AES ILAE North America Symposium: Guiding Evidence-Based Epilepsy Management

Abstract

Clinical practice guidelines (CPG) provide evidence-based recommendations to optimize patient care. Their development should be rigorous and include defining the scope, conducting systematic reviews, evaluating the quality of the evidence and formulating recommendations that are linked to the evidence. When peer reviewed evidence is insufficient to inform CPGs, consensus-based recommendations (CBR) are an alternative. Both CPG and CBR are essential to inform best practices and inform health policy. This review highlights recent epilepsy CPG and CBR about genetic testing, neonatal seizures, pediatric depression, epilepsy surgery referral timing and addresses their impact on outcomes.

Keywords

guideline clinical practice standard consensus-based recommendations Delphi seizure

Introduction

Clinical practice guidelines (CPG) provide evidence-informed recommendations aimed at optimizing patient care.¹ The CPG development process should be rigorous. In 2015, the ILAE Epilepsy Guidelines Working Group published a toolkit outlining this process.² First, guidelines should only be developed when a clear gap in epilepsy care is identified. Next, the scope of the guideline should be defined and the working group and protocol approved. A systematic review is then conducted, the quality and level of evidence are evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system, and recommendations are formulated. Guidelines then undergo peer review, dissemination, and ultimately implementation in the relevant setting(s). Updating CPG every 3 to 5 years is needed as recommendations become outdated.³

When there are insufficient data to generate full CPG, consensus-based recommendations (CBR) may be beneficial. CBR may be partially evidence-informed, but they are largely derived from expert opinion. Although evidence is more limited with CBR than CPG, this type of guidance is crucial to inform clinical care when clinical trials have yet to be performed or cannot be performed given ethical or practical limitations. CBR typically rely on Delphi methodology rather than GRADE due to limited evidence. Otherwise, the development process is similar to a CPG, and should include a systematic review, or at least a scoping review.

CPG and CBR can improve quality care, inform health policy, guide the prioritization of healthcare interventions, support pay-per-performance reimbursement models, and identify evidence gaps. Unfortunately, implementation of recommendations derived from both CPG and CBR can take years or even decades, and much work is necessary to more quickly and widely implement clinical guidelines and CBR.

This review discusses recently developed cutting-edge guidelines or CBR to treat epilepsy. We cover genetic testing for epilepsy, neonatal seizures, and depression in children and adolescent management, timing of referral to evaluate epilepsy surgery, and finally some experience on whether guidelines improve outcomes.

Genetic Testing for Epilepsy

Rationale

A substantial proportion of nonacquired epilepsy is considered to have an underlying genetic etiology, and pathogenic variants in hundreds of genes have been associated with an increased risk of developing seizures or epilepsy.⁴ Identifying a genetic etiology has both clinical and personal utility for individuals with epilepsy.⁵ Increasingly, genetic testing is being pursued in nongenetics specialty clinics, particularly in neurology. The National Society of Genetic Counselors (NSGC) created an evidence-based CPGs for genetic testing in the epilepsies, endorsed by the American Epilepsy Society, to help guide clinicians and inform policy.^6,7

Recommendations

The NSGC CPC strongly recommends that all individuals with unexplained epilepsy be offered genetic testing, regardless of age. Specifically, they strongly recommend broad-based testing such as exome sequencing (ES), genome sequencing (GS), or multigene panel (MGP) as a first-tier test, conditionally recommending ES/GS over MGP. While ES/GS was favored, MGP or other targeted testing may be indicated first-tier for patients with defined epilepsy syndromes.⁷ Testing recommendations were informed predominantly by diagnostic yield (GS, 48%; ES, 24%; MGP >25 genes, 20%; MGP <25 genes, 7%; and chromosomal microarray, CMA, 9%). The authors also weighed the certainty of the evidence, desirable and undesirable effects, patient values, acceptability to stakeholders, feasibility, and cost-effectiveness of the intervention according to the GRADE process.

