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Overview and Recommendations
Background
- •Define epilepsy as a clinical syndrome of recurrent unprovoked seizures, distinguishing between ictogenesis (the acute transition to a seizure) and epileptogenesis (the chronic process of brain transformation into a seizure-prone state). The condition affects approximately 1% of the population and carries significant risks of morbidity, cognitive decline, and sudden unexpected death in epilepsy (SUDEP).
- •Recognize the core pathophysiology involving the tripartite synapse, where disruptions in ion channels (e.g., SCN1A, KCNQ2) and glial regulation of glutamate (via TREK-1 channels) lead to neuronal hyperexcitability. In many cases, an initial insult such as traumatic brain injury or status epilepticus triggers neuroinflammation and maladaptive plasticity, cementing the epileptic network.
- •Classify seizures by onset as focal (originating in one hemisphere), generalized (involving bilateral networks from the start), or unknown. Focal seizures are further categorized by the preservation or impairment of awareness, which is a primary classifier in the 2025 ILAE update.
- •Identify key genetic variants that dictate clinical phenotypes, such as SCN1A loss-of-function in affecting inhibitory interneurons, or KCNQ2 variants leading to a spectrum from self-limited neonatal epilepsy to severe developmental and epileptic encephalopathy (DEE).
- •Understand the role of metabolic and inflammatory triggers, including succinic semialdehyde dehydrogenase deficiency (SSADHD) and autoimmune encephalitis, which may present with drug-resistant seizures and require targeted metabolic or immunosuppressive therapy.
Evaluation
- •Suspect epilepsy in any patient presenting with paroxysmal alterations in consciousness, motor activity, or sensory perception. Prioritize a meticulous reconstruction of the event from witnesses, as patient self-reporting is frequently inaccurate, especially in focal onset impaired awareness seizures (FIAS).
- •Ask about the pre-ictal phase to identify triggers such as sleep deprivation, fever, or specific reflex stimuli like reading. In cases of Febrile Infection-Related Epilepsy Syndrome (FIRES), look for a febrile illness occurring 24 hours to 7 days prior to the onset of status epilepticus.
- •Examine for systemic markers of genetic syndromes, such as macrocephaly in ODLURO syndrome (KMT2E variants) or distinct facial features and microcephaly in Mowat-Wilson syndrome. Assess for neurodevelopmental delays or regression, which suggest a DEE rather than a benign epilepsy syndrome.
- •Obtain a routine or sleep-deprived EEG within 24 hours of the first seizure event to maximize the diagnostic yield for interictal epileptiform discharges (IEDs). If the initial EEG is normal, utilize functional tests or sleep induction (e.g., using melatonin 5 mg in children) to increase sensitivity.
- •Order a high-resolution 3T MRI using a dedicated epilepsy protocol to rule out structural lesions such as focal cortical dysplasia (FCD), hippocampal sclerosis, or multinodular and vacuolating neuronal tumors (MVNT).
- •Rule out non-epileptic mimics by assessing serum biomarkers within 60 minutes of the event; a serum lactate > 2.5 mmol/L or elevated prolactin and ammonia levels strongly suggest an epileptic seizure over syncope or functional/psychogenic non-epileptic seizures (PNES).
- •Monitor for autonomic red flags, such as ictal heart rate increases > 50 bpm or significant peripheral oxygen desaturation (SpO2), which may serve as biomarkers for increased SUDEP risk.
- •Screen for pediatric-specific red flags, including bruising in non-exploratory areas (ears, neck, torso) in infants < 1 year old, which may indicate abusive head trauma as the underlying cause of new-onset seizures.
- •Consider genetic testing (e.g., epilepsy panels or whole-exome sequencing) in patients with early-onset seizures, developmental delay, or a family history of epilepsy, as over 1,000 genes are now associated with epileptic phenotypes.
- •Utilize the STAMP scale (Scale for Objective Diagnostic Components of Paroxysmal Events) to objectively grade the likelihood of an epileptic seizure versus syncope based on clinical semiology.
Management
- •Administer first-line monotherapy for focal epilepsy using Lamotrigine (titrated slowly to 100-200 mg BID) or Levetiracetam (500-1500 mg BID). Lamotrigine is preferred in patients of childbearing potential due to its lower teratogenic risk compared to other agents.
- •Avoid Valproate in women of childbearing potential whenever possible due to high risks of major congenital malformations and adverse neurodevelopmental outcomes; if required, use the lowest effective dose with concurrent folic acid supplementation.
- •Manage Infantile Epileptic Spasms Syndrome (IESS) urgently by initiating ACTH monotherapy, followed by a clinical and EEG assessment on Day 7; if spasms persist, add Vigabatrin (50 mg/kg/day, titrated up to 150 mg/kg/day) to the regimen.
- •Treat status epilepticus (seizure > 5 minutes) as a neurological emergency: start with IV Lorazepam 4 mg (repeated once if needed), followed immediately by a second-line ASM such as IV Levetiracetam 60 mg/kg (max 4500 mg) or Fosphenytoin 20 mg PE/kg.
- •Escalate to Cenobamate (starting at 12.5 mg/day and titrating slowly to 200-400 mg/day) for adults with drug-resistant focal seizures, as it has shown high potency in reducing seizure frequency across all focal subtypes.
