Open research questions in Epilepsy research and treatment

What the literature leaves open

• HANDLING SEIZURE EMERGENCIES Benzodiazepines are the preferred medication for rescue therapy, which is used to stop a seizure, stop it from progressing to a longer episode, or stop it from happening again. When qualified medical professionals are available, the Neurocritical Care Society advises using IV lorazepam to treat status epilepticus. According to Society guidelines, benzodiazepines can be given by IM, rectal, intranasal (IN), or buccal routes when IV Creative Commons Attribution 4.0 International license. Volume 10, Issue 8. 2026 │ ISO 9001:2015 Certified Journal │ 32 Keerthi et al. International Journal of Modern Pharmaceutical Research therapy is not practical. Rectal diazepam gel, however, is the only rescue therapy product available in the US. Clinicians outside of Europe, where buccal midazolam is approved for patients up to the age of 17, may consider the off-label use of diazepam or midazolam oral solutions given buccally or injectable formulations administered intranasally when patients refuse rectal therapy until FDA-approved IM and IN formulations are available. Nevertheless, there is uncertainty regarding the effectiveness of these treatments and the best dosage schedules because they have not been tested in controlled trials. FOR PROPERTIES IDEAL MEDICATION SEIZURE Medications used to treat seizure emergencies need to have a broad therapeutic index and be strong enough to allow for low dosage volumes. They should show an intermediate duration of action (hours) and a quick onset of action (minutes). Drug administration ought to be quick, simple, and secure. When using an extravascular route to treat seizure emergencies, the formulation should show high, consistent, and quick (minutes) absorption. DIAGNOSIS Status epilepticus is the most difficult condition to treat in an emergency. As a result, this clinical state is the focus of the sections on diagnosis and treatment. Status epilepticus manifests clinically in a variety of ways. The pediatric patient's prior state conditions, stage, and type of seizures all play a role. Continuous or recurrent seizures are the basis for the diagnosis, which is simple to identify during the clinical manifestation. It is challenging to rule out non-epilepticus continuous status after persistent status epilepticus, even when motor symptoms go away. When SE first manifests clinically, complicated SE, comorbidity, or infants are involved, a be comprehensive requested. evaluation may instrumental According to published research, serologic tests are not warranted in pediatric age routines due to the low frequency of abnormal values. Hypoglycemia is the only abnormal test found in over 20% of patients. When an infectious etiology is suspected in patients with status epilepticus and a body temperature greater than 38.5°C, a lumbar puncture may be considered. Even in the absence of central nervous system infections, SE may exhibit temperature, in cerebrospinal fluid. According to American Academy of Pediatrics (AAP) guidelines, lumbar punctures and other diagnostic tests should not be routinely performed on pediatric patients experiencing febrile seizures unless the condition warrants it. leukocytosis, pleocytosis and For all patients under one year old who exhibit fever and seizures, a lumbar puncture is strongly advised.

  CLINICAL APPROACHING OF PEDIATRIC EPILEPSY MANAGEMENT · 2026 · DOI

• However, it should be emphasized that the “irritable brain state” remains a conceptual and hypothesis-generating construct; no validated diagnostic criteria exist, and prospective evidence demonstrating that interventions targeting this state reduce the incidence of post-stroke epilepsy is currently lacking.

  Post-Stroke Epileptogenesis as a Dynamic Network Process: State-Dependent Biomarkers, Longitudinal Monitoring, and the Concept of an Irritable Brain State · 2026 · DOI

• Beyond confirmation of the canonical electroclinical phenotype, several gaps emerged: neonatal versus post-neonatal onset stratification by genetic etiology remains largely uncharacterized; genotype-specific EEG biomarkers are lacking except for a single small KCNT1 study; and the clinical significance of atypical EEG features-including burst suppression and hypsarrhythmia-is undefined.

  Epilepsy of infancy with migrating focal seizures: A scoping review of clinical features, diagnostic testing including genetics, long-term outcomes, mortality, and current and emerging therapeutic strategies · 2026 · DOI

• Abstract Objective Use of neuromodulation strategies targeting thalamic nuclei, including deep brain stimulation (DBS) and responsive neurostimulation (RNS), for treatment of pediatric drug‐resistant epilepsy (DRE) is increasing, despite limited evidence for efficacy and safety.

