Seizure Disorders

• Definition: a seizure is the transient clinical manifestation of abnormal, excessively synchronous cortical neuronal discharge; epilepsy is the disease state of enduring predisposition to unprovoked seizures. The International League Against Epilepsy (ILAE) operational definition is satisfied by two unprovoked seizures more than 24 hours apart, or one unprovoked seizure when recurrence risk over the next decade is comparable to that after two (roughly 60% or greater, e.g., with a causative structural lesion or epileptiform EEG), or diagnosis of a defined epilepsy syndrome.
• Why it matters: seizures are among the most common neurologic presentations to the emergency department, and the first task is always to separate a provoked (acute symptomatic) seizure — hypoglycemia, hyponatremia, alcohol withdrawal, meningitis, eclampsia — from unprovoked epilepsy, because the former is treated by correcting the insult and the latter by chronic antiseizure medication (ASM). Prolonged seizure activity is a time-critical emergency with excitotoxic neuronal injury and substantial mortality.

Epidemiology worth recalling

• Lifetime risk: roughly one in ten people has at least one seizure; approximately 1% of the population carries a diagnosis of epilepsy, consistent with the figures in Quick Facts.
• Bimodal age distribution: incidence peaks in the first year of life and again after age 60. In children, genetic/developmental and febrile causes dominate; in older adults, cerebrovascular disease is the single most common identifiable cause, followed by neurodegenerative disease and tumor.
• Seizure type by age: absence epilepsy classically presents in school-age children (girls slightly more often); juvenile myoclonic epilepsy in adolescence; mesial temporal lobe epilepsy in young to middle-aged adults and is the archetype of drug-resistant focal epilepsy.
• Drug-resistant epilepsy, defined by ILAE as failure of two appropriately chosen, adequately dosed, tolerated ASMs, affects roughly a third of patients and is the trigger for surgical referral.

Structural (focal onset until proven otherwise)

• Cerebrovascular disease: cortical infarct, intracerebral or subarachnoid hemorrhage; gliotic scar becomes an epileptogenic focus months to years later. Leading cause of new epilepsy after age 60.
• Traumatic brain injury: penetrating injury, depressed skull fracture, or intracranial hemorrhage; risk of post-traumatic epilepsy scales with severity.
• Neoplasm: low-grade gliomas and meningiomas classically present with a first seizure in an adult.
• Mesial temporal sclerosis: hippocampal sclerosis, often preceded by a prolonged childhood febrile seizure.
• Malformations of cortical development: focal cortical dysplasia, heterotopia, polymicrogyria.

Metabolic/toxic (provoked — treat the cause, not with chronic ASMs)

• Hypoglycemia, hyponatremia, hypocalcemia, hypomagnesemia, uremia, hepatic failure — destabilize membrane potential and neurotransmitter handling.
• Withdrawal states: alcohol and benzodiazepine withdrawal (loss of GABAergic tone with glutamatergic rebound, typically 6–48 hours after the last drink).
• Drugs lowering seizure threshold: bupropion, tramadol, meperidine (normeperidine), certain antibiotics (imipenem, high-dose beta-lactams, fluoroquinolones), and stimulant/cocaine intoxication. Isoniazid overdose depletes pyridoxine-dependent GABA synthesis and requires pyridoxine.