- •Refer patients for a comprehensive presurgical evaluation if they fail two appropriately chosen and tolerated ASM trials (drug-resistant epilepsy). Surgical options include anterior temporal lobectomy (ATL) for mesial temporal lobe epilepsy or Laser Interstitial Thermal Therapy (LITT) for deep-seated lesions.
- •Consider palliative procedures such as Vagus Nerve Stimulation (VNS) or Responsive Neurostimulation (RNS) for patients who are not candidates for resective surgery or who have multifocal seizure onsets.
- •Monitor for medication-induced autonomic changes, such as hypohidrosis (reduced sweating) and hyperthermia in patients taking Zonisamide or Topiramate, particularly in warm environments.
- •Perform therapeutic drug monitoring (TDM) during pregnancy, as physiological changes (increased glomerular filtration) can significantly lower ASM plasma levels, necessitating dose adjustments to maintain seizure control.
- •Implement an Acute Seizure Action Plan for all patients, including rescue medications (e.g., intranasal Midazolam 5-10 mg) for clusters or prolonged events to prevent progression to status epilepticus.
- •Avoid routine ASM prophylaxis in seizure-naive patients with newly diagnosed brain tumors, as evidence from the SPRING trial suggests it does not meaningfully reduce the risk of a first seizure.
- •Evaluate for ASM withdrawal only after a minimum of 2 years of seizure freedom, counseling the patient that the risk of recurrence is approximately 15% compared to 7% if treatment is continued.
- •Refer for specialized metabolic management in cases of vitamin B6-dependent epilepsy (PLPBP-related), where high-dose pyridoxine is the definitive treatment.
- •Monitor cognitive and neuropsychiatric comorbidities, particularly ADHD (present in ~30% of pediatric cases) and depression, which can significantly impact quality of life and ASM adherence.
Board Review — High Yield
- •SCN1A mutation — The hallmark of Dravet Syndrome; avoid sodium channel blockers as they worsen seizures.
- •3 Hz spike-and-wave — Classic EEG finding for Childhood Absence Epilepsy.
- •Hypsarrhythmia — The chaotic EEG pattern associated with West Syndrome (Infantile Spasms).
- •Drug-Resistant Epilepsy — Defined as failure of 2 tolerated and appropriately chosen ASM schedules.
- •SUDEP — Sudden Unexpected Death in Epilepsy; risk is highest with uncontrolled generalized tonic-clonic seizures and nocturnal events.
- •Gelastic seizures — Associated with hypothalamic hamartomas; present as inappropriate bursts of laughter.
- •Todd's Paralysis — Focal neurological deficit (usually hemiparesis) following a focal seizure, typically resolving within 24 hours.
- •BECTS (SeLECTS) — Most common childhood epilepsy; characterized by centrotemporal spikes and nocturnal orofacial seizures.
Deep Dive — Evidence Details
Pathophysiology
- ▸SCN1A loss-of-function primarily impairs GABAergic interneurons, leading to Dravet syndrome and GEFS+.
- ▸SCN8A-related epilepsy typically presents within the first year of life, often with generalized tonic-clonic seizures.
- ▸Potassium channel variants (KCNQ2, KCNA2, KCNC1, KCNJ4) disrupt the 'molecular brake' of neurons, causing various DEEs.
- ▸Neuroinflammation involving IL-1β and IL-6 modulates NMDA and GABA receptors to favor hyperexcitability.
- ▸SLC6A1 variants cause epilepsy by impairing the GAT-1 transporter, affecting synaptic GABA levels.
The pathophysiology of epilepsy is increasingly understood as a complex interplay of genetic variants, ion channel dysfunction, and neuroinflammatory cascades that disrupt the balance between neuronal excitation and inhibition. Central to this process is the dysfunction of voltage-gated ion channels, particularly sodium, potassium, and calcium channels, which regulate intrinsic neuronal excitability and synaptic transmission.
Sodium Channelopathies
Voltage-gated sodium channels (Nav) are critical for the initiation and propagation of action potentials. Pathogenic variants in the SCN1A gene, which encodes the NaV1.1 subunit, are the primary cause of Dravet syndrome (DS) and Genetic Epilepsy with Febrile Seizures plus (GEFS+) [20]D[244]C[250]D. In DS, loss-of-function (LoF) mutations in SCN1A specifically impair the excitability of GABAergic inhibitory interneurons, leading to network hyperexcitability [250]D. This impairment is associated with severe phenotypes including refractory seizures, cognitive deficits, and an increased risk of sudden unexpected death in epilepsy (SUDEP) [1]D[249]D. Recent research also highlights long-lasting remodeling of astrocytes in SCN1A-deficient models, suggesting that non-neuronal cells contribute to the disease progression [254]D.
Variants in SCN8A (encoding NaV1.6) and SCN2A (encoding NaV1.2) also represent significant drivers of developmental and epileptic encephalopathies (DEEs). SCN8A variants often present within the first year of life (mean onset 8.25 months), manifesting as generalized tonic-clonic or focal seizures [245]C[246]. Interestingly, while SCN2A LoF variants are associated with later-onset epilepsy (onset ≥ 3 months), intellectual disability, and autism, the specific mechanism of channel dysfunction does not always predict the clinical phenotype [256]D.
