Clinical Approach to Seizure

Comprehensive Practical Framework

1
Symptom Overview
Overview
2
Pathophysiology
Mechanism
3
History Taking
History
4
Physical Examination
Examination
5
Differential Diagnosis
Differential
6
Investigations
Workup
7
Clinical Decision-Making
Algorithm
8
Pearls and Pitfalls
Summary

1. Symptom Overview

Understanding the clinical significance and classification of seizures

Seizures represent one of the most common neurological emergencies, affecting approximately 8-10% of the general population who will experience at least one seizure during their lifetime. Epilepsy, defined as recurrent unprovoked seizures, has a prevalence of 0.5-1% worldwide, with approximately 3 million adults in the United States living with active epilepsy. Seizures account for approximately 1-2% of all emergency department visits and represent a significant source of morbidity, mortality, and healthcare expenditure. The risk of sudden unexpected death in epilepsy (SUDEP) occurs in approximately 1 per 1,000 patients with epilepsy per year, making accurate diagnosis and management critically important.

Definition

A seizure is a transient occurrence of signs and/or symptoms resulting from abnormal, excessive, or synchronous neuronal activity in the brain. This paroxysmal electrical disturbance may manifest as alterations in motor activity, sensation, behavior, awareness, or autonomic function. Epilepsy is defined as: (1) at least two unprovoked seizures occurring more than 24 hours apart; (2) one unprovoked seizure with a probability of further seizures similar to the general recurrence risk after two unprovoked seizures (≥60%) over the next 10 years; or (3) diagnosis of an epilepsy syndrome.

Key Epidemiology

Lifetime risk of seizure: 8-10% of the general population
Prevalence of epilepsy: 0.5-1% (approximately 50 million people worldwide)
Incidence: Bimodal distribution — highest in children under 1 year and adults over 65 years
First unprovoked seizure recurrence risk: 40-50% within 2 years
Status epilepticus mortality: 15-22% in adults

Classification by Seizure Type (ILAE 2017)

Category	Onset	Characteristics	Clinical Significance
Focal Onset	One hemisphere	Aware or impaired awareness; motor or non-motor onset; may evolve to bilateral tonic-clonic	Suggests localized structural or functional abnormality; amenable to surgical evaluation
Generalized Onset	Both hemispheres simultaneously	Motor (tonic-clonic, tonic, clonic, myoclonic, atonic) or non-motor (absence)	Often genetic etiology; typically responds to broad-spectrum antiseizure medications
Unknown Onset	Cannot be determined	Insufficient information or unwitnessed event	Requires further evaluation; may be reclassified with additional data

Classification by Etiology

Provoked (Acute Symptomatic) Seizures

Seizures occurring in close temporal relationship with an acute systemic, metabolic, or central nervous system insult. These do not constitute epilepsy and typically do not require long-term antiseizure medication.

Metabolic derangements (hypoglycemia, hyponatremia, uremia)
Drug toxicity or withdrawal (alcohol, benzodiazepines)
Acute head trauma (within 7 days)
Acute stroke (within 7 days)
Central nervous system infection
Fever (febrile seizures — pediatric consideration)

Unprovoked Seizures

Seizures occurring without an identifiable acute precipitant. Two or more unprovoked seizures define epilepsy and typically warrant long-term antiseizure medication.

Structural: Remote stroke, traumatic brain injury, tumor, vascular malformation
Genetic: Known or presumed genetic mutation
Infectious: Post-encephalitic, neurocysticercosis
Metabolic: Inborn errors of metabolism
Immune: Autoimmune encephalitis
Unknown: No identifiable etiology

Classification by Duration and Severity

Category	Duration	Clinical Features	Management Implications
Self-limited seizure	Less than 5 minutes	Spontaneous termination; post-ictal recovery	Supportive care; investigate if first seizure or change in pattern
Prolonged seizure	5-30 minutes	Requires intervention for termination	Administer benzodiazepines; prepare for escalation
Status epilepticus	Greater than 5 minutes (convulsive) or greater than 10 minutes (non-convulsive)	Ongoing seizure activity or recurrent seizures without return to baseline	Medical emergency — aggressive treatment protocol; high morbidity and mortality
Refractory status epilepticus	Persists despite first and second-line treatment	Continued seizures after adequate benzodiazepine and antiseizure medication	Anesthetic agents; intensive care unit admission; continuous electroencephalography monitoring

Focal Seizure Semiology by Lobe of Origin

Lobe	Common Manifestations	Distinguishing Features
Temporal	Aura (epigastric rising, déjà vu, fear), automatisms (oral, manual), impaired awareness	Most common focal epilepsy in adults; often medication-resistant; surgical candidate
Frontal	Brief, frequent, nocturnal; hypermotor movements, fencing posture, vocalization	Rapid secondary generalization; often bizarre movements mistaken for psychogenic events
Parietal	Sensory symptoms (tingling, numbness), distorted body image, spatial disorientation	Less common; may have negative symptoms (loss of awareness of body part)
Occipital	Visual phenomena (flashing lights, colors, formed hallucinations), eye deviation, ictal blindness	May spread anteriorly causing temporal or frontal features; differentiate from migraine aura

Generalized Seizure Subtypes

Type	Motor Features	Duration	Associated Syndromes
Generalized tonic-clonic	Tonic stiffening followed by clonic jerking; loss of consciousness	1-3 minutes typically	Juvenile myoclonic epilepsy, genetic generalized epilepsies
Absence	Behavioral arrest, staring, subtle automatisms; abrupt onset and offset	5-30 seconds	Childhood absence epilepsy, juvenile absence epilepsy
Myoclonic	Brief, shock-like jerks; usually bilateral upper extremities	Less than 1 second	Juvenile myoclonic epilepsy, progressive myoclonic epilepsies
Atonic	Sudden loss of muscle tone; drop attacks	1-2 seconds	Lennox-Gastaut syndrome, Dravet syndrome
Tonic	Sustained muscle contraction; may cause falls	10-60 seconds	Lennox-Gastaut syndrome
Clonic	Rhythmic jerking without preceding tonic phase	Variable	Less common in adults

Key Concept: The Critical First Questions

Was this truly a seizure? — Differentiate from syncope, psychogenic events, movement disorders, and other mimics
If seizure, was it provoked or unprovoked? — Determines need for long-term antiseizure medication
What is the seizure type and likely localization? — Guides further workup and treatment selection
Is this an emergency? — Identify status epilepticus, acute symptomatic causes requiring urgent intervention

2. Pathophysiology and Mechanisms

Understanding the underlying mechanisms of seizure generation and propagation

Seizures arise from an imbalance between excitatory and inhibitory neuronal activity, resulting in hypersynchronous electrical discharges. Understanding the mechanisms of seizure generation (ictogenesis) and the development of epilepsy (epileptogenesis) is essential for rational treatment selection and recognizing why certain conditions predispose to seizures. The fundamental principle is that anything causing excessive excitation, reduced inhibition, or abnormal neuronal connectivity can lower the seizure threshold.

Normal Excitation-Inhibition Balance

Component	Excitatory System	Inhibitory System
Primary neurotransmitter	Glutamate	Gamma-aminobutyric acid (GABA)
Key receptors	NMDA, AMPA, kainate receptors	GABA-A (ionotropic), GABA-B (metabotropic)
Ion channel effect	Sodium and calcium influx → depolarization	Chloride influx → hyperpolarization
Clinical relevance	Excessive glutamate activity causes excitotoxicity and seizures	GABA enhancement is the mechanism of benzodiazepines and barbiturates

Mechanisms of Seizure Generation (Ictogenesis)

Increased Excitation

Glutamate excess: Hypoxia, hypoglycemia, trauma

Sodium channel dysfunction: Gain-of-function mutations, drug toxicity

Calcium channel abnormalities: Enhanced calcium influx promotes depolarization

Clinical examples: Traumatic brain injury, pro-convulsant medications, genetic channelopathies

Decreased Inhibition

GABA deficiency: Pyridoxine deficiency, isoniazid toxicity

GABA-A receptor dysfunction: Benzodiazepine/alcohol withdrawal

Chloride gradient disruption: Altered chloride transporters

Clinical examples: Alcohol withdrawal seizures, benzodiazepine withdrawal, anti-GABA receptor antibodies

Abnormal Connectivity

Synaptic reorganization: Mossy fiber sprouting in hippocampal sclerosis

Gliosis: Astrocyte dysfunction, impaired glutamate clearance

Network changes: Altered thalamocortical circuits

Clinical examples: Mesial temporal sclerosis, post-traumatic epilepsy, cortical dysplasia

Cellular Mechanisms of Seizure Activity

Mechanism	Description	Clinical Relevance
Paroxysmal depolarizing shift (PDS)	Large, prolonged depolarization in a group of neurons leading to burst firing	The cellular hallmark of epileptiform activity; represents the “building block” of seizures
Hypersynchronization	Simultaneous firing of large neuronal populations due to enhanced gap junctions and ephaptic transmission	Creates the large-amplitude electroencephalography signals seen during seizures
Failure of surround inhibition	Normally, excited neurons activate surrounding inhibitory interneurons to contain spread	When inhibition fails, seizure activity propagates to adjacent cortex
Kindling	Repeated subthreshold stimulation eventually produces spontaneous seizures	Explains progressive worsening of some epilepsies; “seizures beget seizures”

