Seizures and Epilepsy
Clinical Snapshot
Epilepsy is a neurological disease characterized by an enduring predisposition to generate unprovoked seizures — practically defined by the International League Against Epilepsy (ILAE) as 2 unprovoked seizures more than 24 hours apart, 1 unprovoked seizure with a high (over 60%) probability of recurrence over the next 10 years, or diagnosis of a recognized epilepsy syndrome.[1] A seizure itself is classified as focal if it originates in one cerebral hemisphere or generalized if it engages both hemispheres simultaneously — this single distinction is the primary driver of antiseizure medication (ASM) selection, since several first-line agents differ by seizure type and some agents that work well for one type can worsen another.[2] Managing epilepsy addresses not only seizure prevention but the biological, cognitive, psychological, and social consequences of the disease, and — separate from chronic epilepsy management — status epilepticus is a distinct, time-critical emergency requiring immediate benzodiazepine treatment regardless of whether the underlying cause is known epilepsy or a new provoked seizure.
Recognize the Condition
Seizure semiology — what the seizure actually looks like — is the foundation of both diagnosis and drug selection. The single most important classification is whether a seizure is focal (originates in one hemisphere) or generalized (engages both hemispheres simultaneously), because this determines which first-line antiseizure medications are appropriate and which agents can actually worsen seizure control if the seizure type is misclassified.[2]
Focal (partial) seizures
Focal seizure without impairment of awareness
Usually brief (under 1 minute); motor, sensory, autonomic, or cognitive features; an aura may be present, and when it is, its character can help localize the seizure focus.
Focal seizure with impairment of awareness
Usual duration 1-2 minutes; behavioural arrest often manifesting as a blank stare, frequently with motor automatisms (lip smacking, chewing movements); brief postictal confusion is common. Frequently misdiagnosed as an absence seizure.
Focal to bilateral tonic-clonic seizure
Begins as a focal seizure but evolves to resemble a generalized tonic-clonic seizure. A careful history for focal-onset features (an aura, unilateral onset) distinguishes this from a primary generalized tonic-clonic seizure — a distinction that still matters for drug selection, since the underlying process began focally.
Generalized seizures
Absence seizures
Last only seconds (usually 5-10); no warning aura and no postictal confusion; recur daily, often in clusters, if untreated; onset in childhood or adolescence — this seizure type essentially never begins in adulthood.
Generalized tonic-clonic seizures
Duration 1-2 minutes; a fairly uniform sequence of tonic then clonic motor activity; impaired consciousness, apnea, and cyanosis during the event; postictal stupor, confusion, and headache afterward.
Atonic seizures
Abrupt loss of consciousness and muscle tone with a fall, returning to awareness within seconds, with no other motor features. Occurs as part of a childhood-onset epilepsy syndrome with intellectual disability and other seizure types — virtually never seen as an isolated seizure type in an otherwise healthy adult.
Myoclonic seizures
Brief, bilateral, shock-like jerks. Multifocal, asynchronous myoclonic jerks occurring in the setting of a metabolic encephalopathy are a different, nonepileptic phenomenon and should not be classified the same way.
Status epilepticus — any seizure that fails to self-terminate — is covered separately below (Red Flags and Refer, Choose Initial Treatment, and the Clinical Decision Algorithm), since it requires immediate emergency management rather than routine outpatient ASM selection.
Risk Factors
Risk factors for seizures and epilepsy
- Family history of seizures or other neurologic disease.
- History of recurrent or prolonged seizures in childhood, intracranial infection, head trauma, stroke, or any systemic disorder affecting the CNS.
- Known structural brain abnormality (prior stroke, traumatic brain injury, tumor, cortical malformation).
- A recognized genetic epilepsy syndrome (e.g., childhood absence epilepsy, juvenile myoclonic epilepsy).
- Developmental abnormalities or intellectual disability with childhood-onset epilepsy.
Precipitants of an isolated (provoked) seizure
- Use of prescribed or recreational drugs, or alcohol intoxication or withdrawal.
- Toxic or metabolic derangement from an acute medical illness (e.g., hypoglycemia, hyponatremia).
- An acute brain insult — traumatic brain injury, stroke, or encephalitis — within the preceding 7 days.
Precipitants of breakthrough seizure in known epilepsy
- Medication nonadherence — the most common cause of seizure breakthrough in patients with known epilepsy.
- Intercurrent illness with fever or vomiting.
- Sleep deprivation.
- Alcohol or nonprescription drug use.
- Pregnancy (via pharmacokinetic changes — see Special Populations).
- Addition or withdrawal of a drug that affects seizure threshold or interacts with antiseizure medications.
- Sudden withdrawal from alcohol, benzodiazepines, or barbiturates.
Red Flags & Refer
Any of the following requires urgent escalation — do not manage as routine outpatient epilepsy care.
- Status epilepticus — a convulsive seizure lasting longer than 5 minutes, or recurrent seizures without return to baseline consciousness between them, most likely represents impending status epilepticus and should be treated as an emergency immediately, rather than waiting for the older 30-minute threshold.[3]
- Nonconvulsive status epilepticus — consider this diagnosis in any patient with unexplained coma or persistently altered mental status; any seizure type, including absence or focal seizures, can evolve into this form.
- A first-ever seizure with high-risk features — an abnormal neurologic examination, epileptiform discharges on EEG, an abnormal brain-imaging finding, or dementia — needs urgent neurology referral rather than routine deferred follow-up, since these features substantially raise the probability of recurrence.[4]
- Signs of ASM toxicity — ataxia, nystagmus, altered mental status, or (with phenytoin or carbamazepine specifically) cardiac conduction abnormalities — need prompt reassessment of dose and, where available, a drug level.
- A drug rash while on an ASM — stop the suspected agent immediately; continuing after a definite rash risks a life-threatening hypersensitivity reaction (Stevens-Johnson syndrome, toxic epidermal necrolysis, or DRESS).
