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Seizure

A seizure is a sudden, uncontrolled electrical disturbance in the brain that can cause changes in behavior, movements, feelings, and levels of consciousness.^[1] These episodes typically last from seconds to a few minutes and may vary widely in severity, from brief lapses in awareness to full-body convulsions. Seizures can occur as isolated events provoked by specific triggers or as part of epilepsy, a neurological disorder defined by recurrent, unprovoked seizures due to ongoing abnormal brain activity.^[2] Seizures are classified by the International League Against Epilepsy (ILAE) into four main types: focal onset, generalized onset, unknown onset, and unclassified, based on the onset and spread of abnormal electrical activity in the brain.^[3]^[4] Focal onset seizures begin in one area of the brain and may cause localized symptoms like twitching in a single limb, unusual sensations, or emotional changes, depending on the affected region; they may remain focal or spread to both sides as focal to bilateral tonic-clonic seizures.^[1] Generalized onset seizures involve both sides of the brain from the onset and include subtypes such as tonic-clonic seizures, which feature muscle stiffening followed by jerking and loss of consciousness; absence seizures, marked by brief staring spells; and atonic seizures, which lead to sudden loss of muscle tone. Unknown onset seizures are those where the beginning cannot be determined.^[5] Common causes of seizures include acute factors like high fever, low blood sugar, electrolyte imbalances, head injury, stroke, infections such as meningitis, or withdrawal from alcohol or certain medications. In cases of epilepsy, underlying causes may involve genetic factors, brain malformations, tumors, or unknown origins in about half of instances.^[2] Symptoms often encompass temporary confusion, staring blankly, uncontrollable jerking movements, loss of consciousness, or unusual sensory experiences, though some seizures are subtle and go unnoticed.^[1] Diagnosis typically involves electroencephalography (EEG) to detect abnormal brain waves, while treatment focuses on anti-seizure medications for epilepsy management, lifestyle adjustments, or surgery in refractory cases.^[6]

Clinical Presentation

Symptoms and Signs

Seizures manifest through a range of subjective symptoms and observable signs that disrupt normal brain function, often leading to temporary alterations in behavior, movement, or awareness. Common symptoms include altered consciousness, which may range from brief lapses in awareness to complete loss of responsiveness, as seen in many seizure types where individuals may appear unresponsive or experience a dreamlike state.^[1]^[2] Convulsions, characterized by involuntary jerking or rhythmic muscle contractions of the arms and legs, are prominent in tonic-clonic seizures and cannot be controlled voluntarily.^[1]^[5] Automatisms, such as repetitive actions like lip smacking, hand rubbing, or fumbling with objects, often occur during focal seizures and reflect uncoordinated, purposeless movements.^[1]^[2] Sensory auras, which serve as warning signs, can involve unusual perceptions like déjà vu, sudden fear, odd smells, tastes, or visual flashes, typically preceding focal onset seizures.^[1]^[2] Following the seizure, postictal confusion is common, involving disorientation, memory gaps, fatigue, or sleepiness that can last from minutes to hours, impairing immediate cognitive function.^[1]^[5] Observable signs during a seizure provide clear indicators for bystanders and medical evaluation. Tonic-clonic movements begin with a tonic phase of muscle stiffening, often causing the body to arch or fall, followed by clonic jerking that affects the limbs symmetrically.^[1]^[5] Eye deviation, where the eyes turn forcefully to one side, is a frequent sign in seizures originating from specific brain regions, such as the frontal lobe.^[2] Cyanosis, a bluish discoloration of the lips or skin due to reduced oxygen from labored breathing, may occur during prolonged or intense convulsions.^[5] Incontinence, particularly urinary, is another sign, resulting from loss of muscle control during the event, though it is not universal.^[5]^[7] Variations in symptoms and signs depend on the seizure type, aligning with whether it is focal or generalized onset. For instance, absence seizures typically present as brief staring spells lasting 5 to 10 seconds, often with subtle eye blinking or lip movements, without convulsions or postictal confusion, allowing the person to resume activities unaware of the lapse.^[1]^[2] In contrast, myoclonic seizures involve sudden, brief jerks or twitches of the arms or legs, while atonic seizures cause abrupt loss of muscle tone leading to falls or head drops.^[1]^[3] These manifestations significantly impact daily activities, as seizures can occur unpredictably and interrupt tasks like driving, swimming, or working, increasing risks of injury from falls or accidents.^[1]^[2] Frequent subtle seizures, such as absence episodes, may hinder concentration in school or professional settings, while more overt signs like convulsions demand immediate safety measures to prevent harm.^[3]^[8]

Duration and Phases

Seizures typically last from 30 seconds to 2 minutes, though durations can vary by type, with generalized tonic-clonic seizures often averaging under 2 minutes.^[9]^[10] Prolonged seizures, defined as status epilepticus, exceed 5 minutes for convulsive types or involve recurrent episodes without full recovery, representing a medical emergency.^[11]^[12] Seizure events progress through distinct phases: the prodromal phase, a pre-seizure period that may include subtle warnings like mood changes hours or days prior; the ictal phase, the active seizure itself marked by abnormal electrical activity; and the postictal phase, a recovery period lasting minutes to hours, often involving fatigue, confusion, or amnesia.^[13]^[1] During the ictal phase, manifestations such as convulsions or altered awareness may occur, depending on the brain regions involved.^[5] Several factors influence seizure duration, including the specific seizure type (e.g., focal versus generalized), underlying etiology such as structural brain lesions, age at onset (e.g., onset before 2 years correlating with longer durations), and circadian timing (seizures at certain times of day tending to be briefer).^[10]^[5] Prolonged seizures pose significant risks, including neuronal damage due to excitotoxicity and metabolic stress, with status epilepticus capable of causing cell death in vulnerable brain regions like the hippocampus after durations exceeding 30-60 minutes.^[14]^[15] Such events increase the likelihood of brain injury, though brief, self-limited seizures generally do not lead to permanent harm.^[16]

Classification

The 2025 International League Against Epilepsy (ILAE) classification updates the 2017 framework by simplifying to 21 seizure types from 63, removing "onset" from class names, replacing "awareness" with "consciousness," shifting from motor/nonmotor to observable/nonobservable manifestations, adding epileptic negative myoclonus, and reclassifying absence seizures without the nonmotor label.^[17] The four main classes remain: Focal, Generalized, Unknown, and Unclassified.

Focal Onset Seizures

Focal seizures originate within networks limited to one hemisphere of the brain, as defined by the 2017 International League Against Epilepsy (ILAE) classification, with updates in 2025.^[18]^[17] These seizures account for approximately 60% of cases in adult-onset epilepsy.^[19] They are characterized by initial symptoms that reflect the function of the affected brain region, such as motor, sensory, autonomic, or cognitive disturbances, and may or may not involve alteration of consciousness.^[20] According to the ILAE framework, focal seizures are subclassified based on the level of consciousness and the predominant feature at onset. Focal preserved consciousness seizures occur with maintained consciousness, allowing the individual to remain responsive and recall the event.^[17] These can manifest as motor onset (e.g., twitching or posturing in a specific body part) or nonmotor onset, including sensory phenomena like tingling, autonomic changes such as sweating or heart rate variations, or cognitive/emotional experiences like fear or déjà vu.^[20] In contrast, focal impaired consciousness seizures involve reduced responsiveness and potential amnesia for the event, often beginning with subtle behavioral arrests or automatisms like lip smacking.^[21] Motor and nonmotor features persist in these subtypes, but the impairment in consciousness distinguishes them from preserved consciousness seizures.^[17] Focal seizure activity can propagate within the hemisphere or across to the contralateral side, potentially leading to focal-to-bilateral tonic-clonic seizures where the discharge becomes bilateral and tonic-clonic.^[20]^[17] This evolution occurs when the initial focal discharge recruits sufficient neuronal networks to disrupt bilateral synchrony, transforming a localized event into a more widespread convulsion.^[17] Representative examples illustrate the regional specificity of focal seizures. A Jacksonian march involves progressive clonic movements starting in one body part, such as the hand, and spreading along the motor cortex representation to adjacent areas like the arm and face, reflecting sequential cortical involvement.^[22] Temporal lobe seizures often present with experiential auras, including a sense of déjà vu—an illusory familiarity with unfamiliar surroundings—alongside possible olfactory hallucinations or epigastric rising sensations.^[23] These manifestations highlight how focal discharges in limbic structures can evoke subjective perceptual distortions.^[20]

