, and gene families such as GRIN and HCN. Understanding the network-level effects of gene variants will pave the way for potential gene therapy applications. Given the diverse comorbidities associated with DEEs, a multidisciplinary team approach is essential. Despite ongoing efforts and improved genetic testing, DEEs lack a cure, and treatment complexities persist. This Review underscores the necessity for larger international prospective studies focusing on both seizure outcomes and developmental trajectories.

Report from the child neurology education and training workshop at the International Child Neurology Congress 2024: Expert'saddressing the training gap.

This report summarizes the key findings of a workshop undertaken at the International Child Neurology Congress in 2024 by child neurologists with expertise in training education and invested colleagues. The workshop aimed to explore global issues which have impact on access to child neurology training. The major findings supported a great need for more training programs globally, that consensus is needed for the minimum standards of training, and that training programs can be strengthened via global health partnerships especially with collaborations from regions with more available resources. The group concurred that the phenomena of 'neurophobia' amongst general paediatricians and medical trainees, was a reality, and creates barriers both working with paediatric colleagues, as well as recruiting specialists to the field. Optimal teaching practices for child neurology should include the expansion of learning through global partnerships and virtual educational resources. Measures must be put into place for fledgling training programs, to support colleagues in less resourced settings and to avoid their burn-out. Collegial and collaborative work is essential to support the future of child neurology across the globe, both to reach the current capacity needs but also to meet the necessary growth in the field.

Pre- and Post-Exposure Prophylaxis for HIV in Patients Taking Anti-Seizure Medications.

The prevention of human immunodeficiency virus (HIV) infection has recently emphasized the use of pre- and post-exposure prophylaxis (PrEP and PEP), both of which were highly effective in prevention of HIV infection. Since the last published guidance regarding the cotreatment of people with anti-seizure medications (ASM) and antiretroviral treatments (ARTs) in 2012, both fields have numerous new medication options. Historically, cotreatment of HIV and seizures could be challenging with increased risk of virologic failure and barriers in access to health care due to global availability, social determinants of health, and stigma of both HIV and seizures. In this narrative review, we describe the data-driven and expected bidirectional pharmacokinetic (PK) interactions between guideline-based PrEP and PEP treatment and ASM, as well as overlapping side effects. There are many ASMs with no known interaction with PrEP or PEP regimens. The interactions focus on enzyme inducing ASMs, valproate, and lamotrigine. Most prominently, enzyme inducing ASMs lower serum levels of tenofovir-containing PrEP regimens and elements of PEP (dolutegravir, raltegravir, and ritonavir), which increased risk of virologic treatment failure in people with HIV but have unclear clinical significance on the effectiveness of PrEP and PEP. In addition, ritonavir treatment in PEP may significantly lower lamotrigine serum levels even during the 4 weeks of treatment, which may increase risk for breakthrough seizures during PEP and skin reactions after discontinuation of ritonavir. In addition to PK interactions, overlapping side effects are common including osteopenia, hepatic toxicity, and other gastrointestinal effects. This narrative review aims to be a resource for all clinicians prescribing ASMs so that they can create a welcoming environment to enable successful treatment of seizures and reduce the risk of HIV infection in people at risk. In addition, we highlight knowledge gaps and areas of unmet need that can be addressed with future studies.

Consensus-based recommendations for the diagnosis and treatment of anxiety and depression in children and adolescents with epilepsy: A report from the Psychiatric Pediatric Issues Task Force of the International League Against Epilepsy.