Potassium and Calcium Channel Dysfunction
Potassium channels act as a 'molecular brake' against pathological firing. Dysfunction in KCNQ2 (Kv7.2) and KCNQ3 (Kv7.3) channels, which mediate the M-current, leads to early infantile developmental and epileptic encephalopathies (EIDEE) often characterized by burst-suppression (BS) EEG patterns [241]C[248]D. Other potassium channel genes implicated include KCNA2 (Kv1.2), where variants are linked to spike-and-wave activation in sleep (SWAS) and intellectual disability [251]D, and KCNC1 (Kv3.1), where the A421V variant impairs the high-frequency firing of parvalbumin-positive fast-spiking GABAergic interneurons [12]D. Furthermore, KCNJ4 (Kir2.3) has been identified as a novel cause of refractory epilepsy when inward-rectifier functions are disrupted [255]D.
Calcium channel involvement is exemplified by CACNA1A (Cav2.1) variants. These can result in a spectrum of disorders including focal seizures, ataxia, and hemiplegic migraine, with penetrance sometimes showing sex-stratified differences [242].
Neuroinflammation and Metabolic Pathways
Emerging evidence suggests that neuroinflammation is a fundamental driver of epileptogenesis. The activation of the NLRP3 inflammasome and P2×7 receptor pathways leads to the maturation of pro-inflammatory cytokines like IL-1β and IL-6 [252]D. These cytokines trigger the MyD88 and PI3K/AKT/mTOR cascades, which enhance NMDA receptor activity and glutamate release while suppressing GABAergic inhibition, creating a self-perpetuating cycle of hyperexcitability [252]D. Additionally, variants in the PRUNE1 gene, specifically affecting the DHH motifs, may influence ion coordination and contribute to refractory seizures through altered metabolic and ion channel regulation [243].
Synaptic Transport and Neurodevelopmental Impact
Deficits in synaptic neurotransmitter regulation also play a role. Heterozygous LoF variants in SLC6A1, which encodes the GAT-1 GABA transporter, result in reduced GABA clearance from the synapse, leading to early-onset epilepsy, intellectual disability, and autistic features [247]D. The cumulative effect of these genetic and molecular disruptions often leads to a 'developmental and epileptic encephalopathy' where the epileptic activity itself contributes to progressive cognitive and behavioral impairment beyond what would be expected from the underlying genetic etiology alone [20]D[257]D.
| Gene | Channel/Protein | Primary Pathophysiology | Clinical Phenotype |
|---|---|---|---|
| SCN1A | NaV1.1 (Sodium) | Interneuron hypoexcitability | Dravet Syndrome, GEFS+ |
| SCN8A | NaV1.6 (Sodium) | Altered sodium current | Early-onset DEE, movement disorders |
| KCNQ2 | Kv7.2 (Potassium) | Loss of M-current 'brake' | EIDEE with Burst-Suppression EEG |
| KCNC1 | Kv3.1 (Potassium) | Impaired fast-spiking PV-INs | Myoclonic epilepsy, developmental delay |
| SLC6A1 | GAT-1 (Transporter) | Reduced GABA reuptake | Epilepsy with myoclonic-atonic seizures |
| CACNA1A | Cav2.1 (Calcium) | Altered P/Q-type current | Epilepsy with ataxia or migraine |
History and Physical Examination
- ▸Autonomic signals, particularly ictal heart rate changes > 50 bpm, are objective markers for identifying focal seizures that patients may not report [34].
- ▸Specific antiseizure medications like zonisamide and topiramate can cause hypohidrosis and hyperthermia, requiring clinical monitoring of temperature and sweat function [40].
The clinical evaluation of epilepsy requires a meticulous reconstruction of the seizure event, as patient self-reporting is frequently inaccurate, particularly in focal onset impaired awareness seizures (FIAS) [41]D. Clinicians must distinguish between the prodrome, the ictal event, and the post-ictal state to localize the epileptogenic zone and identify underlying etiologies. ### Presenting Symptoms Patients often present following a paroxysmal event.
Clinical Features and Seizure Variants
- ▸Idiopathic generalized epilepsy (IGE) is increasingly viewed as a neurobiological continuum rather than a set of discrete, separate syndromes [66].
- ▸Status epilepticus (SE) and its refractory variants like NORSE represent critical neurological emergencies with high mortality and long-term sequelae [64][81].
The clinical presentation of epilepsy is highly heterogeneous, reflecting the diverse neurobiological networks involved in seizure generation. Modern classification systems, such as those from the International League Against Epilepsy (ILAE), emphasize that idiopathic generalized epilepsies (IGE) represent a neurobiological continuum rather than strictly isolated syndromes [66]D. Clinical features are categorized by seizure onset (focal vs.
Diagnosis and Workup
- ▸Continuous EEG (≥12 hours) is superior to 60-minute routine EEG for predicting post-stroke epilepsy.
- ▸Integrated PET/MRI is recommended for precise preoperative localization in refractory epilepsy.
- ▸Delayed surgical evaluation after DRE diagnosis significantly worsens outcomes in pediatric populations.
- ▸Glymphatic dysfunction, measured by DTI-ALPS, correlates with the duration of epilepsy.
- ▸SeLEAS (Panayiotopoulos syndrome) is a frequent mimic of pediatric migraine.
- ▸AI-driven seizure prediction models face significant hurdles in clinical translation despite technical accuracy.
