{
  "id": "epilepsy",
  "title": "Epilepsy",
  "lang": "en",
  "source_lang": "en",
  "summary": "Epilepsy is a chronic neurological disorder marked by recurrent, unprovoked seizures caused by abnormal, excessive firing of neurons in the brain.",
  "category": "health",
  "subcategory": "diseases",
  "type": "concept",
  "aliases": [
    "seizure disorder"
  ],
  "generated_at": "2026-10-08",
  "model": "pro/claude-haiku-5-5",
  "url": "https://aiwiki.page/en/epilepsy/",
  "translations": {
    "zh-Hans": {
      "url": "https://aiwiki.page/zh/epilepsy/",
      "json": "https://aiwiki.page/zh/epilepsy.json"
    }
  },
  "sections": [
    {
      "heading": "",
      "text": "Epilepsy is a chronic neurological disorder in which the brain has a lasting tendency to produce unprovoked seizures, which are brief episodes of abnormal, excessive, or synchronous activity of neurons in the brain. A single seizure does not by itself define the condition; the diagnosis generally requires recurrent seizures that are not caused by an acute, temporary trigger. Seizures vary widely, from brief lapses of attention or muscle jerks to generalized convulsions with loss of consciousness, and the disorder affects people of all ages. It is one of the most common serious neurological conditions worldwide, and it carries medical, psychological, and social consequences that extend well beyond the seizures themselves.\n\nEpilepsy matters for several reasons. It is a major cause of disability and premature death, particularly through injuries during seizures and sudden unexpected death in epilepsy. It also serves as an important case study in neuroscience, because it shows how changes in ion channels, synaptic signaling, and network organization can convert normal brain activity into pathological rhythms. Clinically, the field has moved toward more precise classification of seizures and syndromes, genetic diagnosis, and a wider range of treatments, including drugs, surgery, neuromodulation, and dietary therapy, although a substantial share of patients still do not achieve full seizure control.\n\nThis entry proceeds from the definition of epilepsy and the physiology of seizures, through the current classification of seizure types and epilepsy syndromes, the causes and mechanisms of epileptogenesis, and the methods used for diagnosis. It then covers drug and non-drug treatments, the global epidemiology and treatment gap, the historical development of ideas about the disorder, and the social and legal dimensions of living with epilepsy, ending with open research questions."
    },
    {
      "heading": "Definition and diagnostic criteria",
      "text": "Epilepsy has been defined in two stages by the International League Against Epilepsy (ILAE). The 2005 conceptual definition described it as a disorder of the brain marked by an enduring predisposition to generate epileptic seizures. The definitions were conceptual, (theoretical) and not sufficiently detailed to indicate in individual cases whether a person did or did not have epilepsy. Therefore, the ILAE commissioned a second task force to develop a practical (operational) definition of epilepsy, designed for use by doctors and patients. That operational definition, published by Fisher and colleagues in 2014, was adopted as an ILAE position. It also reframed epilepsy as a disease rather than a disorder, a change intended to convey the seriousness of the condition to patients, clinicians and society.\n\nUnder the 2014 criteria, a person has epilepsy if any one of three conditions is met: at least two unprovoked (or reflex) seizures occurring >24 h apart; one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years; or diagnosis of an epilepsy syndrome. The inclusion of reflex seizures, which are provoked by specific stimuli, is deliberate: the authors reasoned that a repeated tendency to respond to such triggers still reflects an enduring predisposition. The 2014 framework also lets a clinician recognize epilepsy after a single seizure, a change that had no counterpart in the earlier two-seizure rule.\n\nA seizure itself is a transient occurrence of signs or symptoms caused by abnormal, excessive or synchronous neuronal activity in the brain. A single seizure is therefore not epilepsy by itself. The 2014 criteria also address the time course of seizures: multiple seizures clustered within 24 hours are treated as one event. One study found that patients whose first presentation involved several seizures in 24 hours had a recurrence rate of 40%, compared with 38% for those with a single seizure.\n\nThe probability of recurrence is central to the second criterion, and the figures are substantial but not uniform. Fewer than half of patients who have a first unprovoked seizure will have a second episode, yet recurrence rates have been reported at about 36% after one year and 40–50% after two years. Interictal epileptiform discharges on EEG raise the estimate further: an adult with epileptiform discharges on routine EEG after a first unprovoked seizure has a 77% probability of having a second seizure, whilst a child with similar findings has a 66% probability. The 60% threshold itself has been debated. Data-driven estimates have placed the 10-year recurrence risk after two unprovoked seizures at about 85%, and an ILAE decision analysis found that the 10-year recurrence rate justifying antiseizure treatment (38%) is substantially lower than the 60% threshold in the current definition.\n\nEpilepsy also has an end point. Under the 2014 report, it is considered resolved for people who had an age-dependent syndrome and are now past the applicable age, or who have been seizure-free for the last 10 years and off antiseizure medicines for at least the last 5 years. The ILAE notes that \"resolved\" is not necessarily the same as remission or cure.\n\nDistinguishing unprovoked seizures from acute symptomatic ones is essential, because the two carry different recurrence risks. In 2010 an ILAE commission defined an acute symptomatic seizure as one occurring at the time of a systemic insult or in close temporal association with a documented brain insult. The commission proposed windows of about one week after stroke, traumatic brain injury, anoxic encephalopathy, or intracranial surgery, and a requirement that severe metabolic derangements be documented within 24 hours. The ILAE also recommended that the term acute symptomatic replace \"provoked,\" \"reactive,\" and \"situation-related\" seizure. Such seizures are excluded from the definition of epilepsy. Febrile seizures are a classic example: they occur with fever above 38 °C in children roughly six months to five years old without CNS infection. A seizure that falls outside the ILAE cut-offs is not automatically unprovoked, a point that is often overlooked in practice.\n\nIn this scheme, a seizure is the event, while epilepsy is a diagnosis made from one or more seizures together with the probability of further events or an identified syndrome. The broader family of epileptic conditions, including the many seizure types and syndromes, is treated in the classification section below."