The Psychiatric Pediatric Issues Task Force of the International League Against Epilepsy (ILAE) aimed to develop recommendations for the diagnosis and treatment of anxiety and depression in children and adolescents with epilepsy. The Task Force conducted a systematic review and identified two studies that assessed the accuracy of four screening measures for depression and anxiety symptoms compared with a psychiatric interview. Nine studies met the eligibility criteria for treatment of anxiety and depressive disorders or symptoms. The risk of bias and certainty of evidence were assessed. The evidence generated by this review followed by consensus where evidence was missing generated 47 recommendations. Those with a high level of agreement (≥80%) are summarized. Diagnosis: (1) Universal screening for anxiety and depression is recommended. Closer surveillance is recommended for children after 12 years, at higher risk (e.g., suicide-related behavior), with subthreshold symptoms, and experiencing seizure worsening or therapeutic modifications. (2) Multiple sources of ascertainment and a formal screening are recommended. Clinical interviews are recommended whenever possible. The healthcare provider must always explain that symptom recognition is essential to optimize treatment outcomes and reduce morbidity. (3) Questioning about the relationship between symptoms of anxiety or depression with seizure worsening/control and behavioral adverse effects of antiseizure medications is recommended. Treatment: (1) An individualized treatment plan is recommended. (2) For mild depression, active monitoring must be considered. (3) Referral to a mental health care provider must be considered for moderate to severe depression and anxiety. (4) Clinical care pathways must be developed. (5) Psychosocial interventions must be tailored and age-appropriate. (6) Healthcare providers must monitor children with epilepsy who are prescribed antidepressants, considering symptoms and functioning that may not improve simultaneously. (7) Caregiver education is essential to ensure treatment adherence. (8) A shared-care model involving all healthcare providers is recommended for children and adolescents with epilepsy and mental health disorders. We identified clinical decisions in the management of depression and anxiety that lack solid evidence and provide consensus-based guidance to address the care of children and adolescents with epilepsy.

The international league against epilepsy primary healthcare educational curriculum: Assessment of educational needs.

OBJECTIVE: To assess the need for an epilepsy educational curriculum for primary healthcare providers formulated by the International League Against Epilepsy (ILAE) and the importance attributed to its competencies by epilepsy specialists and primary care providers and across country-income settings. METHODS: The ILAE primary care epilepsy curriculum was translated to five languages. A structured questionnaire assessing the importance of its 26 curricular competencies was posted online and publicized widely to an international community. Respondents included epilepsy specialists, primary care providers, and others from three World Bank country-income categories. Responses from different groups were compared with univariate and ordinal logistic regression analyses. RESULTS: Of 785 respondents, 60% noted that a primary care epilepsy curriculum did not exist or they were unaware of one in their country. Median ranks of importance for all competencies were high (very important to extremely important) in the entire sample and across different groups. Fewer primary care providers than specialists rated the following competencies as extremely important: definition of epilepsy (p = .03), recognition of seizure mimics (p = .02), interpretation of test results for epilepsy care (p = .001), identification of drug-resistant epilepsy (0.005) and management of psychiatric comorbidities (0.05). Likewise, fewer respondents from LMICs in comparison to UMICs rated 15 competencies as extremely important. SIGNIFICANCE: The survey underscores the unmet need for an epilepsy curriculum in primary care and the relevance of its competencies across different vocational and socioeconomic settings. Differences across vocational and country income groups indicate that educational packages should be developed and adapted to needs in different settings.

Development of an International Standard Set of Outcomes and Measurement Methods for Routine Practice for Infants, Children, and Adolescents with Epilepsy: The International Consortium for Health Outcomes Measurement Consensus Recommendations.

At present, there is no internationally accepted set of core outcomes or measurement methods for epilepsy clinical practice. The International Consortium for Health Outcomes Measurement (ICHOM) convened an international working group of experts in epilepsy, people with epilepsy, and their representatives to develop minimum sets of standardized outcomes and outcome measurement methods for clinical practice. Using modified Delphi consensus methods with consecutive rounds of online voting over 12 months, a core set of outcomes and corresponding measurement tool packages to capture the outcomes were identified for infants, children, and adolescents with epilepsy. Consensus methods identified 20 core outcomes. In addition to the outcomes identified for the ICHOM Epilepsy adult standard set, behavioral, motor, and cognitive/language development outcomes were voted as essential for all infants and children with epilepsy. The proposed set of outcomes and measurement methods will facilitate the implementation of the use of patient-centered outcomes in daily practice.

