What it is:Epilepsy is a chronic tendency to have recurrent, unprovoked seizures, which are bursts of excessive, synchronized electrical firing in the brain. It's not one disease, it's 40+ different syndromes with genetic, structural, infectious, metabolic, immune, or unknown causes. A seizure is a symptom; epilepsy is the diagnosis you give once seizures are recurring and unprovoked.
The core problem:Normal brain activity depends on a balance between excitation (glutamate, sodium and calcium currents) and inhibition (GABA, potassium and chloride currents). When that balance tips and a critical mass of neurons synchronize, you get a seizure. Every antiseizure medication (ASM) works by restoring that balance,either by blocking the channels that let excitation spread or by boosting the currents that shut it down.
What you do about it:Match the drug to the seizure type, start low, titrate slowly to the lowest effective dose, and try monotherapy first since roughly two-thirds of patients do fine on one drug. Get the seizure type wrong and you can make things worse, not better.
Think of ASM selection as a circuit-matching problem, not a memorization problem.Sodium channel blockers stop a focal discharge from spreading to become a big generalized seizure. T-type calcium channel blockers interrupt a completely different thalamocortical loop that only matters in absence seizures. That's why a "great" broad-spectrum drug for focal seizures like carbamazepine can actually make absence seizures worse: it's blocking the wrong circuit and doing nothing to fix the one that's misfiring.
The ILAE framework classifies by three layers, and treatment selection runs off the first one: where does the seizure start(focal, generalized, or unknown onset), what's the underlying etiology(genetic, structural, infectious, metabolic, immune, unknown), and does it fit a recognized epilepsy syndrome(like Lennox-Gastaut). Get the onset type wrong and your first-line drug choice is wrong.
| Category | Subtype | Key features |
|---|---|---|
| Focal (partial) | Without dyscognitive features | Old term "simple partial." No impairment of consciousness. Motor twitching, sensory numbness/tingling, or behavioral changes depending on cortical region involved. |
| With dyscognitive features | Old term "complex partial." Impaired consciousness and awareness, automatisms, amnestic to the event. Classic example: temporal lobe epilepsy. | |
| Generalized | Absence | Young children/adolescents. Sudden blank stare, brief upward eye rotation, seconds long, no aura, no real postictal state. Characteristic 2–4 Hz (course material cites 3 Hz) spike-and-wave EEG. |
| Generalized tonic-clonic (GTC) | Always a loss of consciousness. Tonic muscle contraction then clonic jerking. May bite tongue, lose sphincter control, become cyanotic. Deep postictal sleep. | |
| Myoclonic | Brief shock-like jerks of face, trunk, or limbs. No alteration of consciousness. Can be isolated or rapidly repetitive. | |
| Atonic | Sudden loss of muscle tone: head drop, limb drop, or slumping. The hallmark seizure type of Lennox-Gastaut syndrome. | |
| Unknown onset | - | Onset unwitnessed or not captured on EEG (common during sleep). Treat broad-spectrum until reclassified. |
A tonic-clonic seizure preceded by an aura is a focal seizure that secondarily generalized, not a primary generalized seizure. Auras don't happen before true primary GTC seizures because there's no focal onset to warn you. Also: focal seizures with dyscognitive features and GTC seizures are the ones patients are most often amnestic to; interictally (between seizures), the exam is usually completely normal, so a normal neuro exam doesn't rule anything out.
You need oneof three things: (1) at least 2 unprovoked seizures more than 24 hours apart, (2) 1 unprovoked seizure plus a ≥60% probability of another over the next 10 years, or (3) diagnosis of a recognized epilepsy syndrome. A single seizure from hypoglycemia, alcohol withdrawal, or a febrile illness is not epilepsy, that's a provoked (acute symptomatic) seizure, and it's treated by fixing the trigger, not by starting a lifelong ASM.
A seizure starts small: a handful of neurons fire abnormally. Normally, inhibitory synaptic currents and membrane conductances keep that contained (this is called "surround inhibition"). In a seizure, that containment breaks down and the abnormal firing synchronizes and spreads, either locally (focal seizure) or widely (generalized seizure). You don't get a clinical seizure without that synchronization step.
| Excitatory drivers | Inhibitory brakes |
|---|---|
| Glutamate, sodium and calcium currents, substance P, neurokinin B | GABA, adenosine, potassium currents, neuropeptide Y, opioid peptides, galanin |
Push excitation up or pull inhibition down and you tip toward seizure. Sustained depolarization from this imbalance can itself cause neuronal death, which is part of why prolonged uncontrolled seizures (status epilepticus) are a true emergency and not just a longer version of a normal seizure.
Absence seizures don't run on the same circuit as focal or GTC seizures. They come from an abnormal oscillation between the thalamus and cortex, driven by T-type calcium currents. That's a completely separate mechanism, which is why the drugs that work for it (ethosuximide, valproate) are different from the sodium-channel blockers that dominate focal and GTC treatment.
Sodium channel blockers(carbamazepine, phenytoin, lamotrigine, oxcarbazepine, topiramate, zonisamide, valproate, lacosamide) stabilize the channel's inactivated state and blunt high-frequency repetitive firing, the signature of a spreading focal or GTC discharge. GABA potentiators(benzodiazepines, barbiturates, vigabatrin, tiagabine) boost the inhibitory brake directly. T-type calcium blockers(ethosuximide, valproate) interrupt the thalamocortical absence circuit specifically. Newer-mechanism drugshit other nodes: gabapentin and pregabalin bind the α2δ subunit of presynaptic calcium channels and cut glutamate release; levetiracetam and brivaracetam bind SV2A, a synaptic vesicle protein, and dampen neurotransmitter release; perampanel is a noncompetitive AMPA (glutamate) receptor antagonist.
Carbamazepine, gabapentin, oxcarbazepine, phenytoin, tiagabine, and vigabatrin can worsen absence or myoclonic seizures.They're excellent sodium-channel blockers for focal disease, but they don't touch the thalamocortical T-type calcium circuit that drives absence seizures, and in mixed seizure-type patients they can actually aggravate the seizure types they weren't chosen for. This is a favorite exam distractor: "best broad-spectrum drug" is not the same as "safe for every seizure type."
Symptoms depend entirely on seizure type and where the abnormal firing starts, but they tend to be stereotyped within an individual, meaning the same patient's seizures usually look similar to each other every time.
Presyncope/syncope vs. seizure:both can cause loss of consciousness and even brief jerking (convulsive syncope), which is why the workup asks about triggers (standing, heat, pain vs. no trigger), aura, tongue biting, and incontinence. A serum prolactin drawn 10–20 minutes after a suspected tonic-clonic event can help separate seizure from pseudoseizure, but it does notreliably separate seizure from syncope, since both can transiently raise prolactin.
Diagnosis leans heavily on history, from both the patient and a witness, since patients are often amnestic to their own dyscognitive or GTC seizures.
Epilepsy = (1) ≥2 unprovoked seizures >24 hours apart, OR (2) 1 unprovoked seizure with ≥60% recurrence risk over the next 10 years, OR (3) an epilepsy syndrome diagnosis. Meeting any one of the three is sufficient.
Goals:control or reduce seizure frequency and severity, minimize ASM adverse effects, and support adherence, so the patient can live as normal a life as possible. Complete seizure suppression is not always achievable without unacceptable side effects, so tolerability is a real part of the decision, made together with the patient, not imposed on them. Comorbid anxiety/depression and social factors (driving, job security, stigma) meaningfully affect quality of life and belong in that conversation.
Ketogenic diet, vagus nerve stimulation (VNS), and epilepsy surgery are all real options when the benefit clearly outweighs the risk, usually after ASM monotherapy and reasonable polytherapy attempts haven't worked.