Ion Channels and Their Role in Seizures

Channel Type	Normal Function	Dysfunction Effect	Associated Conditions/Drugs
Voltage-gated sodium channels	Action potential initiation and propagation	Gain-of-function → hyperexcitability; Loss-of-function → can also cause seizures via interneuron dysfunction	SCN1A mutations (Dravet syndrome); phenytoin, carbamazepine, lamotrigine block these channels
Voltage-gated calcium channels	Neurotransmitter release, dendritic integration	T-type channel abnormalities → absence seizures	Ethosuximide blocks T-type calcium channels; effective for absence seizures
Voltage-gated potassium channels	Repolarization, setting resting membrane potential	Loss-of-function → prolonged depolarization, repetitive firing	KCNQ2/3 mutations (benign familial neonatal seizures); retigabine opens these channels
GABA-A receptors (ligand-gated chloride channels)	Fast inhibitory synaptic transmission	Reduced function → decreased inhibition	Benzodiazepines and barbiturates enhance GABA-A function; withdrawal causes seizures

How Metabolic Derangements Cause Seizures

Condition	Mechanism	Threshold/Clinical Notes
Hypoglycemia	Glucose is the primary neuronal fuel; deficiency causes ATP depletion, failure of Na+/K+-ATPase, and membrane depolarization	Usually occurs below 40 mg/dL; may cause focal or generalized seizures
Hyponatremia	Osmotic swelling of neurons increases membrane excitability; rate of change is critical	Risk increases significantly below 120 mEq/L or with rapid decline; correct slowly to avoid osmotic demyelination
Hypocalcemia	Calcium stabilizes neuronal membranes; low levels lower threshold for action potential generation	Usually with ionized calcium below 0.8 mmol/L; may see tetany before seizures
Hypomagnesemia	Magnesium blocks NMDA receptors; deficiency enhances glutamatergic transmission	Often coexists with hypocalcemia; important in eclampsia (magnesium sulfate is treatment of choice)
Uremia	Accumulation of uremic toxins, electrolyte disturbances, and metabolic acidosis all contribute	Seizures occur in severe renal failure; myoclonus is also common
Hepatic encephalopathy	Ammonia toxicity, false neurotransmitters, altered GABA-ergic tone	Seizures less common than in uremia; asterixis and altered consciousness more typical

Drug and Toxin Mechanisms

Pro-convulsant Mechanisms

GABA antagonism: Isoniazid (depletes pyridoxine → reduced GABA synthesis), fluoroquinolones, beta-lactams at high doses
Enhanced glutamate: Tramadol, certain synthetic cannabinoids
Sodium channel activation: Local anesthetic toxicity, bupropion
Withdrawal syndromes: Alcohol, benzodiazepines, barbiturates (GABA-A receptor downregulation)
Lowered threshold: Theophylline, sympathomimetics, anticholinergics

Anticonvulsant Mechanisms

Sodium channel blockade: Phenytoin, carbamazepine, lamotrigine, lacosamide
GABA enhancement: Benzodiazepines (allosteric modulators), barbiturates, vigabatrin (GABA transaminase inhibitor)
Calcium channel blockade: Ethosuximide (T-type), pregabalin/gabapentin (alpha-2-delta subunit)
Glutamate inhibition: Perampanel (AMPA antagonist), topiramate (partial)
Synaptic vesicle modulation: Levetiracetam (SV2A binding)

Epileptogenesis: From Brain Injury to Epilepsy

Epileptogenesis is the process by which a normal brain becomes capable of generating spontaneous, recurrent seizures. This typically involves a latent period between an initial insult and the first unprovoked seizure.

Stage	Timeline	Key Processes
Initial insult	Acute phase	Neuronal death, blood-brain barrier disruption, inflammation, excitotoxicity
Latent period	Weeks to years	Synaptic reorganization, neurogenesis, gliosis, channel expression changes, network remodeling
Chronic epilepsy	Ongoing	Spontaneous recurrent seizures, progressive changes, potential for drug resistance

Seizure Propagation Pathways

Origin	Primary Spread Pattern	Secondary Generalization
Temporal lobe	Hippocampus → entorhinal cortex → contralateral temporal lobe	Via thalamus and corpus callosum; may take 30-60 seconds to generalize
Frontal lobe	Rapid bilateral spread via corpus callosum and subcortical structures	Very rapid secondary generalization; may appear generalized from onset
Generalized onset	Thalamocortical networks involved from onset	Bilateral synchronous activity; classic 3 Hz spike-wave in absence seizures

Often Overlooked Mechanism: Autoimmune Encephalitis

Autoimmune encephalitis is an increasingly recognized cause of new-onset seizures, particularly in young adults. Antibodies against neuronal surface antigens (NMDA receptor, LGI1, CASPR2, GABA-B receptor) directly alter synaptic function. Key clinical clues: subacute onset, psychiatric symptoms, memory impairment, movement disorders, and seizures that are refractory to standard antiseizure medications. Early immunotherapy can be disease-modifying. Always consider autoimmune encephalitis in new-onset refractory status epilepticus (NORSE) of unknown etiology.

Pathophysiology of Status Epilepticus

Why Status Epilepticus Is a Medical Emergency

Prolonged seizure activity leads to progressive pathophysiological changes that make seizures harder to terminate and cause neuronal injury:

GABA-A receptor internalization: After 5-10 minutes, GABA-A receptors are internalized, reducing benzodiazepine effectiveness
NMDA receptor externalization: Enhanced glutamatergic excitation as seizures continue
Excitotoxic injury: Calcium overload leads to neuronal death, particularly in hippocampus
Systemic complications: Hyperthermia, rhabdomyolysis, acidosis, cardiovascular instability
Time-dependent treatment resistance: The longer the seizure, the more refractory it becomes to treatment

3. History Taking

A comprehensive approach to eliciting the seizure history

Red Flags — Require Urgent Evaluation

Prolonged seizure (>5 minutes) — Status epilepticus; immediate treatment required
Multiple seizures without recovery — Status epilepticus; high mortality risk
First seizure with focal neurological deficit — Structural lesion (stroke, tumor, abscess)
Seizure with fever and neck stiffness — Meningitis or encephalitis
New seizure in immunocompromised patient — Central nervous system infection or malignancy

Seizure with severe headache — Subarachnoid hemorrhage, cerebral venous thrombosis
Seizure in pregnancy/postpartum — Eclampsia, posterior reversible encephalopathy syndrome, cerebral venous thrombosis
Seizure with anticoagulation or head trauma — Intracranial hemorrhage
New seizure in cancer patient — Brain metastases, paraneoplastic syndrome, leptomeningeal disease
Progressive confusion after seizure (>30 minutes) — Non-convulsive status epilepticus, Todd’s paralysis with underlying lesion

Critical Principle: The patient often has no memory of the seizure. Witness history is essential. Always attempt to contact someone who observed the event. Video recordings on smartphones are invaluable for characterizing the semiology.

Systematic History: The “SEIZURE” Approach

Use the mnemonic “SEIZURE” to ensure comprehensive history taking:

S — Setting and Start: Where were you? What were you doing? What was the very first thing that happened? Any warning or aura?
E — Evolution and Events: How did the episode progress? What movements occurred? Was consciousness affected? How long did it last?
I — Ictal details: Eye deviation? Head turning? Limb involvement (unilateral vs bilateral)? Automatisms? Incontinence? Tongue biting?
Z — Zero-in on post-ictal state: Confusion? Sleepiness? Weakness (Todd’s paralysis)? Headache? How long to return to normal?
U — Underlying causes: Sleep deprivation? Alcohol/drug use or withdrawal? Missed medications? Illness? Metabolic stressors?
R — Risk factors and past events: Prior seizures? Head injury? Stroke? Brain surgery? Family history of epilepsy? Febrile seizures as a child?
E — Effects on life: Impact on driving, work, relationships? Previous investigations and treatments?

Key Questions to Differentiate Seizures from Mimics

Feature	Suggests Epileptic Seizure	Suggests Syncope	Suggests Psychogenic Non-Epileptic Seizure
Trigger/setting	Sleep deprivation, flashing lights, alcohol withdrawal	Prolonged standing, pain, heat, emotional stress, micturition	Emotional stressor, presence of audience, medical settings
Prodrome/warning	Stereotyped aura (déjà vu, epigastric rising, fear)	Lightheadedness, tunnel vision, warmth, nausea	Variable, may be prolonged; anxiety, palpitations
Onset	Sudden; may have brief warning	Gradual onset; may be prevented by sitting/lying	Gradual; often with eyes closed
Duration	Usually 1-3 minutes (tonic-clonic)	Seconds to less than 1 minute	Often prolonged (>5 minutes); variable
Motor activity	Rhythmic, synchronous; evolves over time	Brief myoclonic jerks may occur (convulsive syncope)	Asynchronous, waxing/waning, side-to-side head movement, pelvic thrusting
Eyes	Open, deviated; pupils dilated and unreactive	Open or closed; eyes may roll up	Closed (often forcefully); resist opening
Injury	Lateral tongue bite, shoulder dislocation, facial injury	Injury from fall possible; tongue tip bite	Injury uncommon; if present, usually minor
Post-ictal state	Confusion, fatigue, headache; minutes to hours	Rapid recovery (seconds to minutes); mild fatigue	Variable; may be rapid; tearfulness common

Targeted Questions by Suspected Cause

Suspected Cause	Key Features	Ask This Question
Alcohol withdrawal	Seizure 6-48 hours after last drink; history of heavy use	“When was your last alcoholic drink? How much do you typically drink per day?”
Benzodiazepine/barbiturate withdrawal	Abrupt discontinuation; may occur later than alcohol withdrawal	“Have you recently stopped or reduced any sleeping pills, anxiety medications, or sedatives?”
Drug toxicity	New medication, overdose, drug interaction	“Have you started any new medications recently? Could you have taken too much of any medication?”
Hypoglycemia	Diabetic patient; missed meal, excess insulin	“Are you diabetic? Did you take your insulin/medication? When did you last eat?”
Sleep deprivation	Known trigger for genetic generalized epilepsies	“How many hours did you sleep last night? Have you had significant sleep loss recently?”
Medication non-adherence	Known epilepsy patient with breakthrough seizure	“Have you missed any doses of your seizure medication? Have you had any trouble getting your prescription filled?”
Central nervous system infection	Fever, headache, altered mental status, neck stiffness	“Have you had fever, severe headache, or neck pain? Any recent infections or travel?”
Structural lesion (tumor, stroke)	New focal seizure; progressive symptoms; risk factors	“Have you had any weakness, numbness, vision changes, or headaches? Any history of cancer?”
Autoimmune encephalitis	Subacute onset; psychiatric symptoms; memory problems; movement disorders	“Over the past weeks, have you noticed personality changes, memory problems, or unusual movements?”
Eclampsia	Pregnant or postpartum; hypertension; edema; proteinuria	“Are you pregnant or have you recently given birth? Any headaches, vision changes, or swelling?”

Aura Types and Their Localizing Value

Aura Type	Description	Likely Origin
Epigastric rising sensation	“A feeling rising from my stomach to my chest/throat”	Mesial temporal lobe (most common aura in temporal lobe epilepsy)
Déjà vu / Jamais vu	Intense familiarity or unfamiliarity with surroundings	Temporal lobe (hippocampus, parahippocampal gyrus)
Fear or anxiety	Sudden intense fear without external cause	Amygdala (mesial temporal lobe)
Olfactory or gustatory	Unpleasant smell (burning, feces) or taste	Mesial temporal lobe; consider uncal herniation if acute
Visual (elementary)	Flashing lights, colors, geometric shapes	Occipital lobe (primary visual cortex)
Visual (complex)	Formed hallucinations (faces, scenes)	Temporal-occipital junction
Somatosensory	Tingling, numbness; may march along body part	Parietal lobe (primary sensory cortex)
Auditory	Buzzing, ringing, or complex sounds/voices	Superior temporal gyrus

Medication and Substance History

Medications That Can Cause Seizures

Antibiotics: Fluoroquinolones (especially with renal impairment), carbapenems (imipenem), isoniazid, metronidazole (high dose)
Psychiatric medications: Bupropion, clozapine, tricyclic antidepressants (overdose), lithium toxicity
Analgesics: Tramadol, meperidine (normeperidine accumulation)
Immunosuppressants: Cyclosporine, tacrolimus (especially with hypomagnesemia)
Chemotherapy: Busulfan, cisplatin, methotrexate (intrathecal)
Local anesthetics: Lidocaine toxicity
Others: Theophylline, baclofen withdrawal, insulin (hypoglycemia)

Substances and Withdrawal

Alcohol: Withdrawal seizures 6-48 hours after last drink; heavy chronic use
Benzodiazepines: Withdrawal can be life-threatening; seizures 2-7 days after cessation
Barbiturates: Withdrawal similar to alcohol/benzodiazepines
Cocaine: Acute intoxication (sympathomimetic); may cause stroke leading to seizures
Amphetamines/MDMA: Acute intoxication; hyperthermia; hyponatremia (MDMA)
Synthetic cannabinoids: Increasingly recognized cause of seizures
GHB (gamma-hydroxybutyrate): Withdrawal can cause seizures

Relevant Past Medical and Family History

Past Medical History

Previous seizures: Type, frequency, age of onset, response to treatment
Head trauma: Especially with loss of consciousness, skull fracture, or intracranial hemorrhage
Stroke or transient ischemic attack: Major risk factor for late-onset epilepsy
Brain surgery or tumor: Surgical scars and lesions are epileptogenic
Central nervous system infection: Meningitis, encephalitis, neurocysticercosis
Perinatal complications: Hypoxic-ischemic injury, prematurity
Developmental delay: Associated with many epilepsy syndromes
Autoimmune disease: Increases risk of autoimmune encephalitis

Family History

Epilepsy: Genetic generalized epilepsies have strong familial component
Febrile seizures: Family history increases risk
Sudden unexplained death: Consider genetic cardiac arrhythmia syndromes (Long QT, Brugada) — can mimic seizures
Neurodegenerative disease: Some cause seizures (e.g., Huntington disease, Alzheimer disease)
Metabolic disorders: Mitochondrial disease, storage disorders

Social History

Occupation: Driving, operating machinery, heights (safety implications)
Driving status: Legal requirements for reporting vary by jurisdiction
Living situation: Alone vs. with others (safety concerns)

Essential Questions for the Witness

“Can you show me what the movements looked like?” (Imitation is often more accurate than description)
“Did the jerking affect both sides equally, or was one side more involved?”
“Which way did the eyes or head turn?”
“Could you get their attention during the episode? Did they respond to you?”
“Did you notice any color change — blue around the lips or pale?”
“How long did the shaking last? How long until they were back to normal?”
“Do you have any video on your phone?” (Invaluable for diagnosis)

4. Physical Examination

A systematic head-to-toe approach for seizure evaluation

Systematic Framework: The physical examination in a patient presenting with seizure serves three purposes: (1) identifying signs of ongoing seizure activity or post-ictal state, (2) detecting the underlying cause, and (3) recognizing complications of the seizure itself. Use a systematic “General → Neurological → Systemic” approach.

General Inspection

Level of consciousness: Alert, drowsy, confused, obtunded, comatose — post-ictal confusion typically resolves within 30 minutes; prolonged alteration suggests non-convulsive status epilepticus or underlying pathology
Respiratory pattern: Tachypnea (metabolic acidosis post-seizure), irregular breathing (brainstem dysfunction), stridor (airway compromise)
Skin: Cyanosis (hypoxia during seizure), diaphoresis, pallor; look for neurocutaneous stigmata (ash-leaf spots, café-au-lait macules, facial angiofibromas)
Positioning: Decorticate or decerebrate posturing suggests severe brain injury
Signs of trauma: Head lacerations, facial bruising, shoulder deformity (posterior dislocation)
Incontinence: Urinary incontinence supports but does not confirm seizure; can occur with syncope

Vital Signs

Vital Sign	What to Look For	Clinical Significance
Temperature	Fever (>38°C), hyperthermia (>40°C)	Fever suggests infection (meningitis, encephalitis); hyperthermia occurs in prolonged status epilepticus and is a poor prognostic sign
Heart rate	Tachycardia, bradycardia, irregularity	Post-ictal tachycardia is common; ictal bradycardia/asystole can occur and may cause falls (ictal syncope)
Blood pressure	Hypertension, hypotension	Severe hypertension: consider posterior reversible encephalopathy syndrome, eclampsia, hypertensive encephalopathy, intracranial hemorrhage. Hypotension: sepsis, medication toxicity
Respiratory rate	Tachypnea, apnea, irregular pattern	Post-ictal tachypnea compensates for lactic acidosis; apnea during seizure is common; persistent respiratory depression suggests ongoing seizure or drug effect
Oxygen saturation	Desaturation during or after seizure	Transient desaturation common during generalized tonic-clonic seizure; persistent hypoxia requires airway intervention
Glucose (point-of-care)	Hypoglycemia (<70 mg/dL), hyperglycemia	Hypoglycemia is a reversible cause — check immediately; hyperglycemia with ketones suggests diabetic ketoacidosis; non-ketotic hyperglycemia can cause focal seizures

Head and Neck Examination

Head

Scalp: Lacerations, hematomas, signs of trauma; palpate for skull fractures
Battle sign: Mastoid ecchymosis — basilar skull fracture
Raccoon eyes: Periorbital ecchymosis — basilar skull fracture
Hemotympanum: Blood behind tympanic membrane — basilar skull fracture
CSF leak: Clear fluid from nose (rhinorrhea) or ear (otorrhea) — skull fracture with dural tear

Neck

Meningismus: Neck stiffness, Kernig sign, Brudzinski sign — meningitis, subarachnoid hemorrhage
Carotid bruits: Cerebrovascular disease as cause of stroke-related seizures
Thyroid: Goiter, thyroidectomy scar — consider hypocalcemia (post-surgical hypoparathyroidism)
Jugular venous pressure: Elevated in heart failure (may contribute to cerebral hypoperfusion)
Lymphadenopathy: Malignancy, infection

Oral Cavity Examination

Tongue Bite: Location Matters

Lateral tongue laceration: Highly specific for generalized tonic-clonic seizure (bitten during tonic phase); look on both sides
Tip of tongue bite: Non-specific; can occur with syncope or psychogenic events
Buccal mucosa laceration: Can occur with seizure but less specific
Gingival hyperplasia: Chronic phenytoin use
Oral candidiasis: Immunocompromise, recent antibiotic or steroid use