- Breakthrough seizures on adequate, adherent therapy — once nonadherence and reversible precipitants are excluded, this pattern needs specialist reassessment rather than an empiric dose increase alone.
- New focal neurologic deficits, suggesting an evolving structural lesion.
- New or worsening mood change, agitation, or suicidal ideation — antiseizure medications as a class carry an increased risk of suicidal thoughts and behaviour, and this needs prompt assessment.
Assessment & Diagnosis
Differentiating epileptic seizures from common mimics
| Feature | Epileptic seizure | Syncope | Psychogenic nonepileptic seizure | Migraine / TIA |
|---|---|---|---|---|
| Typical trigger | Often none identifiable; sleep deprivation, a missed dose, or a metabolic/structural precipitant | Prolonged standing, pain, emotional stress, micturition, or a cardiac cause | Often a psychological stressor; frequently occurs with an audience present | Migraine: a known personal migraine pattern. TIA: vascular risk factors |
| Onset | Sudden; an aura may precede a focal seizure | A gradual prodrome (lightheadedness, tunnel vision, diaphoresis) in most cases | Can be gradual, with waxing and waning intensity | Migraine: gradual visual/sensory march. TIA: sudden focal deficit |
| Duration | Seconds to a few minutes | Seconds, with rapid recovery once supine | Often longer than a true seizure, sometimes many minutes | Migraine aura: roughly 20-60 minutes. TIA: minutes, resolving within 24 hours |
| Motor features | Stereotyped tonic-clonic activity, or focal motor signs matching a specific seizure type | Brief myoclonic jerks can occur (convulsive syncope) but are not a sustained tonic-clonic sequence | Asynchronous, out-of-phase limb movements; pelvic thrusting; side-to-side head movement | Negative or positive sensory/visual symptoms, not rhythmic motor activity |
| Eyes | Typically open during the event | Typically open, with pallor | Often forcibly closed, resisting passive opening | Not applicable |
| Postictal state | Confusion, drowsiness, and headache lasting minutes to hours | Rapid, full return to baseline alertness | Variable — can include tearfulness or a rapid return to normal | Migraine: postdrome fatigue/headache. TIA: no confusion once the deficit resolves |
| Injury / incontinence | Lateral tongue-biting and urinary incontinence are supportive findings but not required for diagnosis | Injury from the fall itself is possible; tongue-biting and incontinence are uncommon | Injury and incontinence are both uncommon | Not applicable |
| Diagnostic clue | Interictal or ictal epileptiform activity on EEG | Normal EEG; a cardiac or orthostatic cause is often identifiable | A normal ictal EEG during a typical event | Migraine: normal imaging. TIA: vascular imaging and risk-factor workup |
History
- Obtain a detailed description of the "spell" from both the patient and a witness — this is the single most important step in diagnosis.
- Ask specifically about an aura (e.g., a rising abdominal sensation, sudden fear, déjà vu) — its presence indicates focal seizure onset and its character can localize the seizure focus; its absence may reflect a generalized seizure, or a focal seizure that spread too rapidly to produce a recognized aura.
- Ask about prior recurrent or prolonged childhood seizures, intracranial infection, head trauma, stroke, other CNS-affecting systemic disease, and family history of seizures or neurologic disease.
- Establish whether a precipitant of an isolated provoked seizure occurred within the preceding 7 days (see Risk Factors).
- In a patient with known epilepsy presenting with seizure recurrence, specifically ask about adherence, intercurrent illness, sleep deprivation, alcohol/substance use, pregnancy, and any recent medication change (see Risk Factors) — nonadherence is the most common identifiable cause.
Physical examination
- Look for evidence of a systemic disorder affecting the CNS (malignancy, infection, autoimmune disease, a drug toxidrome or withdrawal syndrome).
- Look for focal or lateralizing neurologic findings — hemianopia, motor weakness, hemisensory disturbance, reflex asymmetry, language dysfunction.
- Assess for injury sustained during a generalized tonic-clonic seizure — tongue laceration, shoulder dislocation, vertebral compression fracture, burns, or other trauma.
Investigations
First seizure: obtain CBC, glucose, electrolytes, calcium, and renal/hepatic function; add an alcohol level, toxicology screen, and infection screen (urinalysis/culture, especially in older or developmentally challenged patients) when a provoked cause is plausible; obtain a chest x-ray if metastatic disease is a consideration and an ECG to exclude a significant cardiac conduction abnormality.[4]
Obtain an EEG to support the clinical impression of a seizure and to help determine focal versus generalized onset — an interictal EEG may show focal spikes or generalized spike-wave discharges and can help estimate recurrence risk. A normal EEG does not rule out epilepsy or future seizure risk.
Obtain a brain MRI (preferred) in essentially all patients with an unprovoked seizure, unless there is a clear diagnosis of a generalized epilepsy syndrome (e.g., childhood absence epilepsy, juvenile myoclonic epilepsy) or an already-known structural cause. CT can be used in the acute/urgent setting, or when MRI is unavailable or contraindicated.
Obtain a lumbar puncture when the presentation suggests intracranial infection (meningitis, encephalitis) or a CT-negative subarachnoid hemorrhage — it is not routinely indicated for an uncomplicated first seizure without these features.
For a patient with known epilepsy presenting with seizure recurrence, check an ASM serum level where clinically useful — phenytoin, phenobarbital, primidone, carbamazepine, and valproic acid have established, interpretable serum levels. Levels for most other ASMs are difficult to obtain and of limited clinical value, so do not order them as a routine reflex.
Treatment Targets
- Appropriately decide whether antiseizure medication (ASM) therapy is indicated after a first seizure.
- Prevent or minimize seizure recurrence and severity in patients with an established diagnosis of epilepsy.