• Core imbalance: seizures arise when glutamatergic excitation (AMPA and NMDA receptors) outweighs GABAergic inhibition (GABA-A chloride channels), or when intrinsic membrane conductances — voltage-gated Na⁺, K⁺, and Ca²⁺ channels — favor depolarization. Any insult that removes inhibition or adds excitation can produce the same final common pathway.
• Paroxysmal depolarizing shift: within a focus, a group of neurons undergoes a prolonged Ca²⁺-mediated depolarization crowned by a burst of Na⁺-dependent action potentials. Normally, surrounding GABAergic interneurons create surround inhibition that contains the burst — this is why a focal seizure can remain focal and why the interictal EEG shows an isolated spike.
• Propagation and generalization: when surround inhibition fails, the discharge recruits adjacent cortex and then commissural and thalamocortical pathways, producing bilateral tonic–clonic activity with loss of consciousness. Spread along the precentral motor homunculus produces the Jacksonian march; spread to bilateral networks explains why a focal seizure can evolve to a bilateral tonic–clonic seizure.
• Absence seizures are a different circuit: abnormal oscillation in thalamocortical relay neurons driven by T-type calcium channels in the reticular thalamic nucleus generates the 3 Hz generalized spike-and-wave discharge and abrupt, brief loss of awareness without postictal state. This is precisely why ethosuximide, a T-type Ca²⁺ channel blocker, is uniquely effective here.
• Epileptogenesis: repeated or prolonged seizures cause excitotoxic Ca²⁺ influx and selective neuronal loss (hippocampal CA1 and hilar neurons are most vulnerable), followed by reactive gliosis and mossy fiber sprouting that creates recurrent excitatory circuits — the histologic substrate of mesial temporal sclerosis and the self-perpetuating cycle referenced in Key Mechanisms.
• Postictal findings: neuronal metabolic exhaustion plus active inhibition explains postictal confusion and Todd paralysis; intense muscle activity with anaerobic metabolism explains transient lactic acidosis and elevated creatine kinase.
• Benzodiazepine resistance in status: sustained seizing internalizes synaptic GABA-A receptors while trafficking NMDA receptors to the membrane, so efficacy of benzodiazepines falls with time — the mechanistic argument for treating status early.

Generalized tonic-clonic (the stem's default)

• Abrupt loss of consciousness with tonic stiffening then rhythmic clonic jerking, typically lasting 1–2 minutes; a cry at onset reflects forced expiration through a closed glottis.
• Lateral tongue biting, urinary incontinence, cyanosis: tongue laceration on the side of the tongue is far more specific for seizure than tip-biting; bladder incontinence reflects loss of descending sphincter control.
• Postictal confusion, headache, and myalgia lasting minutes to hours — the single most useful feature separating seizure from syncope, in which recovery is nearly immediate.

Focal seizures

• Focal aware (formerly simple partial): preserved awareness; motor march up the homunculus, or sensory/autonomic/psychic symptoms. An aura is itself a focal aware seizure.
• Focal impaired awareness (temporal lobe): rising epigastric sensation, déjà vu, olfactory hallucination, then a blank stare with oral and manual automatisms (lip-smacking, picking) and postictal aphasia if dominant hemisphere.
• Todd paralysis: transient focal weakness after the seizure, mimicking stroke.

Generalized non-convulsive

• Absence: brief lapses many times daily, often precipitated by hyperventilation in the office, with no postictal state — frequently misattributed to inattention or daydreaming in a school-age child with falling grades.
• Myoclonic: early-morning jerks of the arms causing dropped cereal bowls in an adolescent (juvenile myoclonic epilepsy), provoked by sleep deprivation and alcohol.
• Atonic: sudden loss of tone with head drop or fall, seen with Lennox-Gastaut.

Step 2 — exclude provoked causes at the bedside

• Immediate: fingerstick glucose in every patient.
• Laboratory: sodium, calcium, magnesium, renal and hepatic function, CBC, toxicology screen, and a pregnancy test in patients of childbearing potential. A transient anion-gap lactic acidosis and elevated creatine kinase support a true convulsion.
• Lumbar puncture if fever, meningismus, immunocompromise, or persistent altered mental status — after imaging when focal deficit or papilledema is present.

Step 4 — EEG (the confirmatory study)

• Interictal epileptiform discharges (spikes, sharp waves, spike-and-wave complexes) support epilepsy and, per AAN/AES, roughly double the risk of recurrence after a first unprovoked seizure — which is what converts "one seizure" into a treatable diagnosis of epilepsy.
• A normal routine EEG never excludes epilepsy; yield rises with early recording, sleep deprivation, repeat studies, and activation by hyperventilation or photic stimulation.
• Characteristic patterns: generalized 3 Hz spike-and-wave in absence; 4–6 Hz polyspike-and-wave in juvenile myoclonic epilepsy; hypsarrhythmia in infantile spasms; slow (<2.5 Hz) spike-wave in Lennox-Gastaut; anterior temporal sharp waves in mesial temporal lobe epilepsy.
• Continuous or emergent EEG is indicated for unexplained persistent coma or failure to return to baseline after a convulsion, to detect nonconvulsive status epilepticus.