Generalized Onset Seizures

Generalized seizures are epileptic events that originate within and rapidly engage bilaterally distributed networks across both hemispheres of the brain from the outset, without initial focal involvement.^[4] These seizures are characterized by bilateral symmetry in clinical manifestations and typically involve impairment or loss of consciousness, distinguishing them from focal seizures that may begin unilaterally and potentially spread.^[24] According to the International League Against Epilepsy (ILAE) 2025 classification, generalized seizures are subdivided into types such as absence seizures (typical, atypical, myoclonic), generalized tonic-clonic, myoclonic, clonic, negative myoclonic, spasms, tonic, and atonic, based on observable or nonobservable manifestations.^[17] Generalized tonic-clonic seizures begin with a tonic phase of generalized muscle stiffening, followed by a clonic phase of rhythmic jerking, commonly resulting in loss of postural control and potential injury.^[24] Myoclonic seizures involve sudden, brief jerks of the limbs or trunk, while atonic seizures cause abrupt loss of muscle tone, leading to falls or head drops.^[17] Absence seizures manifest as sudden, brief interruptions in activity with staring spells and unresponsiveness, lasting 5-10 seconds without postictal confusion.^[24] These types are frequently associated with syndromes like juvenile myoclonic epilepsy. Many generalized seizures exhibit a genetic predisposition, particularly in idiopathic generalized epilepsies (IGE), where no underlying structural abnormalities are present. Juvenile myoclonic epilepsy (JME), a common IGE syndrome onsetting in adolescence, features myoclonic jerks upon awakening, often progressing to generalized tonic-clonic seizures, with genetic factors such as mutations in GABRA1 or EFHC1 implicated in up to 60% of cases showing familial patterns.^[25] Childhood absence epilepsy similarly involves genetic influences, with polygenic inheritance contributing to typical absence seizures.^[25]

Unknown Onset Seizures

Unknown seizures are those for which there is insufficient information to determine whether the onset is focal or generalized, as defined by the International League Against Epilepsy (ILAE) in its 2025 updated classification.^[17] This category applies when video-EEG monitoring, witness descriptions, or other diagnostic data fail to localize the seizure's initial manifestation to one hemisphere (focal) or bilaterally synchronous (generalized). Such seizures can be reclassified as focal or generalized upon acquisition of additional evidence, such as improved imaging or prolonged EEG recording.^[17] Common scenarios leading to unknown classification include nocturnal events, where the patient is asleep and unwitnessed, or occurrences in non-monitored environments without bystanders to describe the initial symptoms. For instance, a seizure beginning during sleep without video documentation may lack details on asymmetry or bilateral involvement at onset. These situations highlight the diagnostic challenges in real-world settings, where immediate access to advanced monitoring is often unavailable.^[17] Within this category, seizures are further subdivided based on consciousness and manifestations, such as unknown preserved consciousness, unknown impaired consciousness, and unknown bilateral tonic-clonic. These distinctions aid in clinical management despite the uncertainty of onset.^[17]^[26] In clinical practice, unknown seizures represent a notable proportion of cases in initial assessments, underscoring the limitations of initial evaluations and the need for comprehensive evaluation to refine classifications. Some overlap with focal or generalized features may emerge upon further investigation, but initial categorization remains unknown due to evidentiary gaps.^[27]

Unclassified Seizures

Unclassified seizures refer to epileptic events for which insufficient information is available to categorize them as focal, generalized, or unknown, despite clinical confidence that they are epileptic in nature.^[17] This category applies when no descriptive details—such as onset location, manifestations, or consciousness level—can be reliably ascertained.^[17] Common reasons for a seizure to remain unclassified include the brevity of the event, which limits observation; inadequate documentation from witnesses or patients; or presentations that are atypical and do not align with established descriptors in the classification system.^[28] According to the International League Against Epilepsy (ILAE) 2025 updated guidelines, unclassified is a pragmatic, temporary designation reserved for cases where available data fails to fit into the primary classes of focal, generalized, or unknown, emphasizing the need for ongoing evaluation to enable reclassification.^[29] These guidelines build on the 2017 framework by streamlining categories while maintaining unclassified as a fallback for incomplete assessments.^[30] In clinical practice, unclassified seizures necessitate provisional management strategies tailored to the limited presenting features, often involving broad-spectrum antiepileptic drugs to address potential focal or generalized mechanisms.^[31] Treatment decisions prioritize efficacy and safety, with monotherapy used in the majority of cases (approximately 69%), and adjustments made based on factors like spectrum of activity and patient comorbidities.^[31] Further diagnostic efforts, such as prolonged video-electroencephalography (EEG) monitoring, are recommended to gather additional data for precise classification and optimized therapy.^[17] This category is relatively uncommon with access to advanced monitoring, as it underscores gaps in initial evaluation rather than inherent diagnostic ambiguity.^[29] Unclassified seizures may feature within broader epilepsy syndromes, where accumulation of clinical history and ancillary tests can eventually refine the diagnosis to a specific syndrome type.^[32]

Causes and Risk Factors

Provoked Seizures

Provoked seizures, also known as acute symptomatic seizures, are single or multiple epileptic events occurring in close temporal association with an acute systemic, metabolic, or toxic insult, or with an acute central nervous system (CNS) injury, without prior history of epilepsy.^[5] These seizures are distinct from unprovoked events because they arise from identifiable, transient precipitants that directly disrupt neuronal function, rather than from an underlying chronic predisposition.^[33] Common triggers for provoked seizures include metabolic disturbances such as hypoglycemia, which lowers blood glucose levels and impairs brain energy supply, and electrolyte imbalances like hyponatremia or hypocalcemia, which alter neuronal excitability.^[34] Toxic factors encompass alcohol withdrawal, which can induce excitotoxicity through glutamate surges, and exposure to drugs or substances including stimulants or overdoses that affect neurotransmitter balance.^[5] Infectious causes, such as bacterial meningitis or viral encephalitis, provoke seizures by inflaming the meninges or brain parenchyma, leading to irritation and hyperexcitability.^[35] Traumatic insults, particularly acute head injuries, can trigger seizures through direct cortical damage or secondary effects like cerebral edema.^[5] Isolated provoked seizures are generally considered non-epileptic, as they do not confer a diagnosis of epilepsy unless they recur without an identifiable acute trigger.^[36] In contrast, recurrent provoked seizures may occur if the underlying trigger persists or recurs, but they still do not typically indicate a chronic epileptic disorder if the provocations are addressed.^[37] These seizures often resolve once the provoking factor is identified and treated, such as correcting electrolyte levels or managing withdrawal symptoms, thereby restoring normal brain function without the need for long-term antiepileptic therapy.^[38] A classic example is febrile seizures in children, which are provoked by rapid rises in body temperature due to infection and occur in 2-5% of children aged 6 months to 5 years, with peak incidence between 12 and 18 months; these are typically benign, self-limited events that resolve as fever abates.^[39] Management of provoked seizures primarily involves prompt intervention to eliminate the acute trigger, alongside supportive measures to prevent complications.^[5]

Unprovoked Seizures

Unprovoked seizures are defined as epileptic events occurring without an immediate identifiable precipitating factor, such as acute metabolic disturbances, toxins, or structural insults. The International League Against Epilepsy (ILAE) operationalizes this in its definition of epilepsy as the occurrence of two or more unprovoked seizures separated by more than 24 hours.^[40] This distinction from provoked seizures underscores the chronic nature of the underlying brain dysfunction, where seizures arise spontaneously due to inherent epileptogenic processes rather than transient provocations. The risk of seizure recurrence following an initial unprovoked event is substantial, estimated at 40-50% within two years in untreated individuals.^[41] This probability increases markedly after a second unprovoked seizure, reaching 70-80% for further events within four years, highlighting the progressive likelihood of chronic epilepsy.^[42] Factors influencing this risk include epileptiform abnormalities on electroencephalography and a history of remote brain injury, which can elevate recurrence rates beyond these averages. Recurrent unprovoked seizures are frequently associated with specific epilepsy syndromes, which represent distinct clinical entities characterized by seizure types, age of onset, and comorbid features as classified by the ILAE.^[17] These syndromes provide a framework for understanding the patterned recurrence of unprovoked events, guiding prognosis and management. Unprovoked seizures are categorized by etiology as genetic, structural, metabolic, immune, infectious, or unknown per current ILAE guidelines. Genetic etiologies often lack identifiable structural brain abnormalities and involve genetic predispositions without evident neurological deficits.^[5] Structural etiologies stem from remote insults, such as prior trauma, infection, or cerebrovascular events, where the initial provocation has resolved but left enduring epileptogenic changes. Metabolic etiologies include inborn errors like glucose transporter 1 (GLUT1) deficiency syndrome, leading to chronic hyperexcitability. Immune-mediated causes encompass autoimmune encephalitides, such as anti-NMDA receptor encephalitis, triggering seizures through antibody-mediated neuronal dysfunction. Infectious etiologies may arise from remote CNS infections like prior herpes simplex encephalitis, resulting in focal epileptogenesis. Approximately 50% of epilepsy cases have an unknown etiology despite thorough evaluation.^[5] This framework informs diagnostic evaluation and underscores the transition to epilepsy diagnosis upon recurrence.