  Comparative multicenter evaluation of thalamic neuromodulation for treatment‐resistant epilepsy in children · 2026 · DOI

• At present, there are insufficient prospective data to quan- tify how frequently CNB can definitively obviate the need for epilepsy surgery or neuromodulation.

  Optimizing Drug-Resistant Epilepsy Management: Cenobamate’s role in the Surgery/Neuromodulation Pathway · 2026 · DOI

• BACKGROUND AND OBJECTIVES: Although genetic testing is recommended as a standard component of the diagnostic evaluation for epilepsies with unknown etiology, its optimal application in adult populations remains poorly defined.

  Genetic Testing in Adult Patients With Epilepsy · 2026 · DOI

• Future research should examine other clinical populations experiencing a type of emotional stress other than epilepsy to understand the role of psychological flexibility and related factors in PNES. The cross-sectional nature of the study, the inability to use the video-EEG method for PNES diagnosis, and the small sample size are a few of the limitations of the present study.

  Epileptic Versus Psychogenic Nonepileptic Seizures: The Different Roles of Experiential Avoidance, Cognitive Fusion, and Mindfulness · 2026 · DOI

• Future research should focus on investigating the effectiveness of ACT-based interventions in individuals with PNES to increase the amount of evidence necessary for a more profound understanding of the relationship between the psychological resilience model and PNES. Ethics Committee Approval: The Tokat Gaziosmanpaşa University Ethics Committee granted approval for this study (date: 21.11.2019, number: 19-KAEK-220). Informed Consent: Informed consent forms were obtained from all participants. Conflict of Interest: The authors declare that there is no conflict of interest. 10 Financial Disclosure: The authors received no financial support for the research, authorship, and/or publication of this article. Use of AI for Writing Assistance: Not declared. Author Contributions: Concept – ZÇ; Design – SB, OS; Supervision – SB; Fundins – SB; Materials – OS, ZÇ; Data Collection and/or Processing – OS, ZÇ; Analysis and/or Interpretation – SB; Literature Review – ZÇ; Writing – ZÇ; Critical Review – SB. Peer-review: Externally peer-reviewed. REFERENCES Akyüz, F., Gökalp, P. G., Erdiman, S., & Karşıdağ, Ç. (2017). Conversion disorder comorbidity and childhood trauma. Nöro Psikiyatri Arşivi, 54(1), 15–20. American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). American Psychiatric Publishing. Arnold, L. M., & Privitera, M. D. (1996). Psychopathology and trauma in epileptic and psychogenic seizure patients. Psychosomatics, 37(5), 438–443. Ayalp, H. D., & Hisli Şahin, N. (2018). Beş faktörlü bilgece farkındalık ölçeği-kısa formu’nun (BFBFÖ-K) Türkçe uyarlaması. Klinik Psikoloji Dergisi, 2(3), 117–127. [Article in Turkish] Bagherzade, A., & Kataki, S. S. H. (2015). Positive and negative affects and coping strategies in patients with psychogenic non-epileptic seizure, temporal lobe epilepsy and control groups. Biomedical and Pharmacology Journal, 8(1), 133– 139. Baker, G. A., Brooks, J., Buck, D., & Jacoby, A. (2000). The stigma of epilepsy: A European perspective. Epilepsia, 41(1), 98– 104. Bakvis, P., Spinhoven, P., Zitman, F. G., & Roelofs, K. (2011).

  Epileptic Versus Psychogenic Nonepileptic Seizures: The Different Roles of Experiential Avoidance, Cognitive Fusion, and Mindfulness · 2026 · DOI

• However, it remains unclear whether PPR naturally remits with age inde- pendent of treatment; the observed decline may part- ly reflect sampling bias from younger populations [30].

  The value of repeating intermittent photic stimulation in patients with juvenile myoclonic epilepsy · 2026 · DOI

• While prophylactic AED use remains controversial—particularly given the lack of robust evidence supporting its routine application— this practice likely reflects clinician concern regarding perioperative seizures, limited access to continuous electroencephalographic monitoring, and the potentially catastrophic consequences of uncontrolled seizures in children with intracranial tumors [24].

  Seizure Burden and Antiepileptic Drug Utilization in Brain Tumor Patients · 2026 · DOI

• Animal studies suggest that, beyond a critical timepoint (t2), SE induces neuronal injury exceeding what can be expected from the underlying aetiology, but in vivo evidence in humans is scarce.