    },
    {
      "heading": "Physiology of seizures",
      "text": "In healthy tissue, the firing of neurons depends on a continual balance between excitatory and inhibitory input. Glutamate is the primary excitatory neurotransmitter in the brain. Inhibition relies mainly on GABA: GABAergic inhibitory neurons primarily regulate the excitability of neurons. Epilepsy is commonly framed as a disturbance of this equilibrium, typically stemming from heightened excitability or diminished inhibition. Some evidence suggests the brain partly compensates for this risk. Compensation may be accomplished by channel-mediated tonic GABA release from reactive astrocytes, which could explain why seizures in people with severe epilepsy remain intermittent rather than continuous even though the excitation-inhibition balance is shifted toward excitation.\n\nThe synaptic imbalance is measurable during seizures. Extracellular glutamate can increase up to 30 times in the human hippocampus during seizures, while GABAergic neurons and synapses, and the expression and function of GABA receptors, are reduced. At the level of single cells, a seizure involves a sustained depolarization that drives firing. In the paroxysmal depolarizing shift, a rapid depolarization past the threshold potential, maintained by a plateau phase, produces bursts of action potentials, and these spikes become smaller and more closely spaced as the plateau continues. Seizure initiation is characterized by two concurrent events: high-frequency bursts of action potentials, and hypersynchronization of a neuronal population. The membrane potential governs this process because voltage-gated channels respond to it: sodium channels typically open when the membrane depolarizes, allowing sodium ions into the cell and initiating an action potential, while potassium channels open during repolarization. A computational study of persistent sodium currents found that with persistent sodium currents or incomplete inactivation of transient sodium this near balance can sustain long-term depolarized states.\n\nGlutamate receptors contribute in distinct ways. The AMPA channel is in general excitatory, and it conducts calcium, potassium, and sodium. NMDA receptors are more calcium-permeable, and their overactivation carries a cost: excessive glutamate in the synaptic cleft induces excitotoxicity by activating the NMDAR, which promotes calcium influx that leads to neuronal death. Ion gradients underpin all of this. The Na+/K+ ATPase utilizes ATP to establish opposite transmembrane gradients for Na+ and K+, and a multitude of channels then utilize these gradients to modulate the electrical potential across the neuronal membrane. During a seizure, the extracellular potassium concentration substantially increases, while the concentrations of extracellular sodium and calcium decrease. Sustained potassium efflux, in turn, depolarizes the membrane and moves the intracellular voltage toward the threshold for sodium action potential firing.\n\nHow a seizure ends is less settled. Computational models suggest that rising intracellular sodium is a key factor: spontaneous termination was linked to a progressive increase of intracellular sodium concentration mediated by activation of sodium channels during the highly active epileptic state. Calcium also plays a role, since increased calcium entry during the paroxysmal depolarizing shift, or as a result of the action of glutamate at the postsynaptic membrane, activates a calcium-dependent membrane potassium conductance that allows potassium efflux, membrane hyperpolarization, and cessation of firing. In some in vitro work, sodium accumulates during discharge and activates the sodium-potassium pump, which terminates the discharge by restoring the potassium gradient. The same model also predicts a postictal consequence: after seizure termination, the extracellular potassium was reduced below baseline, resulting in postictal depression. Because the mechanisms for spontaneous seizure termination and postictal depression remain poorly understood, these accounts should be read as hypotheses from models and experimental preparations rather than settled human physiology.\n\nSpread is the step that turns a local discharge into a whole-brain event. A seizure may begin in a very discrete region of cortex and then spread to neighboring regions. Propagation occurs when there is sufficient activation to recruit surrounding neurons, and this leads to a loss of surround inhibition and spread of seizure activity into contiguous areas via local cortical connections, and to more distant areas via long association pathways such as the corpus callosum. Speed varies with seizure type. Absence seizures originate in neocortex and spread across the brain quickly within several milliseconds, whereas other seizures propagate from the area of detection to other brain areas within several seconds and tens of seconds. Synchrony itself grows in stages: in chemoconvulsant-induced seizures in rats, it initially developed in a small subset of neurons and gradually spread to involve the entire cortical network only in the later more intense ictal phases. Recordings also suggest that the widespread EEG synchrony may reflect a front of locally hyperactive neurons, and that this dissociation is largely due to the strength of inhibitory neurons in restraining the advancing front of neuronal hyperactivity."
    },
    {
      "heading": "Classification of seizures and epilepsy syndromes",
      "text": "The 2017 operational framework\n\nThe International League Against Epilepsy (ILAE) classification of seizure types has its roots in a system that was used in modified form from 1981 and extended in 2010. The 2017 revision was made because some seizure types can have either a focal or generalized onset, and classification is needed when the onset is unobserved, some missing seizure types needed inclusion, and more transparent names were required. Seizures were first sorted by onset. Focal-onset seizures were defined as originating within networks limited to one hemisphere, while generalized-onset seizures originate within bilaterally distributed networks and engage them rapidly. Events whose origin could not be established formed a separate unknown-onset group, and such a seizure may still show defining motor or nonmotor features.\n\nTwo further features of the 2017 scheme matter for later revisions. First, a basic version and an expanded version existed, and the basic version is the same as the expanded version, but with the subcategories collapsed. Second, focal seizures could be subdivided by whether awareness was retained, giving focal aware and focal impaired-awareness seizures. The 2017 scheme also treated focal to bilateral tonic–clonic seizure as a special category, reflecting propagation rather than a unique seizure type, and it replaced the older term secondarily generalized tonic–clonic seizure.\n\nThe 2025 operational update\n\nThe 2025 revision was developed by a working group of 37 members from all ILAE regions, using a modified Delphi process with a consensus threshold of more than two-thirds for any proposal. It maintains four main seizure classes: focal, generalized, unknown (whether focal or generalized), and unclassified, and it comprises 21 seizure types, in contrast to 63 seizure types in the 2017 classification. The update was driven partly by translation problems: the working group cited difficulties in translating \"awareness\" into several languages, and concerns that the 2017 terminology mapped poorly onto ordinary neurological practice.\n\nSeveral terminology changes followed from this. The word \"onset\" was dropped from the class names, so \"focal-onset seizure\" became \"focal seizure\", and \"unknown-onset seizure\" became \"unknown whether focal or generalized.\" Consciousness replaced awareness as the classifier, and it is now operationally defined by both awareness and responsiveness. Focal and unknown seizures are subdivided by whether consciousness is preserved or impaired. The new \"unclassified\" class covers events that cannot be placed in the other three.\n\nThe 2025 scheme also separates classifiers from descriptors. Classifiers define seizure types, while descriptors provide additional clinical detail. Within the basic version, descriptors distinguish observable from non-observable manifestations, and the expanded version adds the chronological sequence of semiology. The basic version can be applied in resource-limited or primary care settings, while the expanded version supports detailed diagnostic and surgical decisions. Epileptic negative myoclonus is now recognized as a seizure type within the generalized class, alongside absence seizures and generalized tonic–clonic seizures. It is a distinct phenomenon from asterixis seen in toxic–metabolic encephalopathies.\n\nEpilepsy syndromes\n\nSeizure classification operates at a different level from epilepsy syndromes. The ILAE's 2017 framework described three levels: the seizure type, the epilepsy type, and, for some patients, a recognizable syndrome. Syndromes with onset in childhood are divided into three categories: self-limited focal epilepsies, generalized epilepsies, and developmental and/or epileptic encephalopathies. Each syndrome is defined by a set of mandatory seizure types, EEG features, age at onset, and characteristic findings on key investigations. Because certain syndromes correlate strongly with particular causes, identifying one can direct investigations; defining a syndrome often provides a clearer long-term prognosis regarding the likelihood of remission versus drug resistance.\n\nChildhood absence epilepsy is one of the generalized epilepsy syndromes. Its core seizure type is absence, and it is grouped in the ILAE scheme with epilepsy with myoclonic absence and epilepsy with eyelid myoclonia. Dravet syndrome belongs to the developmental and epileptic encephalopathies. It typically presents in the first year of life in a normal child with prolonged, febrile and afebrile, focal (usually hemiclonic) and generalized tonic-clonic seizures. In more than 90% of patients, a pathogenic SCN1A variant is found. Lennox–Gastaut syndrome is also classified as a developmental and epileptic encephalopathy. Its diagnostic criteria, as set out in a more recent ILAE paper, require multiple types of drug-resistant seizures with onset before 18 years, one of which must include tonic seizures, together with cognitive and often behavioral impairment and diffuse slow spike-and-wave on EEG. The earlier 1989 definition had instead limited the syndrome to an age range of roughly 1 to 8 years, showing how syndrome criteria have been refined over time."
