Breakthrough Seizure (Known Epilepsy)

VERSION: 1.0 CREATED: January 27, 2026 STATUS: Approved

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DIAGNOSIS: Breakthrough Seizure in Known Epilepsy

ICD-10: G40.909 (Epilepsy, unspecified, not intractable, without status epilepticus), G40.901 (Epilepsy, unspecified, not intractable, with status epilepticus), G40.919 (Epilepsy, unspecified, intractable, without status epilepticus), G40.911 (Epilepsy, unspecified, intractable, with status epilepticus), R56.9 (Unspecified convulsions), G40.309 (Generalized idiopathic epilepsy, not intractable, without status epilepticus), G40.209 (Localization-related epilepsy, not intractable, without status epilepticus)

CPT CODES: 85025 (CBC with differential), 80053 (CMP (BMP + LFTs)), 82947 (Blood glucose), 84295 (Sodium), 82330 (Calcium, ionized), 83735 (Magnesium), 81003 (Urinalysis), 80307 (Urine drug screen (UDS)), 80320 (Alcohol level), 84703 (Pregnancy test (β-hCG)), 82140 (Ammonia), 83605 (Lactate), 84443 (TSH), 82533 (Cortisol (AM)), 82607 (B12), 82306 (Vitamin D, 25-OH), 70450 (CT head without contrast), 70553 (MRI brain with and without contrast), 93000 (ECG (12-lead)), 95816 (EEG (routine/outpatient)), 95700 (Continuous EEG (cEEG) monitoring), 71046 (Chest X-ray), 96374 (Benzodiazepine (if actively seizing))

SYNONYMS: Breakthrough seizure, seizure in known epilepsy, recurrent seizure, uncontrolled seizure, epilepsy exacerbation, seizure on medications, drug-resistant epilepsy, refractory epilepsy, seizure despite treatment, BTS, non-adherence seizure, subtherapeutic seizure, epilepsy flare, seizure cluster, catamenial seizure, seizure recurrence, poorly controlled epilepsy, intractable epilepsy, pharmacoresistant epilepsy, DRE

SCOPE: Evaluation and management of breakthrough seizures in adults with known epilepsy who are on established antiseizure medication (ASM) regimens. Covers identification of precipitants, medication level assessment, adjustment strategies, and evaluation for secondary causes. Excludes new-onset seizure (separate workup), status epilepticus (see SE template), and non-epileptic events (psychogenic non-epileptic seizures).

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PRIORITY KEY: STAT = Immediate | URGENT = Within hours | ROUTINE = Standard | EXT = Extended/atypical cases | - = Not applicable to this setting

═══════════════════════════════════════════════════════════════ SECTION A: ACTION ITEMS ═══════════════════════════════════════════════════════════════