The "therapeutic range" is a population average, not a target for every individual. Some patients achieve full seizure control below the standard range; others need levels above it. The useful range even shifts by seizure type (higher targets tend to apply to focal seizures with dyscognitive features than to GTC seizures). Where levels earn their keep is documenting nonadherence, catching loss of efficacy, and guiding dosing in renal/hepatic disease, polypharmacy, and pregnancy. For highly protein-bound drugs (valproate is the classic one), check freerather than total levels if you suspect altered protein binding, situations like renal failure, liver disease, hypoalbuminemia, burns, pregnancy, or malnutrition.
Reduced renal/hepatic clearance plus increased CNS receptor sensitivity means the "normal" therapeutic range can be invalid in an elderly patient, they get toxic at lower levels. They're also more likely to be on interacting medications, and CYP-inducing ASMs (carbamazepine, phenytoin, valproic acid, phenobarbital) compound that risk. Hypoalbuminemia is common in this population and is a real problem for highly protein-bound drugs like valproic acid. Lamotrigine is often favored in older adults with focal onset seizuresspecifically because of its effectiveness and tolerability profile.
At 12 months, seizure-free rates run highest for GTC-only (48–55%), lowest for focal-only (23–26%), and in between for mixed types (25–32%). Medication resistanceis defined as inadequate control after two trials of appropriately chosen, dosed, and tolerated ASMs, whether as monotherapy or combination.
Consider withdrawal if the patient has been seizure-free for 2–5 years, has a single seizure type, a normal neuro exam and IQ, and an EEG that's normalized on treatment. Factors that predict a failedwithdrawal attempt: high historical seizure frequency, prior episodes of status epilepticus, mixed seizure types, and abnormal cognition. Whenever you do withdraw, taper gradually, never stop abruptly.
This is the table that actually drives the prescription. Match the seizure type on the left to the drug list on the right, and remember the avoid-list underneath it.
| Seizure type | First-line agents |
|---|---|
| Focal onset | Carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, lacosamide |
| Generalized (GTC, myoclonic, atonic) | Valproate, levetiracetam, lamotrigine, topiramate |
| Absence | Ethosuximide (drug of choice); valproate as an alternative that also covers mixed types |
| Unknown onset / unclassified | Valproate, levetiracetam, lamotrigine, topiramate, broad-spectrum preferred until the type is clarified |
Carbamazepine and phenytoin can worsen these seizure types (and gabapentin, oxcarbazepine, tiagabine, and vigabatrin are on the same caution list). If a patient with known absence or myoclonic epilepsy is on one of these, that's worth flagging even if it was started for a different reason.
The handbook singles out carbamazepine, ethosuximide, gabapentin, levetiracetam, oxcarbazepine, phenytoin, valproic acid, and zonisamideas having the strongest evidence base for use as initial monotherapy in their respective seizure types. Newer agents are often FDA-labeled as adjunctive-only, but are frequently used off-label as monotherapy in practice once there's clinical comfort with them.
Initial total daily dose (TDD) for adults, plus the target serum concentration range where one is defined. Many third-generation agents don't have an established range, you titrate to clinical effect instead.