Genetic and Structural Causes

Genetic causes of seizures often involve mutations in ion channel genes, known as channelopathies, which disrupt neuronal excitability and lead to epilepsy syndromes. For instance, mutations in the SCN1A gene, encoding the NaV1.1 sodium channel, are a primary cause of Dravet syndrome, a severe epileptic encephalopathy characterized by early-onset seizures and developmental delays, resulting from loss-of-function effects that impair inhibitory interneuron activity.^[43]^[44] Other channelopathies, such as those affecting potassium or calcium channels, contribute to a spectrum of generalized epilepsies, highlighting the genetic basis for certain seizure classifications.^[45] Beyond monogenic disorders, polygenic risk scores (PRS) capture the cumulative impact of common genetic variants, increasing susceptibility to various epilepsies across the lifespan. High PRS for genetic generalized epilepsy, for example, elevates the hazard ratio for developing the condition by approximately 1.73 per standard deviation increase, aiding in risk stratification for both idiopathic and symptomatic cases. Recent genome-wide studies in 2025 have refined these PRS, demonstrating their utility in predicting epilepsy onset in diverse populations.^[46]^[47] Emerging therapeutic advances include CRISPR-based gene editing trials targeting SCN1A mutations in Dravet syndrome, with 2025 preclinical studies using CRISPR/dCas9 systems to activate endogenous gene expression, showing promise in rescuing neuronal function in mouse models without off-target effects. These approaches aim to correct haploinsufficiency directly, potentially preventing epileptogenesis in affected individuals.^[48] Structural causes encompass brain abnormalities that create epileptogenic foci, including cortical malformations such as focal cortical dysplasia, which disrupt neuronal migration and layering during development, often leading to refractory focal seizures. Hippocampal sclerosis, marked by neuronal loss and gliosis in the hippocampus, is a frequent substrate for temporal lobe epilepsy, arising from early-life insults or as a consequence of recurrent seizures.^[49]^[50]^[51] Tumors, particularly low-grade gliomas or dysembryoplastic neuroepithelial tumors, irritate surrounding cortex and provoke seizures in up to 80% of cases, while stroke sequelae, such as ischemic lesions in cortical or subcortical regions, underlie post-stroke epilepsy through gliosis and circuit reorganization.^[52]^[53] Developmental disorders like tuberous sclerosis complex (TSC) involve hamartomatous lesions in the brain due to mutations in TSC1 or TSC2 genes, leading to hyperactivation of the mTOR signaling pathway that promotes abnormal neuronal growth and hyperexcitability, manifesting as infantile spasms or focal seizures. mTOR inhibitors like everolimus have shown efficacy in reducing seizure frequency by targeting this pathway, underscoring its central role in TSC-related epileptogenesis.^[54]^[55] Gene-environment interactions further modulate epileptogenesis, where genetic predispositions, such as variants in susceptibility loci, interact with environmental triggers like infections or trauma to lower the seizure threshold and initiate chronic epilepsy. These interactions explain variable expressivity in genetic syndromes and highlight the multifactorial nature of many unprovoked seizures.^[56]^[57]

Pathophysiology

Neuronal Mechanisms

Seizures emerge from neuronal hyperexcitability, characterized by an imbalance between excitatory and inhibitory synaptic transmission in the brain. The primary excitatory neurotransmitter, glutamate, acts through ionotropic receptors such as NMDA, AMPA, and kainate subtypes, which facilitate sodium and calcium influx to depolarize neurons. During seizures, extracellular glutamate levels rise due to impaired uptake by transporters like GLT-1, leading to overstimulation of these receptors and excessive excitation.^[58]^[59] In contrast, gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter, mediates hyperpolarization primarily via GABA_A receptors that allow chloride influx, suppressing action potentials; reduced GABAergic inhibition, often from decreased receptor function or transporter deficits, fails to counterbalance glutamatergic drive, tipping the network toward hyperexcitability.^[58]^[59] At the cellular level, this imbalance manifests in the paroxysmal depolarization shift (PDS), a hallmark of epileptic activity where neurons undergo prolonged depolarizations of 20-40 mV lasting 100-400 ms, accompanied by high-frequency bursts of action potentials. The PDS arises from dysregulation of voltage-gated ion channels: initial sodium influx through voltage-gated sodium channels triggers depolarization, augmented by calcium entry via NMDA receptors and L-type calcium channels (e.g., Cav1.3), while subsequent potassium efflux through calcium-dependent potassium channels (e.g., apamin-sensitive BK channels) contributes to repolarization and after-hyperpolarization. This ion channel interplay, first described in penicillin-induced models, underlies interictal spikes and ictal bursts, propagating abnormal firing across neuronal populations.^[60] Seizure spread involves progressive network sensitization, as exemplified by the kindling model, where repeated subthreshold electrical stimulation of limbic structures like the amygdala initially evokes focal afterdischarges but gradually lowers the seizure threshold, culminating in generalized convulsions after 10-20 sessions. This phenomenon, pioneered by Goddard in 1967 through low-intensity brain stimulation in rats, reflects lasting plastic changes in synaptic efficacy and excitability without structural damage, mimicking epileptogenesis in temporal lobe epilepsy.^[61]^[62] In generalized absence seizures, thalamocortical circuits generate synchronized oscillatory activity at 2.5-5 Hz spike-and-wave discharges, driven by abnormal burst firing in thalamic relay neurons and reticular thalamic nucleus (nRT) interneurons. T-type calcium channels (Cav3 family) enable low-threshold spikes that initiate rhythmic bursts upon hyperpolarization, while hyperpolarization-activated cyclic nucleotide-gated (HCN) channels modulate the transition from tonic to burst modes; enhanced T-type currents in nRT neurons amplify inhibition onto relay cells, promoting cortico-thalamo-cortical synchronization and transient loss of awareness.^[63]

Underlying Brain Changes

In epileptogenic zones, particularly within the hippocampus following injury such as status epilepticus, structural remodeling includes prominent gliosis and mossy fiber sprouting. Gliosis involves the proliferation and hypertrophy of astrocytes, forming a reactive glial scar that secretes pro-synaptogenic factors like thrombospondin-1, which promotes aberrant synapse formation and contributes to network hyperexcitability.^[64] Mossy fiber sprouting refers to the aberrant growth of granule cell axons into the inner molecular layer of the dentate gyrus, creating recurrent excitatory circuits that bypass normal inhibitory controls and facilitate seizure propagation.^[64] These changes, observed in about 60% of patients with mesial temporal lobe epilepsy, represent a maladaptive response to neuronal loss and injury, enhancing the potential for synchronized neuronal firing.^[64] Connectivity alterations in epilepsy involve widespread changes in white matter tracts, as revealed by diffusion tensor imaging (DTI) studies, which demonstrate reduced fractional anisotropy indicating disrupted microstructural integrity. In temporal lobe epilepsy, tracts such as the uncinate fasciculus, inferior longitudinal fasciculus, and fornix exhibit decreased anisotropy and increased diffusivity, reflecting axonal damage, demyelination, and loss of fiber coherence bilaterally.^[65] These modifications, often progressive with disease duration, impair inter-regional communication and contribute to the dissemination of seizure activity across brain networks, with contralateral frontoparietal involvement suggesting secondary remote effects.^[66] Inflammation plays a central role in these brain changes, driven by the breakdown of the blood-brain barrier (BBB) that allows influx of proinflammatory cytokines such as interleukin-1β (IL-1β) and high-mobility group box 1 (HMGB1). BBB disruption, occurring acutely after seizures and persisting in chronic epilepsy, leads to albumin extravasation and activation of transforming growth factor-β (TGF-β) signaling in astrocytes, which upregulates inflammatory pathways like NF-κB and perpetuates cytokine release from glia.^[67] This inflammatory cascade alters astrocytic potassium buffering and synaptic function, fostering an environment conducive to epileptogenesis by amplifying neuronal excitability.^[68] Synaptic plasticity mechanisms, particularly enhanced long-term potentiation (LTP), further contribute to chronic epilepsy by strengthening excitatory synapses in a pathological manner. LTP, involving sustained increases in synaptic efficacy through NMDA receptor-dependent calcium influx and activation of pathways like CaMKII and mTOR, becomes dysregulated post-injury, leading to overconsolidation of hyperexcitable circuits in regions like the hippocampus.^[69] In epileptic tissue, this enhanced LTP disrupts the balance with long-term depression, promoting recurrent seizures and cognitive impairments, while resulting in neuronal hyperexcitability that sustains the epileptogenic process.^[69]