  Mapping the Cerebral Burden of Status Epilepticus - Results from a Longitudinal MRI Study · 2026 · DOI

• Pending future prospective, ideally randomized, investigations, optimal therapeutic strategies across heterogeneous NCSE subtypes remain to be clearly established.

  Treatment adequacy outweighs treatment sequence in non‐convulsive status epilepticus · 2026 · DOI

• Integration of the validated XGBoost model into electronic health record (EHR) systems as a real-time clinical decision support tool for IESS prognostic prediction has not yet been implemented or evaluated; future work must assess the feasibility, user acceptance, and clinical impact of deploying this machine learning model within existing EHR workflows.

  Development and validation of a machine learning model to predict prognostic outcomes in infantile epileptic spasms syndrome · 2026 · DOI

• The study identified conditional predictive relationships showing an interaction between structural abnormalities and treatment duration in IESS prognostic risk stratification; future research should prospectively validate these specific interaction effects between MRI findings, medication exposure duration, and follow-up time to confirm the risk gradient model.

  Development and validation of a machine learning model to predict prognostic outcomes in infantile epileptic spasms syndrome · 2026 · DOI

• The retrospective design using electronic medical records is susceptible to selection and information bias from variable clinical documentation practices; future multi-center prospective studies should employ standardized data collection protocols to ensure consistency and accuracy in IESS clinical variables.

  Development and validation of a machine learning model to predict prognostic outcomes in infantile epileptic spasms syndrome · 2026 · DOI

• The primary outcome was restricted to binary seizure control without incorporating longitudinal neurodevelopmental data; future research must integrate multidimensional long-term endpoints including detailed seizure semiology, interictal EEG patterns, and standardized psychomotor assessments to capture the full prognostic picture in IESS patients.

  Development and validation of a machine learning model to predict prognostic outcomes in infantile epileptic spasms syndrome · 2026 · DOI

• No study has definitively established a direct causal link between neuronal migration disorders and infantile epileptic spasms syndrome (IESS); future research should systematically investigate the mechanistic relationship between specific malformations of cortical development (MCD) such as lissencephaly, pachygyria, polymicrogyria, and cobblestone malformations and IESS pathogenesis.

  Development and validation of a machine learning model to predict prognostic outcomes in infantile epileptic spasms syndrome · 2026 · DOI

• Standardized diagnostic and treatment guidelines for childhood abdominal epilepsy do not exist. Future research must establish evidence-based clinical practice guidelines that specify diagnostic algorithms (including EEG protocols and imaging recommendations), antiepileptic drug selection criteria, ketogenic diet protocols, and surgical candidacy criteria for pediatric patients.

  Research progress on abdominal epilepsy in children · 2026 · DOI

• Epidemiological data on abdominal epilepsy incidence, prevalence, and demographic characteristics in pediatric populations are limited due to diagnostic uncertainty and case report bias. Large-scale epidemiological studies with standardized case definitions are needed to establish accurate prevalence estimates and identify risk factors in children with abdominal epilepsy.

  Research progress on abdominal epilepsy in children · 2026 · DOI

• The pathogenesis of abdominal epilepsy remains incompletely understood despite recognition of abnormal electrical discharges in temporal and insular cortices. In-depth mechanistic studies are needed to elucidate the neurophysiological basis linking insular and temporal lobe epileptiform activity to paroxysmal abdominal pain phenotypes in children.

  Research progress on abdominal epilepsy in children · 2026 · DOI

• Validated diagnostic criteria for abdominal epilepsy in children do not currently exist. Future research must develop and validate standardized diagnostic criteria that integrate clinical manifestations, ictal/interictal EEG abnormalities, video-EEG monitoring protocols, and response to antiepileptic medications into a formal diagnostic framework.

  Research progress on abdominal epilepsy in children · 2026 · DOI

• The literature on abdominal epilepsy is dominated by case reports and small retrospective case series with an absence of controlled studies, prospective cohorts, and randomized trials. Prospective cohort studies and randomized controlled trials comparing antiepileptic drug efficacy, ketogenic diet interventions, and surgical approaches in pediatric abdominal epilepsy populations are needed to establish high-quality evidence for treatment guidelines.