Neurological Examination

Mental Status

Level of consciousness: Glasgow Coma Scale; document time course of improvement
Orientation: Person, place, time, situation
Attention: Digit span, serial 7s, spelling “WORLD” backwards
Language: Fluency, comprehension, naming, repetition — post-ictal aphasia suggests dominant hemisphere focus
Memory: Anterograde and retrograde amnesia for the event is expected
Behavior: Agitation, automatisms (ongoing subtle seizure activity?), psychiatric symptoms (autoimmune encephalitis)

Cranial Nerves

Cranial Nerve	Key Findings	Significance
II (Optic)	Visual field defect, papilledema	Homonymous hemianopia suggests structural lesion; papilledema indicates elevated intracranial pressure (tumor, venous thrombosis, idiopathic intracranial hypertension)
III, IV, VI (Oculomotor)	Pupil asymmetry, gaze deviation, diplopia	Persistent gaze deviation toward lesion (destructive) or away from lesion (irritative/ictal); dilated unreactive pupil suggests uncal herniation
VII (Facial)	Facial asymmetry	Central facial weakness (forehead spared) suggests contralateral hemispheric lesion; may be post-ictal (Todd’s phenomenon)
Fundoscopy	Papilledema, retinal hemorrhages	Papilledema: raised intracranial pressure. Subhyaloid hemorrhages: subarachnoid hemorrhage

Motor Examination

Tone: Increased tone may indicate upper motor neuron lesion; hypotonia in post-ictal period
Power: Test all major muscle groups; focal weakness (Todd’s paralysis) is transient and indicates focal seizure origin
Pronator drift: Sensitive test for subtle upper motor neuron weakness
Reflexes: Asymmetry suggests structural lesion; hyperreflexia with upgoing plantar response indicates upper motor neuron dysfunction
Plantar response: Extensor (Babinski sign) may be transiently present post-ictally; persistent upgoing plantar suggests structural lesion

Todd’s Paralysis (Post-ictal Paresis)

Transient focal weakness following a focal seizure, typically lasting minutes to hours (rarely up to 48 hours). It indicates the seizure originated from the contralateral motor cortex. Important: If weakness persists beyond 24-48 hours, strongly consider an acute structural lesion (stroke, tumor) rather than attributing to Todd’s phenomenon.

Sensory and Cerebellar Examination

Sensory: Hemisensory loss suggests contralateral parietal lesion
Cerebellar: Ataxia, dysmetria, nystagmus — may indicate posterior fossa lesion, chronic alcohol use, or antiseizure medication toxicity (phenytoin, carbamazepine)

Systemic Examination

Cardiovascular

Heart sounds: Murmurs may suggest endocarditis (source of embolic stroke) or structural heart disease
Rhythm: Irregularly irregular pulse suggests atrial fibrillation (stroke risk)
Peripheral pulses: Asymmetry may indicate vascular disease
Edema: Heart failure, nephrotic syndrome (may cause cerebral edema or metabolic derangements)

Respiratory

Aspiration: Focal crackles may indicate aspiration during seizure
Consolidation: Pneumonia can cause seizures via hypoxia, fever, or sepsis

Abdominal

Hepatomegaly: Liver disease (hepatic encephalopathy, alcohol abuse)
Stigmata of chronic liver disease: Spider angiomata, palmar erythema, ascites
Surgical scars: Transplant (immunosuppression), parathyroidectomy (hypocalcemia)

Skin and Extremities

Finding	Description	Associated Condition
Ash-leaf spots	Hypopigmented macules (best seen with Wood lamp)	Tuberous sclerosis complex — cortical tubers cause epilepsy
Facial angiofibromas	Red papules on nasolabial folds and cheeks	Tuberous sclerosis complex
Shagreen patch	Connective tissue nevus on lower back	Tuberous sclerosis complex
Café-au-lait macules	Light brown flat spots (>6 spots or >15 mm is significant)	Neurofibromatosis type 1 — optic gliomas, brain tumors
Port-wine stain (facial)	Vascular malformation in trigeminal distribution	Sturge-Weber syndrome — leptomeningeal angioma causes seizures
Track marks	Injection sites on arms	Intravenous drug use — infection risk, drug-related seizures
Shoulder deformity	Squared-off shoulder, limited external rotation	Posterior shoulder dislocation — classic complication of seizure

Expected Findings by Etiology

Condition	General/Vital Signs	Neurological	Other Findings
Post-ictal state (uncomplicated)	Tachycardia, mild hypertension, normal temperature	Confusion improving over minutes; may have Todd’s paralysis; possible lateral tongue bite	Urinary incontinence; muscle soreness
Status epilepticus	Tachycardia, hypertension, hyperthermia; may progress to hypotension	Ongoing convulsions or subtle motor activity; may appear comatose (non-convulsive status)	Metabolic acidosis, rhabdomyolysis
Structural lesion (tumor, stroke)	Variable; may be normal	Focal neurological deficit (hemiparesis, hemianopia, aphasia); papilledema if mass effect	May have signs of primary cancer
Meningitis/Encephalitis	Fever, tachycardia	Meningismus, altered mental status; may have focal signs in encephalitis	Rash (meningococcal); photophobia
Alcohol withdrawal	Tachycardia, hypertension, hyperthermia, diaphoresis	Tremor, agitation; may have encephalopathy; usually no focal signs	Stigmata of chronic liver disease
Metabolic (hypoglycemia, hyponatremia)	Variable; diaphoresis and tremor with hypoglycemia	Usually non-focal; may have altered consciousness	Signs of underlying cause (diabetes, heart failure)
Eclampsia	Severe hypertension, edema	May have visual disturbance, altered mental status	Pregnancy or recent delivery; proteinuria
Autoimmune encephalitis	May be normal or have low-grade fever	Psychiatric symptoms, memory impairment, movement disorders (orofacial dyskinesias, dystonia)	May have ovarian teratoma (anti-NMDA receptor encephalitis)

Important Teaching Point

A normal physical examination is common in epilepsy patients! Many patients with epilepsy, particularly those with genetic generalized epilepsy or temporal lobe epilepsy without hippocampal sclerosis, have entirely normal neurological examinations between seizures. A normal examination does not exclude significant pathology — neuroimaging and electroencephalography are essential components of the workup. However, any focal neurological finding on examination mandates urgent neuroimaging to exclude a structural lesion.

5. Differential Diagnosis

Systematic approach organized by probability and clinical features

The differential diagnosis of seizure involves two parallel considerations: (1) Was this event truly a seizure, or a seizure mimic? and (2) If it was a seizure, what is the underlying cause? The approach differs based on whether this is a first seizure or a breakthrough seizure in a patient with known epilepsy.

First Unprovoked Seizure in Adults: Etiologies

Probability	Etiology	Key Features	Red Flags
COMMON (approximately 60-70%)	Unknown/Cryptogenic	No identifiable cause after workup; normal MRI and routine EEG	None inherent; important to rule out other causes
	Remote symptomatic (prior brain injury)	History of stroke, traumatic brain injury, brain surgery; latency of months to years	New focal deficits suggest acute lesion, not remote
	Genetic generalized epilepsy	Young adult; morning myoclonus; triggered by sleep deprivation; family history	Onset after age 25 is atypical — consider structural cause
LESS COMMON (approximately 20-30%)	Brain tumor (primary or metastatic)	Progressive headache, focal deficits; seizures in 30-50% of brain tumor patients	New seizure in patient with known cancer; progressive symptoms
	Cerebrovascular disease	Acute stroke (early seizure within 7 days) or remote stroke; focal onset	New focal deficit, sudden onset
	Traumatic brain injury (acute)	Seizure within 7 days of head trauma; higher risk with penetrating injury, hemorrhage	Signs of skull fracture, altered consciousness, focal deficit
	Alcohol withdrawal	Seizure 6-48 hours after last drink; history of heavy use; usually generalized tonic-clonic	Autonomic instability, delirium tremens
UNCOMMON BUT SERIOUS (approximately 5-10%)	Central nervous system infection	Meningitis, encephalitis, brain abscess; fever, headache, altered mental status	Fever, meningismus, rapid deterioration
	Autoimmune encephalitis	Subacute onset; psychiatric symptoms, memory impairment, movement disorders	Refractory seizures, rapid cognitive decline, dyskinesias
	Cerebral venous thrombosis	Headache, seizures, focal deficits; risk factors (oral contraceptives, pregnancy, thrombophilia)	Severe headache, papilledema, hemorrhagic infarcts
	Posterior reversible encephalopathy syndrome	Severe hypertension, headache, visual disturbance, seizures; eclampsia, immunosuppressants	Severe hypertension, cortical blindness, pregnant/postpartum

Acute Symptomatic (Provoked) Seizures

Key Distinction: Provoked seizures occur in close temporal relationship with an acute insult and do not constitute epilepsy. Treatment focuses on correcting the underlying cause rather than long-term antiseizure medication.