Diagnosis

History and Physical Examination

The history and physical examination form the cornerstone of initial assessment for patients presenting with suspected seizures, providing essential clues to differentiate epileptic events from mimics and guide further diagnostic steps. A detailed history begins with obtaining witness accounts of the event, as patients may not recall details due to postictal confusion or amnesia. Witnesses should describe the onset (sudden or gradual), duration, movements (e.g., tonic stiffening or clonic jerking), loss of awareness, and any associated features like oral automatisms or urinary incontinence. Additionally, inquiring about auras—brief subjective sensations such as déjà vu, epigastric rising, or olfactory changes—can indicate focal seizure origins, often preceding generalized convulsions. Frequency of episodes, potential triggers (e.g., sleep deprivation, alcohol, or flashing lights), and any preceding illness or medication changes should also be explored to identify patterns suggestive of provoked versus unprovoked seizures. Family history plays a critical role, as genetic epilepsies account for up to 40% of cases in certain populations, with inquiries targeting relatives with similar events or known epilepsy syndromes. The patient's own medical background, including head trauma, febrile seizures in childhood, or central nervous system infections, helps assess risk factors. Cultural considerations are vital, as stigma surrounding seizures in some communities may lead to underreporting or misattribution to supernatural causes, potentially delaying care; clinicians should foster a nonjudgmental environment to encourage full disclosure. For differential diagnosis, features like prodromal symptoms or rapid recovery might suggest syncope rather than seizure. The physical examination complements the history by systematically evaluating for underlying causes and acute complications. A comprehensive neurological exam assesses for focal deficits, such as hemiparesis, aphasia, or sensory loss, which may point to a structural lesion like a stroke or tumor. Mental status evaluation post-event checks for confusion or memory gaps indicative of postictal states. The general physical exam includes vital signs to detect metabolic derangements (e.g., hypoglycemia or electrolyte imbalances) and inspection of the skin for signs of neurocutaneous syndromes, such as café-au-lait spots in neurofibromatosis or ash-leaf spots in tuberous sclerosis. Red flags in the history or exam, including progressive neurological symptoms, headaches, or focal signs worsening over time, warrant urgent neuroimaging to rule out brain tumors or other space-occupying lesions.

Electroencephalography

Electroencephalography (EEG) serves as the cornerstone for confirming epileptiform activity in individuals presenting with seizures, capturing the brain's electrical signals to identify abnormal patterns indicative of epilepsy.^[70] This non-invasive technique records neuronal activity via scalp electrodes, providing objective evidence that complements clinical history.^[71] In the context of seizure evaluation, EEG distinguishes between interictal (between seizures) and ictal (during seizure) abnormalities, aiding in syndrome classification and treatment planning.^[72] Several types of EEG monitoring are employed based on clinical needs, with routine EEG being the initial standard. A routine EEG typically lasts 20-40 minutes and is performed in a controlled setting, often including activation procedures like hyperventilation or photic stimulation to provoke epileptiform discharges.^[73] For extended observation, ambulatory EEG allows portable recording over 24-72 hours in the patient's daily environment, increasing the chance of capturing spontaneous events without hospitalization.^[71] Video-EEG monitoring combines continuous EEG with synchronized video, usually inpatient for 1-7 days, to correlate behavioral changes with electrographic features, particularly useful for distinguishing epileptic from non-epileptic events.^[70] Key EEG findings in seizures include interictal spikes and sharp waves, which are brief, high-amplitude transients signaling epileptogenic potential, often seen in focal or generalized epilepsies.^[74] Ictal rhythms manifest during seizures, such as the characteristic 3 Hz spike-and-wave complexes in absence seizures, where generalized discharges synchronize bilaterally with impaired consciousness.^[74] These patterns, like polyspike-and-wave in myoclonic epilepsies, provide diagnostic specificity for epilepsy subtypes.^[75] The diagnostic yield of EEG varies by type and duration; a single routine EEG detects interictal epileptiform discharges in approximately 50-60% of epilepsy patients. Prolonged recordings, such as ambulatory or video-EEG, substantially improve sensitivity, achieving up to 80-90% detection rates through repeated captures over extended periods.^[76] Specificity remains high for true epileptiform activity when standardized criteria are applied, though normal variants must be excluded by expert interpretation.^[77] By 2025, advances in artificial intelligence have enhanced EEG analysis for seizure detection, with AI algorithms enabling automated pattern recognition of interictal spikes and ictal rhythms for faster, more accurate interpretation.^[78] Machine learning models, trained on large EEG datasets, achieve high sensitivity in real-time seizure prediction and classification, reducing analysis time from hours to minutes while supporting clinicians in resource-limited settings.^[79] These tools particularly excel in identifying subtle abnormalities in prolonged recordings, improving overall diagnostic efficiency.^[80]

Neuroimaging

Neuroimaging plays a crucial role in evaluating patients with seizures to identify underlying structural abnormalities that may contribute to epileptogenesis, particularly in cases of new-onset or focal epilepsy.^[81] The primary goal is to detect lesions such as tumors, vascular malformations, or developmental anomalies that could be epileptogenic, guiding further management and prognosis.^[82] Computed tomography (CT) is often the initial modality in acute settings, such as emergency departments, due to its availability and speed in detecting urgent conditions like hemorrhage, infarction, or calcified lesions associated with provoked seizures from trauma or vascular events.^[81] However, CT has limited sensitivity for subtle epileptogenic pathologies, identifying abnormalities in less than 30% of unselected epilepsy cases.^[81] In contrast, magnetic resonance imaging (MRI) is the preferred modality for comprehensive structural evaluation, offering superior resolution to identify lesions like mesial temporal sclerosis (also known as hippocampal sclerosis) and malformations of cortical development, which are common in temporal lobe epilepsy.^[82]^[83] Epilepsy-specific MRI protocols enhance diagnostic yield by incorporating thin-slice (1-3 mm) sequences in multiple planes, including T1-weighted, T2-weighted, and fluid-attenuated inversion recovery (FLAIR) imaging, which is particularly sensitive for detecting hippocampal atrophy, signal changes in mesial temporal sclerosis, and gray-white matter blurring in cortical malformations.^[81]^[82] These protocols, recommended by the International League Against Epilepsy for new-onset seizures, can reveal structural abnormalities in 20-30% of patients with new-onset epilepsy, influencing decisions on antiepileptic therapy and surgical candidacy.^[83]^[84] For cases refractory to medication or during presurgical planning, functional neuroimaging modalities such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) provide insights into metabolic or perfusion abnormalities corresponding to epileptogenic zones.^[85] Fluorodeoxyglucose-PET (FDG-PET) typically shows interictal hypometabolism in the affected temporal lobe in 70-80% of temporal lobe epilepsy patients, while ictal SPECT demonstrates hyperperfusion at the seizure onset zone with 60-90% sensitivity for localization.^[81] These functional techniques often complement structural MRI and electroencephalography findings to refine seizure focus localization.^[85]

Laboratory Tests and Differential Diagnosis

Laboratory tests play a crucial role in evaluating seizures, particularly after a first unprovoked event, to identify or exclude treatable provoked causes such as metabolic derangements, electrolyte imbalances, or toxic exposures. According to guidelines from the American Academy of Neurology (AAN), routine laboratory screening is not always required but is recommended based on clinical circumstances, such as history suggesting hypoglycemia or intoxication, with abnormalities identified in up to 15% of cases though often incidental. These tests help differentiate epileptic from non-epileptic events and guide further management. Key laboratory investigations include blood glucose measurement to rule out hypoglycemia as a seizure trigger, especially in patients without a known history of epilepsy. Electrolyte panels assess for imbalances like hyponatremia, hypocalcemia, or hypernatremia, which can provoke seizures in conditions such as renal disease or medication side effects. Toxicology screening is indicated when substance use is suspected, detecting acute intoxications from agents like sympathomimetics or antidepressants. In patients on antiepileptic drugs (AEDs), therapeutic drug level monitoring evaluates compliance and potential toxicity. Genetic testing, including epilepsy gene panels or whole-exome sequencing, is advised for cases with early-onset seizures, family history, or suspected genetic syndromes like Dravet or Lennox-Gastaut, per AAN practice parameters.^[5]^[6]^[86] Differential diagnosis of seizures involves distinguishing epileptic events from non-epileptic paroxysmal phenomena, as misdiagnosis can delay appropriate care. Common mimics include vasovagal syncope, characterized by abrupt loss of consciousness due to transient cerebral hypoperfusion, often with brief duration, prodromal symptoms like nausea, and rapid recovery, sometimes accompanied by convulsive movements. Psychogenic non-epileptic seizures (PNES) present with seizure-like behaviors but lack electrographic correlates; the gold standard for diagnosis is video-EEG monitoring capturing a typical event without ictal EEG changes, confirming the psychogenic origin in up to 20-30% of refractory "epilepsy" cases referred to specialized centers. Migraine aura may mimic focal seizures with transient sensory or visual disturbances, while transient ischemic attack (TIA) can produce focal neurological deficits resembling partial seizures, necessitating exclusion through clinical history and timing.^[5]^[87]^[88]