- Achieve seizure freedom on ASM monotherapy whenever possible before considering polytherapy.
- Prevent or minimize ASM adverse effects, including long-term risks (osteoporosis, teratogenicity, cognitive effects).
- Optimize quality of life — employment, psychosocial functioning, and driving eligibility.
- In status epilepticus, terminate seizure activity as rapidly as possible to limit neuronal injury and systemic complications.
Choose Initial Treatment
Whether to treat after a first seizure
Deciding whether to start an ASM after a single unprovoked seizure is individualized, not automatic — many patients will never need long-term treatment after one seizure. Immediate ASM therapy meaningfully lowers the chance of a second seizure over the next 2 years but does not change the longer-term (beyond 3 years) probability of eventual seizure remission, so the discussion should weigh recurrence risk (highest in the first 2 years; increased by a prior brain insult, epileptiform EEG discharges, a significant imaging abnormality, or a nocturnal seizure) against ASM adverse-effect risk and patient priorities, including driving.[4]
Do not start an ASM for a purely provoked (acute symptomatic) seizure caused by a reversible metabolic derangement or intoxication/withdrawal — treat the underlying cause instead. An exception is the first 7 days after acute traumatic brain injury, where short-term ASM use reduces early seizures without changing the long-term risk of developing epilepsy.
Selecting first-line ASM monotherapy by seizure type
1st line, generalized tonic-clonic levetiracetam or lamotrigine.
Alternative, generalized tonic-clonic — avoid in patients of childbearing potential unless other options fail or are not tolerated valproic acid/divalproex, the most effective agent for idiopathic generalized epilepsy but the agent carrying the highest teratogenic risk among commonly used ASMs (see Special Populations).
1st line, focal (partial) seizures lamotrigine, levetiracetam, or lacosamide — lamotrigine has shown better tolerability than carbamazepine with comparable long-term seizure freedom in head-to-head trial data, and is generally considered the first-choice agent for focal-onset epilepsy on both efficacy and cost-effectiveness grounds.
Alternative, focal seizures oxcarbazepine or carbamazepine remain reasonable options, particularly when cost or interaction profile favours them, though carbamazepine requires HLA-B*15:02 testing in patients of relevant ancestry before use (see Monitoring and Follow-Up).
1st line, absence seizures ethosuximide — effective for absence seizures only, with no protection against generalized tonic-clonic seizures, so it should not be used alone if tonic-clonic seizures also occur.
Alternative, absence seizures valproic acid or lamotrigine.
1st line, myoclonic and tonic/atonic seizures levetiracetam or valproic acid/divalproex (same childbearing-potential caveat as above).
Avoid or use with caution — can worsen these seizure types carbamazepine, gabapentin, oxcarbazepine, phenytoin, and vigabatrin can all exacerbate absence, myoclonic, or tonic/atonic seizures — confirming the seizure type before prescribing is not optional.
Whichever agent is chosen, start at a fraction of the usual maintenance dose (see Drug Tables) unless rapid seizure control is required, evaluate once the usual maintenance dose is reached, and add a second ASM only after the first has genuinely failed at the maximum tolerated dose — gradually withdrawing the first agent once the second reaches maintenance. Reserve polytherapy for patients who have failed 2-3 appropriately selected and dosed monotherapy trials.
Status epilepticus: a stepwise escalation, not a single drug choice
Status epilepticus follows its own emergency algorithm, not a variation on routine ASM selection — each step below has a specific trigger for moving to the next.
1st line (0-10 minutes) — with IV access lorazepam 4 mg IV, repeated once if the seizure persists.
1st line (0-10 minutes) — no IV access midazolam 10 mg IM, intranasal, or buccal (5 mg IM if body weight 13-40 kg; repeat once if seizures persist), or diazepam 20 mg PR — intramuscular midazolam has shown superior effectiveness to intravenous lorazepam specifically in patients without established IV access.[3]
2nd line — use when the seizure persists roughly 10-30 minutes despite an adequate benzodiazepine dose load with one intravenous ASM: levetiracetam 40-60 mg/kg IV over 10 minutes (maximum 4.5 g), fosphenytoin/phenytoin 20 mg/kg IV (maximum rate 50 mg/min, slower in older adults, with ECG monitoring), or valproic acid 15-40 mg/kg IV over 10 minutes (maximum 3 g) — a large randomized comparative-effectiveness trial found these 3 agents equally effective, so the choice is individualized by comorbidity and contraindication rather than by expected superiority of one agent over another.[5]
Refractory status epilepticus — use when seizures persist despite an adequate benzodiazepine and a full second-line IV load admit to intensive care, obtain continuous EEG monitoring and expert neurology/critical-care input, and start a continuous anesthetic-dose infusion: midazolam 10-20 mg IV bolus then 0.05-0.4 mg/kg/hour, propofol 1-2 mg/kg IV bolus then 2-5 mg/kg/hour, or phenobarbital 20 mg/kg IV at 50-75 mg/min — obtain neuroimaging (and a lumbar puncture if meningitis/encephalitis is possible) once the seizure is controlled, if the etiology is not already known.[3]
Non-Pharmacologic Treatment
Lifestyle and general measures
- Encourage adequate sleep — sleep deprivation lowers the seizure threshold in some patients.
- Advise minimal alcohol intake; cocaine and amphetamines must be avoided given their proconvulsant properties.
- Ask specifically about herbal remedies and dietary supplements, since some carry proconvulsant properties or clinically important ASM interactions.
- A ketogenic, modified Atkins, or low-glycemic-index diet can reduce seizure frequency in selected patients, though a strict ketogenic diet is impractical for most adults; involve a dietitian given the risk of nutritional deficiency and diet-ASM interactions.
- Cannabidiol oral solution is Health Canada-approved specifically as adjunctive therapy for seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex — it is not a general-purpose antiseizure treatment, and evidence for recreational cannabis as a seizure treatment remains inconclusive.