    },
    {
      "heading": "Causes and risk factors",
      "text": "The 2017 ILAE framework sorts known causes of epilepsy into six groups: structural, genetic, infectious, metabolic, immune, and unknown. These groups overlap. Tuberous sclerosis is a genetic disorder that produces structural lesions, and some inherited metabolic disorders can be filed under either genetic or metabolic causes. Several risk factors often act together. A person with a family history of epilepsy, for example, has a higher chance of developing epilepsy after a traumatic brain injury than someone without that history.\n\nGenetic causes\n\nGenetic factors are thought to underlie roughly 30% of epilepsies. Many genetic epilepsies are caused by single-gene disorders that affect ion channels or neurotransmitter receptors. Dravet syndrome is the clearest example. Variants in SCN1A, which encodes a sodium channel (Nav1.1) concentrated in inhibitory interneurons, are found in roughly 70–80% of patients. Reduced function of this channel weakens inhibition relative to excitation, which makes networks prone to hyperexcitability. Most of these variants arise de novo, meaning they are new in the affected child, and only a small share of patients have a parent who carries the same variant. More than 2,000 pathogenic SCN1A variants have been reported, including point mutations, insertions and deletions, and whole-gene deletions. Other genes linked to Dravet-like presentations include several genes encoding GABA-A receptor subunits (such as GABRA1, GABRB2, GABRG2, and GABRB3). Large copy-number variants, which delete or duplicate stretches of chromosome containing many genes, form another group. An example is an 11-megabase deletion on chromosome 2 that removed more than 40 genes, including SCN1A. Polygenic susceptibility, in which many common genetic variants each add a small amount of risk, is thought to contribute to common generalized epilepsies, although its contribution is less well defined than that of single-gene disorders.\n\nStructural causes\n\nStructural causes are brain abnormalities that can be seen on neuroimaging, usually MRI. Malformations of cortical development, such as focal cortical dysplasia, form a major group; they can result from genetic errors during brain development or from insults before birth. Hippocampal sclerosis, characterized by neuronal loss and scarring in the hippocampus, is among the most common pathologies found in adults with drug-resistant temporal lobe epilepsy. Tumors, including some low-grade glial tumors and hypothalamic hamartomas, can generate focal seizures. Vascular lesions, such as cavernous malformations, arteriovenous malformations, and scars left after a stroke, are another structural category.\n\nAcquired causes\n\nAcquired epilepsy follows an identifiable brain insult. Stroke, both ischemic and hemorrhagic, is a well-recognized cause of late-onset epilepsy, particularly in older adults, because injured cortex can become a persistent source of abnormal discharges. Traumatic brain injury raises the risk, with greater severity of injury associated with higher risk. Central nervous system infections caused by bacteria, viruses, fungi, or parasites can leave lasting damage; neurocysticercosis is an important cause in parts of the world where the parasite is endemic. Perinatal injury is a significant cause in infancy. Premature birth can lead to bleeding within brain tissue, birth trauma can cause hypoxia and damage, and hypoxic-ischemic encephalopathy can injure the developing brain. Autoimmune causes have been identified in recent decades. Antibodies against NMDA receptors and LGI1, as well as Rasmussen encephalitis, can produce seizures, and some of these forms respond to immunotherapy.\n\nMetabolic and other causes\n\nOver 200 inherited metabolic disorders have been associated with seizures. They typically act through impaired energy supply to the brain, accumulation of toxic substances, abnormal neurotransmission, or deficiency of enzyme cofactors. Some are treatable: pyridoxine-dependent epilepsy results from variants in ALDH7A1, and disorders of vitamin metabolism in infants can improve substantially with timely supplementation. In GLUT1 deficiency, reduced transport of glucose across the blood–brain barrier starves neurons of fuel. Acquired metabolic causes include failure of the liver, kidney, or pancreas and nutritional deficiency.\n\nDespite these categories, the cause remains unidentified for a large share of people with epilepsy. Older reviews described idiopathic epilepsy, with no apparent cause, as presumed to be largely genetic. Even so, the genetic architecture of most such cases is still incompletely understood, and identifying a cause in a given patient often requires genetic testing combined with clinical and imaging evaluation."
    },
    {
      "heading": "Mechanisms of epileptogenesis",
      "text": "Kindling and network reorganization\n\nEpileptogenesis is the process by which a brain that has never had a seizure becomes capable of generating spontaneous, recurrent ones. Much of what is known comes from animal models. In kindling, repeated brief focal seizures, induced electrically or chemically, produce a permanently enhanced sensitivity to the stimulus, with seizures that become longer and more severe over time and eventually evolve into chronic epilepsy. Kindling is also a model of the brain changing in response to its own activity: seizures themselves help drive the progression. Kindling and long-term potentiation (LTP) both lengthen synaptic transmission, but kindling's change is persistent and pathological, whereas LTP is usually regarded as a mechanism of memory storage. The brain's response to excess activity involves changes to synaptic efficacy, the growth of new connections and the loss of existing ones, particularly in the glutamatergic and GABAergic systems. Contributing factors include glutamate receptor activation, immediate early genes, neurotrophic factors, axon guidance molecules, and new synapse formation. In status epilepticus models, neuronal death caused by prolonged seizures can further restructure circuits. The older idea of a single discrete focus has been replaced by a view of epilepsy as a disorder of distributed networks, in which regions remote from the seizure focus, such as basal ganglia structures, also show altered firing.\n\nSynaptic plasticity, sprouting and inhibitory interneurons\n\nSeveral cellular changes have been proposed as the basis of the permanent alterations. Kindling is associated with altered synaptic efficacy, and seizure-driven signalling cascades involving NMDA receptors and downstream second messengers may sustain the process once it has started. The sprouting of axons and dendrites, such as mossy fiber sprouting in the dentate gyrus, was long considered central, but the evidence is mixed: such sprouting does not appear to be essential for the induction of kindling. Epigenetic regulation, including DNA methylation and histone modification, is also being investigated as a way to produce lasting changes in gene expression. Inhibition is another key element. A persistent imbalance between an enhanced excitatory system and insufficient GABAergic inhibition is thought to make seizures more likely, and loss or dysfunction of inhibitory interneurons has been considered a contributing factor, though its role varies among models. Some work after blood–brain barrier injury suggests that the early disturbance involves astrocytes more than a major loss of interneurons.\n\nGlia, inflammation and the blood–brain barrier\n\nGlial cells are no longer regarded as passive support tissue. Astrocytes regulate extracellular potassium and glutamate, and their activation can enhance gap junction coupling and electrical synapse formation, which may amplify neuronal synchrony. Microglia release pro-inflammatory cytokines. Mediators such as IL-1β, TNF-α, HMGB1, TGF-β and prostaglandins can alter neuronal excitability, glial function and the integrity of the blood–brain barrier. Breakdown of the barrier, through disrupted endothelial tight junctions, allows serum albumin and immune cells to enter brain tissue. In experimental models, extravasated albumin activates TGF-β signalling in astrocytes, which may impair potassium buffering, promote synaptic remodelling and increase neuronal hyperexcitability. Once established, barrier dysfunction and inflammation can reinforce each other in a positive feedback loop. Much of the detailed sequence in humans remains uncertain.\n\nDrug resistance\n\nAbout one third of people with epilepsy continue to have seizures despite antiseizure medication, and no single explanation has been accepted. The transporter hypothesis proposes that overexpression of efflux pumps of the ATP-binding cassette family, such as P-glycoprotein, at the blood–brain barrier or within the epileptic focus lowers drug concentrations at the site of action. Experimental rats with drug-resistant seizures show higher hippocampal P-glycoprotein expression, although a definitive proof of principle has been difficult to establish. The target hypothesis holds that receptors or ion channels in the epileptic network are altered so that drugs have less effect. The neural network hypothesis argues that structural changes such as sprouting, synaptic reorganization and gliosis form an abnormal circuit that resists treatment. Support for this idea comes from surgery: after resection of the affected temporal lobe, roughly 60% of patients with formerly drug-resistant temporal lobe epilepsy become seizure-free with continued medication. Inflammatory signalling may contribute by upregulating transport proteins and modifying ion channels. Because no single hypothesis fully explains resistance, it is likely multifactorial."