Management

First Aid and Emergency Response

When someone experiences a seizure, particularly a tonic-clonic type involving convulsions, bystanders play a crucial role in ensuring safety by following established first aid protocols.^[89] The primary goals are to protect the person from harm, monitor the event, and provide supportive care without interfering with the seizure itself.^[90] Key actions include staying calm and remaining with the individual throughout the event, as most seizures are self-limiting and resolve without intervention.^[89] Time the duration of the seizure from the onset of symptoms to help assess severity later.^[90] To prevent injury, clear the area of dangerous objects such as furniture or sharp items, cushion the person's head with a soft object like a folded jacket, and guide them gently to the floor if they are at risk of falling, without attempting to restrain their movements.^[89] Once the active convulsing phase ends and the person is no longer responsive but breathing normally, place them in the recovery position by gently rolling them onto their side, tilting the head slightly backward to keep the airway open, and ensuring the mouth faces downward to allow any fluids to drain.^[90] Loosen any tight clothing around the neck and remove eyeglasses to reduce discomfort.^[89] After the seizure subsides, stay with the person until they are fully alert, offer reassurance, and help them sit in a comfortable position if needed.^[90] Certain actions must be avoided to prevent harm, such as restraining the person's body or limbs, which can lead to muscle strains or fractures.^[89] Do not insert anything into the mouth, including fingers, spoons, or other objects, as this is unnecessary and risks injury to both the person and the helper; contrary to myth, individuals do not swallow their tongue during seizures.^[90] Similarly, refrain from offering food, fluids, or medications during or immediately after the seizure, as the person may not be able to swallow safely and could aspirate.^[89] Emergency medical services should be contacted immediately if the seizure lasts longer than 5 minutes, as prolonged events increase risks like status epilepticus.^[90] Call for help also if another seizure begins shortly after the first (a cluster), if the person sustains an injury, experiences breathing difficulties, does not regain consciousness within a few minutes post-seizure, is pregnant, has diabetes, or if it is their first known seizure.^[89] In rare cases where breathing stops after the seizure ends, begin CPR by checking for responsiveness and providing chest compressions if no pulse or breath is detected, while awaiting professional help.^[90] Training in seizure recognition and basic first aid, including the recovery position and CPR, is recommended for family members, caregivers, and school staff to build confidence in responding effectively.^[89]

Acute Treatment

The acute treatment of seizures prioritizes rapid termination of seizure activity to prevent complications such as neuronal injury or cardiorespiratory compromise. For ongoing seizures, benzodiazepines serve as the first-line pharmacological intervention due to their fast onset and efficacy in stopping convulsive activity. Intravenous lorazepam at a dose of 0.1 mg/kg (maximum 4 mg per dose, repeatable once after 5-10 minutes if needed) is preferred in hospital settings for its reliable absorption and prolonged anticonvulsant effect.^[91] Alternatively, intramuscular midazolam (0.2 mg/kg, maximum 10 mg in adults) provides a viable option when intravenous access is delayed, offering comparable seizure cessation rates with rapid intramuscular absorption.^[92] These agents work by enhancing GABA-mediated inhibition in the central nervous system, typically resolving seizures within minutes in approximately 60-80% of cases.^[93] In cases of status epilepticus—defined as continuous seizure activity lasting more than 5 minutes or recurrent seizures without recovery—a structured, stepwise protocol guides escalation of therapy. Initial benzodiazepine administration remains the cornerstone, followed promptly by a second-line agent such as intravenous fosphenytoin (20 mg PE/kg, maximum 1500 mg) or phenytoin if fosphenytoin is unavailable, infused at a rate not exceeding 150 mg/min to avoid cardiac toxicity.^[91] If seizures persist after 20-40 minutes, third-line options include intravenous phenobarbital (15-20 mg/kg, infused at 50-100 mg/min) or valproate (40 mg/kg, maximum 3000 mg), with careful monitoring for hypotension and respiratory depression.^[92] Refractory status epilepticus, unresponsive to these measures, requires transfer to an intensive care setting for anesthetic agents like propofol (1-2 mg/kg bolus followed by infusion) or high-dose midazolam (0.2 mg/kg bolus then 0.1-0.4 mg/kg/h infusion), often with continuous EEG monitoring to titrate therapy and confirm seizure suppression.^[93] Concurrently addressing provoked seizure triggers, such as electrolyte imbalances or infections, integrates into this protocol to enhance outcomes.^[94] Supportive care is integral to acute management, focusing on maintaining vital functions during and after seizure termination. Airway protection is paramount; positioning the patient in a recovery position or using a nasopharyngeal airway prevents aspiration, while supplemental oxygen is administered to maintain saturation above 94% if hypoxia occurs.^[95] Establishing intravenous access facilitates medication delivery and fluid resuscitation; isotonic fluids like 0.9% saline (initial 10-20 mL/kg bolus if hypotensive) correct hypovolemia or support hemodynamic stability without risking overload.^[96] Blood glucose should be checked and corrected with dextrose if below 70 mg/dL, as hypoglycemia can exacerbate seizures.^[97] As of 2025, intranasal midazolam (5-10 mg for adults, 0.2 mg/kg for children) has gained prominence as a prehospital treatment option, approved for rapid administration by emergency responders without vascular access.^[98] This route achieves seizure cessation in over 70% of pediatric prehospital cases, with studies confirming its noninferiority to intravenous lorazepam and reduced need for intubation compared to rectal alternatives.^[99] Updated guidelines from the American Epilepsy Society endorse its use in community settings to bridge the gap to definitive care.^[92]

Long-Term Therapy

Long-term therapy for epilepsy primarily involves the use of antiepileptic drugs (AEDs) to prevent recurrent seizures, with treatment initiated after a diagnosis of epilepsy rather than after a single unprovoked seizure. First-line AEDs include levetiracetam, which has level A evidence for reducing focal seizures in adults aged 16-59 years, and valproate, which has level A evidence for absence seizures in children and level B for focal seizures in adults.^[100] ^[100] These agents are selected based on seizure type, with ethosuximide recommended as first-line for childhood absence epilepsy due to its superior efficacy over alternatives like lamotrigine in controlling absence seizures.^[101] Therapy typically begins with monotherapy, as it offers similar efficacy to polytherapy but with better tolerability and fewer adverse effects; polytherapy is reserved for cases where monotherapy fails after trialing appropriate agents.^[102] AED selection also considers patient-specific factors, including potential side effects such as teratogenicity, which poses a 4-7% risk of major birth defects with monotherapy exposure during pregnancy, particularly with valproate.^[100] For women of childbearing potential, levetiracetam is often preferred over valproate due to lower teratogenic risks while maintaining efficacy in focal and generalized epilepsies.^[103] Monitoring involves assessing therapeutic drug levels only when clinically indicated, such as for suspected toxicity, nonadherence, or breakthrough seizures, rather than routinely, as evidence does not support universal monitoring for improved outcomes.^[104] Adherence is enhanced through mobile health applications that provide reminders, track dosing, and facilitate self-management, potentially reducing seizure recurrence by up to 70% in adherent patients.^[105] In select patients who achieve seizure freedom, discontinuation of AEDs may be considered after 2-5 years of remission on monotherapy, particularly for those with idiopathic generalized epilepsy or benign focal epilepsy in childhood, though this carries a risk of recurrence that must be weighed against long-term side effects.^[100] ^[106] The unprovoked seizure recurrence risk after discontinuation is approximately 30-50% within 2 years, higher in adults with structural etiologies.^[107] Decisions should involve shared discussion with a neurologist, tapering gradually over months to minimize relapse.^[106]

