Epilepsy is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
Epilepsy is a chronic neurological disorder characterized by an enduring predisposition to generate epileptic seizures — sudden, abnormal electrical discharges in the brain that cause changes in awareness, behavior, sensation, or movement. Defined by the occurrence of at least two unprovoked seizures more than 24 hours apart, epilepsy affects approximately 52 million people worldwide, with a global prevalence of ~658 per 100,000 population ([GBD Epilepsy Collaborators, 2024](https://www.thelancet.com/journals/lanpub/article/PIIS2468-2667(24)00302-5/fulltext)). Approximately 5 million new diagnoses occur annually, with incidence reaching 139 per 100,000/year in low- and middle-income countries. Premature death risk is up to 3 times higher in people with epilepsy compared to the general population ([WHO, 2024](https://www.who.int/news-room/fact-sheets/detail/epilepsy)). [@nature2024]
Epilepsy is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
Epilepsy is a chronic neurological disorder characterized by an enduring predisposition to generate epileptic seizures — sudden, abnormal electrical discharges in the brain that cause changes in awareness, behavior, sensation, or movement. Defined by the occurrence of at least two unprovoked seizures more than 24 hours apart, epilepsy affects approximately 52 million people worldwide, with a global prevalence of ~658 per 100,000 population ([GBD Epilepsy Collaborators, 2024](https://www.thelancet.com/journals/lanpub/article/PIIS2468-2667(24)00302-5/fulltext)). Approximately 5 million new diagnoses occur annually, with incidence reaching 139 per 100,000/year in low- and middle-income countries. Premature death risk is up to 3 times higher in people with epilepsy compared to the general population ([WHO, 2024](https://www.who.int/news-room/fact-sheets/detail/epilepsy)). [@nature2024]
Epilepsy is increasingly recognized as deeply intertwined with [neurodegeneration](/diseases/neurodegeneration). People with late-onset epilepsy have a 2- to 3-fold higher risk of developing dementia, while [Alzheimer's disease](/diseases/alzheimers-disease) patients show subclinical epileptiform activity in up to 31% of cases ([Vossel et al., 2024](https://www.nature.com/articles/s41582-024-00932-4)). Shared mechanisms including [excitotoxicity](/mechanisms/excitotoxicity), tau] hyperphosphorylation, [neuroinflammation](/mechanisms/neuroinflammation), [blood-brain barrier](/entities/blood-brain-barrier) disruption, and [mTOR](/mechanisms/mtor-neurodegeneration) pathway dysregulation link epilepsy to neurodegenerative diseases at the molecular level. [@epilepsia2024]
The International League Against Epilepsy (ILAE) classifies epilepsy at three levels: seizure type, epilepsy type, and epilepsy syndrome. The 2025 updated classification identifies four main seizure classes — Focal, Generalized, Unknown, and Unclassified — comprising 21 seizure types ([Beniczky et al., 2025](https://onlinelibrary.wiley.com/doi/10.1111/epi.18338)). Epilepsy types include focal epilepsy, generalized epilepsy, combined generalized and focal epilepsy, and unknown epilepsy. [@ref]
Strong evidence supports a bidirectional relationship between epilepsy and neurodegeneration: [@refa]
Temporal lobe epilepsy with hippocampal sclerosis (TLE-HS) is the most common drug-resistant focal epilepsy, with hallmark pathology including: [@pmc]
[Autoimmune encephalitis](/diseases/autoimmune-encephalitis)-related epilepsies involve autoantibodies against surface neuronal proteins: [@refb]
| Antibody Target | Mechanism | Clinical Features | [@epilepsia2024a]
|---|---|---| [@pmca]
| Anti-NMDAR | IgG binds NR1 subunit → receptor internalization, reduced Ca²⁺ influx | Most common autoimmune encephalitis; psychiatric symptoms, seizures | [@pmcb]
| Anti-LGI1 | Disrupts trans-synaptic complex regulating transmission | Faciobrachial dystonic seizures, limbic encephalitis | [@sciencedirect2024]
| Anti-CASPR2 | Blocks contactin-2 interaction → hyperexcitability | Neuromyotonia, Morvan syndrome | [@pmcc]
| Anti-GABAₐR | Impairs GABAergic inhibition | Seizures, status epilepticus, limbic encephalitis |
Seizure freedom is achieved faster and more frequently with immunotherapy than antiseizure medications alone in autoimmune epilepsies ([Irani et al., 2016](https://pmc.ncbi.nlm.nih.gov/articles/PMC5042290/)).