- Complementary practices such as yoga and mindfulness-based therapy have some evidence for improving quality of life, mood, and possibly seizure control; meditation, relaxation training, and acupuncture have more limited evidence but low risk, and can be considered for overall wellbeing.
General safety measures and seizure precautions
- People with epilepsy have a higher risk of death from unintentional injury or poisoning than the general population and should be counselled accordingly.
- To reduce burn risk: discourage smoking, and encourage using a microwave and the rear burners of a stove.
- Avoid heights, ladders, and power tools.
- Prefer showers over baths, given drowning risk.
- Assess recreational activities and current/planned employment for environmental hazards, and counsel accordingly.
- Patients with active epilepsy who care for young children should not bathe them unassisted and should not use a change table for diapering.
- Consider referral to an epilepsy support group.
Driving
Assess driving status at every visit after a seizure. Under the current Canadian Medical Association / Canadian Council of Motor Transport Administrators standard, a non-commercial licence generally requires being seizure-free for at least 6 months under ongoing medical care (or a consistent sleep-only/on-waking seizure pattern sustained for at least 12 months); a commercial licence generally requires 5 years seizure-free, occasionally reduced to 3 years for specific epilepsy types on a neurologist's recommendation.[6] Reporting obligations to provincial licensing authorities differ by province (mandatory physician reporting versus patient self-reporting) — reinforce that the patient, not only the prescriber, has a personal obligation to stop driving after any seizure and to understand their own province's specific rule.
Epilepsy surgery and neuromodulation
Refer for consideration of epilepsy surgery and/or neuromodulation when seizures remain medically refractory despite 2 or more appropriately selected and dosed ASM trials — this does not include an ASM that was discontinued solely for adverse effects rather than lack of efficacy.
Special Populations
Pregnancy
Discuss pregnancy planning proactively with every patient of childbearing potential who has epilepsy, well before conception — this is not a conversation to defer until pregnancy is confirmed.
Prepregnancy: reassess whether ongoing ASM treatment is still needed, and — if ASM polytherapy includes valproate or topiramate — consider withdrawing whichever agent contributed least to seizure control, since polytherapy that includes either drug raises congenital-malformation risk above monotherapy. Teratogenic risk is dose-dependent for every ASM but is particularly pronounced for valproate and topiramate; avoid valproic acid in patients of childbearing potential where possible, weighed against the real risk of uncontrolled seizures.
Folic acid: every patient of childbearing potential taking an ASM falls into the moderate-risk category and should receive 1 mg folic acid PO daily; reserve the high-risk 4-5 mg PO daily dose for a personal or family history of neural tube defect. Start at least 3 months before conception and continue until 12 weeks' gestational age; from 12 weeks through the rest of pregnancy and for 4-6 weeks postpartum (or as long as breastfeeding continues), continue a multivitamin with 0.4-1 mg folic acid daily.[7]
During pregnancy: lamotrigine and levetiracetam have the most reassuring safety data among commonly used ASMs and are reasonable first choices. Valproic acid should be avoided where possible given its established association with major congenital malformations and adverse neurodevelopmental outcomes; in a large registry-based active-comparator analysis, this elevated neurodevelopmental risk persisted for valproate after adjusting for confounding by indication, while topiramate and lamotrigine did not show a comparable increased risk once analyzed the same way — reinforcing that valproate, not topiramate, carries the highest neurodevelopmental risk among the commonly used ASMs.[8] Phenobarbital is associated with increased congenital cardiac malformation risk, topiramate with cleft lip/palate and other malformations, and phenytoin/carbamazepine with an increased major-malformation risk generally.
Do not switch ASM during pregnancy to try to "avoid" teratogenicity — the period of highest malformation risk (the first trimester) has often already passed by the time pregnancy is recognized, and a mid-pregnancy switch exposes the fetus to polytherapy risk while exposing the patient to new-drug hypersensitivity risk and a real risk of breakthrough seizures or status epilepticus.
Level monitoring during pregnancy: obtain serial ASM levels when available and feasible; consider a dose adjustment if a level falls more than 25% below a documented prepregnancy reference level. Lamotrigine, levetiracetam, oxcarbazepine, topiramate, and lacosamide levels can all fall substantially during pregnancy from increased volume of distribution and clearance — lamotrigine is the most dramatic example and often needs its dose doubled or more, checked at least monthly; levels then rise quickly after delivery, so the dose must be tapered back down promptly postpartum (over the first 1-2 weeks) to avoid toxicity.
Breastfeeding
Breastfeeding should not be discouraged — while many ASMs transfer into breast milk, milk concentrations are generally well below maternal serum concentrations. Monitor the infant for sedation, poor feeding, or lethargy when the mother takes a barbiturate, a benzodiazepine, ethosuximide, or lamotrigine, since these are the agents most likely to sedate a breastfed infant; infants exposed to barbiturates or benzodiazepines in utero who are not breastfed may show withdrawal symptoms in the first week after delivery.
Reproductive-age patients: contraception and enzyme-inducing ASMs
This is one of the most consequential drug-interaction issues in epilepsy pharmacotherapy — an interaction missed at counselling can directly lead to an unplanned pregnancy while on a teratogenic ASM.
| Enzyme-inducing ASMs (reduce efficacy of hormonally based contraception and other hepatically metabolized drugs) | Non-enzyme-inducing ASMs (contraceptive efficacy not affected) |
|---|---|
| Carbamazepine, clobazam, eslicarbazepine, oxcarbazepine, perampanel (8 mg/day or higher), phenobarbital, phenytoin, primidone, rufinamide, topiramate (200 mg/day or higher) | Brivaracetam, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, valproic acid, vigabatrin |
Combined oral contraceptives, the contraceptive patch, the vaginal ring, the progestin-only pill, and some progestin implants are all less effective when combined with an enzyme-inducing ASM. Preferentially recommend an intrauterine device (hormonal or nonhormonal) or a depot progesterone injection, since these are not significantly affected by enzyme induction; encourage condom use alongside any hormonal method both for a second layer of contraceptive protection and for STI prevention.[9] If a patient specifically prefers to continue a combined oral contraceptive despite enzyme-inducer use, some experts support using 2 tablets/day of a low-dose product to approximate a higher ethinyl estradiol exposure, always with a reliable backup barrier method, since no single-tablet Canadian product reaches an equivalent dose on its own.[10]
The lamotrigine-specific interaction runs the other direction: combined hormonal contraceptives induce lamotrigine glucuronidation and can substantially lower lamotrigine serum levels, risking breakthrough seizures. Check a lamotrigine level before and after starting a combined hormonal contraceptive, and expect to need a meaningfully higher lamotrigine dose while the contraceptive is used — with a corresponding dose reduction if the contraceptive is later stopped, to avoid lamotrigine toxicity.
Older adults
Start ASMs at a lower initial dose and titrate more slowly, given increased sensitivity to sedation, cognitive effects, and falls risk. Favour agents with fewer drug interactions (levetiracetam, lamotrigine, gabapentin) given the high burden of concurrent medications in this population, and reduce doses of renally cleared agents (e.g., levetiracetam, gabapentin) for reduced creatinine clearance.
Renal and hepatic impairment
Renally cleared ASMs (levetiracetam, gabapentin, vigabatrin, and others — see Drug Tables) require dose reduction as creatinine clearance falls. Hepatically metabolized ASMs with enzyme-inhibiting or enzyme-inducing properties (valproic acid, carbamazepine, phenytoin, phenobarbital) need caution, and for some, dose adjustment, in significant hepatic impairment; valproic acid in particular carries a rare but serious hepatotoxicity risk that warrants closer monitoring in any degree of pre-existing hepatic disease.
Pediatrics
This chapter focuses on adult epilepsy management. Pediatric-specific considerations — including that childhood absence epilepsy is generally treated first-line with ethosuximide rather than the adult generalized-epilepsy approach, and that several agents in the Drug Tables below (e.g., rufinamide, stiripentol) are specifically pediatric-onset-syndrome indications — should be managed with pediatric neurology/epilepsy specialist input rather than extrapolated directly from adult dosing.
Monitoring & Follow-Up
Therapeutic drug monitoring
Do not rely on a serum ASM level alone to guide therapy — treat the patient, not the level. Some patients achieve seizure control at a low level; others experience dose-related toxicity within the so-called therapeutic range. A useful practice is to obtain a level when the patient is seizure-free and free of dose-related toxicity, to serve as a personal reference point if seizures or toxicity occur later. Routine levels are most useful for phenytoin, phenobarbital, primidone, carbamazepine, and valproic acid; levels for most newer ASMs are harder to obtain and rarely change management, so do not order them reflexively.
Baseline and periodic monitoring
- Obtain a baseline CBC and liver aminotransferases before starting an ASM with hypersensitivity, blood-dyscrasia, or hepatotoxicity potential (e.g., carbamazepine, valproic acid); repeat at 4-6 weeks, then space out the interval if results remain stable — yearly is appropriate once stable.
- Test for HLA-B*15:02 before starting carbamazepine in patients with ancestry from a country with higher carrier prevalence (China, Thailand, Malaysia, India) given the sharply increased Stevens-Johnson syndrome/toxic epidermal necrolysis risk in carriers.
- Monitor bone density per standard osteoporosis guidance in patients on long-term valproic acid or an enzyme-inducing ASM, and consider calcium/vitamin D supplementation.
- Reassess adherence at every visit — it is the most common identifiable cause of breakthrough seizures.
- Reassess driving eligibility, mood/psychiatric symptoms, and quality of life at every visit, not only seizure frequency.
- Switching between brand and generic, or between different generic products, has not been shown to harm most low-risk patients — but a minority may be sensitive to small formulation changes and warrant extra caution, particularly with lamotrigine given its narrow hypersensitivity-related titration window.
Discontinuing antiseizure medication
ASM withdrawal can be considered in selected patients after a substantial, sustained period of seizure freedom, always in consultation with a neurologist or epilepsy specialist — this decision carries real implications for driving, personal safety, and psychological wellbeing, and even prolonged seizure freedom does not eliminate recurrence risk with withdrawal. The long-term risk of seizure recurrence is higher for patients who taper their ASM after 2 years of seizure freedom compared with those who continue therapy, so the decision to taper should weigh this against the burdens of continued long-term treatment on a genuinely individualized basis.[11]
Common Errors to Avoid
- Relying on a serum ASM level alone to guide dosing instead of the patient's actual seizure control and tolerability.
- Missing the enzyme-inducing-ASM/hormonal-contraception interaction — a preventable cause of unplanned pregnancy on a teratogenic drug.
- Starting valproic acid or topiramate first-line in a patient of childbearing potential without first discussing lower-risk alternatives.
- Continuing an ASM after a definite drug rash develops, risking a life-threatening hypersensitivity reaction.
- Titrating lamotrigine faster than the recommended slow schedule, even when the patient wants faster seizure control.
- Using an oral, rather than parenteral/rectal/intranasal, benzodiazepine for status epilepticus, where minutes matter.
- Assuming a normal EEG rules out epilepsy.
- Attributing breakthrough seizures to "drug failure" before actively excluding nonadherence and reversible precipitants.
- Stopping an ASM abruptly rather than tapering, including when a patient decides on their own to discontinue.
- Missing folic acid supplementation in a patient of childbearing potential taking an ASM.
- Switching ASM therapy during pregnancy to try to reduce teratogenic risk — this typically increases risk rather than reducing it.
- Failing to address driving and safety counselling after any seizure, regardless of whether the patient raises it.