Development of an International Standard Set of Outcomes and Measurement Methods for Routine Practice for Adults with Epilepsy: The International Consortium for Health Outcomes Measurement Consensus Recommendations.

At present, there is no internationally accepted set of core outcomes or measurement methods for epilepsy clinical practice. Therefore, the International Consortium for Health Outcomes Measurement (ICHOM) convened an international working group of experts in epilepsy, people with epilepsy and their representatives to develop minimum sets of standardized outcomes and outcomes measurement methods for clinical practice that support patient-clinician decision-making and quality improvement. Consensus methods identified 20 core outcomes. Measurement tools were recommended based on their evidence of strong clinical measurement properties, feasibility, and cross-cultural applicability. The essential outcomes included many non-seizure outcomes: anxiety, depression, suicidality, memory and attention, sleep quality, functional status, and the social impact of epilepsy. The proposed set will facilitate the implementation of the use of patient-centered outcomes in daily practice, ensuring holistic care. They also encourage harmonization of outcome measurement, and if widely implemented should reduce the heterogeneity of outcome measurement, accelerate comparative research, and facilitate quality improvement efforts.

Ketogenic dietary therapy utilization in Kenya: A qualitative exploration of dietitian's perceptions.

This study utilized a qualitative design to explore dietitians' perceptions regarding Ketogenic Diet Therapy (KDT) for patients with drug-resistant epilepsy in Kenya. Dietitians from Kenya were selected and consented. Audio-recorded interviews were conducted, followed by thematic analysis of verbatim transcripts to identify recurring patterns. The study enrolled 18 dietitians, fourteen of whom correctly described their understanding of KDT for managing drug-resistant epilepsy. There was a lack of confidence in their capacity to initiate the KDT with all expressing the need for further training and facilitation. Only one dietitian reported having initiated and maintained KDT. There was an overall positive view regarding KDT and willingness to implement KDT for patients with drug-resistant epilepsy. Dietitians expressed concerns regarding the availability of national policies, inadequate staffing to support families who require KDT, and the cost of implementing this intervention. Dietitians expressed interest in virtual training to enhance their understanding of KDT. Dietitians in Kenya are mostly aware of KDT utilization for the management of drug-resistant epilepsy. However, they cited poor capability and various barriers to implementation. There is a need for policies to facilitate KDT as a treatment option for the benefit of patients with drug-resistant epilepsy.

Improving epilepsy diagnosis across the lifespan: approaches and innovations.

Epilepsy diagnosis is often delayed or inaccurate, exposing people to ongoing seizures and their substantial consequences until effective treatment is initiated. Important factors contributing to this problem include delayed recognition of seizure symptoms by patients and eyewitnesses; cultural, geographical, and financial barriers to seeking health care; and missed or delayed diagnosis by health-care providers. Epilepsy diagnosis involves several steps. The first step is recognition of epileptic seizures; next is classification of epilepsy type and whether an epilepsy syndrome is present; finally, the underlying epilepsy-associated comorbidities and potential causes must be identified, which differ across the lifespan. Clinical history, elicited from patients and eyewitnesses, is a fundamental component of the diagnostic pathway. Recent technological advances, including smartphone videography and genetic testing, are increasingly used in routine practice. Innovations in technology, such as artificial intelligence, could provide new possibilities for directly and indirectly detecting epilepsy and might make valuable contributions to diagnostic algorithms in the future.

Reducing epilepsy diagnostic and treatment gaps: Standardized paediatric epilepsy training courses for health care professionals.