Category	Specific Causes	Time Window	Management Focus
Metabolic	Hypoglycemia (<40 mg/dL), hyponatremia (<120 mEq/L or rapid decline), hypocalcemia, hypomagnesemia, uremia, hepatic encephalopathy	During metabolic derangement	Correct metabolic abnormality; short-term antiseizure medication if recurrent
Drug/toxin-induced	Cocaine, amphetamines, tramadol, bupropion, isoniazid, fluoroquinolones, theophylline, local anesthetic toxicity	During intoxication	Supportive care, specific antidotes if available (pyridoxine for isoniazid)
Withdrawal	Alcohol (6-48 hours), benzodiazepines (2-7 days), barbiturates, baclofen	During withdrawal period	Appropriate taper/substitution; benzodiazepines for alcohol withdrawal
Acute structural	Acute stroke (within 7 days), acute traumatic brain injury (within 7 days), intracranial hemorrhage	Within 7 days of insult	Treat underlying condition; consider short-term antiseizure medication for prevention
Infectious	Meningitis, encephalitis (especially herpes simplex virus), brain abscess, neurocysticercosis	During acute infection	Antimicrobial therapy; antiseizure medication during acute phase
Other	Eclampsia, posterior reversible encephalopathy syndrome, hypertensive encephalopathy	During acute condition	Blood pressure control, delivery in eclampsia, magnesium sulfate

Breakthrough Seizure in Known Epilepsy

Step-by-Step Approach:

Step 1: Check medication adherence — missed doses are the most common cause
Step 2: Review for precipitating factors — sleep deprivation, alcohol, illness, new medications
Step 3: Check antiseizure medication levels if applicable (phenytoin, carbamazepine, valproate, phenobarbital)
Step 4: Consider drug interactions — new medications reducing antiseizure medication efficacy
Step 5: Evaluate for new pathology if no clear precipitant — repeat neuroimaging if indicated

Cause	Frequency	Key Questions
Medication non-adherence	Most common	“Have you missed any doses? Had trouble getting your prescription?”
Sleep deprivation	Very common	“How many hours have you slept recently?”
Alcohol use	Common	“Have you been drinking alcohol? More than usual?”
Intercurrent illness	Common	“Have you been sick with fever, vomiting, or diarrhea?”
Drug interaction	Less common	“Have you started any new medications, including over-the-counter or supplements?”
Subtherapeutic drug level	Less common	Check levels; consider generic substitution, malabsorption
Disease progression	Uncommon	Consider repeat imaging if no other explanation; new structural lesion?

Seizure Mimics: The Critical Differential

Condition	Approximate Frequency	Key Distinguishing Features
Syncope (including convulsive syncope)	Most common mimic (up to 20% of “seizure” referrals)	Trigger (prolonged standing, pain); prodrome (lightheadedness, tunnel vision); brief duration (<1 minute); rapid recovery; brief myoclonic jerks may occur
Psychogenic non-epileptic seizures (PNES)	5-20% of epilepsy clinic referrals	Variable, prolonged episodes; asynchronous movements; preserved awareness despite “convulsion”; eyes closed; suggestible; emotional triggers; no post-ictal confusion
Transient ischemic attack	Less common	Negative symptoms (weakness, numbness, vision loss) rather than positive symptoms; usually no altered consciousness
Migraine with aura	Less common	Visual symptoms evolve slowly over 5-60 minutes; followed by headache; no loss of consciousness
Transient global amnesia	Uncommon	Sudden anterograde amnesia lasting hours; repetitive questioning; no other neurological deficits; full recovery
Movement disorders	Uncommon	Paroxysmal dyskinesias, tics, myoclonus; preserved consciousness; stereotyped movements
Cardiac arrhythmia	Uncommon but serious	Sudden collapse, may have brief convulsive movements; palpitations; family history of sudden death; abnormal ECG
Sleep disorders	Uncommon	REM sleep behavior disorder, parasomnia, narcolepsy with cataplexy; events occur during sleep or sleep-wake transitions
Hypoglycemia	Uncommon	Diabetic patient; confusion, diaphoresis, tremor; may progress to seizure if untreated

Anatomical Approach to Seizure Etiology

Cortical/Hemispheric

Brain tumor (primary, metastatic)

Stroke (ischemic, hemorrhagic)

Traumatic brain injury

Cortical dysplasia

Mesial temporal sclerosis

Cavernous malformation

Arteriovenous malformation

Meningeal/Infectious

Bacterial meningitis

Viral encephalitis (herpes simplex virus)

Brain abscess

Neurocysticercosis

Tuberculoma

Fungal infection (immunocompromised)

Leptomeningeal carcinomatosis

Systemic/Metabolic

Hypoglycemia

Hyponatremia

Hypocalcemia, hypomagnesemia

Uremia

Hepatic encephalopathy

Hypoxia

Thyroid storm, myxedema

Toxic/Drug-Related

Alcohol withdrawal

Benzodiazepine/barbiturate withdrawal

Cocaine, amphetamines

Medication toxicity (see drug table)

Organophosphate poisoning

Carbon monoxide poisoning

Heavy metals (lead)

Drug-Induced Seizures

Drug or Drug Class	Mechanism	Risk Factors	Management Notes
Bupropion	Dose-dependent lowering of seizure threshold; inhibits GABA	Doses >450 mg/day, bulimia, alcohol withdrawal, history of seizures	Contraindicated in patients with seizure history; avoid in eating disorders
Tramadol	Lowers seizure threshold; serotonergic effects; inhibits GABA	High doses, concomitant serotonergic drugs, history of epilepsy	Risk increases with dose; avoid in epilepsy patients if possible
Fluoroquinolones	GABA-A receptor antagonism	Renal impairment, concurrent NSAIDs, history of seizures	Risk varies by agent; avoid in patients with epilepsy if alternatives exist
Carbapenems (imipenem)	GABA antagonism; imipenem has highest risk	Renal impairment, central nervous system pathology, high doses	Meropenem has lower seizure risk; adjust dose for renal function
Isoniazid	Depletes pyridoxine (vitamin B6), reducing GABA synthesis	Overdose, chronic use without pyridoxine supplementation, malnutrition	Treat with high-dose pyridoxine (gram-for-gram of isoniazid ingested)
Tricyclic antidepressants	Sodium channel blockade (in overdose); anticholinergic effects	Overdose, therapeutic use in susceptible patients	Overdose is medical emergency; sodium bicarbonate for QRS widening
Clozapine	Dose-dependent lowering of seizure threshold	Doses >600 mg/day, rapid titration	Seizure risk 3-5% at high doses; consider prophylactic antiseizure medication
Theophylline	Adenosine receptor antagonism; stimulant effects	Toxicity (level >20 mcg/mL), drug interactions	Monitor levels; seizures may be refractory and indicate need for hemodialysis
Baclofen	Withdrawal of GABA-B agonism causes rebound excitation	Abrupt discontinuation, intrathecal pump malfunction	Never stop abruptly; withdrawal can cause status epilepticus, hyperthermia
Cyclosporine/Tacrolimus	Neurotoxicity, posterior reversible encephalopathy syndrome	High levels, hypomagnesemia, hypertension	Check levels and magnesium; may need to reduce dose or switch agents

Quick Reference: “If You See This, Think This”

Clinical Clue	Think This First	Next Step
Young adult, morning myoclonus, triggered by sleep deprivation	Juvenile myoclonic epilepsy	EEG (generalized polyspike-wave); avoid carbamazepine, phenytoin
Seizure 24-48 hours after stopping alcohol	Alcohol withdrawal seizure	Benzodiazepines; monitor for delirium tremens; thiamine
Fever, headache, confusion, temporal lobe seizures	Herpes simplex encephalitis	Empiric acyclovir immediately; lumbar puncture; MRI brain
Pregnant/postpartum with hypertension and seizure	Eclampsia	Magnesium sulfate; blood pressure control; delivery planning
Subacute psychiatric symptoms, memory loss, orofacial dyskinesias	Anti-NMDA receptor encephalitis	CSF studies, antibody panel; pelvic imaging (ovarian teratoma); immunotherapy
Known cancer patient with new focal seizure	Brain metastases	Contrast MRI brain; consider leptomeningeal disease
Recent head trauma with seizure	Acute symptomatic seizure (traumatic)	CT head; short-term antiseizure medication; neurosurgical evaluation if indicated
Focal seizure with aura of epigastric rising, déjà vu	Temporal lobe epilepsy	MRI for mesial temporal sclerosis; video-EEG if surgery candidate
Brief staring spells with immediate recovery	Absence seizure (or focal seizure with impaired awareness)	EEG to differentiate; 3 Hz spike-wave = absence (generalized)
Prolonged event with waxing-waning, eyes closed, no post-ictal confusion	Psychogenic non-epileptic seizure	Video-EEG for definitive diagnosis; psychiatric evaluation; avoid polypharmacy

6. Diagnostic Investigations

A stepwise, cost-effective approach guided by clinical suspicion

The investigation of seizures aims to: (1) identify reversible causes requiring immediate treatment, (2) classify the seizure type and epilepsy syndrome, (3) determine etiology to guide prognosis and treatment, and (4) assess risk of recurrence. The approach differs for emergency evaluation versus outpatient workup of first seizure versus established epilepsy.