Initial Evaluation and Differential Diagnosis
The diagnosis of epilepsy remains primarily clinical, requiring the differentiation of seizures from other paroxysmal events. In pediatric populations, self-limited epilepsy with autonomic seizures (SeLEAS), formerly Panayiotopoulos syndrome, is frequently misdiagnosed as childhood migraine due to the prevalence of ictal or postictal headaches [276]C. A retrospective review found that a significant proportion of pediatric patients labeled with 'migraine' actually met the criteria for SeLEAS upon EEG review [276]C. Furthermore, clinicians must assess for seizure-related injuries; shoulder dislocations occurring during seizures are associated with specific injury patterns that may require specialized orthopedic evaluation [275]C.
Electroencephalography (EEG)
EEG remains the cornerstone of epilepsy workup, though its yield is influenced by timing and patient state. In patients with altered consciousness, the use of sedative agents like midazolam (median dose 0.89 mg/kg/h) and propofol can impact the detection of epileptiform activity [258]. Continuous EEG (cEEG) for ≥12 hours provides a significantly higher diagnostic yield and prognostic value for predicting post-stroke epilepsy (PSE) compared to a 60-minute short EEG (sEEG) in patients who have not experienced acute symptomatic seizures [265]. In pediatric postmalarial cases, quantitative EEG measures during the acute illness phase serve as markers for subsequent epileptogenesis [268]C. Emerging research into resting-state EEG biomarkers suggests that spectral-topological network signatures can help identify drug-resistant epilepsy (DRE) early in the diagnostic process [274]C.
Advanced Neuroimaging
Magnetic resonance imaging (MRI) protocols are evolving to include microstructural and network-based analyses. Focal to bilateral tonic-clonic seizures (FBTCS) are associated with specific morphological abnormalities in the insular cortex, which may aid in individual-level identification [267]. Hippocampal structural changes in focal epilepsy appear to be duration-dependent, suggesting that hippocampal abnormalities evolve as the disease progresses rather than solely serving as an initial substrate [272]. For refractory epilepsy, integrated PET/MRI is now recommended as a 'one-stop' diagnostic tool to improve the precision of preoperative epileptogenic zone (EZ) localization [271]. Additionally, diffusion tensor imaging (DTI-ALPS) has demonstrated that longer epilepsy duration is significantly correlated with glymphatic system dysfunction [260].
Preoperative Evaluation for Drug-Resistant Epilepsy (DRE)
For the 30% of patients who develop DRE, timely surgical evaluation is critical. Delays in surgical referral after a DRE diagnosis are associated with worsened seizure outcomes in children [269]. Preoperative workup now integrates noninvasive brain network dynamics, such as Global Diffusion Efficiency (GEDIFF) and Network Density (KDEN), to predict surgical success without the immediate need for invasive monitoring [261]. When invasive monitoring is required, stereoelectroencephalography (SEEG) utilizing 1/f spectral signatures can act as a proxy for excitation-inhibition (E/I) dynamics to localize the EZ [262]. Structural and functional network connection strength (SNCS/FNCS) in preoperative 'disconnected networks' also serves as a predictor for postoperative seizure freedom [277]. Notably, while piriform cortex resection was previously thought to be essential for seizure freedom in temporal lobe epilepsy, recent connectivity-based segmentations found no significant link between the extent of subregion resection and outcomes [264]C.
Systemic and Biomarker Assessment
Epilepsy workup is increasingly addressing systemic impacts and genetic etiologies. Strain echocardiography (LVGLS, RVGLS) has revealed subclinical cardiac involvement and myocardial deformity in epilepsy patients, suggesting a need for cardiac risk assessment [266]. In neonatal-onset cases, genomic testing is essential to categorize infants into functional gene groups, which informs neurodevelopmental prognosis [270]. For patients considering neuromodulation, preoperative thalamic volume asymmetry has emerged as a potential predictor for response to vagus nerve stimulation (VNS) [263]C. Finally, longitudinal studies of patients on levetiracetam (LEV) show that the medication may modulate complex brain networks and improve executive functions over an 18-month period [273].
Artificial Intelligence in Diagnostics
Artificial intelligence (AI) models are being developed for real-time seizure prediction. While these models show technical promise in experimental prototypes, a 'bench-to-bedside' gap remains due to limited generalizability and the lack of standardized evaluation for real-world clinical deployment [259].
| Diagnostic Tool | Key Finding | Evidence Level |
|---|---|---|
| cEEG (≥12h) | Higher yield for PSE prediction vs. sEEG | 3b [265] |
| PET/MRI | One-stop multidimensional EZ localization | 1c [271] |
| DTI-ALPS | Correlates epilepsy duration with glymphatic decay | 2a [260] |
| SEEG (1/f) | Proxy for E/I dynamics in EZ localization | 3b [262] |
| Strain Echo | Detects subclinical myocardial deformity | 3b [266] |
Differential Diagnosis of Epilepsy
- ▸Serum lactate and ammonia measured within 60 minutes are highly effective for distinguishing epileptic seizures from syncope and functional seizures.
- ▸Home video recordings provide high interobserver reliability and diagnostic accuracy for differentiating sleep-related hypermotor epilepsy from non-epileptic disorders of arousal.
The differential diagnosis of epilepsy is broad, as many transient neurological events can mimic epileptic seizures (ES). Accurate differentiation is critical because misdiagnosis leads to inappropriate treatment with antiseizure medications (ASMs) and delays the of the underlying condition [119]D[126]D. The diagnostic process relies on a combination of clinical semiology, serum biomarkers, and electrophysiological data to distinguish ES from functional seizures, syncope, and sleep disorders [121][139]D.