- Prescribing carbamazepine, gabapentin, oxcarbazepine, phenytoin, or vigabatrin without confirming the seizure type is not absence, myoclonic, or atonic — each can worsen these seizure types.
Clinical Decision Algorithm
Drug Tables
How to use this table: Doses are adult doses and require patient-specific confirmation, including renal/hepatic adjustment. This chapter focuses on adult epilepsy management — pediatric dosing for these agents is weight-based and specialist-directed, and is not covered here. Select any drug name to open its complete Pharmasist Drug Database page.
Status Epilepticus (Acute/Parenteral) Agents
| Drug | Dosage | Adverse effects | Comments |
|---|---|---|---|
| Lorazepam | IV, status epilepticus: 4 mg IV, may repeat once if seizure persists | Sedation, respiratory depression with repeated dosing or when combined with other CNS depressants | 1st-line benzodiazepine for status epilepticus when IV access is available; give immediately. |
| Diazepam | Rectal, no IV access: 20 mg PR (rectal gel, or IV solution given rectally) IV, status epilepticus: IV solution per institutional protocol when IV access is available | Sedation, respiratory depression | Shorter clinical seizure-control duration than lorazepam owing to rapid redistribution; an option when IV access is unavailable or lorazepam is not on hand. |
| Midazolam | IM/intranasal/buccal, no IV access: 10 mg (5 mg if 13-40 kg); may repeat once Refractory status, continuous infusion: Load 10-20 mg IV bolus, then 0.05-0.4 mg/kg/hour | Sedation, respiratory depression, hypotension | Superior to IV lorazepam specifically when IV access is not yet established. Also used as a refractory-status continuous infusion in an ICU setting. |
| Fosphenytoin | 2nd-line IV load: 20 mg/kg IV, maximum rate 50 mg/min, slower in older adults; monitor ECG | Hypotension, cardiac arrhythmia with rapid infusion | Preferred over phenytoin salt for IV loading given a lower infusion-site/cardiovascular reaction risk. Equally effective to levetiracetam and valproic acid IV loading per randomized trial data. |
| Valproic acid (IV) | 2nd-line IV load: 15-40 mg/kg IV over 10 minutes, maximum 3 g | Hepatotoxicity (rare), hyperammonemia, thrombocytopenia | Equally effective to levetiracetam and fosphenytoin IV loading; avoid as first choice in patients of childbearing potential when an equally effective alternative exists. |
| Levetiracetam (IV) | 2nd-line IV load: 40-60 mg/kg IV over 10 minutes, maximum 4.5 g | Somnolence, irritability | Minimal drug interactions and no cardiac monitoring required during infusion, unlike fosphenytoin — often preferred for this reason. |
| Propofol | Refractory status, continuous infusion: 1-2 mg/kg IV bolus, then 2-5 mg/kg/hour | Hypotension, propofol infusion syndrome with prolonged high-dose use, respiratory depression | ICU-only refractory-status agent requiring continuous hemodynamic and respiratory monitoring. |
| Phenobarbital (IV) | Refractory status, IV load: 20 mg/kg IV at 50-75 mg/min | Sedation, hypotension, respiratory depression | Reserved for refractory status once a benzodiazepine and a second-line IV load have both failed. |
Barbiturates
| Drug | Dosage | Adverse effects | Comments |
|---|---|---|---|
| Phenobarbital (oral) | Initial: 30 mg PO at bedtime; increase by 30 mg/day every 2 weeks Maintenance: 90-120 mg/day PO at bedtime | Sedation, rash, depression, diminished libido | Potent hepatic enzyme inducer with many interactions; declining use given its adverse-effect profile relative to newer agents. If used, initiate and follow with epilepsy specialist input. |
| Primidone | Initial: 125 mg PO at bedtime x3 days, then 125 mg BID x3 days, then 125 mg TID x3 days Maintenance: 500-1000 mg/day PO in 3-4 divided doses | Sedation, rash, depression, diminished libido | Metabolized to phenobarbital but has independent antiseizure activity; requires slow titration and multiple-times-daily dosing to maintain a stable phenobarbital ratio. Not currently in the Pharmasist Drug Database. |
Benzodiazepines (chronic adjunctive therapy)
| Drug | Dosage | Adverse effects | Comments |
|---|---|---|---|
| Clobazam | Initial: 5-15 mg/day PO, preferably at bedtime Maintenance: 20-40 mg/day PO in 1-2 divided doses | Sedation, irritability; tolerance with loss of effect over time | Enzyme-inducing — reduces hormonal contraceptive efficacy (see Special Populations). Cannabidiol, fluoxetine, and fluvoxamine can raise levels via CYP2C19 inhibition. Stiripentol requires a clobazam dose reduction before initiation. |
Carboxylic Acid Derivatives
| Drug | Dosage | Adverse effects | Comments |
|---|---|---|---|
| Valproic acid (oral, chronic) | Initial: 250 mg BID PO; increase by 250 mg/day every 3-4 days Maintenance: 750-1000 mg/day PO in 2-4 divided doses | Nausea, weight gain, tremor, hair loss, rare blood dyscrasias/hepatotoxicity, teratogenicity | Broad spectrum without hepatic enzyme induction, though it does inhibit metabolism of several other drugs, including lamotrigine. Least desirable option for patients of childbearing potential given teratogenic/neurodevelopmental risk. |
| Divalproex sodium | Initial: 250 mg BID PO; increase by 250 mg/day every 3-4 days Maintenance: 750-1000 mg/day PO in 2 divided doses | Nausea, weight gain, tremor, hair loss, rare blood dyscrasias/hepatotoxicity, teratogenicity | Enteric-coated formulation with somewhat better GI tolerability than valproic acid. Same childbearing-potential caveat applies. |
GABA Derivatives