The NSGC CPG included specifications for the scope and limitations of the major testing modalities, providing general guidance on variant types that could be detected or missed based on technologies used at the time. With this, along with diagnostic yield, the authors developed tiered-testing strategies.⁷ Notably, technologies continue to evolve and are often laboratory-dependent, so providers should inquire with the testing laboratory regarding coverage for specific genes and variant types.

Second, the NSGC CPG strongly recommends that genetic testing be selected, ordered and interpreted by a qualified healthcare provider in the setting of appropriate pre- and posttest genetic counseling. A qualified healthcare provider has proficiency in genetics, is knowledgeable about the scope, benefits and limitations of testing, and can evaluate and interpret results in the context of a patient's clinical presentation.⁸ Experiences surrounding misinterpretation and miscommunication of variants of uncertain significance and incomplete testing leading to the potential for missed diagnoses were the basis for this recommendation.⁹

Limitations and Gaps

Broad in scope, the NSGC CPG was limited to genetic testing of the unexplained epilepsies. It was informed by the corresponding systematic evidence review, which was limited to studies that utilized GS, ES, MGP, and/or CMA. Included studies were predominantly retrospective comprising heterogeneous populations with variable testing approaches. Testing that occurred sequentially (ie, ES after nondiagnostic MGP) could not be differentiated from discrete testing (ie, ES as first-tier), which could have impacted yield. Only 4 studies incorporated GS, which had limited clinical availability at the time. Understanding of the genetic contributions to the epilepsies, the technologies to detect variants and the ability to interpret variants, continue to evolve, and will be assessed in future iterations.

Treatment of Seizures in the Neonate

Rationale

The ILAE diagnostic framework recommends that critically ill neonates or neonates with a clinical suspicion for seizures undergo conventional electroencephalography (CEEG) monitoring.¹⁰ Thus, a screening approach in which CEEG is performed for neonates at risk for seizures has replaced a confirmatory approach in which CEEG is performed only after observation of concerning events. This approach has been associated with a greater probability of successful acute seizure treatment.¹¹ In this diagnostic framework, electrographic seizures identified on CEEG are definite (gold standard) seizures. Electrographic seizures are then classified as electrographic-only (no clinical signs) or electroclinical (clinical signs).¹⁰ The ILAE framework is consistent with an American Clinical Neurophysiology Society guideline that recommends CEEG to improve the accuracy of seizure diagnosis, identify seizures in neonates at risk for seizures, confirm amplitude integrated electroencephalography (EEG) events are seizures, and assess for seizure control during management.¹² The approach is also aligned with recommendations from other groups.¹³ EEG resources are limited, and there is growing evidence that evidence-based targeted CEEG use may identify the majority of neonates experiencing seizures.^14–22

Recommendations

The recent ILAE Guideline and Consensus Statement on Treatment of Seizures in the Neonate provided an evidence-based recommendation that phenobarbital be administered as the first-line antiseizure medication (ASM).²³ This recommendation was based on a study that demonstrated phenobarbital and phenytoin were equally but incompletely effective²⁴ and the NeoLEV Trial which demonstrated that phenobarbital was significantly more effective than levetiracetam at achieving seizure cessation at 1 and 24 h.²³ Other recommendations were all consensus-based¹: Phenobarbital should be the first-line ASM regardless of etiology.² Phenytoin or levetiracetam may be used as a second-line ASM for most etiologies, but levetiracetam may be the preferred second-line ASM in neonates with cardiac disorders.¹² Phenytoin or carbamazepine (sodium channel blockers) may be used as first-line ASM if a channelopathy is likely due to a family history or as a second-line ASM if a channelopathy is suspected given clinical or EEG features.⁴ Treating neonatal seizures (including electrographic-only seizures) to achieve a lower seizure burden may be associated with improved outcomes.⁵ Following secession of acute provoked seizures without evidence for neonatal onset epilepsy, ASM should be discontinued before discharge regardless of magnetic resonance imaging (MRI) or EEG findings. Studies have indicated that discontinuing ASM prior to discharge is not associated with a greater risk for subsequent epilepsy or neurodevelopmental disorders.^25–27 A trial of pyridoxine may be attempted in neonates with clinical or EEG features of vitamin B6 dependent epilepsy or seizures unresponsive to a second-line ASM without an identified etiology.⁶ Each unit should have a standardized pathway for neonatal seizure management. The guideline provides an example pathway with typical ASM dosing.