Immediate stabilization of an actively seizing patient

• ABCs and glucose: lateral decubitus positioning, oxygen, suction, IV access, fingerstick glucose with dextrose (plus thiamine before or with glucose in alcohol use disorder) and correction of sodium, calcium, or magnesium.
• Status epilepticus (≥5 minutes of continuous activity or recurrent seizures without recovery) follows the American Epilepsy Society 2016 guideline: first phase is a benzodiazepine — lorazepam IV, midazolam 10 mg IM when no IV access, or diazepam. Underdosing benzodiazepines is the most common error.
• Second phase (AES 2016): a non-benzodiazepine ASM given IV — fosphenytoin, valproate, or levetiracetam; the ESETT trial found no difference in efficacy among these three, so choose by comorbidity (avoid valproate in hepatic disease and pregnancy; avoid fosphenytoin with hypotension or heart block).
• Refractory status: intubation and continuous infusion anesthesia with midazolam, propofol, or pentobarbital under continuous EEG, in line with Neurocritical Care Society recommendations.

Chronic therapy

• When to start: per AAN/AES, ASMs after a first unprovoked seizure reduce short-term recurrence but do not clearly change long-term remission — start when an epileptiform EEG, structural lesion, nocturnal event, or unacceptable recurrence risk is present. A truly provoked seizure is treated by fixing the provocation.
• Drug selection follows seizure type as outlined in the article's First-Line Treatment table; monotherapy at an adequate dose is the goal, escalating dose before adding a second agent.
• Drug-resistant epilepsy (two failed appropriate ASMs, ILAE definition): refer for video-EEG and surgical evaluation. Anterior temporal lobectomy for mesial temporal sclerosis is superior to continued medical therapy in randomized data. Non-resective options include laser interstitial thermal ablation, vagus nerve stimulation, responsive neurostimulation, and the ketogenic diet (especially in children and glucose transporter/pyruvate dehydrogenase deficiency).

Contraindications and cautions

• Carbamazepine, oxcarbazepine, phenytoin, and gabapentin can worsen absence and myoclonic seizures — a favorite exam trap.
• Valproate is contraindicated in pregnancy and avoided in patients who may become pregnant without effective contraception (ACOG and AAN guidance), and in hepatic or mitochondrial POLG disease; lamotrigine and levetiracetam are preferred peripartum with folate supplementation and level monitoring, since levels fall in later pregnancy.
• Never stop an ASM abruptly; taper over weeks.

Disease-related (emergencies flagged)

• Status epilepticus — EMERGENCY: >5 minutes of seizing causes excitotoxic neuronal death, hyperthermia, rhabdomyolysis, and progressive benzodiazepine resistance; mortality rises with duration.
• Nonconvulsive status epilepticus — EMERGENCY: suspect when a patient fails to return to baseline after a convulsion or has unexplained coma; the finding that reveals it is only on EEG.
• SUDEP (sudden unexpected death in epilepsy): presumed peri-ictal cardiorespiratory and autonomic dysfunction; risk is greatest with frequent generalized tonic-clonic seizures, nocturnal seizures, and nonadherence — the reason seizure freedom is the therapeutic target.
• Injury and aspiration: tongue laceration, vertebral compression fracture, posterior shoulder dislocation (classic), burns, drowning, motor vehicle crash; aspiration pneumonia from an unprotected airway.
• Metabolic sequelae: lactic acidosis, rhabdomyolysis with myoglobinuric acute kidney injury (dark urine, markedly elevated creatine kinase), neurogenic pulmonary edema.
• Psychosocial: depression and anxiety at rates well above the general population, cognitive decline with refractory epilepsy, and driving restrictions.

