Epilepsy

Overview

• Definition: epilepsy is a disease of the brain defined by at least two unprovoked seizures occurring more than 24 hours apart, or one unprovoked seizure together with a recurrence risk similar to that after two unprovoked seizures (at least 60%).
• Not the same as a seizure: a single seizure is a clinical event; epilepsy is the underlying disease of recurrent unprovoked seizures, and a single provoked seizure from an acute, reversible cause (fever, hypoglycemia, alcohol withdrawal) does not establish epilepsy.
• Classification by onset: seizures are divided into focal (one hemisphere) and generalized (both hemispheres from onset), a distinction that drives both antiepileptic drug (AED) selection and the search for a structural or genetic cause.
• Etiologic range: epilepsy can be structural (mesial temporal sclerosis, cortical dysplasia, tumor, prior stroke), genetic, or unknown, particularly with a normal brain MRI.
• Chronic disease: most patients require ongoing AED therapy, seizure-precaution counseling, and comorbidity screening.

Epidemiology

• Bimodal age distribution: new-onset epilepsy incidence peaks in early childhood and again over age 60, now the fastest-growing group of newly diagnosed patients.
• Temporal lobe epilepsy is the most common adult-onset focal epilepsy, frequently tied to mesial temporal sclerosis and hippocampal atrophy.
• Juvenile myoclonic epilepsy is the most common idiopathic generalized epilepsy in adults, onset typically in the teens to twenties.
• Recurrence risk after a first unprovoked seizure is approximately 40% over 2 years, falling to 20% to 30% with normal MRI/EEG and no risk factors.
• Older adults have a higher recurrence risk after a first seizure (50% to 60%) than younger adults (40%), driven largely by stroke and dementia.

Risk factors

• Prior brain trauma, meningitis, or stroke: structural cortical injury is a major risk factor for later epilepsy, though an acute symptomatic seizure within the first week after such an injury does not itself establish the diagnosis.
• Mesial temporal sclerosis, cortical dysplasia, cavernous malformation, or brain tumor: structural lesions on MRI are common causes of focal epilepsy.
• Family history of epilepsy: relevant for idiopathic generalized epilepsies, which often have complex polygenic inheritance.
• Significant EEG or MRI abnormality after a first seizure: raises recurrence risk to at least 60%, the treatment threshold.
• Perinatal brain injury or cerebral palsy: an established risk factor for childhood-onset epilepsy.
• Sleep deprivation, alcohol, and stress: classic triggers in juvenile myoclonic epilepsy ("college seizures").

Pathophysiology

• Focal epilepsy arises from a discrete hyperexcitable, abnormally synchronized cortex area, from mesial temporal sclerosis, malformation, or old injury, generating a focus that can remain localized or secondarily generalize.
• Idiopathic generalized epilepsy reflects diffuse, often channelopathy-driven network hyperexcitability without a focal structural lesion.
• Provoking factors versus triggers: a provoking factor (toxin, metabolic derangement, acute injury) can cause a seizure with or without underlying epilepsy and, if reversible, does not establish the diagnosis; a trigger (sleep deprivation, alcohol, stress) in pre-existing epilepsy lowers the seizure threshold but does not itself cause epilepsy.
• Seizure spread and postictal state: focal discharge can propagate to a tonic-clonic seizure, after which cortical inhibition produces postictal confusion and fatigue lasting hours.
• AED mechanism: most AEDs dampen hyperexcitability through sodium or calcium channel blockade or enhanced GABAergic inhibition, which is why treatment is chosen by seizure type rather than underlying cause.

Clinical features

• Diagnostic criteria (definition of epilepsy): at least two unprovoked seizures more than 24 hours apart, or one unprovoked seizure with a recurrence risk of at least 60% (typically from a significant structural or epileptiform EEG abnormality).
• Stereotyped seizure semiology: epileptic seizures are stereotyped from event to event in the same patient; marked variability between events suggests an alternative diagnosis such as functional seizures.
• Focal aware seizures (auras): localized symptoms by region of onset, such as an epigastric rising sensation, déjà vu, or fear with temporal lobe onset, or focal motor jerking with frontal onset.
• Focal impaired-awareness seizures: automatisms, staring, and altered responsiveness (formerly complex partial seizures).
• Generalized tonic-clonic seizures: whole-body stiffening with an ictal cry, then rhythmic bilateral jerking lasting 1 to 3 minutes, then postictal confusion and lethargy lasting hours.
• Absence seizures: brief (under 15 seconds), abrupt-onset staring spells without postictal confusion, occurring many times daily, classically in school-age children.
• Myoclonic seizures: single, quick, subsecond jerks with preserved awareness, required for juvenile myoclonic epilepsy and often unrecognized until a tonic-clonic seizure prompts evaluation.
• Todd paralysis: transient postictal focal weakness after a focal-onset seizure, supporting a focal rather than primary generalized origin.