Limitations and Gaps

Pathways linking CEEG data to rapid and effective clinical management are needed. Studies have indicated that even when CEEG is performed, some neonates with seizures do not receive ASM, some neonates without seizures are administered ASM, and that ASM administration is often delayed.^27,28 More rapid administration of ASM is associated with lower seizure burden, and greater likelihood of seizure termination.²⁹

Diagnosis and Treatment of Anxiety and Depression in Children and Adolescents With Epilepsy

Rationale

Children and adolescents with epilepsy are at increased risk for mental health disorders, particularly anxiety and depression, compared with the general population and peers with other chronic diseases.³⁰ These comorbidities exacerbate psychosocial dysfunction, academic underachievement, and quality-of-life impairment, and may worsen seizure control or medication adherence.³¹

The changing epidemiology of child and adolescent mental health, coupled with the global shortage of mental health specialists calls for an immediate and coordinated policy response with integrated mental health services.³²

This guideline targets healthcare providers involved in the care of children and adolescents with epilepsy—neurologists, pediatricians, psychologists, and allied professionals—offering structured recommendations for screening, diagnostic assessment, and treatment of anxiety and depressive symptoms and disorders.³³

Recommendations

Universal and systematic screening for anxiety and depression is strongly recommended for all children and adolescents with epilepsy beginning at age ≥7 years, at epilepsy onset, and at least annually thereafter.³⁴ Standardized rating instruments translated and validated in the interviewee language are useful for detection of symptoms.³⁴ A broadband behavioral checklist is advisable and can be complemented by rating scales for symptoms of depression and anxiety.³⁵ Assessment of symptoms and disorders is time-consuming; to remain feasible in busy clinical settings, it must involve additional staff.

Screening should incorporate multiple informants—child, caregiver, and clinician—using various strategies of administration (eg, on-site, online).³⁶ A structured psychiatric interview is recommended whenever possible.

Children identified at higher risk—those older than 12 years, with prior psychiatric or behavioral problems, subthreshold affective symptoms, or recent changes in seizure control or medication—require closer monitoring.³⁷ Communication with families should emphasize that recognizing and addressing mood and anxiety symptoms is integral to optimizing seizure management and preventing crisis situations, including self-harm.³⁷

Screening alone does not automatically improve outcomes; screening needs to be associated with follow-up, referral systems, monitoring, and treatment capacity. An individualized, stepped-care treatment approach is recommended.³⁸ For mild depression, active monitoring and psychoeducation may suffice, whereas moderate-to-severe depression or anxiety warrant referral to a qualified mental-health professional.³⁸ Psychosocial interventions, particularly cognitive behavioral therapy (CBT), have the most consistent evidence for efficacy and safety and constitute an evidence based recommendation.³⁹ Pharmacotherapy is recommended, with neurological and psychiatric follow-up to monitor mood, functionality, and suicidality.⁴⁰

Implementation of structured care pathways and a shared-care model linking neurologists, mental-health providers, and caregivers is essential to coordinate treatment, monitor progress, and ensure adherence.

Limitations and Gaps

The certainty of evidence underpinning most recommendations remains low to very low. Diagnostic studies are limited by small samples, heterogeneous epilepsy syndromes, and variable psychometric validation. Treatment evidence relies primarily on nonpharmacological trials with methodological constraints; only 1 large multicenter randomized controlled trial supports modified CBT as an effective intervention.³⁹ Further research should evaluate the longitudinal impact of systematic mental-health screening on suicide prevention and functional outcomes in pediatric epilepsy.

Timing of Referral for Epilepsy Surgery

Rationale

Epilepsy surgery can be life-changing for people whose seizures do not respond to medication, yet most patients are referred far too late, often after decades of uncontrolled seizures. This delay increases risks of injury, delayed development, poor memory, mood problems, and in rare cases, death. Early referral is key to improving outcomes but deciding when to refer has not always been clear for doctors, patients, or families.

To address this, the Surgical Therapies Commission of the International League Against Epilepsy assembled an international group of epilepsy experts to review the evidence and create clear recommendations on the timing of referral for epilepsy surgery evaluation.⁴¹ The team included 61 experts from North America, Europe, Asia/Oceania, Latin America, the Eastern Mediterranean, and Africa. After multiple rounds of thorough debate and review, the main message was clear: earlier referrals lead to better outcomes, and referral should happen much earlier than it usually does.

Recommendations

More specifically, the experts recommend that:

Any adult or child who continues to have seizures after trying 2 appropriate AZM should be referred for an evaluation at a specialized epilepsy center. At that point, the chance of becoming seizure-free with additional medications alone is very low, and the risk of seizure-related harm is too high.

Referral does not mean surgery will happen, but it allows experts to confirm the diagnosis, discuss all treatment options with patients and families, and prevent years of avoidable risks. Patients should therefore be referred regardless of the likelihood of eventual surgery because the referral will offer a chance of better care.

Even if seizures are controlled on medication, surgery should be considered in both adults and children when seizures are caused by a brain lesion in noneloquent cortex that can be easily and safely removed without impact on critical functions. Early referral may help protect brain development and learning in children, and avoid unnecessary medication toxicity and seizure-related complications in adults. This recommendation has gained additional support since its publication.^42–44

Older age is not a contraindication for surgical referral. Surgery should still be considered in patients older than 70 years of age with no surgical contraindications.

Referral for surgical evaluation should not be offered for patients with drug-resistant epilepsy who use/abuse alcohol and/or recreational substances and are not cooperative with management.

In short, the expert consensus is that delays in referral are harmful and unnecessary. The best time to refer is as soon as medications have clearly failed—after 2 well-chosen attempts. This shift in practice could reduce the burden of uncontrolled seizures and give more patients access to life-changing treatments sooner.

Limitations and Gaps

The consensus recommendations do not represent a guideline as the exercise identified that further research is needed to clarify risk versus benefit balance of epilepsy surgery for patients with ongoing seizures in the context of nonadherence to ASM without previously documented drug resistance.

Do Guidelines Improve Outcomes? Lessons from the United Kingdom

Clinical guidelines are structured recommendations designed to optimize patient care through evidence-based practice.⁴⁵ They are not designed to be a set of rules, but can assist healthcare professionals make decisions about appropriate and effective care. Ultimately, they can standardize care pathways and thereby raise standards of care but can also identify resource gaps and highlight areas needing further research. In the United Kingdom, epilepsy guidelines have evolved over 2 decades, with guidelines on the epilepsies published by both the National Institute for Care and Excellence (NICE) and the Scottish Intercollegiate Guideline Network (SIGN). NICE originally published guidelines for the diagnosis and management of the epilepsies in primary and secondary care in 2004; there was a subsequent pharmacological update in 2012, and more recently a complete update published in 2022 (https://www.nice.org.uk/guidance/ng217).⁴⁶ SIGN has separate guidance for adults (https://www.sign.ac.uk/media/1079/sign143_2018.pdf)⁴⁷ and children (https://www.sign.ac.uk/media/1844/sign-159-epilepsy-in-children-final.pdf)⁴⁸ but efforts have been made to ensure alignment. The guidance has allowed standardization of the care pathway in England, Wales, and Scotland with clear expectations as to who should review and manage individuals with epilepsy.

Originally the scope of the 2022 NICE guideline was to have 2 guidelines, 1 each for adult and pediatric epilepsies. However, it was recognized there would be much overlap, so although 2 guideline groups were formed, each took a series of independent questions, reflecting advances in diagnosis, treatment, and holistic management since 2004. As per NICE methodology, initial questions were generated and finalized after stakeholder review, and evidence subsequently synthesized using the GRADE. There was liaison with the Cochrane library to avoid duplication. A health economic analysis was undertaken with regard to monotherapy in focal and generalized seizures, nurse provision, and epilepsy surgery in adults. In a series of meetings over 2.5 years, guidance was developed for each group (see Table 1 for topics covered). The guidance (see Table 1 for topics covered) was then made available for stakeholder review, and comments responded to with adjustment of the guidance where applicable. In addition, research recommendations were provided on antibody testing, treatment of complex epilepsies, risk prediction for epilepsy related death, vagal nerve stimulation, and psychological treatments.