Seizures induce elevations in extracellular [glutamate](/entities/glutamate), contributing to excitotoxic neuronal damage through excessive Ca²⁺ influx via extrasynaptic GluN2B-containing [NMDA receptor](/entities/nmda-receptor) receptors]. During status epilepticus, [GABA](/entities/gaba) receptors are internalized while [NMDA receptor](/entities/nmda-receptor) receptors migrate to synapses, reducing inhibition and enhancing excitability. Downregulation of glutamate transporter EAAT2 (GLT-1) reduces glutamate clearance, sustaining excitotoxic damage ([PMC, 2023](https://pmc.ncbi.nlm.nih.gov/articles/PMC10045847/)).
Loss of GABAergic interneurons — particularly parvalbumin-positive ([PV+](/cell-types/pv-interneurons) and somatostatin-positive subtypes — is a hallmark of epileptic foci. In hippocampal sclerosis, selective loss of inhibitory interneurons disinhibits pyramidal [neurons](/entities/neurons), creating hyperexcitable circuits. Pro-inflammatory cytokines from activated [microglia.
Activated [microglia.
Tuberous Sclerosis Complex (TSC), caused by mutations in TSC1 (hamartin) or TSC2 (tuberin), is the prototypic monogenic [mTOR](/mechanisms/mtor-neurodegeneration) pathway disorder. [mTOR](/mechanisms/mtor-neurodegeneration) hyperactivation affects protein synthesis, cell growth, synaptic plasticity, and neuronal excitability. DEPDC5 mutations (also in the [mTOR](/mechanisms/mtor-neurodegeneration) pathway) are now recognized as a major cause of focal cortical dysplasia type II and familial focal epilepsy. Everolimus (an [mTOR](/mechanisms/mtor-neurodegeneration) inhibitor) is approved for TSC-associated subependymal giant cell astrocytomas and effectively reduces seizures ([PMC, 2023](https://pmc.ncbi.nlm.nih.gov/articles/PMC10275542/)).
Network hyperexcitability in epilepsy activates tau] kinases (especially [GSK-3β](/entities/gsk-3-beta) and the [mTOR](/mechanisms/mtor-neurodegeneration) pathway, leading to abnormal tau] phosphorylation. Hyperphosphorylated [tau](/proteins/tau) loses its microtubule-stabilizing function, leading to axonal transport collapse, synaptic dysfunction, and neuronal death — mirroring [Alzheimer's disease](/diseases/alzheimers-disease) pathology. Reducing tauopathy alleviates both epileptic seizures and spatial memory impairment in animal models ([Frontiers in Aging Neuroscience, 2022](https://pmc.ncbi.nlm.nih.gov/articles/PMC9340804/)).
| Gene | Protein / Channel | Condition | Mechanism |
|---|---|---|---|
| SCN1A | Nav1.1 sodium channel | Dravet syndrome, GEFS+ | Loss-of-function impairs GABAergic interneuron firing |
| KCNQ2 | Kv7.2 potassium channel | Benign familial neonatal epilepsy | Loss-of-function reduces M-current |
| SCN2A | Nav1.2 sodium channel | Early-infantile DEE | Both gain- and loss-of-function; phenotype varies |
| SCN8A | Nav1.6 sodium channel | Early-infantile DEE | Gain-of-function; severe drug-resistant epilepsy |
| CDKL5 | Cyclin-dependent kinase-like 5 | CDKL5 deficiency disorder | X-linked; epileptic spasms |
| STXBP1 | Munc18-1 | Ohtahara syndrome | Impairs synaptic vesicle docking/fusion |
| TSC1/TSC2 | Hamartin/Tuberin | Tuberous sclerosis | [mTOR](/mechanisms/mtor-neurodegeneration) hyperactivation; cortical tubers |
| DEPDC5 | DEPDC5 ([mTOR](/mechanisms/mtor-neurodegeneration) pathway) | Familial focal epilepsy | Autosomal dominant; focal cortical dysplasia |
Over 1,800 mutations in SCN1A alone have been identified, with ~90% arising de novo ([GeneReviews](https://www.ncbi.nlm.nih.gov/books/NBK1318/); [IJMS, 2023](https://www.mdpi.com/1422-0067/24/22/16280)).
Fluid Biomarkers:
Neuroimaging:
First-generation: Phenytoin, carbamazepine, valproate, phenobarbital, ethosuximide.
Second-generation: Lamotrigine, levetiracetam, topiramate, oxcarbazepine, gabapentin, pregabalin, zonisamide, lacosamide.
Recently approved ASMs:
Interactive diagram showing EPILEPSY key relationships in the SciDEX knowledge graph (15 connections shown).
The study of Epilepsy has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
Recent advances in Epilepsy have focused on understanding disease mechanisms, identifying biomarkers, and developing novel therapeutic approaches. Key developments include: