Epilepsy and Seizures

Neuronal Hyperexcitability Mechanisms

• Imbalanced excitatory-inhibitory neurotransmission: Excessive glutamate (AMPA and NMDA receptor activation) and/or decreased gamma-aminobutyric acid (GABA) signaling creates a net excitatory state. Reduced GABAergic inhibition through loss of inhibitory interneurons or decreased GABA receptor expression is particularly important in temporal lobe epilepsy.
• Voltage-gated ion channel dysfunction: Mutations affecting sodium channels (SCN1A, SCN1B), potassium channels (KCNQ2/3), and calcium channels (CACNA1A) reduce the threshold for action potential generation and impair neuronal repolarization, increasing seizure propensity. These channelopathies explain several genetic epilepsy syndromes including benign familial neonatal epilepsy and generalized epilepsy with febrile seizures plus (GEFS+).
• Structural network abnormalities: Cortical dysplasia, mesial temporal sclerosis, and other lesions create focal areas of abnormal connectivity where neurons fire hypersynchronously. Repeated seizure activity causes secondary changes including glial activation, neuroinflammation, and altered blood-brain barrier permeability.

Seizure Propagation and Generalization

• Focal-to-generalized spread: Seizures begin in a focal network (epileptogenic zone) and propagate through cortico-cortical and thalamic connections. The thalamus acts as a relay center amplifying seizure activity and promoting bilateral generalization through reticular nucleus disinhibition.
• Loss of dendritic inhibition: Suppression of feedforward inhibition allows seizure activity to spread beyond the initial focus, while collapse of feedback inhibition prevents termination of sustained activity.
• Neuroplasticity and epileptogenesis: Chronic seizure activity triggers long-term potentiation in excitatory synapses, axonal sprouting, and dendritic remodeling that progressively lower seizure threshold and promote "acquired epilepsy" or secondary generalization in initially focal-onset disorders.

Genetic Predisposition

• Monogenic epilepsy syndromes: SCN1A mutations (severe myoclonic epilepsy of infancy), KCNQ2/3 mutations (benign neonatal familial convulsions), PCDH19 mutations (epilepsy and mental retardation restricted to females)
• Complex inheritance: Generalized epilepsy with febrile seizures plus, absence epilepsy, and juvenile myoclonic epilepsy show polygenic inheritance with incomplete penetrance
• First-degree relatives: 2-5-fold increased seizure risk in relatives of affected individuals

Structural/Lesional Causes

• Mesial temporal sclerosis (most common cause of temporal lobe epilepsy): Neuronal loss and gliosis in CA1 and CA3 regions of hippocampus
• Cortical malformations: Focal cortical dysplasia, polymicrogyria, heterotopia, and lissencephaly create disorganized networks with reduced inhibitory input
• Neoplastic: Low-grade tumors (gliomas, hamartomas) and high-grade lesions; tumor-related epilepsy occurs in 10-20% of brain cancers
• Traumatic brain injury: Post-traumatic seizures develop in 5-50% depending on severity; early seizures (<1 week) carry lower recurrence risk than late seizures (>1 week)
• Cerebrovascular disease: Stroke, cavernous angiomas, arteriovenous malformations, and vascular malformations
• Hippocampal sclerosis and neurodegenerative changes: Seen in temporal lobe epilepsy, mesial temporal epilepsy syndrome

Acquired/Metabolic Causes

• Infections: Meningitis, encephalitis (HSV, VZV, CMV), neurocysticercosis, toxoplasmosis, brain abscess; post-infectious seizures reflect neuroinflammation and permanent structural changes
• Metabolic derangements: Hypoglycemia, hyponatremia (<115 mEq/L), hypocalcemia, hypomagnesemia, hepatic encephalopathy, uremia
• Toxic/Drug-related: Withdrawal from alcohol, benzodiazepines, or antiepileptic drugs; cocaine and other stimulants; theophylline toxicity; certain antibiotics (fluoroquinolones, cephalosporins)
• Anoxic encephalopathy and post-hypoxic myoclonus: Myoclonic seizures post-cardiac arrest carry poor prognosis
• Autoimmune encephalitis: Anti-NMDA receptor, anti-LGI1, anti-CASPR2, anti-GABAb encephalitis present with seizures, behavioral changes, and autonomic instability

Systemic/Developmental Factors

• Febrile seizures: Occur in 2-5% of children; brief, generalized seizures triggered by fever; genetic predisposition + immature CNS; GEFS+ represents familial syndrome with breakthrough afebrile seizures
• Hypoxic-ischemic encephalopathy: In neonates and infants, accounts for significant early seizure burden and neurodevelopmental injury
• Eclampsia and preeclampsia: Seizures from severe hypertension, cerebral edema, and endothelial dysfunction in pregnancy
• Age-related vulnerability: Infants (<1 year) and elderly (>65 years) have lower seizure thresholds due to developmental immaturity and comorbid brain pathology, respectively