AIM: To evaluate improvement in knowledge and clinical behaviour among healthcare professionals after attendance at paediatric epilepsy training (PET) courses. METHOD: Since 2005, 1-day PET courses have taught evidence-based paediatric epilepsy management to doctors and nurses in low-, middle-, and high-income countries. A cohort study was performed of 7528 participants attending 252 1-day PET courses between 2005 and 2020 in 17 low-, middle-, and high-income countries, and which gathered data from participants immediately after the course and then 6 months later. Training outcomes were measured prospectively in three domains (reaction, learning, and behaviour) using a mixed-methods approach involving a feedback questionnaire, a knowledge quiz before and after the course, and a 6-month survey. RESULTS: Ninety-eight per cent (7217 of 7395) of participants rated the course as excellent or good. Participants demonstrated knowledge gain, answering a significantly higher proportion of questions correctly after the course compared to before the course (88% [47 883 of 54 196], correct answers/all quiz answers, vs 75% [40 424 of 54 196]; p < 0.001). Most survey responders reported that the course had improved their epilepsy diagnosis and management (73% [311 of 425]), clinical service (68% [290 of 427]), and local epilepsy training (68% [290 of 427]). INTERPRETATION: This was the largest evaluation of a global epilepsy training course. Participants reported high course satisfaction, showed knowledge gain, and described improvements in clinical behaviour 6 months later. PET supports the global reduction in the epilepsy 'treatment gap' as promoted by the World Health Organization.

Which terms should be used to describe medications used in the treatment of seizure disorders? An ILAE position paper.

A variety of terms, such as "antiepileptic," "anticonvulsant," and "antiseizure" have been historically applied to medications for the treatment of seizure disorders. Terminology is important because using terms that do not accurately reflect the action of specific treatments may result in a misunderstanding of their effects and inappropriate use. The present International League Against Epilepsy (ILAE) position paper used a Delphi approach to develop recommendations on English-language terminology applicable to pharmacological agents currently approved for treating seizure disorders. There was consensus that these medications should be collectively named "antiseizure medications". This term accurately reflects their primarily symptomatic effect against seizures and reduces the possibility of health care practitioners, patients, or caregivers having undue expectations or an incorrect understanding of the real action of these medications. The term "antiseizure" to describe these agents does not exclude the possibility of beneficial effects on the course of the disease and comorbidities that result from the downstream effects of seizures, whenever these beneficial effects can be explained solely by the suppression of seizure activity. It is acknowledged that other treatments, mostly under development, can exert direct favorable actions on the underlying disease or its progression, by having "antiepileptogenic" or "disease-modifying" effects. A more-refined terminology to describe precisely these actions needs to be developed.

Clinical practice applicability and relevance to non-specialists of a paediatric EEG online learning tool.

BACKGROUND: Paediatric electroencephalography (EEG) training is inadequate amongst healthcare practitioners and technicians managing children with epilepsy in sub-Saharan Africa. An entry level handbook was developed for healthcare practitioners in sub-Saharan Africa and subsequently made globally accessible via the International Child Neurology Teaching Network. AIM: To investigate the usefulness of a paediatric online EEG handbook. METHOD: A survey of the ICNApedia online EEG handbook was circulated (December 2021-June 2022), to all 108 handbook registered participants (39 countries) via the research electronic data capture (REDCap) from the University of Cape Town (UCT). RESULTS: Fifty participants from 25 countries responded: 8 from high income, 16 upper-middle income, 21 lower-middle income and 5 from low-income. 32 (64%) fully and 18 (36%) partially completed the survey. 35/50 (70%) had completed the handbook and seven respondents had partially completed the handbook. Responses supported the handbook as a good entry point to learn EEGs, especially for paediatrics. Likert scale ratings supported the handbook as relevant for gaining/enhancing knowledge and improving diagnosis and management of patients with confidence. The handbook was considered user friendly, comprehensible, and provided a practical experience. For improving EEG reading skills the handbook helped skills development via reinforcement and good illustrations. 29/32 (90%) of respondents confirmed that they are using learnt skills from the handbook in their current work. CONCLUSION: In resource limited settings non-specialist clinicians often provide extended services including EEG interpretation. The survey supports that the handbook is supporting this niche skills area, especially for the accessibility of knowledge gained. The handbook will continue to be adapted in-line with survey feedback.