Differential diagnosis

• Seizure (single, provoked): an isolated seizure from an acute reversible cause (fever, hypoglycemia, alcohol or benzodiazepine withdrawal, acute head trauma) does not meet the definition of epilepsy and is not treated with long-term AEDs once the provoking factor resolves.
• Status epilepticus: a prolonged or repetitive seizure without return to baseline is a life-threatening emergency and a possible complication of epilepsy, not itself the underlying diagnosis.
• Febrile seizure: occurs in a young child with fever and no CNS infection or prior afebrile seizure; a single simple febrile seizure does not establish epilepsy.
• Syncope (including convulsive syncope): a prodrome of lightheadedness and brief (under 1 minute) loss of consciousness with rapid return to normal mentation, versus the longer duration and postictal confusion of a tonic-clonic seizure.
• Functional seizures: asynchronous, variable, often prolonged (over 5 minutes) events with closed or resisting eyelids and a normal postictal state, confirmed by video EEG with no ictal correlate.
• Migraine with aura: visual or sensory symptoms evolve over minutes and are typically followed by headache, unlike the abrupt onset of a focal seizure aura.
• Transient ischemic attack: negative symptoms (weakness, numbness, vision loss) rather than the positive symptoms (jerking, tingling, flashing lights) of a seizure.
• Sleep disorders (parasomnias, REM behavior disorder): nocturnal events lacking stereotyped semiology and an epileptiform EEG correlate.
• Movement disorders (tics, paroxysmal dyskinesia): episodic abnormal movements without loss of awareness or an EEG correlate.
• Toxic-metabolic encephalopathy: fluctuates with the underlying derangement rather than occurring as discrete stereotyped events.

Diagnosis

• Establishing basis: epilepsy is diagnosed clinically by meeting the seizure-recurrence definition (two unprovoked seizures more than 24 hours apart, or one unprovoked seizure with at least a 60% recurrence risk), based primarily on a detailed history from the patient and witnesses.
• First, obtain a detailed history to distinguish a true seizure from a nonepileptic mimic, characterize the semiology, and determine whether the event was provoked or unprovoked.
• Then obtain brain MRI in every patient with a first seizure, with coronal T2/FLAIR and thin-slice T1 sequences through the hippocampus given the frequency of temporal lobe epilepsy; head CT is used first only to rapidly exclude hemorrhage.
• Obtain outpatient EEG for epileptiform abnormalities (focal sharp waves or generalized spike-and-wave discharges); a single routine EEG is only 40% to 50% sensitive, so a normal study does not exclude epilepsy.
• If the diagnosis remains uncertain after routine EEG and imaging, or events do not respond to treatment, refer for video EEG monitoring in an epilepsy unit, the gold standard for capturing and classifying events.
• Determine the 2-year recurrence risk to guide treatment: approximately 20% to 30% with no risk factors and normal MRI/EEG (treatment withheld), versus at least 60% with two unprovoked seizures or one seizure plus a significant abnormality (treatment recommended).

Clinical pearl. Video EEG capturing the actual event is the only way to reliably distinguish epilepsy from its most common mimics, syncope and functional seizures; when the diagnosis is uncertain or treatment is failing, refer early rather than escalating antiepileptic drug therapy empirically.