Seizure Semiology by Type

• Tonic-clonic seizures: Sudden loss of consciousness, rigid extension of limbs (tonic phase), followed by rhythmic jerking (clonic phase); tongue biting, urinary/fecal incontinence, postictal confusion (15-30 minutes), myalgia, headache
• Absence seizures: Brief (5-20 second) behavioral arrests without postictal confusion; "staring spells"; may have subtle automatisms (eye fluttering, lip smacking); occur dozens of times daily; hyperventilation provokes attacks; typically onset 4-8 years
• Atonic seizures: Sudden loss of muscle tone with collapse ("drop attacks"); high injury risk; typical of Lennox-Gastaut syndrome
• Tonic seizures: Sustained muscle contraction; occur predominantly in sleep; often brief (10-20 seconds)
• Myoclonic seizures: Brief, isolated or repetitive jerks; may precede tonic-clonic seizure in juvenile myoclonic epilepsy (JME); worse upon morning awakening

• Focal aware (previously "simple partial"): Preserved consciousness; motor manifestations (Jacksonian march along motor cortex), sensory symptoms (tingling, visual phenomena), autonomic changes (palpitations, flushing), psychic symptoms (fear, déjà vu), olfactory hallucinations
• Focal impaired awareness (previously "complex partial"): Altered consciousness; automatisms (lip smacking, hand fumbling, picking motions, undressing); temporal lobe involvement; postictal confusion; may progress to generalization
• Focal-to-bilateral tonic-clonic: Begin focally, then generalize; significant postictal period

Associated Symptoms and Signs

• Aura: Sensory, motor, or autonomic warning preceding seizure onset; helps localize epileptogenic zone
• Postictal state: Period of altered consciousness, confusion, fatigue, headache, and myalgia lasting minutes to hours; Todd's paralysis (transient focal weakness) localizes prior seizure
• Status epilepticus: Prolonged seizure activity (>5 minutes) or repetitive seizures without intervening consciousness; medical emergency with high mortality
• SUDEP: Sudden, unexpected, non-traumatic death in person with epilepsy, often during sleep; most common cause of epilepsy-related death in younger patients; unclear mechanism but possibly cardiac arrhythmia, respiratory depression, or severe postictal cerebral edema

Physical Examination Findings During and Between Seizures

• Ictal findings: Tachycardia, hypertension, hyperthermia, pupillary dilation, plantar extensor response (Babinski sign)
• Interictal period: Usually neurologically normal between seizures; focal neurological deficits (weakness, visual field defect) may indicate structural lesion
• Chronic findings: Gum hypertrophy (phenytoin), coarsened facial features and tremor (some older AEDs), skin reactions

Clinical History and Seizure Classification

• Detailed eyewitness account: Description of initial symptoms, motor manifestations, duration, recovery period, and injury patterns essential for semiology-based classification
• International League Against Epilepsy (ILAE) 2017 seizure classification: Generalized onset vs. focal onset vs. unknown onset; further subdivided by consciousness (aware/impaired) and motor manifestations (tonic, clonic, atonic, etc.)
• Provocation assessment: Recent head trauma, withdrawal from sedating substances, sleep deprivation, fever, stress, catamenial pattern (perimenstrual seizure exacerbation)

Electroencephalography (EEG)

• Interictal EEG: Gold standard for seizure diagnosis; demonstrates epileptiform discharges (spikes, sharp waves, spike-wave complexes) during seizure-free periods; focal discharges localize epileptogenic zone
• Generalized 3-Hz spike-wave: Classic for childhood absence epilepsy; highly specific
• Generalized polyspike-wave: Typical of juvenile myoclonic epilepsy
• Temporal lobe spikes: Indicate mesial temporal sclerosis or temporal lobe epilepsy
• Hypsarrhythmia: High-amplitude, chaotic background with multifocal spikes; pathognomonic for infantile spasms (West syndrome)
• Ictal EEG: Performed during video-EEG monitoring to capture seizure; low-amplitude fast activity ("electrodecremental response") evolving to rhythmic activity most common pattern
• Sensitivity limitations: Normal interictal EEG does not exclude epilepsy (seen in 30-50% of newly diagnosed cases); may require prolonged monitoring or repeated studies

Neuroimaging

• MRI (brain): First-line imaging; superior detection of structural lesions including mesial temporal sclerosis, focal cortical dysplasia, vascular malformations, tumor, gliosis
• High-resolution protocol: 3mm coronal T2/FLAIR through temporal lobes for temporal lobe epilepsy evaluation
• Temporal lobe epilepsy findings: Hippocampal atrophy, signal hyperintensity, loss of internal structure
• CT (brain): Rapid alternative when acute intracranial pathology suspected (hemorrhage, acute ischemia); less sensitive for chronic epileptogenic lesions
• PET/ICTAL SPECT: Functional imaging for presurgical evaluation; interictal PET shows hypometabolism in epileptogenic focus; ictal SPECT shows hyperperfusion; reserved for drug-resistant epilepsy candidates for surgery
• MEG (magnetoencephalography): Non-invasive mapping of seizure origin; not standard but helpful for surgical planning in certain centers

Laboratory Investigations

• Routine labs: Serum glucose, electrolytes (sodium, calcium, magnesium), liver function, renal function to exclude metabolic causes and baseline toxicity assessment for AEDs
• AED levels: Therapeutic drug monitoring for certain AEDs with narrow therapeutic ranges (phenytoin, phenobarbital, valproic acid, carbamazepine, levetiracetam controversial); baseline and after dose adjustments
• Phenytoin: 10-20 μg/mL; nonlinear kinetics
• Valproic acid: 50-100 μg/mL
• Carbamazepine: 4-12 μg/mL
• Genetic testing: Indicated for genetic epilepsy syndromes (infantile spasms, severe myoclonic epilepsy of infancy, benign familial neonatal epilepsy); panel testing identifies SCN1A, CDKL5, PCDH19, KCNQ2/3
• Autoimmune workup: CSF oligoclonal bands, serum/CSF autoimmune antibodies (anti-NMDA, anti-LGI1, anti-CASPR2) if autoimmune encephalitis suspected
• Lumbar puncture: When infection or autoimmune etiology suspected; CSF analysis for cells, protein, glucose, culture, PCR for HSV/VZV
• Ancillary tests: Skin or hair biopsy (neuronal ceroid lipofuscinosis), very long chain fatty acids (adrenoleukodystrophy), serum/urine amino acids, organic acids

Diagnostic Criteria (ILAE 2014)

Epilepsy diagnosed when

1. 1.At least 2 unprovoked (or reflex) seizures occurring >24 hours apart, OR
2. 2.1 unprovoked seizure and high recurrence risk (based on EEG, imaging, syndrome), OR
3. 3.Diagnosis of an epilepsy syndrome (e.g., childhood absence epilepsy, temporal lobe epilepsy)

First-Line Antiepileptic Drugs (AEDs)

• Levetiracetam (Keppra): Unique mechanism of SV2A protein binding; no drug interactions; minimal hepatic metabolism; renal excretion
• Advantages: No monitoring required, excellent tolerability, minimal interactions, pregnancy category C
• Disadvantages: Behavioral/mood changes (10-15% of patients), requires renal adjustment, expensive
• Starting dose: 500 mg BID, titrate by 500-1000 mg/day every 1-2 weeks to target 2000-3000 mg/day
• High-yield point: Most commonly prescribed new-onset AED in North America

• Valproic acid/Divalproex (Depakote): GABA agonist and inhibitor of histone deacetylase; broad spectrum; highly protein-bound
• Advantages: Effective for generalized and focal seizures, behavioral benefits
• Disadvantages: Hepatotoxicity (rare but serious), pancreatitis, weight gain, teratogenicity (neural tube defects 1-2%, fetal valproate syndrome with developmental delay), thrombocytopenia, hyperammonemia, interactions with other medications
• Contraindicated in women of childbearing potential unless no alternatives
• Monitoring: LFTs, ammonia level, CBC; therapeutic level 50-100 μg/mL
• Starting dose: 250-500 mg daily, divided dosing, titrate to 15-60 mg/kg/day

• Lamotrigine (Lamictal): Sodium channel blockade and glutamate inhibition
• Advantages: Effective for focal and generalized seizures, mood benefits (particularly depression), modest weight loss potential
• Disadvantages: Slow titration required (risk of serious rash), requires CYP3A4/2C9 monitoring, interactions with valproic acid (slows metabolism; require lower dosing), drug interactions
• Black box warning: Stevens-Johnson syndrome (SJS)