    },
    {
      "heading": "Diagnosis and evaluation",
      "text": "Epilepsy is diagnosed clinically. No single test establishes it, and a sound diagnosis rests on the history, the examination, and the results of targeted investigations. Because seizures usually begin without warning and last from seconds to a few minutes, the clinician often has to reconstruct the event from later accounts. Witnesses such as family members, caregivers, and bystanders are therefore central. Questions about what happened before the event, whether the person stayed responsive, which body parts moved, how the person behaved during the event, and how recovery unfolded help define the likely seizure type and where it begins. A detailed witness description, ideally with a video recorded on a phone, is often more informative than any scan.\n\nElectroencephalography\n\nElectroencephalography (EEG) records brain electrical activity through electrodes placed on the scalp. A routine recording usually lasts about 20 to 40 minutes, so it captures only a small sample of brain activity. Abnormal findings that appear between seizures, called interictal discharges, include spikes, sharp waves, and spike-and-wave complexes. Their presence supports the diagnosis, but they are intermittent and can occur in people without epilepsy. A normal routine EEG therefore does not exclude epilepsy. To improve the yield, clinicians may use sleep-deprived recordings or ambulatory monitoring over 24 hours or longer.\n\nProlonged video-EEG monitoring, usually performed over several days in an epilepsy monitoring unit, records an actual event with synchronized video and EEG. It is the main reference standard for confirming that an event is epileptic, classifying the seizure type, and localizing its origin. Interpretation requires specialist expertise, because misreading EEG patterns is a recognized source of diagnostic error. Automated EEG analysis is being studied as a way to speed up review of long recordings.\n\nNeuroimaging\n\nMagnetic resonance imaging (MRI) is the preferred structural study. Epilepsy protocols use thin slices and sequences designed to show the hippocampus, temporal lobes, and cerebral cortex. These images can reveal hippocampal sclerosis, cortical malformations, tumors, scars from earlier injury, and vascular lesions. Computed tomography is faster and is often used in emergency settings, but it is less sensitive for subtle abnormalities. Many people with epilepsy have normal MRI scans, so a normal result does not rule out the condition. In presurgical evaluation, a structural lesion on MRI is associated with a better postsurgical seizure outcome.\n\nPositron emission tomography (PET) with fluorodeoxyglucose measures glucose metabolism and can show a region of reduced activity between seizures. Ictal single-photon emission computed tomography (SPECT), in which a tracer is injected during a seizure, can show increased perfusion at the seizure focus; subtraction techniques then overlay these images on MRI. These methods are used mainly when surgery is being considered, to localize an epileptogenic zone that is not clear from the other data.\n\nDifferential diagnosis\n\nMisdiagnosis is common. At referral epilepsy centers, 20% to 30% of patients who were diagnosed with epilepsy were found to have been misdiagnosed in several series. The most frequent mimic is psychogenic nonepileptic seizures (PNES), which account for the large majority of misdiagnoses at these centers and are often recognized only after years of treatment. Syncope is the second most common misdiagnosis and may be more frequent in general neurology practice. The confusion arises partly from the mistaken belief that seizures can produce a motionless, flaccid loss of consciousness; in fact, cardiac or noncardiac syncope can resemble atonic or convulsive seizures.\n\nOther conditions that may resemble seizures include breath-holding spells and benign paroxysmal vertigo in children, classic migraine, transient global amnesia, transient ischemic attacks, panic attacks, hypoglycemia, and sleep disorders such as parasomnias and narcolepsy. PNES and epilepsy can coexist, with reported rates in some cohorts of roughly 10% to 22%, which complicates the diagnosis of drug-resistant cases. No single semiological sign reliably separates PNES from epileptic seizures, so clinicians weigh clusters of features, and video-EEG remains the reference method.\n\nGenetic testing\n\nWhen an epilepsy appears in infancy or early childhood, shows developmental delay, or runs in a family, clinicians may suspect a monogenic form and order gene panels or exome sequencing. Identifying the causal variant can change management, since some drug classes worsen certain genetic epilepsies. Genetic results can also be uncertain, so they are interpreted together with clinical and EEG findings."
    },
    {
      "heading": "Pharmacological treatment",
      "text": "Mechanistic classes\n\nAntiseizure medications (ASMs) reduce the hyperexcitability that produces seizures, but they do not correct the underlying defect, and their actions are only partly understood. The largest group acts on voltage-gated ion channels. Phenytoin, carbamazepine, lamotrigine, oxcarbazepine and lacosamide block voltage-gated sodium channels, while gabapentin and pregabalin bind the α2δ subunit of voltage-gated calcium channels These agents act mainly on action potential firing and do not directly alter excitatory or inhibitory synaptic responses. Their effect is use-dependent: the block increases with increased frequency of neuronal discharge, so they suppress the rapid firing of a seizure more than normal activity.\n\nA second group strengthens GABA-mediated inhibition. Vigabatrin irreversibly inhibits GABA-aminotransferase, the enzyme responsible for the metabolic degradation of GABA, and tiagabine acts on the synapse by limiting GABA reuptake ASMs that enhance the synaptic GABA level, include vigabatrin and tiagabine. Cenobamate acts as a positive allosteric modulator of GABA-A receptors and it blocks persistent rather than transient sodium currents. A third group dampens glutamate signalling; topiramate, for instance, acts on several targets including AMPA receptors Similarly, topiramate (TPM) has multiple probable sites of action, including sodium channels, GABA receptors, and glutamate (AMPA) receptors.\n\nLevetiracetam and brivaracetam form a distinct class by binding the synaptic vesicle protein SV2A. Of them, levetiracetam and brivaracetam show a high affinity to the synaptic vesicle protein type 2 A (SV2A), and levetiracetam is believed to inhibit excitatory neurotransmitters release (vesicular exocytosis) and thereby reduce synaptic excitability. It received FDA approval in 1999 Since its FDA approval in 1999, LEV (tradename: Keppra) has emerged as a highly effective ASM for the treatment of treatment of myoclonic and generalized tonic-clonic seizures. Many older drugs are multi-target: valproate, for example, combines sodium-channel blockade with effects on GABA degradation and reuptake valproate (a voltage-gated sodium channel blocker, an inhibitor of the GABA degradative enzymes and an inhibitor of GABA re-uptake). Newer agents such as cannabidiol, fenfluramine and everolimus act through pathways outside these classic groups There are also several ASMs with predominant mechanisms of action that are not related to modulation of the voltage- and ligand-gated sodium and calcium channels or to enhancement of the GABA brain concentration. Importantly, ASMs inhibit or prevent seizures, but they neither cure epilepsy nor prevent epileptogenesis.\n\nDrug selection, titration and monitoring\n\nSelection starts with the seizure type and epilepsy syndrome, because some drugs can aggravate other seizure types. Sodium-channel blockers are generally avoided in generalized epilepsies with absence or myoclonic seizures, whereas ethosuximide, which acts on calcium channels, is a standard option for childhood absence epilepsy. In Dravet syndrome, sodium-channel blockers are generally avoided, which is consistent with the finding that reduced sodium current in interneurons and impaired inhibitory function is believed to be the pathogenic mechanism in Dravet syndrome cases associated with haploinsufficiency of the SCN1A gene.\n\nTreatment usually begins at a low dose and is raised stepwise until seizures are controlled or adverse effects limit further increases. Common early effects include dizziness, unsteadiness, diplopia and cognitive slowing. Some serious reactions are specific to particular drugs: lamotrigine and carbamazepine carry a risk of severe skin reactions, carbamazepine and oxcarbazepine can cause hyponatraemia, and valproate requires monitoring for liver toxicity. Serum-level monitoring is used mainly for older agents such as phenytoin, carbamazepine, valproate and phenobarbital, where concentration correlates with both benefit and toxicity.\n\nSeizure freedom with successive drugs and drug resistance\n\nThe first drug is the most productive. In a cohort of previously untreated patients, 222 (47 percent) became seizure-free during treatment with their first antiepileptic drug and 67 (14 percent) became seizure-free during treatment with a second or third drug. Only a small proportion were controlled by combinations: In 12 patients (3 percent) epilepsy was controlled by treatment with two drugs. The reason for failure of the first drug mattered. Among those who did not respond, the chance of later seizure freedom was smaller (11 percent) when treatment failure was due to lack of efficacy than when it was due to intolerable side effects (41 percent) or an idiosyncratic reaction (55 percent).\n\nIn a 30-year longitudinal cohort, the second and third regimens provided an additional 11.6% and 4.4% likelihoods of seizure freedom, respectively. Only 2.12% of patients attained optimal seizure control with subsequent AEDs. The same study reported that despite the availability of many new AEDs with differing mechanisms of action, overall outcomes in newly diagnosed epilepsy have not improved. Early comparisons showed similar rates for established and newer single drugs, 67 percent and 69 percent respectively.\n\nThe International League Against Epilepsy (ILAE) definition of drug-resistant epilepsy, proposed in 2010, requires failure of adequate trials of two tolerated, appropriately chosen and used antiepileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom. Sustained freedom means seizure-free for more than one year, or has sporadic seizures separated by a period three times the longest interval between seizures. About one in three people with epilepsy develop DRE. Dosing matters for this classification: in one analysis, patients in whom the first AED failed at doses above the various cutoffs (particularly 50% and 75% DDD) had lower probability of becoming seizure-free at last follow-up. Higher pretreatment seizure frequency and psychiatric comorbidity are among the factors associated with poorer outcomes particularly high pretreatment seizure density and concomitant psychiatric comorbidities.\n\nPregnancy, older adults, interactions and withdrawal\n\nPregnancy requires specific attention. Valproate carries a higher risk of major congenital malformations, including neural tube defects, and prenatal exposure has been associated with reduced cognitive outcomes in children, so many regulators restrict its use in people who can become pregnant. Folic acid supplementation is standard for people taking ASMs who are planning or in early pregnancy. Pregnancy increases the clearance of several drugs, including lamotrigine and levetiracetam, so serum levels often require closer monitoring and dose adjustment.\n\nIn older adults, slower drug clearance, polypharmacy and comorbidity increase the risk of adverse effects. Concerns include falls, cognitive slowing and hyponatraemia, and renally cleared drugs such as levetiracetam and gabapentin require dose reduction when kidney function declines. Enzyme-inducing drugs, including phenytoin, carbamazepine, phenobarbital and primidone, accelerate the metabolism of many other medicines, among them hormonal contraceptives and warfarin, while valproate can raise lamotrigine concentrations. Cannabidiol can increase levels of the active metabolite of clobazam.\n\nAbrupt withdrawal of an ASM can provoke seizures, including status epilepticus, and withdrawal from benzodiazepines or barbiturates can itself cause seizures. Tapering is therefore usually gradual, often over months. Discontinuation after prolonged seizure freedom is sometimes considered, but relapse is a real risk, and the decision depends on the syndrome, the duration of seizure freedom and other clinical factors."