| Drug | Dosage | Adverse effects | Comments |
|---|---|---|---|
| Gabapentin | Initial: 300 mg once daily PO; increase by 300 mg/day every 5-7 days Maintenance: 900-3600 mg/day PO in 3 divided doses | Tremor, vision changes, GI upset | No known significant drug interactions and renally (not hepatically) cleared — useful when interaction risk matters, but not effective for primary generalized seizures and may worsen absence/myoclonic/atonic seizures. May be considered as initial monotherapy specifically in elderly patients with focal seizures. |
| Vigabatrin | Initial: 1000 mg/day PO in 1-2 divided doses Maintenance: 2000-4000 mg/day PO in 1-2 divided doses | Irreversible visual field defects (the dose-limiting concern), psychosis, depression | If used, initiate and follow with epilepsy specialist input given the visual field risk, which requires baseline and periodic visual field testing. May worsen absence, myoclonic, or atonic seizures. |
Hydantoin Derivatives
| Drug | Dosage | Adverse effects | Comments |
|---|---|---|---|
| Phenytoin (immediate-release) | Maintenance: 300-400 mg/day PO in 2-3 divided doses | Gingival hyperplasia, rash (5-10%, rarely severe), dose-related encephalopathy, coarse facial features with long-term use | Inexpensive but has nonlinear (saturation) pharmacokinetics that complicate dose titration, and is a potent hepatic enzyme inducer. |
| Phenytoin (extended-release) | Maintenance: 300-400 mg/day PO, once daily or divided BID | Gingival hyperplasia, rash (5-10%, rarely severe), dose-related encephalopathy, coarse facial features with long-term use | Extended-release capsule allows once-daily dosing; otherwise the same profile as immediate-release. |
Iminostilbene Derivatives
| Drug | Dosage | Adverse effects | Comments |
|---|---|---|---|
| Carbamazepine (immediate-release) | Initial: 100 mg BID PO; increase by 200 mg/day every 3-4 days Maintenance: 400-1200 mg/day PO in 2-4 divided doses, with meals when possible | Rash (5-10%, rarely severe), hyponatremia, transient neutropenia (common), aplastic anemia (rare) | Autoinduction of its own metabolism can affect half-life and require dose retitration in the first weeks. Substrate and potent inducer of multiple CYP450 enzymes — many interactions. Test HLA-B*15:02 before use in patients of relevant ancestry. May worsen absence, myoclonic, or atonic seizures. |
| Carbamazepine (controlled-release) | Initial: 100 mg BID PO; increase by 200 mg/day every 3-4 days Maintenance: 800-1200 mg/day PO in 2 divided doses with meals | Rash (5-10%, rarely severe), hyponatremia, transient neutropenia (common), aplastic anemia (rare) | Twice-daily dosing may improve adherence and tolerability versus immediate-release; the same interaction and HLA-testing considerations apply. |
| Eslicarbazepine acetate | Initial: 400 mg once daily PO for 1 week Maintenance: 800 mg once daily PO (maximum 1200 mg once daily) | Dizziness, fatigue, somnolence, nausea, hyponatremia, rash with carbamazepine cross-reactivity, PR-interval prolongation | Once-daily dosing without autoinduction. Substrate and inducer of CYP3A4, and inhibitor of CYP2C19 — meaningful interaction potential despite the dosing convenience. |
| Oxcarbazepine | Initial: 300 mg BID PO; increase by up to 600 mg/day at weekly intervals Maintenance: 1200-2400 mg/day PO in 2 divided doses | Similar to carbamazepine but with slightly higher hyponatremia risk; rash with carbamazepine cross-reactivity | No autoinduction, but still reduces hormonal contraceptive efficacy as an enzyme inducer. |
Succinimide Derivatives
| Drug | Dosage | Adverse effects | Comments |
|---|---|---|---|
| Ethosuximide | Initial: 500 mg/day PO in 1-2 divided doses; increase by 250 mg/day every 4-7 days Maintenance: 750-1000 mg/day PO | GI upset | No effect on generalized tonic-clonic seizures — do not use as monotherapy if tonic-clonic seizures also occur. |
Other Antiseizure Medications
| Drug | Dosage | Adverse effects | Comments |
|---|---|---|---|
| Brivaracetam | Initial: 100 mg/day PO in 2 divided doses; increase by 50 mg/day weekly Maintenance: 100-200 mg/day PO | Sleepiness, nausea, decreased energy, dizziness, irritability, depression | Broad spectrum with minimal interactions and rapid titration; a parenteral form is available for bridging when oral intake is not possible. |
| Cannabidiol (oral solution) | Initial: 2.5 mg/kg PO BID; increase after 1 week to 5 mg/kg PO BID Maintenance: 5-10 mg/kg PO BID, maximum 20 mg/kg/day | Somnolence, decreased appetite, diarrhea, transaminase elevation (especially with concomitant valproate) | Health Canada-approved specifically as adjunctive therapy for seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex — not a general-purpose ASM. Clobazam levels rise significantly with concomitant use via CYP2C19 inhibition. |
| Cenobamate | Initial: 12.5 mg daily PO for 2 weeks, then 25 mg daily for 2 weeks, then 50 mg daily for 2 weeks, then 100 mg daily for 2 weeks, then 150 mg daily for 2 weeks Maintenance: 200 mg once daily PO | Sleepiness, dizziness, fatigue, diplopia, headache, aggression, hyperkalemia | Adjunctive therapy for focal-onset seizures. Requires dose reduction of clobazam, lacosamide, phenytoin, and phenobarbital when co-administered — always follow the full slow titration schedule below. |
| Lacosamide | Initial: 50-100 mg/day PO in 2 divided doses; increase by 50 mg/day every 1-2 weeks Maintenance: 200-400 mg/day PO in 2 divided doses | Dizziness, nausea, ataxia, PR-interval prolongation | No known significant drug interactions; a parenteral form is available. Use caution in patients with cardiac conduction abnormalities. |