Surgical and Interventional Management
- ▸Epilepsy surgery achieves seizure freedom in 50–70% of drug-resistant cases.
- ▸Shorter duration of epilepsy is a consistent predictor of better postoperative outcomes across multiple pathologies.
- ▸sEEG is increasingly preferred over subdural electrodes due to its safety profile and comparable accuracy.
- ▸Tailored hippocampal resection in TLE may help preserve neurocognitive function, specifically verbal memory.
- ▸Hemispheric surgery is the standard for Rasmussen encephalitis but requires careful functional trade-off analysis.
- ▸Socioeconomic barriers significantly limit access to epilepsy surgery in developing regions like Latin America.
Overview and Patient Selection
Surgical intervention is a primary consideration for drug-resistant epilepsy (DRE), defined as the failure of two or more appropriately chosen and tolerated antiseizure medications. While resective surgery remains the gold standard, achieving seizure freedom in 50–70% of cases [279], success depends heavily on precise localization of the epileptogenic zone (EZ) and patient-specific pathology [279]. Recent meta-analyses indicate that shorter epilepsy duration is a significant predictor of favorable outcomes, particularly in pediatric populations and specific pathologies like polymicrogyria [280][284].
Invasive Monitoring and Localization
When non-invasive evaluations (MRI, scalp EEG, PET) are inconclusive, invasive monitoring is employed.
- Stereoelectroencephalography (sEEG): This technique has increasingly replaced subdural electrodes (SDE) due to its less invasive nature [101]D. Robot-assisted sEEG implantation offers comparable accuracy and safety to frame-based methods, with no significant difference in complication rates [150]. Computational frameworks using sEEG-derived 1/f spectral signatures are being developed to improve EZ identification by mapping excitation-inhibition (E/I) dynamics [262].
- Subdural Electrodes (SDE): While declining in use, SDE remains valuable for mapping the epileptogenic network. However, it carries a risk of extra-axial hemorrhage (subdural or epidural) in approximately 20% of cases [285]C.
- Predictive Scoring: The 5-SENSE score is utilized to predict the likelihood of identifying a focal EZ during sEEG. In pediatric cohorts, it demonstrates a specificity of 75%, though its sensitivity is lower (49%) [287].
- Stimulation-Induced Seizures (SIS): During sEEG, electrical stimulation is used for functional mapping. In children, SIS are common and their characteristics vary based on cortical architecture and underlying etiology [286].
Resective and Ablative Procedures
Temporal Lobe Epilepsy (TLE)
Anterior temporal lobectomy (ATL) is the most common procedure for mesial temporal lobe epilepsy (MTLE) associated with hippocampal sclerosis (HS) [278].
- Predictors of Success: Preoperative clinical, neuroimaging, and neuropsychological factors are critical for predicting seizure freedom [278].
- Cognitive Outcomes: A major concern in ATL is postoperative verbal memory decline, particularly when the language-dominant hemisphere is involved [290]. Research indicates that the graded extent of hippocampal resection is directly related to neurocognitive outcomes; tailoring the resection to spare parts of the hippocampus may mitigate deficits [289].
Extratemporal and Hemispheric Surgery
- Polymicrogyria (PMG): Surgical strategies for PMG range from limited resections to hemispheric approaches. Approximately 70% of patients achieve Engel Class I outcomes at ≥12 months follow-up, with shorter epilepsy duration (median 8.0 years) being a key predictor of success [280][147].
- Rasmussen Encephalitis (RE): Hemispheric surgery is considered curative for RE-associated DRE [282]. While it provides high rates of seizure freedom, it necessitates a balance with motor and cognitive functional outcomes [288]C.
- Low-Grade Tumors: Epilepsy associated with gangliogliomas (GGs) and dysembryoplastic neuroepithelial tumors (DNETs) often responds well to surgical resection, though long-term recurrence rates vary [283].
Minimally Invasive Alternatives
Laser interstitial thermal therapy (LITT) has emerged as a minimally invasive alternative to open resective surgery for nontumoral epilepsy. While LITT offers shorter recovery times, meta-analyses suggest that open surgery may still provide superior seizure freedom rates in certain populations [144].
Emergency Interventions
For super-refractory status epilepticus (SRSE)—status epilepticus persisting for >24 hours despite anesthetic management—surgical interventions including focal resection, hemispherectomy, or neuromodulation may be considered as salvage therapy [281]C.
Global Perspectives and Methodology
In Latin America, epilepsy surgery remains underutilized due to socioeconomic barriers, geographic centralization, and economic constraints [145]. Methodologically, the use of Bayesian estimation in surgical outcome studies is recommended to attenuate the exaggeration of effect sizes often seen in underpowered studies with small sample sizes [151].
| Pathology | Procedure Type | Success Rate (Engel I) | Key Predictor |
|---|---|---|---|
| MTLE-HS | ATL / Tailored Resection | High (Variable) | Preoperative Imaging/EEG [278] |
| Polymicrogyria | Hemispheric to Limited | ~70% | Shorter Duration (<8 yrs) [280] |
| Rasmussen Encephalitis | Hemispheric Surgery | High | Early Intervention [282] |
| Low-Grade Tumors | Lesionectomy | High | Extent of Resection [283] |
Special Populations: Pediatrics, Pregnancy, and Geriatrics
- ▸Levetiracetam monotherapy in children does not appear to adversely affect cardiac parameters over a one-year period.