Scoping review and expert-based consensus recommendations for assessment and management of psychogenic non-epileptic (functional) seizures (PNES) in children: A report from the Pediatric Psychiatric Issues Task Force of the International League Against Epilepsy.

Limited guidance exists regarding the assessment and management of psychogenic non-epileptic seizures (PNES) in children. Our aim was to develop consensus-based recommendations to fill this gap. The members of the International League Against Epilepsy (ILAE) Task Force on Pediatric Psychiatric Issues conducted a scoping review adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-SR) standards. This was supplemented with a Delphi process sent to pediatric PNES experts. Consensus was defined as ≥80% agreement. The systematic search identified 77 studies, the majority (55%) of which were retrospective (only one randomized clinical trial). The primary means of PNES identification was video electroencephalography (vEEG) in 84% of studies. Better outcome was associated with access to counseling/psychological intervention. Children with PNES have more frequent psychiatric disorders than controls. The Delphi resulted in 22 recommendations: Assessment-There was consensus on the importance of (1) taking a comprehensive developmental history; (2) obtaining a description of the events; (3) asking about potential stressors; (4) the need to use vEEG if available parent, self, and school reports and video recordings can contribute to a "probable" diagnosis; and (5) that invasive provocation techniques or deceit should not be employed. Management-There was consensus about the (1) need for a professional with expertise in epilepsy to remain involved for a period after PNES diagnosis; (2) provision of appropriate educational materials to the child and caregivers; and (3) that the decision on treatment modality for PNES in children should consider the child's age, cognitive ability, and family factors. Comorbidities-There was consensus that all children with PNES should be screened for mental health and neurodevelopmental difficulties. Recommendations to facilitate the assessment and management of PNES in children were developed. Future directions to fill knowledge gaps were proposed.

Dravet syndrome: A systematic literature review of the illness burden.

We performed a systematic literature review and narrative synthesis according to a pre-registered protocol (Prospero: CRD42022376561) to identify the evidence associated with the burden of illness in Dravet syndrome (DS), a developmental and epileptic encephalopathy characterized by drug-resistant epilepsy with neurocognitive and neurobehavioral impairment. We searched MEDLINE, Embase, and APA PsychInfo, Cochrane's database of systematic reviews, and Epistemonikos from inception to June 2022. Non-interventional studies reporting on epidemiology (incidence, prevalence, and mortality), patient and caregiver health-related quality of life (HRQoL), direct and indirect costs and healthcare resource utilization were eligible. Two reviewers independently carried out the screening. Pre-specified data were extracted and a narrative synthesis was conducted. Overall, 49 studies met the inclusion criteria. The incidence varied from 1:15 400-1:40 900, and the prevalence varied from 1.5 per 100 000 to 6.5 per 100 000. Mortality was reported in 3.7%-20.8% of DS patients, most commonly due to sudden unexpected death in epilepsy and status epilepticus. Patient HRQoL, assessed by caregivers, was lower than in non-DS epilepsy patients; mean scores (0 [worst] to 100/1 [best]) were 62.1 for the Kiddy KINDL/Kid-KINDL, 46.5-54.7 for the PedsQL and 0.42 for the EQ-5D-5L. Caregivers, especially mothers, were severely affected, with impacts on their time, energy, sleep, career, and finances, while siblings were also affected. Symptoms of depression were reported in 47%-70% of caregivers. Mean total direct costs were high across all studies, ranging from $11 048 to $77 914 per patient per year (PPPY), with inpatient admissions being a key cost driver across most studies. Mean costs related to lost productivity were only reported in three publications, ranging from approximately $19 000 to $20 000 PPPY ($17 596 for mothers vs $1564 for fathers). High seizure burden was associated with higher resource utilization, costs and poorer HRQoL. The burden of DS on patients, caregivers, the healthcare system, and society is profound, reflecting the severe nature of the syndrome. Future studies will be able to assess the impact that newly approved therapies have on reducing the burden of DS.