1. LABORATORY WORKUP

1A. Essential/Core Labs

Test	ED	HOSP	OPD	ICU	Rationale	Target Finding
Antiseizure medication (ASM) levels	STAT	STAT	ROUTINE	STAT	CRITICAL: Subtherapeutic levels are #1 cause of breakthrough seizures; check ALL ASMs with available assays	Therapeutic ranges (see Appendix); subtherapeutic = adjust dose or assess adherence
CBC with differential (CPT 85025)	STAT	STAT	ROUTINE	STAT	Infection as precipitant; baseline for ASM hematologic effects; thrombocytopenia (valproate)	Normal; leukocytosis → infection workup; low platelets → consider valproate toxicity
CMP (BMP + LFTs) (CPT 80053)	STAT	STAT	ROUTINE	STAT	Electrolyte abnormalities (hyponatremia common with carbamazepine/oxcarbazepine); renal function (affects ASM dosing); hepatic function (ASM metabolism, toxicity); glucose (hypoglycemia as seizure cause)	Normal; hyponatremia <130 mEq/L can provoke seizures; elevated LFTs → ASM hepatotoxicity
Blood glucose (CPT 82947)	STAT	STAT	ROUTINE	STAT	Hypoglycemia is reversible seizure cause; hyperglycemia (DKA) can also cause seizures	70-180 mg/dL; hypoglycemia <60 mg/dL → treat immediately
Sodium (CPT 84295)	STAT	STAT	ROUTINE	STAT	Hyponatremia: carbamazepine and oxcarbazepine cause SIADH; <125-130 mEq/L can provoke seizures	135-145 mEq/L; <130 → correct slowly (risk of osmotic demyelination)
Calcium, ionized (CPT 82330)	STAT	STAT	ROUTINE	STAT	Hypocalcemia can cause seizures; also check if hypocalcemic tetany suspected	Normal ionized Ca; low → replete
Magnesium (CPT 83735)	STAT	STAT	ROUTINE	STAT	Hypomagnesemia lowers seizure threshold; chronic ASM use may deplete Mg	>2.0 mg/dL; low → replete
Urinalysis (CPT 81003)	STAT	STAT	ROUTINE	STAT	UTI is common occult infection that provokes seizures, especially in elderly	Normal; pyuria/bacteriuria → treat UTI
Urine drug screen (UDS) (CPT 80307)	STAT	STAT	-	STAT	Illicit drug use (cocaine, amphetamines) can provoke seizures; drug interactions with ASMs; adherence assessment	Negative; positive → specific drug-related seizure risk assessment
Alcohol level (CPT 80320)	STAT	-	-	STAT	Alcohol withdrawal seizures; intoxication; binge drinking	Negative or low; elevated or history of recent heavy use → alcohol withdrawal protocol
Pregnancy test (β-hCG) (CPT 84703)	STAT	STAT	ROUTINE	STAT	Pregnancy affects ASM levels (increased clearance, volume distribution); teratogenicity concerns; seizure risk in pregnancy	Document result; if positive → urgent neurology/OB consultation; ASM teratogenicity counseling

1B. Extended Workup (Second-line)

Test	ED	HOSP	OPD	ICU	Rationale	Target Finding
Free (unbound) ASM levels	-	URGENT	ROUTINE	URGENT	For highly protein-bound drugs (phenytoin, valproate) in patients with hypoalbuminemia, renal failure, pregnancy, or polypharmacy; free level is the active fraction	Free phenytoin: 1-2 mcg/mL; free valproate: 5-15 mcg/mL; adjusted interpretation based on clinical context
Ammonia (CPT 82140)	STAT	STAT	-	STAT	Valproate-induced hyperammonemic encephalopathy (can occur with normal LFTs); confusion/lethargy post-ictal vs. encephalopathy	<35 μmol/L; elevated → valproate toxicity; consider discontinuation
Lactate (CPT 83605)	STAT	STAT	-	STAT	Post-ictal lactate elevation (typically resolves within 2h); persistent elevation may indicate status epilepticus or alternative cause	Mildly elevated post-ictal (normalizes quickly); persistent elevation concerning
Prolactin	-	URGENT	ROUTINE	-	Elevated 10-20 min post-seizure (2-3x baseline); helps distinguish epileptic seizure from psychogenic non-epileptic seizure (PNES); must be drawn within 20 min	2-3x baseline within 20 min of convulsive seizure; normal in PNES
TSH (CPT 84443)	-	ROUTINE	ROUTINE	-	Thyroid dysfunction can affect seizure threshold and ASM metabolism	Normal
Cortisol (AM) (CPT 82533)	-	ROUTINE	ROUTINE	-	Adrenal insufficiency; chronic ASM use (enzyme inducers) may affect cortisol	Normal
B12 (CPT 82607) / Folate (CPT 82746)	-	ROUTINE	ROUTINE	-	Phenytoin and carbamazepine can deplete folate; B12 deficiency neuropathy; pregnancy planning	Normal; low → supplement
Vitamin D, 25-OH (CPT 82306)	-	ROUTINE	ROUTINE	-	Enzyme-inducing ASMs (phenytoin, carbamazepine, phenobarbital) increase vitamin D metabolism → osteoporosis risk	>30 ng/mL; low → supplement

1C. Rare/Specialized (Refractory or Atypical)