| Lamotrigine | Initial: 25 mg/day PO; after 2 weeks increase to 25 mg BID, then increase by 25-50 mg/day every 2 weeks Maintenance: 100-400 mg/day PO in 2 divided doses | Rash (5-10%, rarely a severe hypersensitivity reaction); insomnia | Always titrate slowly regardless of urgency. Valproic acid roughly doubles levels; enzyme-inducing ASMs lower them; combined hormonal contraceptives can lower levels substantially (see Special Populations). |
| Levetiracetam (oral, chronic) | Initial: 1000 mg/day PO in 2 divided doses; increase by 1000 mg/day weekly Maintenance: 1000-3000 mg/day PO in 2 divided doses | Somnolence, irritability, psychiatric/behavioural symptoms | Broad-spectrum with minimal drug interactions and rapid titration; a parenteral form is available. |
| Perampanel | Initial (not on an enzyme inducer): 2 mg PO at bedtime; increase by 2 mg every 2 weeks Initial (on an enzyme-inducing ASM): 4 mg PO at bedtime; titrate as above Maintenance: 4-8 mg PO at bedtime, maximum 12 mg at bedtime | Dizziness, fatigue, sleepiness, unsteadiness, weight gain; serious psychiatric reactions including aggression and irritability | Once-daily bedtime dosing. Substrate of CYP3A4 with significant interaction potential; concurrent CNS depressants, including alcohol, increase somnolence and reduced-alertness risk. |
| Rufinamide | Initial: 400 mg/day PO in 2 divided doses; increase by 5 mg/kg/day every 2 weeks Maintenance: 1800-3200 mg/day PO in 2 divided doses | Headache, sleepiness, dizziness, nausea/vomiting, rash (rarely severe), QTc shortening | Adjunctive treatment for generalized seizures in Lennox-Gastaut syndrome. If used, initiate and follow with epilepsy specialist input. |
| Stiripentol | Maintenance: 50 mg/kg/day PO in 2-3 divided doses, increased over 3 days to the recommended dose | GI upset, anorexia, weight loss, ataxia, agitation, neutropenia | Adjunctive therapy specifically for Dravet syndrome. Inhibits several CYP450 enzymes; not recommended with carbamazepine, phenytoin, or phenobarbital, and requires a clobazam dose reduction before initiation. If used, initiate and follow with epilepsy specialist input. |
| Topiramate | Initial: 50-100 mg/day PO in 2 divided doses; increase by 50 mg/day weekly for 4 weeks, then by 100 mg/day weekly Maintenance: 200-400 mg/day PO in 2 divided doses | Cognitive/memory impairment (common and often dose-limiting), kidney stones, weight loss, paresthesias | Broad spectrum with relatively few interactions, but slow titration is needed to minimize cognitive effects. Enzyme-inducing at 200 mg/day or higher, reducing hormonal contraceptive efficacy at that dose. Teratogenic risk is dose-dependent; avoid where possible in patients of childbearing potential (see Special Populations). |
References
- ILAE Official Report: A practical clinical definition of epilepsy — Epilepsia, International League Against Epilepsy (Fisher RS, Acevedo C, Arzimanoglou A, et al.). Epilepsia 2014;55(4):475-482
- Operational classification of seizure types by the International League Against Epilepsy: Position Paper of the ILAE Commission for Classification and Terminology — Epilepsia, International League Against Epilepsy (Fisher RS, Cross JH, French JA, et al.). Epilepsia 2017;58(4):522-530
- Evidence-based guideline: Treatment of convulsive status epilepticus in children and adults — Epilepsy Currents, American Epilepsy Society Guideline Committee (Glauser T, Shinnar S, Gloss D, et al.). Epilepsy Curr 2016;16(1):48-61
- Evidence-based guideline: Management of an unprovoked first seizure in adults — Neurology, American Academy of Neurology and American Epilepsy Society (Krumholz A, Wiebe S, Gronseth GS, et al.) — reaffirmed February 10, 2024. Neurology 2015;84(16):1705-1713
- Randomized trial of three anticonvulsant medications for status epilepticus (ESETT) — New England Journal of Medicine (Kapur J, Elm J, Chamberlain JM, et al.). N Engl J Med 2019;381(22):2103-2113
- CMA Driver's Guide: Determining Medical Fitness to Operate Motor Vehicles, 10th Edition — Canadian Medical Association / Canadian Council of Motor Transport Administrators. CMA Driver's Guide, 10th ed., February 2025
- Guideline No. 427: Folic Acid and Multivitamin Supplementation for Prevention of Folic Acid-Sensitive Congenital Anomalies — Journal of Obstetrics and Gynaecology Canada, Society of Obstetricians and Gynaecologists of Canada (Wilson RD, O'Connor DL). J Obstet Gynaecol Can 2022;44(6):707-719
- Risk of autism after prenatal topiramate, valproate, or lamotrigine exposure — New England Journal of Medicine (Hernandez-Diaz S, Straub L, Bateman BT, et al.). N Engl J Med 2024;390(12):1069-1079
- SIGN 143: Diagnosis and management of epilepsy in adults — Scottish Intercollegiate Guidelines Network. SIGN 143, May 2015, revised 2018
- FSRH Clinical Effectiveness Unit Guidance: Drug Interactions with Hormonal Contraception — Faculty of Sexual and Reproductive Healthcare. FSRH CEU Guidance, updated 2022
- Antiseizure medication withdrawal in seizure-free patients: Practice advisory update summary — Neurology, American Academy of Neurology Guideline Subcommittee (Gloss D, Pargeon K, Pack A, et al.). Neurology 2021;97(23):1072-1081
Professional reference only. Apply clinical judgment and verify patient-specific decisions against current authoritative guidance and product information.