Surgical and Other Interventions

For patients with drug-resistant epilepsy, defined by the International League Against Epilepsy (ILAE) as failure of adequate trials of two tolerated and appropriately chosen antiepileptic drug (AED) schedules, surgical and other non-pharmacological interventions offer options to achieve seizure control when medications prove insufficient.^[108] These approaches target the underlying epileptogenic focus or modulate neural activity, with candidacy determined by presurgical evaluation confirming a well-localized seizure onset zone, often using stereo-electroencephalography (SEEG) for invasive mapping in complex cases.^[109] The ILAE's 2017 classification of epilepsies emphasizes identifying focal epilepsy types amenable to intervention, guiding patient selection for procedures that can lead to seizure freedom or significant reduction.^[110] Resective surgery remains the most established intervention for drug-resistant focal epilepsy, involving removal of the epileptogenic zone to eliminate or substantially reduce seizures. Temporal lobectomy, the most common resective procedure, targets mesial temporal lobe epilepsy and achieves seizure freedom in 60-70% of suitable patients at long-term follow-up, with outcomes influenced by precise localization of hippocampal sclerosis or other lesions.^[111] This surgery improves quality of life by mitigating seizure-related morbidity, though risks include visual field deficits or memory changes, particularly in dominant hemisphere cases. Implantable devices provide neuromodulation alternatives for patients ineligible for resection due to multifocal or eloquent cortex involvement. Vagus nerve stimulation (VNS) involves implanting a device that delivers electrical pulses to the vagus nerve, resulting in a greater than 50% seizure reduction in 26-40% of patients within the first year, with efficacy increasing to over 50% reduction in more than half of users by five years.^[112] Responsive neurostimulation (RNS) uses intracranial leads to detect and interrupt seizure activity in real-time, yielding median seizure frequency reductions of 50-75% over 1-9 years, with approximately 70-80% of patients achieving at least 50% improvement.^[113] Both devices are FDA-approved for adults with focal seizures refractory to medications and offer adjustable, non-destructive therapy. Among non-invasive options, the ketogenic diet— a high-fat, low-carbohydrate regimen—serves as an effective adjunct for children with drug-resistant epilepsy, particularly those with structural or genetic etiologies. In pediatric cohorts, it achieves seizure freedom in 30-55% of patients and greater than 50% reduction in up to 85% after 3-12 months, with benefits linked to metabolic shifts altering neuronal excitability.^[114] Laser interstitial thermal therapy (LITT), a minimally invasive ablation technique using MRI-guided laser probes, targets deep or periventricular foci, delivering seizure freedom (Engel class I) in about 64% of patients at one year, especially in mesial temporal lobe epilepsy.^[115] These interventions complement each other in multidisciplinary care, prioritizing those with confirmed focal pathology per ILAE criteria to optimize outcomes.^[116]

Prognosis and Outcomes

Short-Term Recovery

The postictal state refers to the period immediately following a seizure during which the brain recovers from the ictal activity, typically lasting from minutes to hours.^[1] Common symptoms include confusion, drowsiness, headache, nausea, and hypertension, which can impair daily functioning until resolution.^[117] In most cases, this phase begins as the seizure subsides and ends when the individual returns to their baseline mental and physical state, often within 5 to 30 minutes for generalized seizures, though it may extend longer in focal or prolonged events.^[117] Several factors influence the duration and severity of the postictal state. Longer seizure durations, such as those seen in status epilepticus, are associated with more extended recovery periods, sometimes lasting hours to days due to greater neuronal exhaustion.^[118] Seizure type plays a role, with focal seizures often resulting in shorter postictal electroencephalographic changes (mean of about 275 seconds) compared to generalized ones.^[119] Patient age also affects recovery, as older individuals tend to experience more prolonged confusion and impairment, particularly in the presence of underlying brain dysfunction.^[120] A notable complication during short-term recovery is Todd's paralysis, a temporary focal weakness or hemiparesis that can affect one side of the body or specific limbs following a seizure.^[121] This phenomenon, which typically resolves within minutes to hours but can last up to 36 hours in some instances, arises from postictal neuronal inhibition rather than structural damage.^[122] It occurs more frequently after focal motor seizures originating in the contralateral hemisphere.^[2] Supportive measures are essential to facilitate short-term recovery and prevent complications. Rest in a safe, quiet environment allows the brain to recuperate, while ensuring adequate hydration helps mitigate risks like dehydration from physical exertion during the seizure.^[6] Proper first aid, such as positioning the person on their side and providing reassurance, can ease the transition into the postictal phase.^[90] Additionally, many jurisdictions impose driving restrictions, requiring individuals to be seizure-free for at least 6 months before resuming operation of a motor vehicle, to ensure safety during potential recovery periods.^[123]

Long-Term Risks and Quality of Life

Recurrent seizures in epilepsy pose significant long-term health risks, including sudden unexpected death in epilepsy (SUDEP), physical injuries, and cognitive decline. SUDEP occurs at a rate of approximately 1 per 1,000 adults with epilepsy annually, with rates escalating to 3-9 per 1,000 in those with refractory epilepsy due to factors like frequent generalized tonic-clonic seizures.^[124] Injuries from seizures, such as fractures, burns, and head trauma, affect up to 50% of patients over their lifetime, often resulting from falls or convulsions, and are more prevalent in uncontrolled cases.^[125] Cognitive decline is also common, with 30-40% of individuals with chronic epilepsy experiencing impairments in memory, attention, and executive function, potentially accelerated by ongoing seizures and antiepileptic drug effects.^[126] These risks profoundly impact quality of life, particularly through mental health challenges and employment barriers. Anxiety and depression affect 30-50% of people with epilepsy, often linked to the unpredictability of seizures and social stigma, leading to reduced daily functioning and higher suicide risk compared to the general population.^[127] Employment discrimination remains a major obstacle, with up to 50% of individuals facing difficulties in securing or maintaining jobs due to employer concerns over seizure-related accidents or absenteeism, resulting in higher unemployment rates and financial strain.^[128] Despite these challenges, many achieve seizure control; approximately 60-70% of patients enter remission with appropriate antiepileptic drug treatment, though relapse can occur in 20-40% upon discontinuation. Adherence to long-term therapy significantly influences these outcomes, enhancing remission prospects and mitigating risks.^[129] As of 2025, advancements in wearable technology offer promising tools for improving quality of life through seizure detection and monitoring. FDA-cleared platforms, such as the EpiWatch app for Apple Watch, use artificial intelligence and physiological sensors like heart rate and motion trackers to detect tonic-clonic seizures in real time and alert caregivers, enabling timely interventions. Emerging research in wearable AI also shows potential for seizure forecasting to support proactive management.^[130]^[131]^[132]

Epidemiology

Incidence and Prevalence

The annual incidence of unprovoked seizures, which often lead to epilepsy diagnoses, ranges from 50 to 70 per 100,000 person-years in high-income countries.^[133] In low- and middle-income countries, this rate is nearly three times higher, at approximately 139 per 100,000, due to greater exposure to risk factors such as infections and trauma.^[8] These figures reflect cumulative incidence estimates from systematic reviews and global health data, highlighting disparities in healthcare access and preventive measures.^[134] Epilepsy prevalence is estimated at 0.5% to 1% of the global population, with approximately 52 million people affected worldwide as of 2021 (the most recent comprehensive data available).^[8]^[135] The lifetime risk of developing epilepsy is about 1 in 26 individuals.^[136] In the United States, active epilepsy affects approximately 1% of adults, totaling about 2.9 million cases in 2021–2022.^[137] Incidence trends show a decline in high-income countries, particularly among younger age groups, attributed to advancements in perinatal and neonatal care that reduce birth-related complications.^[138] Globally, the number of cases increased to 51.7 million as of 2021, with age-standardized rates having slightly decreased in some regions due to improved diagnostics and prevention; projections suggest continued absolute growth driven by population increases, especially in low- and middle-income countries.^[135] Incidence exhibits a bimodal distribution, with peaks in children—where febrile seizures contribute significantly, affecting 2–5% of young children—and in the elderly over 75 years, often linked to cerebrovascular events like stroke.^[8]^[139] In the elderly, rates can exceed 100 per 100,000 annually in high-risk populations.^[138]

Demographic Patterns

Seizures exhibit a bimodal age distribution in their incidence, with peaks occurring in infancy and among individuals older than 65 years. In young children, particularly those under one year of age, the higher rates are often linked to perinatal complications, genetic factors, and developmental disorders, while in the elderly, they are frequently associated with cerebrovascular diseases, neurodegenerative conditions, and brain tumors. This pattern results in the lowest incidence rates during young and middle adulthood, typically between ages 20 and 40.^[140]^[141] Regarding gender, there is a slight male predominance in the overall incidence and prevalence of epilepsy, with males experiencing rates approximately 10-20% higher than females across most age groups. This disparity may stem from biological factors such as hormonal influences on seizure thresholds and higher exposure to risk factors like trauma in males, though it varies by epilepsy syndrome— for instance, certain idiopathic forms show less pronounced differences.^[142]^[143] Geographically, seizure disorders are more prevalent in low-socioeconomic-status (SES) areas, particularly in low- and middle-income countries (LMICs), where rates can be up to twice as high as in high-income regions due to increased exposure to risk factors such as central nervous system infections, head trauma from accidents or violence, and perinatal injuries. In these settings, limited access to preventive healthcare exacerbates the burden, leading to higher untreated cases and poorer outcomes.^[144]^[145]^[146] Ethnic and racial disparities in seizures are evident, particularly in access to diagnosis and treatment, with higher untreated rates observed in regions like sub-Saharan Africa and parts of Asia. In low-income countries across these areas, up to 75% of individuals with epilepsy receive no treatment, driven by barriers such as stigma, inadequate healthcare infrastructure, and economic constraints, resulting in elevated morbidity and mortality. Ethnic minorities within high-income countries, including African Americans and Hispanics, also face higher prevalence and disparities in care due to socioeconomic factors and systemic biases.^[147]^[144]^[148] Comorbidities are common in seizure disorders, with approximately 25-30% of individuals with symptomatic epilepsy—where seizures arise from identifiable structural or metabolic causes—also experiencing intellectual disability. This association is particularly strong in cases linked to early-life brain injuries, genetic syndromes, or developmental encephalopathies, where seizures can further impair cognitive function and complicate management.^[149]^[150]

History

Early Observations

Early observations of seizures date back to ancient civilizations, where they were often interpreted through supernatural lenses. In ancient Greece, around 400 BCE, Hippocrates described epilepsy—then known as the "sacred disease"—as a natural affliction originating from the brain rather than divine intervention, attributing it to an excess of phlegm that disrupted cerebral function.00182-5/fulltext) He rejected prevailing beliefs that seizures were caused by gods or demons, arguing instead that they stemmed from physiological imbalances akin to other illnesses, marking a pivotal shift toward a rational, medical understanding.^[151] Throughout various ancient and medieval societies, seizures were frequently attributed to demonic possession, reflecting deep-seated cultural fears of the unknown. In Babylonian texts from around 2000 BCE, epilepsy was linked to evil spirits invading the body, necessitating rituals like incantations or exorcisms to expel them.^[152] Similar myths persisted in Greco-Roman and early Christian cultures, where convulsions were seen as signs of satanic influence or witchcraft, leading to social ostracism or punitive treatments rather than medical care.^[153] These interpretations underscored the stigma surrounding seizures, often blending religious and folk beliefs across diverse societies from Mesopotamia to medieval Europe. In the medieval Islamic world, Avicenna (Ibn Sina), in his influential Canon of Medicine completed around 1025 CE, advanced a more scientific view by classifying epilepsy as a disorder of the brain and head. He detailed its symptoms, causes, and management within a dedicated chapter on neurological conditions, emphasizing humoral imbalances and environmental triggers while building on Hippocratic principles.00026-0/fulltext) Avicenna's work synthesized ancient Greek knowledge with empirical observations, recommending lifestyle adjustments and herbal remedies to prevent seizures, thus reinforcing epilepsy's status as a treatable brain ailment.^[154] By the 19th century, observations became more anatomically precise, with British neurologist John Hughlings Jackson revolutionizing the field through his studies in the 1870s. In his 1870 paper "A Study of Convulsions," Jackson described focal seizures as originating from localized brain discharges, distinguishing them from generalized ones by their progressive, "marching" spread across motor areas.^[155] He proposed that these events reflected irritative lesions in specific cortical regions, laying the groundwork for modern classifications of partial versus generalized epilepsy.^[156] This focus on localization bridged early descriptive accounts to contemporary neurology.

Modern Developments

The early 20th century marked a pivotal shift in epilepsy management with the introduction of more effective pharmacological treatments. Prior to 1912, potassium bromide had been the primary anticonvulsant since the mid-19th century, but it was limited by toxicity and sedation. That year, German neurologist Alfred Hauptmann introduced phenobarbital as the first modern antiepileptic drug (AED), demonstrating its efficacy in reducing seizure frequency with fewer side effects than bromides.^[157]^[158] In 1909, the International League Against Epilepsy (ILAE) was founded to advance research and standardize nomenclature, laying the groundwork for systematic classification of seizures and epilepsies.^[159] A major breakthrough came in 1924 when German psychiatrist Hans Berger invented electroencephalography (EEG), enabling the first recordings of human brain electrical activity and revealing characteristic patterns during seizures, such as flattening of waves post-ictally.^[160]^[161] This non-invasive tool revolutionized diagnosis by allowing objective identification of epileptiform discharges.^[162] The ILAE's efforts culminated in formal classifications, with the 1981 revision providing a clinical and EEG-based framework for epileptic seizures that emphasized focal versus generalized onset.^[163] This was updated in 2017 to incorporate advances in genetics and imaging, introducing a multi-level system starting with seizure type (focal, generalized, unknown, or unclassified) and extending to epilepsy types and syndromes for more precise diagnosis and treatment.^[110]^[164] The mid-to-late 20th century saw the expansion of the AED era, improving seizure control for refractory cases. Carbamazepine, approved by the FDA in 1974 for partial seizures after initial use for trigeminal neuralgia, became a cornerstone therapy by stabilizing sodium channels to prevent neuronal hyperexcitability.^[165] In the 1990s, lamotrigine emerged as a broad-spectrum AED, approved between 1990 and 1995, offering efficacy against both focal and generalized seizures through glutamate inhibition and sodium channel modulation, with a favorable side-effect profile.^[166] Non-pharmacological interventions also advanced, notably with the vagus nerve stimulator (VNS), approved by the FDA in 1997 as adjunctive therapy for drug-resistant partial-onset seizures in patients aged 12 and older.^[167] The implantable device delivers intermittent electrical pulses to the vagus nerve, modulating brain activity to reduce seizure frequency by approximately 50% in many patients over time.^[168] By 2025, optogenetics represented a cutting-edge milestone in preclinical seizure research, enabling precise optical control of neurons in animal models. Studies in mice demonstrated transcranial optogenetic inhibition of hyperexcitable circuits, rapidly halting induced seizures without affecting surrounding tissue, paving the way for targeted neuromodulation therapies.^[169]

Societal and Cultural Aspects

Stigma and Public Perception

Throughout history, epilepsy has been shrouded in stigma, often interpreted as divine punishment or a manifestation of supernatural forces. In ancient times, such as in Greek society around the 5th century BCE, it was regarded as the "sacred disease," inflicted by gods as retribution for moral failings or ancestral sins, leading to rituals and sacrifices as treatments.^[170] During the medieval period, beliefs shifted toward demonic possession, with seizures attributed to evil spirits or witchcraft, resulting in exorcisms, social isolation, and persecution under texts like the Malleus Maleficarum (1487).^[171] By the 19th century, epilepsy was increasingly linked to mental illness, classified as a form of madness or degeneracy, leading to institutionalization in psychiatric asylums and associations with moral depravity or violence.^[171] These views fostered deep-seated fear and exclusion, perpetuating the notion of epilepsy as a curse rather than a medical condition.^[170] In contemporary society, stigma persists due to the unpredictability of seizures, manifesting as discrimination in employment and education. Misconceptions about safety risks and productivity lead to higher unemployment rates among people with epilepsy (PWE), with studies showing approximately 40-60% unemployment compared to 4-5% in the general population, often driven by fear of disclosure and job loss.^[172]^[173] For instance, 44% of PWE report being denied jobs due to their condition, while in schools, barriers arise from inadequate accommodations and peer biases, limiting access to equal educational opportunities.^[172] This fear of unpredictability exacerbates social isolation, as many PWE hide their diagnosis to avoid judgment, further entrenching discriminatory attitudes rooted in ignorance.^[174] As of 2025, the Epilepsy Foundation continues campaigns like #ChangeOurEpilepsyStory, encouraging story-sharing to combat stigma during Epilepsy Awareness Month.^[175]^[176] Media portrayals have reinforced harmful misconceptions, such as the myth that individuals can swallow their tongue during a seizure, which is anatomically impossible and leads to dangerous interventions like forcing objects into the mouth.^[177] Films and television often depict seizures with exaggerated violence, excessive foaming, or immediate need for emergency aid, perpetuating stereotypes that heighten public fear and stigma.^[178] Surveys indicate that exposure to such fictional representations correlates with belief in these myths, with up to one-third of respondents endorsing unsafe first-aid practices.^[178] Efforts to combat stigma have intensified through advocacy, particularly by the Epilepsy Foundation, which has run public awareness campaigns since the 1970s to dispel myths and promote understanding.^[179] Initiatives like the "Entitled to Respect" radio campaign (2001–2002) targeted youth, increasing knowledge of epilepsy facts, while the #ChangeOurEpilepsyStory pilot (2023) focused on underserved communities to encourage open dialogue and reduce barriers.^[179]^[175] These programs have shown short-term gains in public awareness, though sustained attitude shifts require ongoing evaluation.^[179] Overall, such stigma contributes to diminished quality of life for PWE by fostering emotional distress and social withdrawal.^[172]