Management

• First, determine whether treatment is indicated: withhold AED therapy after a single unprovoked seizure with normal MRI and EEG and no risk factors (recurrence risk 20% to 30%), and start AED therapy once the recurrence risk reaches at least 60% (two unprovoked seizures, or one seizure with a major MRI or EEG abnormality).
• Choose the first AED by seizure type, not by cause:
  • focal seizures: lamotrigine or levetiracetam preferred first-line
  • generalized seizures: levetiracetam, lamotrigine, or valproate, with valproate avoided in women of childbearing potential when possible
  • absence seizures specifically: ethosuximide, if tonic-clonic seizures are not also present
• If seizures continue despite an adequately dosed first AED, switch to or add a second appropriately chosen agent rather than empirically escalating the first drug alone.
• If two adequately dosed, appropriately chosen AEDs fail, the patient has drug-resistant epilepsy and should be referred to an epilepsy center for video EEG monitoring and surgical evaluation, since the chance of freedom from a third AED is under 10%.
• In selected surgical candidates, particularly temporal lobe epilepsy from mesial temporal sclerosis, resection achieves seizure freedom in 60% to 70%; vagus nerve stimulation and the ketogenic diet are palliative when resection is not feasible.
• If a seizure becomes prolonged (5 minutes or more) or repetitive without return to baseline, treat as status epilepticus per that protocol; this is the one situation in which epilepsy management becomes a true emergency.
  • lorazepam 0.1 mg/kg IV (maximum 4 mg), repeat once after 5 to 10 minutes if ongoing
  • then load levetiracetam 60 mg/kg IV once (maximum 4500 mg) or fosphenytoin if seizure continues
• In older adults and in pregnancy, prefer levetiracetam, lamotrigine, or gabapentin, which are better tolerated and no less effective than older AEDs; avoid valproic acid, phenobarbital, phenytoin, and topiramate when possible given higher rates of adverse effects, teratogenicity, or cognitive impairment.
• Reassess for AED taper after 2 to 5 years of seizure freedom in appropriate candidates, avoiding taper in juvenile myoclonic epilepsy or when major risk factors for recurrence remain.

Complications

• Sudden unexpected death in epilepsy (SUDEP): risk is approximately 1 in 1000 overall, rising to approximately 1 in 100 in drug-resistant epilepsy, particularly with uncontrolled tonic-clonic seizures and multiple AEDs.
• Status epilepticus: the most immediately life-threatening complication, with risk of hypoxic injury, aspiration, and death if not treated promptly.
• Injury and drowning risk: seizures during driving, swimming, or bathing carry substantial injury risk, driving seizure-precaution counseling.
• AED adverse effects: rash (including Stevens-Johnson syndrome with rapid lamotrigine titration), mood change, osteoporosis with enzyme-inducing AEDs and valproic acid, and teratogenicity with older agents.
• Psychiatric comorbidity: depression, anxiety, and suicidality are more common in epilepsy and a class warning of AEDs, requiring ongoing screening.
• Cognitive and psychosocial impact: memory difficulties, driving restriction, and employment limitations add substantially to disease burden.

Prognosis

• Most patients achieve good seizure control with one or two appropriately chosen AEDs.
• Drug-resistant epilepsy affects a minority but carries higher morbidity, including SUDEP risk approaching 1 in 100.
• Temporal lobe epilepsy from mesial temporal sclerosis responds particularly well to surgery, with 60% to 70% achieving seizure freedom.
• Juvenile myoclonic epilepsy is usually well controlled but typically requires lifelong AED therapy given a high relapse rate off medication.
• Most women with epilepsy have normal, healthy pregnancies on levetiracetam or lamotrigine, with malformation rates approaching the general population.
• The best predictor of seizure control during pregnancy is seizure frequency in the preceding 9 to 12 months.

Prevention

• Preconception counseling and folate supplementation should be offered to all women with epilepsy of childbearing potential.
• Avoid known seizure-threshold-lowering drugs (tramadol, meperidine, bupropion, fluoroquinolones, carbapenems, cefepime) whenever an alternative exists.
• Seizure precaution counseling, including driving restriction (typically 3 to 12 months seizure-free by state law) and avoiding unsupervised swimming, tub bathing, heights, and open flames, should follow any seizure.
• Bone health monitoring (bone density testing, calcium and vitamin D) is recommended with chronic valproic acid or enzyme-inducing AED use.
• Home safety planning for SUDEP risk reduction (bed monitors, shared bedrooms, adherence) should be discussed openly in drug-resistant epilepsy.

Key points

• Epilepsy requires two unprovoked seizures more than 24 hours apart, or one with at least a 60% recurrence risk; a single provoked seizure is not epilepsy.
• AED choice is guided by seizure type, not underlying cause; levetiracetam and lamotrigine are preferred first-line for most adults.
• Drug-resistant epilepsy is failure of two adequately dosed AEDs and warrants referral for surgical evaluation.
• Status epilepticus is a life-threatening complication and emergency, not the diagnosis itself.
• SUDEP risk is approximately 1 in 1000 overall and 1 in 100 in drug-resistant epilepsy.
• Levetiracetam and lamotrigine are preferred in older adults and pregnancy; valproic acid, phenobarbital, and phenytoin should be avoided when possible.