    },
    {
      "heading": "Surgical, neuromodulatory and dietary therapies",
      "text": "Presurgical evaluation and resective surgery\n\nSurgery is considered for focal epilepsy that persists despite adequate medication trials, especially when the seizure onset zone can be localized to a limited region, most often the mesial temporal lobe. The presurgical workup combines long-term video-EEG to capture habitual seizures and map their onset, MRI to detect lesions such as hippocampal sclerosis or small cortical malformations, PET to show regions of abnormal glucose uptake, and neuropsychological testing to estimate what a proposed resection would cost in memory and language. When the lesion, electrical findings and imaging do not agree, intracranial electrodes may be implanted to define the boundaries before resection. Candidacy depends on whether these data converge on a removable focus and whether the expected seizure benefit outweighs the functional risk.\n\nTemporal lobe surgery has the strongest evidence base. In a 2001 randomized trial of 80 adults with temporal lobe epilepsy, 58% of surgically treated patients were free of seizures that impair awareness at one year, compared with 8% of those kept on medication, and about 10% had adverse effects of surgery. The Early Randomized Surgical Epilepsy Trial, published in 2012, enrolled 38 participants with mesial temporal lobe epilepsy after two failed drug trials; under a conservative analysis that counted participants with incomplete follow-up as not seizure free, 11 of 15 surgical participants were seizure free in the second year, against none of 23 in the medical group. A 2019 meta-analysis of the randomized trials gave an overall seizure-freedom rate of roughly 70% for temporal lobe surgery in medically refractory cases, while noting that small trial samples make further randomized designs difficult. A randomized comparison with stereotactic radiosurgery found seizure remission in 52% of radiosurgery patients versus 78% after open anterior temporal lobectomy, so minimally invasive alternatives remain less effective in that comparison. Despite this evidence, surgery is markedly underused, and referral often occurs decades after seizures begin.\n\nNeuromodulation: VNS, DBS and RNS\n\nNeuromodulation is used when no safe resection is possible, for example when the focus lies in eloquent cortex or is poorly defined, and three devices are FDA-approved for reducing seizure frequency in drug-resistant epilepsy. Vagus nerve stimulation (VNS) uses a pulse generator implanted in the chest, with a lead wound around the vagus nerve in the neck; it acts through vagal afferent pathways that modulate thalamocortical circuits and reduces seizures in roughly half of patients, usually as adjunctive therapy in both children and adults. Responsive neurostimulation (RNS) implants electrodes in the cortex or deep structures, records intracranial EEG continuously, and delivers brief pulses only when it detects epileptiform activity. Reported seizure reductions rise over time: about 40% after three months and 50–55% at two years in one series. Deep brain stimulation (DBS) targets the thalamus; the anterior nucleus is used for focal and secondarily generalized seizures, while the centromedian nucleus is used for generalized syndromes such as Lennox–Gastaut syndrome.\n\nComparative data are limited because no head-to-head trials exist. Evidence from randomized trials suggests that RNS and DBS produce larger seizure reductions than VNS in the first year, with differences narrowing during longer follow-up. Cognitive outcomes are an important consideration: most studies of chronic VNS report no cognitive change, whereas most studies of chronic RNS and DBS report improvement, though the authors of a systematic review judged the cognitive evidence to be sparse and of variable quality.\n\nKetogenic and modified Atkins diets\n\nThe classic ketogenic diet is high in fat and very low in carbohydrate, with protein restricted and a fat-to-(carbohydrate plus protein) ratio typically around 3:1 to 4:1. The modified Atkins diet (MAD) is less restrictive, does not require weighing food, and in trials has been limited to about 20 g of net carbohydrate per day. The mechanisms remain incompletely understood. The leading explanation is that the diet shifts cellular energy use from glucose toward ketone bodies such as beta-hydroxybutyrate, mimicking fasting and altering neuronal metabolism and mitochondrial function. Other proposals include enhanced GABAergic signalling, reduced glutamatergic activity, and a higher GABA-to-glutamate ratio, but none has been established as the main mechanism; many researchers now think multiple effects contribute.\n\nEvidence is strongest in children, where the classic diet is a well-established option for drug-resistant epilepsy. In adults, results are more mixed. A randomized trial in adults and adolescents found that MAD significantly improved seizure control compared with antiseizure medication alone, whereas a meta-analysis restricted to patients aged 16 and older found no significant seizure reduction, with high heterogeneity and very low certainty of evidence. A UK tertiary-centre cohort reported that 60% of adults had some improvement in seizure frequency, 38% had at least a 50% reduction, and 30% experienced worsening at some point, while retention fell to 29% at twelve months. Common reasons for stopping were side effects, including weight loss, gastrointestinal symptoms and low mood, and the restrictiveness of the diet. Adding a ketogenic formula during the first month of MAD improved long-term adherence without producing a greater short-term seizure reduction. Because the diets alter micronutrient intake and produce mild metabolic acidosis, nutritional monitoring and attention to kidney stone risk are part of standard practice.\n\nProcedural treatments in severe syndromes\n\nRare and severe early-life syndromes require specialized approaches. Infantile spasms, which are characterized by clusters of brief flexor or extensor spasms and a distinctive EEG pattern known as hypsarrhythmia, are typically treated first with hormonal therapy (ACTH or oral prednisolone) or the antiseizure drug vigabatrin, and the ketogenic diet is sometimes used as an alternative or adjunct. When an infant's spasms are linked to a focal structural lesion, resective or disconnective procedures such as hemispherotomy may be considered, and the timing of treatment is important because delays are associated with poorer developmental outcomes."