Treatment of seizures in the neonate: Guidelines and consensus-based recommendations-Special report from the ILAE Task Force on Neonatal Seizures.

Seizures are common in neonates, but there is substantial management variability. The Neonatal Task Force of the International League Against Epilepsy (ILAE) developed evidence-based recommendations about antiseizure medication (ASM) management in neonates in accordance with ILAE standards. Six priority questions were formulated, a systematic literature review and meta-analysis were performed, and results were reported following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 standards. Bias was evaluated using the Cochrane tool and risk of Bias in non-randomised studies - of interventions (ROBINS-I), and quality of evidence was evaluated using grading of recommendations, assessment, development and evaluation (GRADE). If insufficient evidence was available, then expert opinion was sought using Delphi consensus methodology. The strength of recommendations was defined according to the ILAE Clinical Practice Guidelines development tool. There were six main recommendations. First, phenobarbital should be the first-line ASM (evidence-based recommendation) regardless of etiology (expert agreement), unless channelopathy is likely the cause for seizures (e.g., due to family history), in which case phenytoin or carbamazepine should be used. Second, among neonates with seizures not responding to first-line ASM, phenytoin, levetiracetam, midazolam, or lidocaine may be used as a second-line ASM (expert agreement). In neonates with cardiac disorders, levetiracetam may be the preferred second-line ASM (expert agreement). Third, following cessation of acute provoked seizures without evidence for neonatal-onset epilepsy, ASMs should be discontinued before discharge home, regardless of magnetic resonance imaging or electroencephalographic findings (expert agreement). Fourth, therapeutic hypothermia may reduce seizure burden in neonates with hypoxic-ischemic encephalopathy (evidence-based recommendation). Fifth, treating neonatal seizures (including electrographic-only seizures) to achieve a lower seizure burden may be associated with improved outcome (expert agreement). Sixth, a trial of pyridoxine may be attempted in neonates presenting with clinical features of vitamin B6-dependent epilepsy and seizures unresponsive to second-line ASM (expert agreement). Additional considerations include a standardized pathway for the management of neonatal seizures in each neonatal unit and informing parents/guardians about the diagnosis of seizures and initial treatment options.

The mutational profile in a South African cohort with inherited neuropathies and spastic paraplegia.

Introduction: Limited diagnostics are available for inherited neuromuscular diseases (NMD) in South Africa and (excluding muscle disease) are mainly aimed at the most frequent genes underlying genetic neuropathy (GN) and spastic ataxias in Europeans. In this study, we used next-generation sequencing to screen 61 probands with GN, hereditary spastic paraplegia (HSP), and spastic ataxias for a genetic diagnosis. Methods: After identifying four GN probands with PMP22 duplication and one spastic ataxia proband with SCA1, the remaining probands underwent whole exome (n = 26) or genome sequencing (n = 30). The curation of coding/splice region variants using gene panels was guided by allele frequencies from internal African-ancestry control genomes (n = 537) and the Clinical Genome Resource's Sequence Variant Interpretation guidelines. Results: Of 32 GN probands, 50% had African-genetic ancestry, and 44% were solved: PMP22 (n = 4); MFN2 (n = 3); one each of MORC2, ATP1A1, ADPRHL2, GJB1, GAN, MPZ, and ATM. Of 29 HSP probands (six with predominant ataxia), 66% had African-genetic ancestry, and 48% were solved: SPG11 (n = 3); KIF1A (n = 2); and one each of SPAST, ATL1, SPG7, PCYT2, PSEN1, ATXN1, ALDH18A1, CYP7B1, and RFT1. Structural variants in SPAST, SPG11, SPG7, MFN2, MPZ, KIF5A, and GJB1 were excluded by computational prediction and manual visualisation. Discussion: In this preliminary cohort screening panel of disease genes using WES/WGS data, we solved ~50% of cases, which is similar to diagnostic yields reported for global cohorts. However, the mutational profile among South Africans with GN and HSP differs substantially from that in the Global North.