Emergency Department Investigations

Immediate Bedside Tests

Point-of-care glucose: Check immediately — hypoglycemia is rapidly reversible and life-threatening if missed
Oxygen saturation: Hypoxia during/after seizure; aspiration risk
ECG: Arrhythmia as cause (long QT, Brugada) or consequence; QTc prolongation from medications

Baseline Investigations for All Patients with Seizure

Investigation	Purpose	What to Look For	Practical Points
Serum glucose	Identify hypoglycemia	<70 mg/dL (symptomatic); <40 mg/dL (seizure threshold)	Point-of-care testing; treat immediately if low
Serum sodium	Identify hyponatremia	<120 mEq/L or rapid decline >10 mEq/L in 24 hours	Rate of change matters; correct slowly to avoid osmotic demyelination
Serum calcium (ionized preferred)	Identify hypocalcemia	Ionized calcium <1.0 mmol/L	Check with magnesium; hypomagnesemia causes refractory hypocalcemia
Serum magnesium	Identify hypomagnesemia	<1.5 mg/dL; critical if <1.0 mg/dL	Essential in pregnancy (eclampsia treatment); alcoholism
Renal function (BUN, creatinine)	Identify uremia; guide medication dosing	Elevated BUN and creatinine; uremic encephalopathy	Many antiseizure medications require renal dose adjustment
Complete blood count	Infection, hematologic abnormality	Leukocytosis (infection), thrombocytopenia (DIC in status epilepticus)	Transient leukocytosis common post-ictally; does not confirm infection
Liver function tests	Hepatic encephalopathy; guide medication dosing	Elevated transaminases, low albumin, elevated ammonia	Many antiseizure medications hepatically metabolized
Toxicology screen (urine/serum)	Drug intoxication or withdrawal	Cocaine, amphetamines, benzodiazepines, opioids, alcohol	May not detect synthetic drugs; clinical suspicion remains important
Blood alcohol level	Intoxication or withdrawal	Level and timing help determine withdrawal risk	Withdrawal seizures typically occur when level is declining or zero
Antiseizure medication levels	Therapeutic monitoring in known epilepsy	Subtherapeutic levels; supratherapeutic (toxicity)	Useful for phenytoin, carbamazepine, valproate, phenobarbital; less useful for newer agents
Pregnancy test	All women of childbearing age	Pregnancy changes management (eclampsia risk, medication teratogenicity)	Guides medication selection; consider eclampsia if positive

Neuroimaging

CT Head (Non-contrast)

Indications for Emergent CT

First seizure in any adult
New focal neurological deficit
Persistent altered mental status
Recent head trauma
Anticoagulation therapy
Known malignancy
Immunocompromised patient
History of HIV/AIDS
Fever with suspected central nervous system infection
Status epilepticus

What CT Can Detect

Intracranial hemorrhage (acute)
Large mass lesions
Acute hydrocephalus
Major stroke (may be subtle early)
Skull fractures (trauma)
Cerebral edema
Calcified lesions (neurocysticercosis)

CT Limitations

Misses many structural causes of epilepsy
Poor visualization of temporal lobes, posterior fossa
Cannot detect mesial temporal sclerosis
Small tumors, cavernomas may be missed

MRI Brain (Epilepsy Protocol)

MRI is the Gold Standard for Epilepsy Workup

MRI should be performed in all patients with new-onset epilepsy unless there is a clear, identifiable, and reversible provoked cause. MRI detects structural abnormalities in approximately 25-30% of patients with epilepsy.

MRI Finding	Description	Associated Condition
Hippocampal sclerosis	Atrophy and T2/FLAIR hyperintensity of hippocampus	Mesial temporal lobe epilepsy — most common surgically remediable epilepsy
Focal cortical dysplasia	Cortical thickening, blurring of gray-white junction, T2/FLAIR signal abnormality	Developmental malformation; often drug-resistant; surgical candidate
Cavernous malformation	“Popcorn” lesion with hemosiderin rim on susceptibility-weighted imaging	Vascular malformation; may be multiple; surgical option
Brain tumor	Mass with enhancement, surrounding edema, mass effect	Primary (glioma, meningioma) or metastatic
Encephalomalacia	Old infarct or traumatic injury; gliosis, volume loss	Remote symptomatic epilepsy (post-stroke, post-traumatic)
Temporal lobe encephalitis pattern	T2/FLAIR hyperintensity in medial temporal lobes (may be bilateral)	Herpes simplex encephalitis, autoimmune encephalitis
Posterior reversible encephalopathy syndrome pattern	Bilateral parieto-occipital T2/FLAIR hyperintensity	Posterior reversible encephalopathy syndrome (hypertension, eclampsia, immunosuppressants)

Electroencephalography (EEG)

EEG Purpose: The EEG supports the diagnosis of epilepsy, helps classify seizure type (focal versus generalized), identifies epilepsy syndrome, and guides medication selection. A normal EEG does NOT exclude epilepsy — interictal EEG is normal in up to 50% of patients with epilepsy on a single routine recording.

Types of EEG Studies

Study Type	Duration	Indication	Yield
Routine EEG	20-40 minutes	Initial evaluation of suspected epilepsy; post-seizure workup	Detects interictal abnormalities in approximately 30-50% of epilepsy patients
Sleep-deprived EEG	20-40 minutes after sleep deprivation	Increases yield when routine EEG is normal	Increases detection by 20-30%; sleep and sleep deprivation activate epileptiform discharges
Ambulatory EEG	24-72 hours	Capture events; quantify seizure frequency; medication adjustment	Higher yield due to prolonged recording; captures sleep
Continuous EEG (cEEG) monitoring	Hours to days (ICU)	Status epilepticus monitoring; altered mental status in critically ill; post-cardiac arrest	Detects non-convulsive seizures in 10-30% of comatose ICU patients
Video-EEG monitoring	Days (inpatient)	Seizure characterization; presurgical evaluation; differentiate epileptic versus non-epileptic events	Gold standard for capturing events and correlating semiology with EEG

Key EEG Findings and Their Significance

EEG Finding	Description	Clinical Significance
3 Hz generalized spike-wave	Rhythmic spike-and-wave complexes at 3 Hz, bilateral synchronous	Childhood/juvenile absence epilepsy; responds to ethosuximide, valproate
4-6 Hz generalized polyspike-wave	Fast spike-wave with polyspikes, generalized	Juvenile myoclonic epilepsy; lifelong treatment usually needed
Focal sharp waves or spikes	Epileptiform discharges localized to one region	Focal epilepsy; location helps identify seizure focus
Temporal intermittent rhythmic delta activity (TIRDA)	Rhythmic delta activity over temporal region	Highly associated with temporal lobe epilepsy; lateralizing value
Periodic lateralized epileptiform discharges (PLEDs/LPDs)	Periodic sharp waves or spikes, lateralized to one hemisphere	Acute destructive lesion (stroke, encephalitis, tumor); high seizure risk
Generalized periodic discharges (GPDs)	Periodic discharges synchronous across both hemispheres	Anoxic brain injury, Creutzfeldt-Jakob disease, severe metabolic encephalopathy
Electrographic seizure	Rhythmic, evolving pattern with clear onset and offset	Confirms seizure diagnosis; non-convulsive status epilepticus if prolonged without clinical correlate

Lumbar Puncture

Indications

Fever with seizure: Rule out meningitis, encephalitis
Immunocompromised patient: Opportunistic infections
Suspected autoimmune encephalitis: CSF antibodies, inflammatory markers
Suspected subarachnoid hemorrhage: If CT negative but clinical suspicion high
HIV-positive with new seizure: Cryptococcal meningitis, toxoplasmosis workup
Suspected carcinomatous meningitis: Cytology, flow cytometry

CSF Analysis

Cell count and differential: Pleocytosis in infection/inflammation
Protein: Elevated in infection, malignancy, autoimmune
Glucose: Low in bacterial meningitis, TB, fungal
Gram stain and culture: Bacterial meningitis
HSV PCR: Herpes simplex encephalitis (obtain early)
Autoimmune panel: Anti-NMDA receptor, LGI1, CASPR2, GABA-B antibodies
Cytology: Leptomeningeal carcinomatosis
Oligoclonal bands: Multiple sclerosis, other inflammatory conditions

Before Lumbar Puncture

Obtain CT head if: focal neurological deficit, papilledema, altered consciousness, immunocompromise, or new seizure — to rule out mass lesion/elevated intracranial pressure
Do not delay antibiotics for lumbar puncture if bacterial meningitis is suspected
Check coagulation studies and platelet count

Targeted Investigations by Suspected Etiology

If Suspecting Autoimmune Encephalitis

First-Line Tests

MRI brain: May show T2/FLAIR hyperintensity in medial temporal lobes
CSF analysis: Lymphocytic pleocytosis, elevated protein, oligoclonal bands
Serum autoimmune panel: Anti-NMDA receptor, LGI1, CASPR2, GABA-B, AMPA receptor antibodies
CSF autoimmune panel: Higher sensitivity for some antibodies (anti-NMDA receptor)

Additional Workup

Pelvic ultrasound/MRI (women): Ovarian teratoma (anti-NMDA receptor encephalitis)
CT chest/abdomen/pelvis: Occult malignancy (paraneoplastic)
PET-CT: If conventional imaging negative but paraneoplastic suspected
EEG: May show extreme delta brush (anti-NMDA receptor), focal slowing