    },
    {
      "heading": "Epidemiology and global burden",
      "text": "Prevalence and incidence\n\nThe Global Burden of Disease (GBD) 2021 analysis put the number of people with epilepsy in 2021 at 51.7 million, counting idiopathic and secondary forms together, which corresponds to an age-standardised prevalence of 658 per 100,000 (51.7 million, 95% UI 44.9–58.9, age-standardised prevalence 658 per 100,000). Secondary epilepsy, which follows from an identifiable brain insult, accounted for the larger share of cases, at 53.1% of epilepsy from idiopathic and secondary epilepsy combined. Expressed against the whole population, about 0.7% of people were living with active epilepsy that year 0.7% of the population had active epilepsy.\n\nIncidence estimates depend on the method used. One GBD-based figure gives an age-standardised incidence of 42.8 per 100,000 in 2021 In 2021, the global age-standardised incidence rate (ASIR) of epilepsy was 42.8 per 100 000 population, whereas a meta-analysis of 58 countries reported 61.6 per 100,000 person-years and projected 4.6 million new cases a year Global incidence is estimated at 61.6 cases per 100,000 person-years. Our meta-analysis predicts 4.6 million new cases of epilepsy every year worldwide. Age shapes both measures. Incidence is highest in the youngest and oldest groups, with rates significantly higher among children under five and adults over 70 The incidence of epilepsy was significantly higher among children aged <5 years and adults aged >70 years., and prevalence peaks in the late teens and rises again after about 50 The prevalence peaked in the 15–19 age group and increased progressively after the age of 50–54 years..\n\nRegionally, the same review found the highest prevalence in Africa and Latin America and the highest incidence in the Middle East and Latin America The highest estimated prevalence is found in Africa and Latin America, although the highest incidence is reported in the Middle East and Latin America.. Because these regions are largely low- and middle-income countries, the burden falls most heavily where health resources are scarcest making the highest disease burden fall disproportionately on regions with the fewest healthcare resources..\n\nMortality\n\nThe GBD 2021 age-standardised mortality rate was 1.74 per 100,000, and it was highest among people aged 70 and over The global age-standardized mortality rate (ASMR) of epilepsy was 1.74 per 100,000 population; while the older adult group aged 70+ has the highest ASMR of 5.67. Excess mortality relative to the general population is consistently documented. Reported standardised mortality ratios are roughly 1.6 to 3.0 in high-income countries and as high as 7.2 in low- and middle-income countries in one review The standardised mortality rates are 1.6–3.0 times higher than the general population in high-income countries, and up to 7.2 times higher in low- and middle-income countries, while another reports a value of 19.8 for the latter group, so the figures vary with study design and setting to 19.8 [95% confidence interval (CI) 9.7–45.1] in low- and middle-income countries.\n\nSudden unexpected death in epilepsy (SUDEP) is a principal concern. Its estimated incidence is about 1.2 per 1,000 person-years Mortality from definite/probable Sudden Unexpected Death in EPilepsy (SUDEP) is estimated at 1.2 per 1000 person-years., and it accounts for an estimated 2–18% of all epilepsy deaths SUDEP comprises between 2 and 18 per cent of all deaths in epilepsy. When witnessed, SUDEP usually follows a convulsive seizure most SUDEP cases occur following a convulsive seizure that triggers a severe alteration of respiratory and cardiac function. Status epilepticus carries substantial mortality of its own Status epilepticus (SE) is associated with a significant mortality. Non-seizure causes also matter, and they differ by income level. In low-income regions, accidents and suicides make up a much larger share of deaths than in high-income regions, and drowning alone accounts for about 17% in low-income regions, accidents and suicides account for a much larger proportion of deaths (40.75 vs. 7.65%), with drowning alone contributing 17.26%.. In children, causes directly tied to epilepsy, such as SUDEP, drowning, injuries and status epilepticus, make up a large fraction of deaths In children with epilepsy, causes of death directly related to epilepsy, such as SUDEP, drowning, injuries, or status epilepticus, are also very common, namely 22%–45%. Despite these risks, the number of epilepsy deaths and DALYs fell between 1990 and 2021 From 1990 to 2021, the number of epilepsy-related deaths and DALYs both decreased..\n\nThe treatment gap\n\nThe ILAE defines the treatment gap as the difference between the number of people with active epilepsy and the number whose seizures are being appropriately treated \"The difference between the number of people with active epilepsy and the number whose seizures are being appropriately treated in a given population at a given point in time, expressed as a percentage\". Estimates have historically been much higher in poorer countries, at about 75% in low-income countries and 50% in middle-income countries The treatment gap has been shown to be 75% in low-income countries and 50% in middle-income countries. Within-region variation is large: the gap ranged from 5.6% in Norway to 100% in Togo and Uganda the epilepsy treatment gap ranged from fairly low in high-income countries, such as 5·6% in Norway, to 100% in low-income African countries such as Togo and Uganda. Recent meta-analysis suggests the gap has narrowed in low- and low-middle-income countries over the past decade or so, particularly in Africa, though the authors note that this improvement is plausible but not firmly proven Our findings suggest a reduction in the gap in LMICs, particularly in the last 5–10 years. Africa demonstrated more significant progress compared to Asia.\n\nSeveral barriers explain the gap. The first is human resources: in sub-Saharan Africa, shortages of trained health workers, limited diagnostic equipment, inadequate anti-epileptic drug supplies, cultural beliefs, and social stigma contribute to the large treatment gap for epilepsy. Neurology capacity is especially thin, with a median of 0.1 neurologists per 100,000 people in LMICs in 2017 compared with 7.1 in high-income countries The WHO reported that in 2017 there was a median of 0.1 neurologists per 100 000 population in LMICs compared with 7.1 per 100 000 population in high-income countries. Drug cost and supply are a further constraint Inadequate supplies and costs of anti-epileptic medications, and diagnostic failure compounds the problem, since many patients go undiagnosed or are misdiagnosed many patients remaining undiagnosed or misdiagnosed due to lack of skilled healthcare professionals, inadequate diagnostic facilities, and limited access to specialized care.. Rurality is also a factor, with an estimated 73% of people with epilepsy in LMICs untreated in rural areas compared with 46% in urban settings Overall, 56% (range 7%–98%) of PWE in LMICs remain untreated, with 73% remaining untreated in rural regions compared to 46% in urban settings. Among the reforms proposed, the addition of levetiracetam to the WHO Essential Medicines List is intended to make safer antiseizure drugs more accessible Levetiracetam has been added to the WHO Essential Medicines List (EML), paving way to safer, less teratogenic antiseizure medications (ASMs)..\n\nDisease burden\n\nMost people with epilepsy live in low- and middle-income settings Nearly 80% of the people with epilepsy live in low- and low-middle-income countries (LMICs).. In the GBD 2021 analysis, the age-standardised DALY rate was 177.85 per 100,000 The age-standardized DALYs rate (ASDR) were 177.85 per 100,000 population, and the pattern across development levels is uneven: high-SDI areas have the highest incidence and prevalence, while low-SDI regions have the highest mortality and DALY rates high sociodemographic index (SDI) areas consistently presented the highest incidence and prevalence rates, whereas low-SDI regions always exhibited the highest mortality and DALY rates.. Earlier estimates put the global DALY burden at about 13 million It affects over 50 million people worldwide, with an estimated disease burden of 13 million disability-adjusted life years (DALYs), and epilepsy has been described as the most common chronic neurological disorder Epilepsy is the most common chronic neurological disorder, affecting over 65 million people worldwide, of whom 80% are estimated to live in low- or middle-income countries (LMICs).."