Economic Burden

The economic burden of seizures and epilepsy encompasses both direct medical costs, such as medications and hospitalizations, and indirect costs, including lost productivity and unemployment. Direct costs for antiepileptic drugs (AEDs) typically range from about $500 annually for generics to $10,000 or more for brand-name drugs per patient in the United States (as of 2018, with brand prices continuing to increase).^[180]^[181] Hospitalizations represent another major direct expense, with median health plan-paid costs of approximately $22,305 per epilepsy-related admission and mean charges averaging $30,709, often driven by status epilepticus or uncontrolled seizures.^[182]^[183] Indirect costs arise primarily from reduced workforce participation, with unemployment rates among working-age individuals with epilepsy estimated at 40-60%, compared to much lower rates in the general population, leading to annual productivity losses of about $9,504 per affected person.^[184]^[173] These losses are exacerbated by seizure-related absenteeism and early retirement, contributing substantially to the overall economic impact. In the United States, total annual health care spending for epilepsy and seizures was $24.5 billion in 2019, with $5.4 billion for epilepsy and $19 billion for seizures, influenced by the prevalence of approximately 2.9 million affected adults (as of 2021-2022).^[137] In low-resource settings, the economic burden is disproportionately higher relative to income levels, with out-of-pocket expenses for medications and care often consuming a significant portion of household budgets, leading to catastrophic health expenditures and further productivity declines due to limited access to treatment.^[8]^[185] Recent advancements, such as telemedicine, have shown per-visit savings of about $30 for patients through reduced travel (as of 2022), with extensions into 2025 while maintaining care quality.^[186]

Research Directions

Current Advances

Recent advances in genomics have significantly expanded the understanding of seizure disorders through whole-exome sequencing (WES), which has identified over 500 genes associated with epilepsy, enabling more precise genetic diagnoses. Comprehensive epilepsy gene panels, such as the Genomics England panel encompassing more than 600 genes, incorporate these findings to achieve diagnostic yields of up to 50% in severe cases, particularly in pediatric and adult cohorts where monogenic etiologies predominate.^[187] This approach has revealed both established genes like SCN1A and emerging ones implicated in ion channelopathies and synaptic disorders, facilitating targeted genetic counseling and potential precision medicine strategies.^[188] In electroencephalography (EEG) analysis, artificial intelligence (AI) and machine learning (ML) models have improved seizure prediction, particularly with implantable devices that provide continuous intracranial EEG monitoring. These systems, such as responsive neurostimulation implants, utilize deep learning algorithms to detect pre-seizure patterns with accuracies around 80-82%, allowing for proactive interventions like electrical stimulation to abort impending seizures.^[189] For instance, patient-specific ML models trained on long-term EEG data from implants have demonstrated sensitivity and specificity in the 75-85% range, outperforming traditional threshold-based methods by identifying subtle oscillatory changes hours before onset.^[190] Blood-based biomarkers, notably neurofilament light chain (NfL), have emerged as reliable indicators of post-seizure neuronal damage, reflecting axonal injury following convulsive events or status epilepticus. Elevated serum NfL levels, often exceeding 25 pg/mL in acute settings compared to under 10 pg/mL in stable epilepsy patients, correlate with seizure duration, treatment resistance, and long-term cognitive outcomes, providing a non-invasive proxy for brain injury assessment.^[191] Recent studies confirm that plasma NfL rises significantly after generalized tonic-clonic seizures, with levels normalizing over weeks in responsive cases but persisting in refractory epilepsy, underscoring its utility in monitoring disease progression and therapeutic efficacy.^[192] Wearable devices, including smartwatches, leverage autonomic signals like heart rate variability (HRV) to detect pre-ictal changes, offering ambulatory seizure forecasting without invasive procedures. These devices identify ictal tachycardia or HRV alterations exceeding 50 beats per minute as precursors, achieving prediction sensitivities of 80-86% in real-world settings through integrated ML algorithms that process photoplethysmography data.^[193] For example, wrist-worn sensors have forecasted seizures up to 1-3 hours in advance with balanced accuracy around 82%, enabling user alerts and reducing sudden unexpected death in epilepsy risks by promoting timely interventions.^[194]

Emerging Therapies

Gene therapy approaches targeting genetic causes of epilepsy, particularly Dravet syndrome, represent a promising frontier in treatment. Antisense oligonucleotides (ASOs), such as zorevunersen (STK-001) developed by Stoke Therapeutics, aim to increase SCN1A gene expression to address the underlying sodium channel dysfunction. This therapy has advanced to Phase 3 clinical trials, with the global EMPEROR study initiating in mid-2025 to evaluate its efficacy in reducing seizure frequency and improving cognitive outcomes over 52 weeks in approximately 150 patients with SCN1A variants.^[195] The first patient was dosed in August 2025, marking a pivotal step toward potential regulatory approval by late 2025 or early 2026, pending positive results.^[196] Closed-loop neuromodulation devices offer adaptive interventions by delivering stimulation in response to real-time brain activity, minimizing side effects compared to continuous methods. Deep brain stimulation (DBS) systems, such as the Medtronic Percept PC, incorporate EEG monitoring to automatically trigger thalamic stimulation upon detecting seizure precursors, enabling seizure suppression and forecasting in patients with drug-resistant epilepsy.^[197] Recent preclinical studies have demonstrated that cortical closed-loop electrical stimulation can prevent interictal epileptiform discharges and mitigate seizure progression in focal epilepsy models by inhibiting pathological EEG patterns.^[198] These devices are in early clinical evaluation, with ongoing trials assessing long-term safety and efficacy for broader application. Expansions of cannabidiol (CBD) therapy continue to build on its established role in seizure management, with FDA approval for Epidiolex in treating seizures associated with Lennox-Gastaut syndrome (LGS) since 2018. Recent analyses confirm its sustained efficacy in reducing seizure frequency by up to 40% in refractory LGS cases when added to standard regimens, with a favorable safety profile in pediatric populations.^[199] Emerging formulations and real-world studies in 2025 highlight CBD's potential for off-label use in diverse drug-resistant epilepsies, including optimized oral solutions that improve bioavailability and tolerability for long-term administration.^[200] Stem cell-based neuronal transplants hold potential for restoring inhibitory circuits in focal epilepsy, targeting epileptogenic foci through cell replacement and neuromodulation. Preclinical models in 2025 using human-induced pluripotent stem cell-derived interneurons have shown integration into hippocampal networks, reducing hyperexcitability and spontaneous seizures in rodent temporal lobe epilepsy paradigms. These grafts promote GABAergic inhibition and circuit rewiring, with early 2025 clinical trials initiating safety assessments of interneuron transplants for drug-resistant focal epilepsy in humans.00445-4)

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In conclusion, status epilepticus is likely to cause some brain injury although the frequency at which this leads to MTS and epilepsy remains uncertain.
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An EEG is critical to evaluate people with seizures and there are many different types. Ambulatory, inpatient, and other types of EEGs have pros and cons.
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Evidence-based recommendations for management of epilepsy and seizures in non-specialized health settings. Anti-seizure medicines for management of acute tonic ...<|control11|><|separator|>
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Antiseizure Medication Withdrawal in Seizure-Free Patients
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Patients with prolonged convulsions and repetitive complex partial seizures often have severe and prolonged delirium, typically lasting from hours up to 1–2 ...
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Epilepsy and Employment
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“On the Sacred Disease” is a flaming pamphlet against beliefs in supernatural causes of epilepsy. Hippocrates' statement that it has natural causes like all ...
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A review of the historical interaction between Christianity and epilepsy
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An Introduction to the Life and Work of John Hughlings Jackson
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In 1870 Jackson published a long paper on 'A study of convulsions'. It became the foundational document of modern epileptology.Jackson's Cultural and... · Some Additional Background...
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