- ▸Perampanel is effective as adjunctive therapy in children as young as 7 months.
- ▸Severe maternal morbidity is a risk factor for the development of epilepsy in offspring.
- ▸Late-onset epilepsy in seniors (≥65) often has better seizure control outcomes than early-onset persistent epilepsy.
- ▸Undiluted IV push valproic acid is a safe alternative to slow infusion for emergent seizure management.
- ▸Rural disparities significantly impact epilepsy mortality and status epilepticus rates.
Pediatrics
Pediatric epilepsy management requires addressing unique etiologies, developmental impacts, and treatment safety profiles. Genetic factors play a significant role; for instance, tubulinopathies (mutations in genes such as TUBA1A, TUBB2A, and TUBB4A) present a broad spectrum of neurodevelopmental disorders and seizure profiles in children [298]C. Beyond seizures, families often face significant 'information work' to manage comorbidities like sleep disturbances, which are frequently under-addressed in standard care [291]. Furthermore, the social impact of epilepsy is profound, with stigma significantly affecting the emotional and physical wellbeing of children [295].
Pharmacotherapy in Children
Recent evidence highlights the efficacy and safety of newer antiseizure medications (ASMs) in pediatric populations:
- Levetiracetam: A longitudinal study of children with genetic generalized epilepsy receiving levetiracetam monotherapy for one year found no significant adverse effects on cardiac repolarization or echocardiographic parameters [292]C.
- Perampanel: In young children (7–46 months) with drug-resistant epilepsy (DRE), adjunctive perampanel demonstrated a responder rate (≥ 50% seizure reduction) of 39.5% at 3 months, increasing to 47.1% at 12 months [294].
- Cenobamate: Real-world data in pediatric focal DRE (median age 11.5 years) suggests it is a promising adjunctive therapy, though data remains more limited than in adults [309].
- Zonisamide: Machine learning models are being developed to predict zonisamide concentrations in children to facilitate individualized dosing regimens [304].
Surgical and Interventional Considerations
For pediatric DRE, Vagus Nerve Stimulation (VNS) remains a standard intervention. Response to VNS may be associated with peripheral blood inflammatory biomarkers; indices such as the neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII) are being investigated as predictors of treatment success [296]. In cases requiring surgical resection, such as those involving pleomorphic xanthoastrocytomas (PXAs), 76% of patients present with tumor-related epilepsy, and early surgical intervention is critical for seizure control [305]. Noninvasive preoperative evaluations using scalp EEG source imaging and brain network topological dynamics (e.g., Global Diffusion Efficiency) are showing promise in predicting surgical outcomes [261].
Pregnancy and Neonatal Outcomes
Managing epilepsy during pregnancy involves balancing maternal seizure control with fetal neurodevelopmental risks. Severe maternal morbidity (SMM) during the period from 20 weeks' gestation to 42 days postpartum has been associated with an increased risk of epilepsy diagnosis in the offspring [300].
Regarding in utero ASM exposure, a semiprospective cohort study of children aged 3–18 years found that prenatal exposure to monotherapies of carbamazepine, lamotrigine, or levetiracetam did not necessarily result in poorer neurocognitive outcomes compared to unexposed children, though data on newer agents remains a priority for ongoing research [293]C.
Geriatrics
Epilepsy in older adults (≥ 65 years) is of increasing clinical relevance due to aging global populations. This population includes those with early-onset persistent epilepsy (EOPE, onset < 40 years) and late-onset epilepsy (LOE, onset ≥ 65 years) [307].
Clinical Characteristics and Risks
- Seizure Freedom: Patients with LOE may achieve higher rates of seizure freedom compared to those with EOPE [307].
- Fracture Risk: Older adults with epilepsy have a substantially elevated risk of fractures. When comparing newer ASMs, lacosamide monotherapy has been evaluated against levetiracetam for its skeletal safety profile [297].
- Bidirectional Associations: Traumatic brain injury (TBI) in mid-to-late life is associated with an increased incidence of epilepsy; conversely, pre-existing epilepsy may predispose older veterans to TBI [306].
- Hydrocephalus: Adult-onset hydrocephalus is associated with an increased hazard ratio for incident epilepsy over time [299].
Special Considerations Across Populations
- Intellectual Disabilities: In individuals with intellectual disabilities, the onset of new physical health problems or sensory impairments is often temporally associated with incident challenging behaviors, which may complicate epilepsy management [302].
- Emergency Management: Rapid administration of undiluted IV push valproic acid (up to 4000 mg) has been found safe and well-tolerated, potentially reducing delays in treating emergent seizures or status epilepticus [301].
- Surgical Biomarkers: High-frequency oscillations (HFOs) are being refined as biomarkers for the seizure-onset zone (SOZ), with research indicating that sleep states significantly influence their spatial distribution and reliability for surgical planning [303]C.
- Disparities: Rural residence in the United States is linked to poorer clinical outcomes, including higher risks of presenting in status epilepticus and increased in-hospital mortality, likely due to limited access to specialized epilepsy centers [308].
| Timepoint | Responder Rate (≥50% Reduction) |
|---|---|
| 3 Months | 39.5% |
| 6 Months | 41.4% |
| 12 Months | 47.1% |
Landmark Trials and Key Evidence
- ▸ANT-DBS is effective for drug-resistant focal epilepsy even after VNS failure [312].