    },
    {
      "heading": "Historical understanding and treatment",
      "text": "Mesopotamia, Egypt, and China\n\nThe earliest known descriptions come from Mesopotamia. The first description of an epileptic seizure appears in a text from 2000 B.C., written in the Akkadian language, used in the region of Mesopotamia. The clinical picture, with the head turned to one side, rigid limbs, open eyes, and foam at the mouth, is recognizable today. Mesopotamian writers attributed the attack to supernatural agency. One Akkadian text links the condition to the moon god and describes treatment by exorcism, the patient underwent treatment by means of exorcism. A later Babylonian medical handbook, the Sakikku, offers lists of signs and symptoms, treatments, outcomes, and different seizure types.\n\nEgyptian sources add a different kind of evidence. The Edwin Smith Surgical Papyrus, written circa 1700 BC, records a patient with a head wound whose body shuddered when the exposed brain was touched. Modern commentators often read this as an early sign that the brain itself could produce convulsive responses, although the papyrus does not describe epilepsy as such. In China, documentation of epilepsy is also found in Chinese texts, dating to approximately 770-221 B.C. A group of physicians published The Yellow Emperor's Classic of Internal Medicine, which outlined generalized seizures. Treatment there drew on herbs, massage, and acupuncture within a framework of yin-yang and five-phase theory.\n\nThe Hippocratic challenge and its limits\n\nIn classical Greece the condition was called the \"sacred disease,\" and the name reflected its perceived divine origin. The treatise <i>On the Sacred Disease</i>, traditionally attributed to Hippocrates but probably the work of several writers, argued against this view. Its author held that the disorder was not \"any more divine or sacred than other diseases\" and had natural causes. The text located the disorder in the brain, suggest that it is hereditary rather than contagious, and attributed it to an excess of phlegm. The same tradition also recorded that convulsions which were always contralateral to the head wound, linking seizures to head injury.\n\nRationalism did not displace religious explanations. Like many philosophers, however, Hippocrates was ahead of his time and the idea of mysticism remained, and in Rome epilepsy was still regarded as an omen from the gods. Through the medieval period and into early modern Europe, the disorder was commonly thought to involve spirits or demonic possession, and the idea that the brain was the seat of the problem coexisted with these beliefs.\n\nNineteenth- and twentieth-century drugs\n\nSystematic drug treatment began with bromide. The story began on 11th May 1857 when Charles Locock commented in the Lancet on his use of potassium bromide in 15 cases of \"hysterical\" epilepsy in young women. Bromide was used for roughly a century, but the bromide ion proved to be highly toxic at therapeutic concentrations. Its use was so widespread that patients at Oslo University Hospital's National Centre for Epilepsy were given bread with potassium bromide additives as late as in 1960.\n\nThe next major advance was accidental. PB had been marketed the previous year as a hypnotic (Luminal) by F. Bayer and Company. In 1912 the German psychiatrist Alfred Hauptmann, who lived above a ward of patients with epilepsy, gave them phenobarbital to quiet the night-time noise and noticed that their seizures fell in frequency. Even though he published his findings, phenobarbital did not become a drug of first choice against epilepsy until around 1920, perhaps because his article was published in German. The mechanism was clarified only in 1979, when researchers showed that it lengthens the opening of the chloride channel in the GABA_A-receptor.\n\nPhenytoin marked the shift to deliberate screening. When Tracy Putnam was appointed to the directorship of the neurological unit at the Boston City Hospital in 1934, he set out to discover a less sedative AED than PB. Together with Houston Merritt, Putnam used electrically induced seizures in animals to test compounds, and the result was the launching of phenytoin in 1938. The first observational clinical studies on phenytoin were published in 1938, with regulatory approval occurring a year later, and these early trials had no control groups. Several other agents followed in the 1950s and 1960s, including Ethosuximide 1958, Carbamazepine 1965, and valproate in 1967.\n\nThe vocabulary of treatment changed along with the drugs. Early agents were called anticonvulsants, a term that emphasized symptomatic control but did not distinguish between seizure types or address disease mechanisms. Later the term \"antiepileptic drugs\" became standard, and today the field increasingly uses \"antiseizure medications.\"\n\nNeurophysiology and surgery in the twentieth century\n\nThe recording of brain electrical activity made it possible to study epilepsy objectively. On July 6th of 1924 Hans Berger, a German psychiatrist, first recorded electric signals from the human brain via scalp electrodes. The first recording was made on a 17-year-old patient who had undergone repeated surgery on the skull, a patient who was not being evaluated for epilepsy as such. Berger's first report appeared only in 1929, and his findings were met with incredulity and derision by the German medical and scientific establishments. Berger's later series of papers included EEG changes associated with various stimulations, mental states, and medical conditions, including epilepsy and dementia. Their significance was confirmed in 1934 by E. Adrian and B. H. C. Matthews. Clinical EEG spread slowly after that, and in Boston the first laboratory for routine EEG study was established with Frederic Gibbs during Putnam's tenure.\n\nSurgery developed more slowly and was guided by the work of John Hughlings Jackson, whose 19th-century description of focal motor seizures spreading along the body remains the basis of the term \"Jacksonian\" seizure. In the twentieth century, Wilder Penfield and Herbert Jasper at the Montreal Neurological Institute used electrical stimulation during surgery to map functional cortex before removing epileptogenic tissue, including temporal lobe resections. This approach laid the groundwork for modern presurgical evaluation.\n\nAttitudes toward people with epilepsy\n\nMoral and religious ideas have repeatedly shaped how people with epilepsy were treated. Ancient interpretations linked the disease to spirits, and throughout early history, seizures were thought to be the work of evil spirits possessing the body, and the only treatment available was to perform a sacred ritual to dispel the spirit. Medical advice could also carry moral content. Hippocrates recommended marriage and pregnancy as a means of controlling seizures, and this manner of thinking was also prevalent in the 19th century, as doctors would recommend marriage for women with epilepsy. In the early twentieth century, marriage restrictions and compulsory sterilization were applied to people with epilepsy in several countries, reflecting eugenic assumptions that the condition was primarily hereditary. Such policies have since been widely repudiated, but the stigma they reinforced persists in modern attitudes."
    },
    {
      "heading": "Social, psychological, and legal dimensions",
      "text": "Stigma and discrimination\n\nEpilepsy has carried social meanings far beyond its clinical features. In many European societies, seizures were long read as signs of intellectual or moral inferiority, and people with the condition were excluded from marriage, schooling, and paid work. Medical understanding has advanced since then, but popular attitudes have changed more slowly. A 2014 community survey in Mali found that two-thirds of respondents believed epilepsy was contagious, more than half attributed it to supernatural power, and traditional healers were the most common first choice for treatment. Similar misconceptions, especially that the condition is contagious or is simply a psychiatric problem, can also affect the quality of care people receive from health professionals.\n\nThe most measurable effects appear in education and work. People with epilepsy have lower rates of marriage, educational attainment, income, and employment than the general population. In employment, about three-quarters of discrimination complaints in one U.S. analysis concerned treatment after hiring, such as promotion, dismissal, discipline, and harassment, rather than refusal to hire. The stigma is reinforced by the fact that epilepsy is often invisible. Disclosure is required to obtain legal protection or accommodation, yet many advocacy groups have advised job seekers to delay disclosure until after an offer, to avoid being screened out. Surveys of employers have also shown considerable scepticism, with a substantial minority regarding the employment of people with epilepsy as a major problem. Children are affected in classrooms, where misinformation and exclusion persist even where inclusion policies exist. Stigma has consequences beyond discrimination itself: research indicates that the stigma, not only the illness, reduces self-efficacy and quality of life, and that people may hide their diagnosis to protect their jobs.\n\nPsychiatric comorbidity and quality of life\n\nDepression and anxiety are the most frequent psychiatric comorbidities of epilepsy. A 2025 systematic review and meta-analysis of 54 studies of adults, covering publications from 2018 to 2024, pooled prevalence estimates of about 40% for depressive symptoms and 36% for anxiety symptoms. Frequent correlates included female sex, polytherapy, temporal lobe epilepsy, higher seizure frequency, and drug-resistant disease. Psychosis, bipolar disorder, suicidality, and functional (psychogenic nonepileptic) seizures also occur more often in people with epilepsy than in the general population. Proposed explanations include shared neurobiological mechanisms, the effects of antiseizure medication, and psychosocial stress, and these conditions are often under-recognised because their symptoms overlap with those of epilepsy.\n\nComorbidity has a large influence on quality of life, which in many studies predicts health outcomes as strongly as seizure characteristics do. In patients with treatment-resistant epilepsy, depression has been found to be the most powerful predictor of poor quality of life, even after accounting for seizure frequency and severity. A mediation analysis of 849 adults found that depression largely carried the effect of anxiety on quality of life, while a larger study in Saudi Arabia linked depression, anxiety, and stigma with lower scores, together explaining a modest share of the variation. Depression is also associated with poorer medication adherence and higher mortality. Cognitive impairment, including memory and attention problems, is commonly reported, and in older adults depression can resemble or worsen cognitive decline, making diagnosis more difficult.\n\nDriving, workplace accommodation, and legal protection\n\nDriving is one of the most visible restrictions. In the United States, every state permits some people with epilepsy to drive, but the rules differ widely: 28 states (including the District of Columbia) require a single fixed seizure-free period, with a median of six months and a range of three to twelve months, while 23 states use more individualised assessments. Some states require physicians to report patients, and in several states physicians who help determine fitness to drive do not have legal immunity for those judgements. Internationally, approaches range from bans on anyone who has ever had a seizure to seizure-free intervals of roughly six months to two years, and the question of who bears responsibility for preventing unsafe driving remains a bioethical debate. Restrictions are especially burdensome where public transport is limited, and studies have found that some patients drive in violation of their restrictions, which can discourage honest reporting.\n\nLegal frameworks in several countries protect people with epilepsy from discrimination. In the United States, the Americans with Disabilities Act of 1990 prohibits discrimination in employment, education, and public services and requires reasonable accommodation, and several schools, colleges, and employers have settled cases under it. Internationally, the UN Convention on the Rights of Persons with Disabilities, adopted in 2006, supports the rights of people with epilepsy to education, work, and equal participation, although national implementation varies considerably. Legal protection does not by itself eliminate stigma, and there is little evidence on whether policy reforms or employer education improve career outcomes.\n\nSelf-management and family support\n\nMuch day-to-day management is carried out by the person with epilepsy. Common self-management tasks include keeping a seizure diary, taking medication consistently, recognising personal triggers such as sleep loss, and planning around activities with higher risk, such as swimming, heights, or cooking with open flames. Patient education programmes aim to build this knowledge, and seizure action plans can help schools and workplaces respond appropriately. Educational initiatives also target the wider community; for example, a South African protocol for primary schools aims to reduce stigma by teaching learners about epilepsy.\n\nFamily members and other caregivers often provide transport, supervision, first aid during seizures, and emotional support, particularly for children and for adults with frequent or unpredictable seizures. Their role can also carry strain, and the psychological wellbeing of caregivers is an important part of care planning. Because the people who live with epilepsy spend most of their time outside clinics, the effectiveness of education, employment support, and family involvement largely depends on coordinated support from schools, employers, and health services."