Test	ED	HOSP	OPD	ICU	Rationale	Target Finding
ASM pharmacogenomics (HLA typing)	-	-	ROUTINE	-	HLA-B15:02 (carbamazepine/SJS risk in Asian populations); HLA-A31:01 (carbamazepine hypersensitivity in Europeans); before starting new ASMs	Negative for risk alleles; positive → avoid associated ASM
Carbamazepine-10,11-epoxide level	-	ROUTINE	ROUTINE	-	Active metabolite of carbamazepine; may be elevated when total level appears therapeutic (especially with inhibitors like valproate); correlates with toxicity	<9 mcg/mL; elevated → toxicity even with normal carbamazepine level
Autoimmune encephalitis panel	-	EXT	EXT	-	If new seizure semiology, cognitive decline, or refractory seizures in previously controlled patient; autoimmune etiology	Negative; positive → autoimmune encephalitis workup
CSF analysis	-	EXT	-	EXT	If infection, autoimmune encephalitis, or CNS malignancy suspected as new cause	Normal; abnormal → specific diagnosis
Genetic epilepsy panel	-	-	EXT	-	If genetic cause suspected (family history, syndromic features, drug-resistant epilepsy); may guide ASM selection	Specific mutations (SCN1A, SCN2A, KCNQ2, etc.) may inform treatment choices (e.g., avoid sodium channel blockers in Dravet syndrome)

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2. DIAGNOSTIC IMAGING & STUDIES

2A. Essential/First-line

Study	ED	HOSP	OPD	ICU	Timing	Target Finding	Contraindications
CT head without contrast (CPT 70450)	STAT	STAT	-	STAT	NOT routinely needed for uncomplicated breakthrough seizure in known epilepsy with return to baseline; INDICATED if: Head trauma (fall during seizure), prolonged post-ictal state (>30 min), focal neurologic deficit, new seizure semiology, anticoagulation, fever + seizure, first seizure at this facility	Acute hemorrhage; mass lesion; edema; hydrocephalus; prior surgical changes	None (for non-contrast); pregnancy (benefit outweighs minimal risk)
MRI brain with and without contrast (CPT 70553)	-	URGENT	ROUTINE	-	NOT acutely needed if stable known epilepsy with unchanged seizures; INDICATED if: Change in seizure semiology, increased seizure frequency without clear precipitant, new focal deficit, concern for progressive lesion, presurgical evaluation	Tumor; mesial temporal sclerosis; cortical dysplasia; vascular malformation; new structural cause	MRI-incompatible implants; VNS devices (check MRI compatibility of specific device)
ECG (12-lead) (CPT 93000)	STAT	STAT	ROUTINE	STAT	Post-ictal arrhythmia; syncope vs. seizure; QTc prolongation (some ASMs); baseline for ASM changes	Normal; arrhythmia may indicate cardiac cause; prolonged QTc (avoid QT-prolonging ASMs)	None

2B. Extended

Study	ED	HOSP	OPD	ICU	Timing	Target Finding	Contraindications
EEG (routine/outpatient) (CPT 95816)	-	URGENT	ROUTINE	-	Within 24-48h if possible (higher yield closer to seizure); characterize epileptiform activity; confirm epileptic vs. non-epileptic; guide ASM choice; localization	Epileptiform discharges (spikes, sharp waves); focal vs. generalized; specific epilepsy syndrome features	None
Continuous EEG (cEEG) monitoring (CPT 95700)	-	STAT	-	STAT	INDICATED if: Prolonged or fluctuating alteration of consciousness; concern for nonconvulsive status epilepticus (NCSE); ICU patient with unexplained encephalopathy; frequent seizures	Ictal patterns; NCSE; interictal epileptiform activity; quantify seizure burden	None; resource-dependent
Ambulatory EEG (outpatient)	-	-	ROUTINE	-	Capture typical events if infrequent; home monitoring for 24-72h or longer	Ictal events; interictal discharges; seizure frequency	Patient cooperation required
Video-EEG monitoring (EMU admission)	-	-	ROUTINE	-	Characterize events if diagnostic uncertainty (epileptic vs. PNES); presurgical evaluation; medication taper for surgery	Ictal semiology; EEG correlation; localization for surgery	Requires specialized unit
Chest X-ray (CPT 71046)	STAT	STAT	-	STAT	Aspiration pneumonia (common post-ictal complication); ETT position if intubated	Infiltrate; aspiration pattern	None