| Medication | Initial adult TDD | Target serum range |
|---|---|---|
| First Generation | ||
| Carbamazepine | 400 mg | 4–12 mcg/mL |
| Clonazepam | up to 1.5 mg | 20–70 ng/mL |
| Ethosuximide | 500 mg | 40–100 mcg/mL |
| Phenobarbital | 300 mg (LD 15–20 mg/kg) | 10–40 mcg/mL |
| Phenytoin | 300 mg (LD 15–20 mg/kg) | Total 10–20 mcg/mL · Free 0.5–3 mcg/mL |
| Primidone | 100–125 mg | 5–10 mcg/mL |
| Valproate / Divalproex | 10–15 mg/kg | 50–100 mcg/mL |
| Second Generation | ||
| Felbamate | 1200 mg | 30–60 mcg/mL |
| Gabapentin | 300–900 mg | 2–20 mcg/mL |
| Lamotrigine | 25 mg | 4–20 mcg/mL |
| Levetiracetam | 1000 mg | 12–46 mcg/mL |
| Oxcarbazepine | 600 mg | 3–35 mcg/mL (MHD metabolite) |
| Tiagabine | 4 mg (less if not on inducers) | 0.02–0.2 mcg/mL |
| Topiramate | 25–50 mg | 5–20 mcg/mL |
| Zonisamide | 100 mg | 10–40 mcg/mL |
| Third Generation | ||
| Brivaracetam | 100 mg | Not defined |
| Cenobamate | 12.5 mg | Not defined |
| Eslicarbazepine | 400 mg | Not defined |
| Lacosamide | 100–200 mg | Not defined |
| Perampanel | 2 mg | Not defined |
| Pregabalin | 150 mg | Not defined |
| Third Generation - Specific Epilepsy Syndromes | ||
| Cannabidiol | 5 mg/kg | Not defined |
| Clobazam | 5–10 mg (weight-based) | 0.03–0.3 ng/mL |
| Fenfluramine | 0.1–0.2 mg/kg (dose depends on concomitant stiripentol/clobazam) | Not defined |
| Rufinamide | 400–800 mg | Not defined |
| Stiripentol | 50 mg/kg | 4–22 mg/L |
| Vigabatrin | 1000 mg | 0.8–36 mcg/mL |
Pediatric initial doses differ substantially (often mg/kg-based) and are not reproduced here; consult a pediatric-specific reference before dosing a minor.
Blocks voltage-gated sodium channels in their inactivated state, which quiets repetitive high-frequency firing. First-line for focal and GTC seizures; also useful for comorbid trigeminal neuralgia and bipolar disorder. Avoid in absence or myoclonic seizures, it can worsen them.
Dosing quirk:food, especially fat, enhances bioavailability. Controlled/sustained-release given every 12 hours is bioequivalent to immediate-release every 6 hours, and the sustained-release capsule can be opened and sprinkled on food for patients who can't swallow pills.
Carbamazepine induces its own metabolism. Autoinduction starts 3–5 daysafter initiation and is complete by 21–28 days, meaning levels that looked fine at week 1 can fall meaningfully by week 4 without a dose change. Reversal after stopping the drug is comparatively fast.
Boxed warning:increased SJS/TEN risk with the HLA-B*1502allele (screen in patients of Asian, Southeast Asian, or South Asian ancestry, ~15% carrier prevalence in these populations); also aplastic anemia and agranulocytosis. Continue therapy unless WBC drops below 2500/mm³ or ANC below 1000/mm³. The active metabolite, carbamazepine-10,11-epoxide, contributes to idiosyncratic reactions. Cannot be used within 14 days of an MAO inhibitor.
Interactions:potent inducer of CYP3A4, CYP1A2, CYP2B6, and CYP2C9/19, so it lowers levels of most other ASMs and hormonal contraceptives. Erythromycin/clarithromycin (CYP3A4 inhibitors) meaningfully raise carbamazepine levels, a clinically significant interaction to know cold.
Sodium channel blocker used for focal seizures, GTC seizures, and (as IV fosphenytoin) status epilepticus. Avoid in absence or myoclonic seizures.
Within the usual therapeutic range, phenytoin metabolism becomes saturable, so a small dose increase can cause a disproportionately large jump in serum level. That's why titration follows a level-dependent scale rather than a flat percentage increase: if the level is <7 mcg/mL, add 100 mg/day; if 7–12 mcg/mL, add only 50 mg/day; if >12 mcg/mL, add ≤30 mg/day. Above 50 mcg/mL, phenytoin can actually exacerbate seizures.
Practical points:oral absorption becomes saturable above 400 mg single doses; the IM route is avoided due to erratic absorption (use IV fosphenytoin instead, it's a prodrug de-esterified in the blood); only extended-release formulations are appropriate for once-daily dosing, most adults can be on once-daily but children usually need more frequent dosing; don't switch brands without close monitoring. Folic acid supplementation enhances phenytoin clearanceand can cause loss of seizure control, worth remembering since folate is so commonly co-prescribed. Phenytoin acid (tablets/suspension) and phenytoin sodium (capsules/injection) aren't 1:1 equivalent: 92 mg acid ≈ 100 mg sodium salt.
Monitor free levelsin renal/hepatic impairment, hypoalbuminemia, or pregnancy, since these alter protein binding and make total levels misleading. Boxed-warning-level concerns: HLA-B*1502 SJS/TEN risk in Asian ancestry, CYP2C9*3 carriers at higher SCAR (severe cutaneous adverse reaction) risk, and purple glove syndrome with IV administration.
Works through three mechanisms at once: sodium channel blockade, GABA potentiation, and T-type calcium channel modulation. That breadth is why it's first-line for absence, myoclonic, atonic, and GTC seizures, useful in mixed seizure disorders, and also approved for focal onset seizures.
Hepatotoxicity(highest risk in children <2 years and anyone with a mitochondrial disorder), fetal risk(neural tube defects, other major malformations, decreased IQ), and pancreatitis(including fatal hemorrhagic pancreatitis). Contraindicated in significant hepatic dysfunction, POLG-related mitochondrial disorders, and urea cycle disorders.
Hyperammonemia(with or without encephalopathy) is a known risk, and it's specifically higher when valproate is combined with topiramate, a pairing worth double-checking in polytherapy. Dose-dependent thrombocytopenia can occur above roughly 100 mcg/mL.
Interactions:valproate is a broad hepatic enzyme inhibitor(the opposite direction of carbamazepine/phenytoin/phenobarbital), and it also displaces some drugs from albumin. It raises levels of lamotrigine (roughly 2-fold, and doubles lamotrigine's rash/SJS risk, hence the mandatory dose reduction when combined), phenobarbital, topiramate, and several others. Carbapenem antibiotics and combined oral contraceptives can lower valproate levels.
Lamotrigine:sodium channel blocker, useful for focal seizures, GTC, and as an alternative for absence; also a mood stabilizer in bipolar disorder. Slow titration is mandatory, rash risk (including SJS/TEN) rises sharply with fast titration or with concurrent valproate (which roughly doubles lamotrigine levels). Standard titration: 25 mg daily x2 weeks → 50 mg daily x2 weeks → increase by 50 mg every 1–2 weeks toward a 200–400 mg/day target; cut the dose in half if adding valproate, and titrate faster if the patient is already on an enzyme inducer. Rash typically shows up after 3–4 weeks of therapy.
Levetiracetam:binds SV2A and modulates neurotransmitter release rather than touching ion channels directly. Minimal CYP interactions makes it a favorite in polypharmacy patients. Renally eliminated (66% unchanged), so dose-adjust in renal impairment. Watch for behavioral adverse effects, irritability, agitation, depression, rare psychosis, especially relevant in patients with underlying psychiatric disease.
Oxcarbazepine:prodrug converted to the active MHD metabolite, a sodium channel blocker. Doesn't autoinduce (unlike its cousin carbamazepine) and has a linear dose-concentration relationship. Its signature adverse effect is hyponatremia, up to 25% incidence, meaningfully higher than carbamazepine.
Topiramate:multi-mechanism (sodium channel blockade, GABA-A enhancement, AMPA/kainate antagonism, weak carbonic anhydrase inhibition). First-line for focal and generalized seizures, and doubles as migraine prophylaxis and a weight-loss adjunct. Adverse effects track the carbonic anhydrase piece: kidney stones, metabolic acidosis, and cognitive slowing/word-finding difficulty are the ones patients complain about most. Efficacy plateaus above 400 mg/day in patients already on other ASMs, so pushing higher usually just buys more side effects without more seizure control.
Benzodiazepines and barbiturates are both positive allosteric modulators of GABA-A, but they work differently: benzodiazepines increase the frequencyof chloride channel opening, while barbiturates increase the durationof opening. That mechanistic difference is why barbiturates carry more respiratory depression risk at high doses.