Table 1.

Topics Covered in NICE Guidance (2022).

Diagnosis and assessment of epilepsy

Information and support

Referral to tertiary specialist services

Principles of treatment, safety, monitoring, and withdrawal

Treating epileptic seizures in children, young people, and adults

Treating childhood onset epilepsies

Treating status epilepticus, repeated or cluster seizures, or prolonged seizures

Non pharmacological treatments

Psychological, neurobehavioral, cognitive, and developmental comorbidities in epilepsy

Reducing the risk of epilepsy-related death including sudden unexpected death in epilepsy

NICE: National Institute for Care and Excellence.

A key question, however, is do we have evidence that these guidelines have impacted care? Certainly, guidance allows audit at a local level. Epilepsy12 is a national audit of pediatric care within 12 months of presentation with epilepsy (https://www.rcpch.ac.uk/work-we-do/clinical-audits/epilepsy12).⁴⁹ It is commissioned by the Healthcare Quality Improvement Partnership as part of the National Clinical Audit and Patient Outcomes Programme. Established in 2009 it aims to help epilepsy services and those who commission health services, to measure and improve the quality-of-care for children and young people with seizures and epilepsies. It takes 12 key quality measures of care from the NICE and SIGN guidance including timely specialist assessment, MRI/EEG, mental health screening, and care planning. Currently annual cohorts are reported from 120 services, reporting almost in real time at multiple levels (national, commissioning, hospital, and individual). Cohort sizes have grown significantly annually, with most key performance indicators (acknowledging adjustment in some over time) showing improvement from 2017 to 2025. This said, there are some frustrations with little change in percent of the cohort receiving optimized referral to tertiary care or epilepsy surgery. This finding has allowed further targeted analysis to ensure improvement. Challenges remain, including evolving performance indicators and variation in care linked to service capacity, deprivation, and intellectual disability. Efforts are underway to refine audit questions and transition from retrospective to live reporting.

The evidence provided by Epilepsy12 suggests guidelines do make a difference to care processes but also highlight areas of difficulty. However, sustaining progress requires continuous training, stakeholder engagement, and addressing systemic barriers.

Conclusions and Future Directions

The guidelines and CBR reviewed here range from genetic testing and neonatal seizure management to management of mental health comorbidities, epilepsy surgery referral, and system-level implementation. Such guidance can help standardize care, reduce variation, and identify evidence gaps. However, we showed that much ongoing research is needed to fill some of the knowledge gaps identified.

Lastly, we confirmed that guidelines alone are insufficient to improve health outcomes. The UK Epilepsy12 example demonstrates the impact of effective dissemination, audit, feedback, and collaboration with local resources to ensure this important evidence is translated into timely, equitable, patient-centered care.

Footnotes

Acknowledgments

The authors thank Dr Rachel Marin for her assistance and support with reference formatting in the final stages of this manuscript.

Declaration of Conflicting Interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: NJ is the chair of the ILAE Standards and Best Practice Council. NSA receives royalties from Demos Publishing and does consulting for Ceribell and UCB Pharma. JHC has participated in clinical trials sponsored by Zogenix/UCB Pharma, GW Pharma/Jazz Pharmaceuticals, Stoke Therapeutics, Encoded, Epigenyx, Lundbeck, and Ultragenyx, and sat on advisory boards for Nutricia, Biocodex, UCB, Stoke Therapeutics, and Takeda, unrelated to this work and all with remuneration to department. She was topic advisor to the NICE epilepsies guideline group 2018-2022. The other authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Nathalie Jette

Kette Valente

Lara Jehi

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