    },
    {
      "heading": "Research frontiers and open questions",
      "text": "Preventing epileptogenesis\n\nClinicians have long known that a seizure-free latent period can separate a brain insult from the first seizure. Gowers first recognized in 1881 that there is often a seizure-free interval lasting months to years between brain insults and the onset of symptomatic epilepsy. That gap is the basis of the search for antiepileptogenic treatment, but the record so far is weak. A registry analysis of trials after acquired brain injury found only 3 of 15 completed pharmacologic trials had a late-prevention aim, indicating that the ClinicalTrials.gov-registered pipeline of completed antiepileptogenesis-oriented research remains limited.\n\nEarlier failures have shaped current thinking. A wide variety of experimental studies and clinical trials using chronic antiseizure drug therapy during the extended post-injury period have had minimal success. One explanation is that these drugs suppress seizure activity without substantially altering the process that makes the brain epileptic, and that dose, duration, or timing may have been wrong. A randomized, double-blind trial of biperiden in adults with traumatic brain injury, which enrolled 123 people, was halted early during the COVID-19 pandemic and suggests that there was insufficient evidence regarding the effect of biperiden in preventing PTE after TBI, which underpins the need for larger studies.\n\nPreclinical work is pointing to other candidates. Experimental screens have flagged topiramate, levetiracetam, carisbamate, and valproate as possibly the most promising existing drugs, while a rat study of post-traumatic epilepsy suggested that brivaracetam and other drugs targeting SV2A should be considered for human clinical trials of prevention of post-traumatic epilepsy after head injury. The main obstacle is practical: a full-scale trial in traumatic brain injury is expensive, which is why NINDS funded a multicenter program aimed at identifying relevant biomarkers and performing rigorous preclinical trials so that later clinical trials become feasible. Whether any disease-modifying treatment can actually stop epileptogenesis in humans remains unanswered.\n\nPrecision and genetic therapies\n\nMonogenic epilepsies are the most obvious targets for precision treatment. Dravet syndrome illustrates the approach. Its most often caused by a mutated copy of the SCN1A gene, which impacts the function of sodium ion channels in the brain. The antisense oligonucleotide zorevunersen aims to act on that cause rather than suppress seizures: it is a disease-modifying therapy that acts on the underlying process causing them, targeting the channelopathy and boosting protein production from the healthy SCN1A gene. Results from the open-label MONARCH and ADMIRAL studies, reported in the New England Journal of Medicine, were encouraging but preliminary. Reported early improvements extended to communication, coping and motor skills, as well as other markers of quality of life, though the sample was small and uncontrolled.\n\nOther approaches include vector-based gene therapy, which the field regards as more durable but faces a packaging problem. One review notes that the size of the gene, which, with a suitable promoter, would be too large for an AAV vector, which is a particular difficulty for Dravet syndrome. In mouse models, the antisense strategy known as TANGO has shown preclinically to prevent SUDEP and reduce seizures in a mouse model of Dravet syndrome. Whether such genotype-matched therapies can be extended beyond rare monogenic conditions to the common, polygenic forms is an open question.\n\nMachine learning and automated EEG analysis\n\nDeep learning has become a major research direction for EEG-based detection and prediction. A 2026 review noted that deep learning has significantly advanced automated epilepsy seizure detection and prediction, enabling improved feature learning and temporal modeling from EEG signals. Detection and prediction are different tasks. Prediction requires identifying a preictal state, which has to be distinguished from ordinary interictal activity, and that is harder than recognizing a seizure already under way. Architectural findings suggest a division of labor: spectrogram-based CNNs are highly effective for seizure detection, while hybrid CNN RNN and LSTM/GRU models better capture long-range temporal dependencies required for prediction.\n\nReported performance is hard to compare across studies. Published accuracies are often built on small or homogeneous datasets, and one review cautions that progress remains constrained by heterogeneous datasets, inconsistent evaluation protocols, and limited cross-study comparability, often leading to optimistic performance estimates that do not translate to real-world settings. Clinically meaningful metrics include the false-positive rate per hour and the fraction of time spent in a warning state, rather than overall accuracy alone. Whether these systems can be made reliable enough for everyday use, including for wearable devices, is unresolved.\n\nDrug resistance, sudden death, and the global treatment gap\n\nSeveral large questions have no settled answers. Roughly a third of people with epilepsy do not achieve seizure control with a series of appropriately chosen medications, and the reasons remain disputed. Proposed mechanisms include altered drug targets, overexpression of efflux transporters at the blood–brain barrier, and network-level changes that make seizures resistant to any single drug. None has been proven to explain most cases, and the field still lacks a biomarker that predicts resistance before treatment begins.\n\nSudden unexpected death in epilepsy (SUDEP) is another gap. Its biology is not fully understood, and candidate explanations, including cardiac and respiratory failure during or after a seizure, have not been resolved into a single mechanism. Because the risk is concentrated in people with uncontrolled seizures, better understanding of SUDEP may depend on the same seizure-control and monitoring tools now under development.\n\nFinally, the treatment gap remains the largest challenge in low- and middle-income countries, where many people with active epilepsy receive no treatment. Cost, limited diagnostic capacity, unreliable drug supply, and stigma all contribute. Closing the gap probably requires cheap, long-established medicines delivered through primary care rather than new drugs alone, but the most effective delivery models are still being tested."
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  "sources": [
    {
      "title": "The 2014 Definition of Epilepsy: A perspective for patients and caregivers // International League Against Epilepsy",
      "url": "https://www.ilae.org/guidelines/definition-and-classification/the-2014-definition-of-epilepsy-a-perspective-for-patients-and-caregivers"
    },
    {
      "title": "The New Definition and Classification of Seizures and ...",
      "url": "https://www.sciencedirect.com/science/article/am/pii/S0920121117303819"
    },
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  ],
  "license": "https://creativecommons.org/licenses/by/4.0/"
}