- ▸RNS shows sustained 3-year efficacy in real-world focal epilepsy populations [310].
- ▸Soticlestat (TAK-935) has been rigorously tested in phase 3 trials for LGS and Dravet syndrome [313, 314].
- ▸Prophylactic levetiracetam is frequently used in glioma surgery despite guidelines, but its efficacy in preventing seizures in seizure-naive patients is a subject of ongoing RCT synopsis [193].
- ▸Serum uric acid serves as a genetically linked risk marker for post-stroke epilepsy [316].
- ▸Early ASM discontinuation in neonates after provoked seizure resolution is safe [318].
- ▸Suicidality at diagnosis is a marker for potential future drug resistance [211].
- ▸SEEG-derived 1/f spectral signatures are being used to localize the epileptogenic zone via E/I dynamics [262].
Recent clinical evidence has significantly expanded the therapeutic landscape for epilepsy, particularly in the domains of neuromodulation, pediatric encephalopathies, and post-stroke management. The 2026 landscape is defined by large-scale randomized controlled trials (RCTs) and long-term post-approval studies that refine the use of both pharmacological and device-based interventions.
Neuromodulation and Surgical Interventions
The efficacy of deep brain stimulation (DBS) and responsive neurostimulation (RNS) has been reinforced by high-level evidence. The FRANCE study, a phase 3 randomized clinical trial, demonstrated that bilateral DBS of the anterior nucleus of the thalamus (ANT) is superior to best medical treatment (BMT) in patients with drug-resistant focal or multifocal epilepsy who had previously failed vagus nerve stimulation (VNS) [312]. Concurrently, a 3-year post-approval study of the RNS System involving 324 patients across 32 centers confirmed real-world effectiveness, reporting a significant median percent change in seizure frequency at the 3-year mark [310]. In specialized pediatric populations, such as those with SCN1A-associated developmental and epileptic encephalopathies (e.g., Dravet syndrome), network-targeted bilateral thalamic RNS (centromedian or anterior nucleus) has emerged as a viable intervention for high seizure burdens [320]C.
Pharmacological Advances in Pediatric Encephalopathies
Two major phase 3 trials, SKYWAY and SKYLINE, evaluated soticlestat (a cholesterol 24-hydroxylase inhibitor) as adjunctive therapy. In the SKYWAY study of Lennox-Gastaut syndrome (LGS), soticlestat was tested against placebo over a 16-week period [313]. Similarly, the SKYLINE trial investigated soticlestat in children and young adults with Dravet syndrome, focusing on monthly convulsive seizure frequency [314]. While soticlestat represents a novel mechanism, stiripentol remains a historical cornerstone, with early phase 2 data showing a reduction in median seizure frequency from 31 to 14 per month in LGS patients [319]. For pediatric drug-resistant focal epilepsy, real-world evidence for cenobamate has shown promise in reducing seizure frequency in children (median age 11.5 years) [309].
Acute Management and Emergency Protocols
Management of status epilepticus (SE) remains a critical focus. Secondary analysis of the ESETT trial highlighted persistent delays in real-world SE treatment timelines despite established guidelines [192]. For intermittent seizure clusters, diazepam nasal spray has been validated using the novel SEIVAL (SEIzure interVAL) endpoint, which measures the time between clusters to assess long-term effectiveness [311]. In the ICU setting, the use of midazolam and propofol has been scrutinized for its impact on EEG diagnostic yield; a multicenter analysis (CERTA) of 364 patients found that these sedatives can influence the detection of epileptiform abnormalities in patients with altered consciousness [258].
Post-Stroke Epilepsy (PSE) and Prevention
The relationship between stroke and epilepsy is increasingly characterized by vascular and metabolic markers. The ODYSSEY study identified a strong association between PSE and vascular cognitive disorder (VCD) in young stroke patients (aged 18–49), suggesting that epilepsy-related network alterations or stroke severity may drive cognitive decline [317]. Genetically, Mendelian randomization has identified serum uric acid (SUA) as a sex-dependent risk marker for PSE after acute ischemic stroke [316]. Regarding prevention, the BIA-2093-213 phase 2a trial investigated eslicarbazepine acetate as a potential antiepileptogenic agent in high-risk stroke patients (SeLECT score ≥5), though it remains a proof-of-concept endeavor [194].
Special Populations and Etiology
In neonatal care, a prospective cohort study demonstrated that early discontinuation of antiseizure medications (ASM) after the resolution of acute provoked neonatal seizures (prior to hospital discharge) is a safe practice that does not adversely affect long-term outcomes [318]. In older adults (aged ≥55), ischemic stroke remains the leading etiology for new-onset seizures, though the demographic landscape is shifting as this population grows [321]. Furthermore, psychiatric comorbidities at the time of diagnosis, specifically suicidality, have been identified as predictors for future treatment resistance in focal epilepsy [211]D. Finally, genetic research into tubulinopathies has identified 12 distinct pathogenic variants across seven genes (e.g., TUBA1A, TUBB2A), expanding the phenotypic spectrum of pediatric neurodevelopmental epilepsies [298]C.