Vigabatrinis an irreversible inhibitor of GABA transaminase (the enzyme that breaks GABA down), which is a fundamentally different way to boost GABA tone. It carries a boxed warning for permanent, progressive bilateral vision lossthat can appear after weeks to years of exposure, requires REMS program registration, and mandates eye exams every 3 months. Its real niche is infantile spasms, where the seizure-control benefit is judged to outweigh the vision risk.
Tiagabineblocks GAT-1, the GABA reuptake transporter, prolonging GABA's action in the synapse. It's been associated with new-onset seizures and status epilepticus, including in patients without epilepsy, an unusual and important safety signal for a drug meant to control seizures.
These aren't specific to one drug, they're patterns you should watch for across almost any ASM.
The most widely recognized idiosyncratic ASM reaction. HLA-B*1502raises SJS/TEN risk with carbamazepine (and possibly phenytoin, lamotrigine, oxcarbazepine), and occurs in roughly 15% of people of Asian, Southeast Asian, or South Asian descent, patients with this variant should not use these ASMs. HLA-A*3101is linked to carbamazepine-induced skin reactions in Chinese, Japanese, and European populations, and carbamazepine should be avoided there too.
A continuous seizure lasting longer than 5 minutes, or repeated seizures over 30 minuteswithout full recovery of consciousness in between. Past that window, the risk of lasting neurologic injury climbs, which is why it's treated as a true neurologic emergency, not a longer version of a routine seizure.
Diazepam IV (or rectal gel), lorazepam IV, or midazolam IM are the initial drug therapy. These act fast because they potentiate GABA directly, the quickest way to restore the excitation/inhibition balance in an ongoing seizure.
If benzodiazepines don't terminate the seizure, IV phenytoin (or its prodrug fosphenytoin, which avoids the tissue-damage risk of IV phenytoin and can be given faster) is the classic second-line loading strategy, phenytoin's ability to be loaded IV or orally to reach steady-state levels quickly is exactly what makes it useful here, distinct from its role as a chronic oral maintenance drug.
Never stop a benzodiazepine or barbiturate abruptly after prolonged use, withdrawal itself can precipitate status epilepticus.Any planned taper off these agents needs to be slow and supervised.
Hormones actively modulate seizure threshold: estrogen is pro-convulsant, progesterone is anticonvulsant.That single fact explains most of what follows in this section.
3.5–4x the baseline riskof major congenital malformations, plus documented neurodevelopmental and cognitive effects in exposed children. Avoid in pregnancy when at all possible; if it's genuinely the only option that controls seizures, keep the dose at 500–600 mg/day or less.
| Parameter | When | Watching for |
|---|---|---|
| Seizure/side-effect diary | Ongoing, every visit | True efficacy and tolerability; clinical response matters more than serum levels |
| Serum ASM concentration | Situational: suspected nonadherence, loss of efficacy, renal/hepatic disease, polypharmacy, pregnancy | Subtherapeutic or toxic levels; use free levels if protein binding is in question |
| CBC and LFTs | Baseline, then with any fever/rash/lethargy/vomiting, especially in the first 6 months | Blood dyscrasias, hepatotoxicity (carbamazepine, valproate, felbamate especially) |
| Sodium | Periodically on carbamazepine or oxcarbazepine | SIADH-driven hyponatremia (up to 25% with oxcarbazepine) |
| Bone density, vitamin D, calcium | Periodically on long-term enzyme-inducing ASMs or valproate | Osteomalacia, osteoporosis |
| Mood / behavior / suicidality screen | Every visit | New or worsening depression, agitation, suicidal ideation, class-wide risk, more prominent with levetiracetam |
| Adherence | Every visit | Up to 60% of patients struggle here; it's the most fixable cause of "treatment failure" |
| EEG | Periodically, and before considering ASM withdrawal | Persistent epileptiform activity; normalization supports a withdrawal attempt |