Treatment-related

• Phenytoin/fosphenytoin: zero-order kinetics with unpredictable toxicity (nystagmus → ataxia → confusion), gingival hyperplasia, hirsutism, cerebellar atrophy, megaloblastic anemia from folate interference, DRESS, and purple glove syndrome with IV infiltration.
• Carbamazepine: agranulocytosis and aplastic anemia, SIADH-mediated hyponatremia, and **SJS/TEN in HLA-B*1502 carriers** — the FDA advises testing patients of Southeast Asian ancestry before starting.
• Valproate: hepatotoxicity, pancreatitis, hyperammonemic encephalopathy, thrombocytopenia, weight gain, tremor, and neural tube defects with in utero exposure.
• Lamotrigine: SJS/TEN — EMERGENCY, risk driven by rapid titration and co-administration with valproate (which inhibits its glucuronidation).
• Levetiracetam: irritability, agitation, and mood disturbance.
• Topiramate/zonisamide: nephrolithiasis, metabolic acidosis, word-finding difficulty, weight loss, acute angle-closure glaucoma.
• Vigabatrin: irreversible peripheral visual field constriction requiring scheduled perimetry.
• Enzyme inducers (phenytoin, carbamazepine, phenobarbital) accelerate vitamin D and hormone metabolism → osteoporosis and oral contraceptive failure.

• Glucose first, always: in any seizing or postictal patient the single best next step before advanced workup is a fingerstick glucose, then electrolytes and toxicology. Hypoglycemia and hyponatremia are the provoked causes that reverse instantly.
• Five minutes defines status epilepticus and the first drug is a benzodiazepine (lorazepam IV, or midazolam 10 mg IM when there is no IV), per the American Epilepsy Society 2016 guideline; escalate to fosphenytoin, valproate, or levetiracetam, which the ESETT trial showed are equivalent.
• 3 Hz spike-and-wave provoked by hyperventilation = absence, and ethosuximide (T-type Ca²⁺ channel blocker) is first line. The distractor is carbamazepine or phenytoin — sodium channel blockers worsen absence and myoclonic seizures.
• Lateral tongue bite plus postictal confusion favors seizure; instant recovery favors syncope; normal EEG during a typical spell favors psychogenic nonepileptic seizures, diagnosed definitively by video-EEG. A normal routine EEG alone never excludes epilepsy.
• Todd paralysis — transient postictal focal weakness — is the classic stroke mimic; look for a preceding witnessed convulsion before attributing new hemiparesis to infarct.
• Prolonged febrile seizure in childhood → mesial temporal sclerosis → drug-resistant temporal lobe epilepsy, the association most often tested, and the leading indication for anterior temporal lobectomy once two appropriate medications fail (ILAE definition of drug resistance).
• Pregnancy: valproate is teratogenic and contraindicated; lamotrigine and levetiracetam are preferred, with folate supplementation and level monitoring because clearance rises in the second and third trimesters. Do not confuse a seizure in late pregnancy with epilepsy — eclampsia is treated with magnesium sulfate.
• Never stop an antiseizure medication abruptly — withdrawal can precipitate status epilepticus even after years of seizure freedom.

• Seizure = abnormal neuronal firing; epilepsy = tendency to recurrent seizures (≥2 unprovoked seizures)
• ~10% of population experiences a seizure; 1-2% have epilepsy
• EEG is gold standard diagnostic test; normal EEG does NOT exclude seizures
• Status epilepticus = continuous or recurrent seizures >5 minutes; medical emergency with high mortality
• Pregnancy increases seizure frequency by 25-30% due to altered antiepileptic drug (AED) metabolism

1. 1.Confusing seizures with syncope/pseudoseizures — Seizures have abnormal EEG, post-ictal confusion, tongue biting, and incontinence; syncope has rapid recovery; pseudoseizures lack EEG changes and are stress-related.

1. 1.Starting AEDs after a single provoked seizure — Only treat if unprovoked recurrent seizures (epilepsy diagnosis) OR high recurrence risk; single provoked seizure does NOT require AED therapy.

1. 1.Abruptly stopping AEDs — Withdrawal can precipitate status epilepticus; always taper gradually over weeks even if seizure-free for years.