| Trial/Study | Intervention | Population | Primary Outcome/Finding |
|---|---|---|---|
| FRANCE [312] | ANT-DBS | Drug-resistant focal epilepsy | Superior to best medical treatment (BMT) |
| SKYWAY [313] | Soticlestat | Lennox-Gastaut syndrome | Evaluated % change in major motor seizures |
| SKYLINE [314] | Soticlestat | Dravet syndrome | Evaluated monthly convulsive seizure frequency |
| RNS Post-Approval [310] | Responsive Neurostimulation | Focal epilepsy | Sustained efficacy at 3 years in real-world setting |
| BIA-2093-213 [194] | Eslicarbazepine acetate | High-risk post-stroke | Phase 2a antiepileptogenesis proof-of-concept |
| SPRING [193] | Levetiracetam | Seizure-naive glioma surgery | Evaluated >50% reduction in seizure risk |
Guidelines and Resources
- ▸The 2025 ILAE seizure classification categorizes seizures into focal, generalized, unknown, and unclassified.
- ▸Structural MRI is recommended for all infants (1–24 months) with new-onset epilepsy.
- ▸Lamotrigine, levetiracetam, and zonisamide are preferred for new-onset focal epilepsy.
- ▸Drug-resistant epilepsy (DRE) is defined as failure of two appropriate antiseizure medications.
- ▸Prophylactic ASMs are not recommended for patients with brain tumors who have not had a seizure.
- ▸Adults tapering ASMs after 2 years of seizure freedom have a 15% recurrence risk vs 7% if they continue.
- ▸Psychological interventions are the primary evidence-based treatment for functional seizures.
Seizure Classification and Diagnostic Standards
The International League Against Epilepsy (ILAE) updated its seizure classification in 2025, building upon the 2017 operational framework to enhance clinical relevance [234]. The system distinguishes four primary classes: focal, generalized, unknown, and unclassified [234]. For infants aged 1–24 months, the ILAE Neuroimaging Task Force recommends structural MRI following a first afebrile seizure or new-onset epilepsy to identify structural brain abnormalities [322]. Minimum standards for routine and sleep EEG recording have been established by the IFCN and ILAE to ensure diagnostic quality, utilizing PRISMA and GRADE methodologies [218]. Furthermore, the role of EEG remains critical in defining epilepsy syndromes—clusters of signs and symptoms that facilitate targeted therapy and research [237]. Alternative patient-oriented classification systems propose a five-dimensional approach focusing on the epileptogenic zone, semiology, etiology, seizure frequency, and comorbidities [238].
Pharmacological Management and Monitoring
Treatment of new-onset focal epilepsy should prioritize lamotrigine, levetiracetam, or zonisamide [217]. In pediatric populations, carbamazepine, lamotrigine, or levetiracetam are recommended as first-line monotherapy for focal seizures [222]. Therapeutic drug monitoring (TDM) is indicated to establish an individual therapeutic concentration once clinical control is achieved, or to assess potential causes for changes in drug response [216]. For patients who have been seizure-free for 2 years, tapering antiseizure medications (ASMs) may be considered, though adults face a higher recurrence risk (15%) compared to those continuing therapy (7%) [219]. In pediatric patients, there is no significant difference in recurrence risk between tapering after 2 years versus 4 years of seizure freedom [219].
Special Populations and Comorbidities
Pregnancy and Neurodevelopment
Updated 2024 guidelines from the AAN, AES, and SMFM address the risks of in utero ASM exposure [215]. The guidelines provide evidence-based conclusions on major congenital malformations (MCMs), adverse perinatal outcomes, and neurodevelopmental effects in children born to people with epilepsy of childbearing potential (PWECP) [215].
Brain Tumors and COVID-19
In patients with newly diagnosed brain tumors who have not experienced a seizure, clinicians should not prescribe prophylactic anticonvulsants to reduce the risk of a first seizure [220]. During the COVID-19 pandemic, the Israeli Chapter of the ILAE issued recommendations regarding drug-drug interactions (DDIs) between investigational anti-COVID-19 drugs and ASMs, emphasizing the need to monitor ASM pharmacokinetics and potential seizure exacerbation [240].
Drug-Resistant Epilepsy (DRE) and Surgery
DRE is defined by the ILAE as the failure of two appropriate and well-tolerated ASM schedules to achieve sustained seizure freedom [235][236]. Patients meeting these criteria should be referred to specialized Epilepsy Units for rapid assessment [236]. For pediatric patients, dedicated surgical centers are recommended for refractory cases, even when Class 1 evidence is limited, to address unique developmental features [223]. Neuropathological work-up of focal cortical dysplasias (FCD) follows a consensus system: Type I (lamination defects) and Type II (dysmorphic neurons/balloon cells) [239].
Functional Seizures and Wearable Technology
Management of functional seizures (formerly psychogenic non-epileptic seizures) should involve psychological interventions, which are possibly effective in increasing seizure freedom and improving quality of life [226]. For outpatient monitoring, the ILAE and IFCN recommend the use of wearable devices for automated seizure detection, particularly for generalized tonic-clonic seizures, to improve safety and data accuracy [227][228].
| Patient Group | Recommended ASMs | Evidence Level |
|---|---|---|
| Adults | Lamotrigine, Levetiracetam, Zonisamide | Level B [217] |
| Children | Carbamazepine, Lamotrigine, Levetiracetam | Level A-C [222] |
| Brain Tumor (No Seizure) | Prophylaxis Not Recommended | Class I-III [220] |
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