If Suspecting Genetic Epilepsy

Clinical Indications for Genetic Testing

Early-onset epilepsy (<2 years)
Developmental delay with epilepsy
Multiple seizure types
Family history of epilepsy
Drug-resistant epilepsy of unknown cause
Features of specific syndrome (e.g., Dravet syndrome)

Types of Genetic Tests

Epilepsy gene panel: Tests known epilepsy genes (50-500+ genes)
Whole exome sequencing: Broader coverage; higher yield in unknown cases
Chromosomal microarray: Copy number variants
Single gene testing: If specific syndrome suspected (e.g., SCN1A for Dravet)

Cardiac Evaluation (Rule Out Arrhythmia)

Test	Indication	What to Look For
12-lead ECG	All patients with transient loss of consciousness	Long QT (>470 ms men, >480 ms women), Brugada pattern, Wolff-Parkinson-White, heart block, arrhythmia
Holter monitor (24-48 hours)	Suspected arrhythmia; recurrent unexplained events	Paroxysmal arrhythmias, heart rate variability, pauses
Event recorder / Implantable loop recorder	Infrequent events; differentiate seizure from arrhythmia	Capture ECG during event; correlate with symptoms
Echocardiogram	Suspected structural heart disease	Cardiomyopathy, valvular disease (embolic stroke risk)

Investigation Summary by Clinical Scenario

Scenario	Essential Investigations	Consider Adding
First unprovoked seizure (ED)	Glucose, electrolytes, renal/liver function, CBC, ECG, CT head, toxicology	MRI brain (can be outpatient), EEG (within 24-48 hours if possible)
First seizure outpatient workup	MRI brain (epilepsy protocol), EEG (routine, consider sleep-deprived)	Ambulatory EEG if routine normal; cardiac evaluation if syncope possible
Breakthrough seizure in known epilepsy	Antiseizure medication levels, basic metabolic panel, toxicology if indicated	Repeat MRI if no recent imaging; review compliance and precipitants first
Status epilepticus	Full metabolic panel, antiseizure medication levels, toxicology, CT head, continuous EEG	Lumbar puncture (after CT), MRI when stable, autoimmune panel if refractory
Fever and seizure	Blood cultures, lumbar puncture (after CT if indicated), MRI brain	HSV PCR, consider arbovirus panel, autoimmune encephalitis panel
Suspected psychogenic non-epileptic seizures	Video-EEG monitoring (gold standard)	Psychological/psychiatric evaluation; MRI and routine EEG to rule out coexisting epilepsy

EEG Timing Matters

EEG yield is highest within 24-48 hours of a seizure. Post-ictal slowing and epileptiform discharges are more likely to be captured early. If possible, arrange EEG before discharge from the emergency department or within the first 24-48 hours as an outpatient. Delaying EEG by weeks significantly reduces diagnostic yield.

7. Pattern Recognition and Clinical Decision-Making

Practical algorithms and decision pathways

Step 1: Is This Urgent?

Clinical Scenario	Urgency Level	Immediate Action
Ongoing convulsive seizure >5 minutes	EMERGENT	Activate status epilepticus protocol; IV benzodiazepine immediately; airway management; call for help
Multiple seizures without return to baseline	EMERGENT	Treat as status epilepticus; IV access; benzodiazepine; prepare second-line agents
Post-ictal but not awakening (>30 minutes)	EMERGENT	Consider non-convulsive status epilepticus; emergent EEG; CT head if not done
Seizure with fever and altered mental status	EMERGENT	Empiric antibiotics and acyclovir; lumbar puncture after CT; blood cultures
Seizure in pregnancy/postpartum with hypertension	EMERGENT	IV magnesium sulfate; blood pressure control; obstetric consultation; delivery planning
Seizure with new focal neurological deficit	URGENT	Emergent CT head (stroke, hemorrhage, mass); consider stroke code if acute onset
First seizure with complete recovery	URGENT	Full workup in ED; CT head; labs; observation; arrange outpatient MRI and EEG
Breakthrough seizure in known epilepsy, now at baseline	SEMI-URGENT	Check medication levels; assess for precipitants; adjust medications if needed; may not require ED
Witnessed event, uncertain if seizure	ROUTINE	Detailed history from patient and witness; ECG; consider outpatient neurology referral

Status Epilepticus Treatment Algorithm

Time-Critical Treatment: “Time is Brain”

GABA-A receptors internalize rapidly during prolonged seizures, making benzodiazepines progressively less effective. Treatment should be aggressive and escalated quickly if seizures do not terminate.

Time	Stage	Treatment	Key Points
0-5 minutes	Stabilization	ABCs; oxygen; IV access; glucose check; position safely	Protect airway; do not force objects into mouth; time the seizure
5-10 minutes	First-line therapy	Benzodiazepine: IV lorazepam 4 mg (may repeat once) OR IV diazepam 10 mg OR IM midazolam 10 mg	IM midazolam if no IV access; intranasal or buccal routes also effective
10-20 minutes	Second-line therapy	Antiseizure medication loading: IV fosphenytoin 20 mg PE/kg OR IV valproate 40 mg/kg OR IV levetiracetam 60 mg/kg	Choose based on comorbidities; fosphenytoin contraindicated in heart block; valproate avoid in pregnancy/liver disease
20-40 minutes	Second-line therapy (continued)	If seizures persist: give additional second-line agent OR repeat loading dose	Can use second agent from different class; prepare for intubation
>40 minutes	Refractory status epilepticus	Anesthetic agents: IV propofol OR IV midazolam infusion OR IV pentobarbital; continuous EEG monitoring	Requires intubation and ICU; goal is burst suppression on EEG; high mortality

Step 2: First Seizure Decision Pathway

Key Question: Was this seizure provoked or unprovoked?

Provoked (acute symptomatic): Treat underlying cause; short-term antiseizure medication may be appropriate; long-term treatment usually not indicated
Unprovoked: Risk of recurrence approximately 40-50%; decision to treat depends on risk factors, patient preferences, and driving/safety implications

Clinical Scenario	Recurrence Risk	Recommendation
Provoked seizure (metabolic, drug/alcohol, acute illness)	Low (if cause corrected)	Correct underlying cause; no long-term antiseizure medication; short-term treatment during acute phase may be appropriate
First unprovoked seizure, normal MRI and EEG	~35%	Shared decision-making; treatment optional; discuss driving restrictions, safety
First unprovoked seizure with abnormal EEG (epileptiform)	~60%	Strong consideration for treatment; meets ILAE criteria for epilepsy diagnosis
First unprovoked seizure with structural lesion on MRI	~65-70%	Recommend treatment; high recurrence risk; meets ILAE criteria for epilepsy
First seizure occurring during sleep	Higher than wake seizure	Consider treatment; nocturnal seizures increase SUDEP risk
Two or more unprovoked seizures	>60%	Treatment recommended; this defines epilepsy

Step 3: Antiseizure Medication Selection

Seizure Type	First-Line Options	Avoid	Special Considerations
Focal seizures (with or without secondary generalization)	Levetiracetam, lamotrigine, oxcarbazepine, lacosamide	Ethosuximide (ineffective)	Carbamazepine/oxcarbazepine effective but more drug interactions
Generalized tonic-clonic (primary)	Levetiracetam, lamotrigine, valproate	Carbamazepine, oxcarbazepine, phenytoin (may worsen some generalized epilepsies)	Valproate highly effective but teratogenic; avoid in women of childbearing potential
Absence seizures	Ethosuximide, valproate, lamotrigine	Carbamazepine, phenytoin, gabapentin (may worsen)	Ethosuximide only treats absence; if concurrent tonic-clonic, use valproate or lamotrigine
Juvenile myoclonic epilepsy	Levetiracetam, valproate, lamotrigine	Carbamazepine, phenytoin, gabapentin (may worsen myoclonus)	Usually requires lifelong treatment; high relapse rate if discontinued
Unknown seizure type	Levetiracetam, lamotrigine, valproate	Narrow-spectrum agents until type clarified	Broad-spectrum agents safest when classification uncertain

Special Population Considerations

Population	Preferred Agents	Avoid or Use Caution	Key Considerations
Women of childbearing potential	Levetiracetam, lamotrigine, oxcarbazepine	Valproate (teratogenic — neural tube defects, cognitive effects)	Preconception counseling; high-dose folic acid; lamotrigine levels drop in pregnancy
Elderly	Levetiracetam, lamotrigine, lacosamide	Phenytoin, carbamazepine (drug interactions, bone loss, cognitive effects)	Start low, go slow; watch for drug interactions with polypharmacy
Renal impairment	Agents with hepatic metabolism or low renal clearance	Dose-adjust levetiracetam, gabapentin, pregabalin, topiramate	Check package insert for renal dosing; some agents removed by dialysis
Hepatic impairment	Levetiracetam, lacosamide, gabapentin (renally cleared)	Valproate (hepatotoxic), carbamazepine, phenytoin	Avoid hepatically metabolized drugs; protein binding altered
Patient on multiple medications	Levetiracetam, lacosamide, gabapentin (few interactions)	Phenytoin, carbamazepine, phenobarbital (CYP450 inducers)	Enzyme inducers affect oral contraceptives, anticoagulants, chemotherapy