Disease-related — emergencies first

• Status epilepticus (true emergency): failure of seizure-terminating mechanisms with GABA-A receptor internalization and NMDA receptor externalization at the synapse — this is why benzodiazepine efficacy falls the longer a seizure runs. Signaled by convulsions >5 minutes or failure to regain awareness between seizures. Per the American Epilepsy Society 2016 guideline, a benzodiazepine is the initial therapy: IV lorazepam 0.1 mg/kg (max 4 mg per dose, may repeat once), or IM midazolam 10 mg for patients >40 kg if no IV access; the ESETT trial showed fosphenytoin, valproate, and levetiracetam are comparable second-phase agents. Complications include rhabdomyolysis, lactic acidosis, hyperthermia, aspiration, and neuronal excitotoxic injury.
• Nonconvulsive status epilepticus: persistent unexplained obtundation after a witnessed seizure or in ICU patients; requires urgent continuous EEG, not repeat imaging.
• SUDEP: presumed postictal central apnea and/or malignant arrhythmia; strongest risk factor is frequent generalized tonic-clonic seizures, so seizure control and nocturnal supervision are the mitigations.
• Trauma and aspiration: posterior shoulder dislocation, vertebral compression fracture, tongue laceration, drowning, burns; atonic drop attacks cause head injury.
• Psychiatric and psychosocial: depression, anxiety, and elevated suicide risk; cognitive decline and driving restrictions (state-determined seizure-free intervals).

Treatment-related

• Severe cutaneous reactions: lamotrigine, carbamazepine, and phenytoin cause SJS/TEN and DRESS — mucosal involvement, skin pain, eosinophilia, or transaminitis mandates immediate drug cessation (emergency). FDA labeling advises HLA-B*1502 testing before carbamazepine in patients of Southeast Asian ancestry.
• Valproate: idiosyncratic hepatotoxicity (highest risk in infants and POLG mutations), hemorrhagic pancreatitis, and hyperammonemic encephalopathy — new confusion with normal drug level; also thrombocytopenia and neural tube defects.
• Carbamazepine: aplastic anemia/agranulocytosis, hyponatremia via SIADH-like effect, and hepatic enzyme autoinduction reducing its own and oral contraceptive levels.
• IV phenytoin: hypotension and bradyarrhythmia from the propylene glycol diluent with fast infusion, plus purple glove syndrome; fosphenytoin is preferred. Chronic use causes gingival hyperplasia, cerebellar atrophy with ataxia, and osteomalacia from vitamin D catabolism.
• Topiramate: carbonic anhydrase inhibition → nephrolithiasis, metabolic acidosis, acute angle-closure glaucoma.
• Vigabatrin: irreversible peripheral visual field constriction requiring periodic perimetry.
• Abrupt AED withdrawal: precipitates breakthrough seizures or status epilepticus.

• Absence epilepsy: child with dozens of brief staring spells provoked by hyperventilation and 3-Hz generalized spike-and-wave — first-line is ethosuximide, which blocks thalamic T-type calcium channels. Valproate is equally effective for seizures but worse on attention; lamotrigine is less effective. Distractor to avoid: this is not ADHD, and there is no postictal confusion.
• Juvenile myoclonic epilepsy: teen with early-morning jerks (spills cereal) plus a generalized tonic-clonic seizure, 4-6 Hz polyspike-and-wave, sleep deprivation as trigger. Treat with a broad-spectrum agent (levetiracetam, or valproate in males). The one association examiners test: narrow-spectrum agents can aggravate myoclonic and absence seizures — carbamazepine, oxcarbazepine, and phenytoin (sodium channel blockers), plus gabapentin/pregabalin (α2δ subunit ligands of voltage-gated calcium channels) and tiagabine/vigabatrin (GABAergic agents). Separate the mechanism from the clinical effect: only the first group blocks sodium channels.
• Infantile spasms (West syndrome): flexor clusters on awakening with hypsarrhythmia. Best next step is treatment with ACTH (or oral corticosteroid); vigabatrin is preferred when tuberous sclerosis is the cause — look for ash-leaf macules and cardiac rhabdomyoma.
• Single best next step in an acutely seizing patient: stabilize ABCs, time the seizure, and obtain a fingerstick glucose (send serum electrolytes concurrently); give a benzodiazepine at 5 minutes of ongoing convulsion (American Epilepsy Society). For a first unprovoked seizure in an adult who has returned to baseline, the workup is MRI brain and EEG; the American Academy of Neurology notes that immediate AED therapy lowers short-term recurrence risk but does not change long-term seizure freedom, so treatment is individualized.
• Drug-resistant epilepsy is failure of two appropriately chosen, adequately dosed AEDs (ILAE) — refer for video-EEG and epilepsy surgery evaluation, not a third drug. Anterior temporal lobectomy for mesial temporal sclerosis is the highest-yield surgical answer.
• Pregnancy: avoid valproate (neural tube defects, reduced IQ) and topiramate; lamotrigine and levetiracetam are preferred, with folic acid supplementation and awareness that lamotrigine levels fall as pregnancy progresses.
• Psychogenic nonepileptic spells: side-to-side head shaking, pelvic thrusting, eyes forced closed, long duration without acidosis or postictal confusion — video-EEG is diagnostic, not a higher AED dose.
• Todd's paralysis is postictal, resolves over hours, and localizes the focus; it mimics stroke — do not let it derail evaluation for an acute infarct in the right stem.