  Research progress on abdominal epilepsy in children · 2026 · DOI

• The paper demonstrates that full medication coverage independently predicted better QOL while uncontrolled seizures and adverse-effect burden independently reduced QOL, but the optimal balance between seizure control achieved through polytherapy versus tolerability burden from dose-related adverse effects has not been modeled. Dose-response analyses examining this tolerability-efficacy trade-off in relation to QOLIE-15 dimensions are needed.

  Development, psychometric validation, and correlates of the 15-item quality of life in epilepsy scale (QOLIE-15) · 2026 · DOI

• The finding that retirement was associated with better QOL despite being typically considered a loss of employment status is explained by hypothesized reductions in seizure triggers and job-related stressors, but empirical quantification of which specific occupational stressors or seizure trigger reductions mediate this relationship has not been directly measured in the QOLIE-15 validation cohort.

  Development, psychometric validation, and correlates of the 15-item quality of life in epilepsy scale (QOLIE-15) · 2026 · DOI

• The strong independent associations between cognitive complaints (ABNAS scores), stigma (ESS), anxiety (LAS-10), and QOL in QOLIE-15 regression models suggest these psychosocial factors contribute additively, but mechanistic studies examining whether cognitive impairment and anxiety interact to amplify stigma perception and QOL reduction remain absent.

  Development, psychometric validation, and correlates of the 15-item quality of life in epilepsy scale (QOLIE-15) · 2026 · DOI

Most-cited papers in Epilepsy research and treatment

• A Randomized, Controlled Trial of Surgery for Temporal-Lobe Epilepsy · New England Journal of Medicine · 2001 · 2,951 citations
• Global disparities in the epilepsy treatment gap: a systematic review · Bulletin of the World Health Organization · 2009 · 380 citations
• Learning disability and epilepsy in an epidemiological sample of individuals with tuberous sclerosis complex · Psychological Medicine · 2003 · 242 citations
• Managing Epilepsy in Tuberous Sclerosis Complex · Journal of Child Neurology · 2004 · 171 citations
• Third-Generation Antiseizure Medications for Adjunctive Treatment of Focal-Onset Seizures in Adults: A Systematic Review and Network Meta-analysis · Drugs · 2022 · 108 citations
• Efficacy and Mortality in Treatment of Refractory Generalized Convulsive Status Epilepticus in Children: A Meta-Analysis · Journal of Child Neurology · 1999 · 105 citations
• Pharmacological Treatment of Neonatal Seizures · Journal of Child Neurology · 2013 · 90 citations
• Cerebellar Lesions in Tuberous Sclerosis Complex · Journal of Child Neurology · 2006 · 90 citations
• Status Epilepticus in Children: Etiology, Clinical Features, and Outcome · Journal of Child Neurology · 1988 · 90 citations
• Screening Electroencephalograms in Autism Spectrum Disorders: Evidence-Based Guideline · Journal of Child Neurology · 2005 · 73 citations

Most recent work

• Evaluation of metformin for epilepsy prevention or seizure control in people without evidence of diabetes: retrospective cohort study · Journal of Neurology Neurosurgery & Psychiatry · 2026
• Investigating the Influence of Anti-Seizure Medications on Aperiodic EEG Activity · bioRxiv · 2026
• Individualized and stereotypical seizure semiology in a porcine model of post-traumatic epilepsy. · bioRxiv · 2026
• In-vivo evidence for increased tau deposition in temporal lobe epilepsy · bioRxiv · 2026
• Burst-Suppression EEG in Early Infantile Developmental and Epileptic Encephalopathies · Neurology · 2026
• Efficacy of Levetiracetam in Patients With Pediatric Epilepsy · Neurology · 2026
• Responsive stimulation of the thalamus for idiopathic generalized epilepsy: Results of the randomized controlled <scp>NAUTILUS</scp> trial through 18 months · Epilepsia · 2026
• Rural-Urban Disparities in Epilepsy Outcomes in the United States · Neurology · 2026
• Perspectives on the burden of drug‐resistant epilepsy and treatment priorities: Findings from a multistakeholder survey · Epilepsia Open · 2026
• Development, psychometric validation, and correlates of the 15-item quality of life in epilepsy scale (QOLIE-15) · Scientific Reports · 2026

Related topics in Medicine