“What Do I Do If…” Decision Reference

Clinical Situation	Immediate Action	Next Step
Patient seizing in front of me	Note time; protect from injury; position on side; do NOT restrain or put anything in mouth	If >5 minutes or repeated: activate emergency response; give benzodiazepine
Seizure stops but patient not waking up	Maintain airway; check glucose; assess for ongoing subtle seizure activity (eye deviation, twitching)	If >20-30 minutes without improvement: consider non-convulsive status; emergent EEG
Patient on antiseizure medication has breakthrough seizure	Check medication adherence; check drug levels if applicable; review for precipitants	If compliant with therapeutic levels: consider dose increase or add-on therapy; reassess diagnosis
First seizure in patient with known brain tumor	Start antiseizure medication; assess for tumor progression	Brain MRI with contrast; oncology consultation; levetiracetam preferred (few interactions with chemotherapy)
Suspected alcohol withdrawal seizure	Benzodiazepines (lorazepam, diazepam, or chlordiazepoxide per protocol); thiamine	Monitor for delirium tremens (24-72 hours); CIWA protocol; supportive care; CT if focal features
Pregnant patient with seizure	Left lateral position; magnesium sulfate if eclampsia suspected; check blood pressure	Obstetric consultation; delivery planning if eclampsia; continue safe antiseizure medication
Patient wants to stop antiseizure medication	Discuss risks; seizure-free for at least 2 years is minimum; normal EEG and imaging favorable	If appropriate: slow taper over months; counsel about driving, SUDEP risk; monitor closely
Patient with epilepsy wants to drive	Review local regulations (seizure-free interval varies by jurisdiction, typically 3-12 months)	Document counseling; some jurisdictions require physician reporting; patient safety paramount

Troubleshooting Refractory Seizures

When Seizures Are Not Controlled: Ask These Questions

Is the diagnosis correct? Up to 20% of “refractory epilepsy” is actually psychogenic non-epileptic seizures — consider video-EEG
Is the patient taking the medication? Non-adherence is the most common cause of breakthrough seizures
Is the drug level therapeutic? Check levels for phenytoin, carbamazepine, valproate, phenobarbital
Is the medication appropriate for the seizure type? Carbamazepine can worsen absence and myoclonic seizures
Are there drug interactions? Enzyme inducers lower levels of concomitant medications
Are there modifiable triggers? Sleep deprivation, alcohol, stress, missed medications
Is there a new structural lesion? Consider repeat MRI if not done recently
Has the patient been evaluated for epilepsy surgery? Focal epilepsy with identifiable lesion may be curable
Are there autoimmune or metabolic causes? Consider autoimmune encephalitis panel, metabolic workup

When to Refer to Epilepsy Specialist

Indications for Epilepsy Center Referral

Drug-resistant epilepsy (failed 2 appropriate medications)
Considering epilepsy surgery evaluation
Diagnostic uncertainty (seizure versus non-epileptic events)
Frequent seizures despite treatment
Pregnancy planning in woman with epilepsy
Desire to discontinue medications
Concern for medication side effects

Surgical Evaluation May Be Appropriate If

Focal epilepsy with identifiable lesion
Mesial temporal lobe epilepsy (especially with hippocampal sclerosis)
Failed 2 or more appropriate antiseizure medications
Seizures significantly impacting quality of life
Discrete lesion amenable to resection

Note: Surgery can be curative in up to 60-70% of appropriate candidates with temporal lobe epilepsy

8. Clinical Pearls and Pitfalls

Practical wisdom — learn from successes and avoid common mistakes

Must-Know Clinical Pearls

Witness history is gold: The patient often has no memory of the seizure. Always contact a witness and ask if they have smartphone video — this can be diagnostic.

Lateral tongue bite is highly specific: A laceration on the lateral aspect of the tongue strongly suggests generalized tonic-clonic seizure. Tip-of-tongue bites are non-specific and occur in syncope.

Convulsive syncope is common: Brief myoclonic jerks can occur during syncope due to cerebral hypoperfusion. This does not mean the patient has epilepsy — the key is rapid recovery and presence of typical syncope prodrome.

EEG timing matters: EEG yield is highest within 24-48 hours of a seizure. Arrange early EEG whenever possible — a negative EEG weeks later is much less informative.

Normal EEG does not exclude epilepsy: A single routine EEG is normal in up to 50% of patients with epilepsy. If clinical suspicion is high, repeat EEG, sleep-deprived EEG, or ambulatory monitoring may be needed.

Think autoimmune encephalitis in refractory new-onset seizures: Subacute onset with psychiatric symptoms, memory impairment, and movement disorders should prompt autoimmune testing. Early immunotherapy can be disease-modifying.

Alcohol withdrawal seizures cluster: If a patient has one alcohol withdrawal seizure, there is a 25-30% chance of another within 6 hours. Continue monitoring and benzodiazepine prophylaxis.

Pyridoxine for isoniazid seizures: Isoniazid-induced seizures are often refractory to benzodiazepines. Administer pyridoxine (vitamin B6) gram-for-gram of isoniazid ingested (or 5 grams empirically if amount unknown).

Critical Pitfalls to Avoid

Do not diagnose epilepsy based on a single provoked seizure: Seizures due to hypoglycemia, hyponatremia, drug toxicity, or alcohol withdrawal do not constitute epilepsy and generally do not require long-term antiseizure medication.

Do not delay benzodiazepines in status epilepticus: Every minute of ongoing seizure activity causes progressive neuronal injury and treatment resistance. Give benzodiazepines immediately when seizure exceeds 5 minutes.

Do not assume prolonged post-ictal state is normal: If altered consciousness persists beyond 30 minutes, strongly consider non-convulsive status epilepticus and obtain emergent EEG.

Do not attribute all seizures to epilepsy without excluding mimics: Syncope (including convulsive syncope) and psychogenic non-epileptic seizures are commonly misdiagnosed as epilepsy. Video-EEG is the gold standard when diagnosis is uncertain.

Do not use carbamazepine, phenytoin, or oxcarbazepine for genetic generalized epilepsies: These sodium channel blockers can worsen absence and myoclonic seizures. Use broad-spectrum agents (levetiracetam, valproate, lamotrigine) when generalized epilepsy is suspected.

Do not prescribe valproate to women of childbearing potential without counseling: Valproate is highly teratogenic (neural tube defects, cognitive impairment) and should be avoided when alternatives exist. Document risk discussion.

Do not stop antiseizure medications abruptly: Sudden discontinuation can precipitate status epilepticus, even in patients who may not truly have epilepsy. Always taper gradually.

Do not attribute persistent focal deficit solely to Todd’s paralysis: While Todd’s paralysis is real, it should resolve within 24-48 hours. Persistent focal deficit requires urgent imaging to exclude stroke or other structural lesion.

Key Takeaways

Differentiate seizure from mimics first: Syncope (with or without convulsive movements), psychogenic non-epileptic seizures, and cardiac arrhythmias are commonly mistaken for epileptic seizures.
Provoked versus unprovoked determines management: Provoked seizures require treatment of the underlying cause; unprovoked seizures may require long-term antiseizure medication.
Status epilepticus is a medical emergency: Mortality is 15-22% in adults. Treatment must be rapid and escalating — benzodiazepines first, then antiseizure medication loading, then anesthetics if refractory.
MRI is essential for all new-onset epilepsy: CT is inadequate for detecting many epilepsy etiologies. MRI with epilepsy protocol should be performed in all patients without a clear provoked cause.
EEG supports but does not make the diagnosis: Clinical history remains paramount. A normal EEG does not exclude epilepsy; an abnormal EEG in isolation does not confirm it.
Medication selection should be individualized: Consider seizure type, epilepsy syndrome, comorbidities, childbearing potential, and drug interaction profile.
Drug-resistant epilepsy requires specialist evaluation: Approximately 30% of patients will not achieve seizure freedom with medications. Early referral for surgical evaluation can be life-changing.
SUDEP (sudden unexpected death in epilepsy) is a real risk: Occurs in approximately 1 per 1,000 patient-years. Risk factors include uncontrolled generalized tonic-clonic seizures, nocturnal seizures, and polytherapy.
Driving and safety counseling is essential: Document discussion of driving restrictions, SUDEP risk, safety precautions (swimming, heights, bathing), and pregnancy planning.
Consider autoimmune encephalitis in new-onset refractory seizures: Treatable cause that requires high index of suspicion. Look for psychiatric symptoms, memory impairment, and movement disorders.

Quick Reference Algorithm

Systematic Approach to Seizure:

Stabilize: ABCs, protect from injury, check glucose, time the seizure — if ongoing >5 minutes, treat as status epilepticus
Characterize the event: Obtain detailed history from patient and witnesses — was this truly a seizure? What type?
Identify the cause: Provoked (metabolic, toxic, structural) versus unprovoked? Check labs, imaging, consider EEG
Assess urgency: Red flags requiring immediate action? New focal deficit? Signs of infection? Ongoing seizure activity?
Determine if treatment is indicated: Single provoked seizure — treat cause. Two unprovoked seizures or high-risk first seizure — consider long-term antiseizure medication
Select appropriate medication: Match to seizure type, epilepsy syndrome, patient factors, and comorbidities
Counsel on safety: Driving restrictions, SUDEP, safety precautions, medication adherence, when to seek emergency care
Arrange follow-up: Outpatient neurology, MRI if not done, EEG if not done, reassess treatment response