2C. Rare/Advanced

Study	ED	HOSP	OPD	ICU	Timing	Target Finding	Contraindications
MRI epilepsy protocol	-	-	ROUTINE	-	High-resolution imaging for epileptogenic lesion identification; 3T preferred; includes thin-cut coronal T2/FLAIR through temporal lobes	Mesial temporal sclerosis; focal cortical dysplasia; cavernous malformation; low-grade tumor	Same as standard MRI
PET (FDG) or SPECT (ictal/interictal)	-	-	EXT	-	Presurgical localization; hypometabolism (interictal PET) or hyperperfusion (ictal SPECT) at seizure focus	Focal hypometabolism (interictal); focal hyperperfusion (ictal)	Radiation exposure; specialized availability
MEG (magnetoencephalography)	-	-	EXT	-	Presurgical localization; dipole source analysis; specialized centers	Source localization complementary to EEG	Limited availability; metal implants
Neuropsychological testing	-	-	ROUTINE	-	Presurgical evaluation; cognitive baseline; localization (memory lateralization for temporal lobe epilepsy)	Lateralized deficits; cognitive baseline for surgery comparison	Patient cooperation

Lumbar Puncture

Study	ED	HOSP	OPD	ICU	Timing	Target Finding	Contraindications
LP — Generally NOT indicated	-	EXT	-	EXT	NOT routinely indicated for uncomplicated breakthrough seizure; INDICATED if: Suspected meningitis/encephalitis (fever, meningismus, altered mentation beyond typical post-ictal); suspected autoimmune encephalitis; immunocompromised patient with seizure	Normal in uncomplicated breakthrough; pleocytosis → infection or autoimmune; elevated protein; specific antibodies	Mass lesion with mass effect; coagulopathy

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3. TREATMENT PROTOCOLS

3A. Acute/Emergent Treatment

Treatment	Route	Indication	Dosing	Contraindications	Monitoring	ED	HOSP	OPD	ICU
Benzodiazepine (if actively seizing) (CPT 96374)	IV	-	0.1 mg/kg :: IV :: - :: Lorazepam 0.1 mg/kg IV (max 4 mg), may repeat x1 in 5 min; OR Midazolam 10 mg IM (if no IV access); OR Diazepam 0.2 mg/kg IV (max 10 mg); Intranasal midazolam 5-10 mg if no IV; Rectal diazepam 0.2-0.5 mg/kg (home rescue)	-	First-line for acute seizure termination; lorazepam preferred IV (longer CNS duration); follow status epilepticus protocol if seizure continues >5 min	STAT	STAT	-	STAT
Protect patient during seizure	-	-	N/A :: - :: per protocol :: Clear environment of hazards; DO NOT restrain or put anything in mouth; turn on side (recovery position) when safe; suction secretions; monitor airway; time the seizure	-	Prevent injury; prepare for airway management if prolonged	STAT	STAT	-	STAT
Post-ictal care	-	-	92% :: - :: - :: Recovery position; monitor airway (aspiration risk); supplemental O2 if SpO2 <92%; assess for injuries (tongue laceration, shoulder dislocation, vertebral fracture); reassurance; reorientation	-	Post-ictal period is self-limited (typically 5-30 min); prolonged alteration → consider NCSE, repeat seizure, or alternative diagnosis	STAT	STAT	-	STAT
Administer home ASM (if missed)	-	-	N/A :: - :: per protocol :: If patient missed doses → give maintenance ASM immediately; if patient does not have medication with them → administer from ED/hospital supply	-	Non-adherence is most common cause of breakthrough seizure; restoring therapeutic levels is priority	STAT	STAT	-	STAT
Loading dose (if significantly subtherapeutic)	IV	-	15-20 mg :: IV :: - :: Phenytoin/Fosphenytoin: 15-20 mg PE/kg IV (if level very low); Valproate: 20-30 mg/kg IV (if level very low); Levetiracetam: 1000-1500 mg IV (if not on levetiracetam — can be added); Note: Loading the same drug patient is already taking risks toxicity → use cautiously	-	For significantly subtherapeutic levels or if need rapid therapeutic concentration; adjust for partial levels	STAT	STAT	-	STAT
Treat precipitant	-	-	N/A :: - :: per protocol :: Infection: Antibiotics for UTI, pneumonia; Electrolyte abnormality: Correct (hyponatremia slowly); Drug/alcohol withdrawal: Appropriate protocol; Sleep deprivation: Education, sleep hygiene	-	Treating the precipitant may be more important than adjusting ASMs	STAT	STAT	ROUTINE	STAT

3B. ASM Adjustment Strategies

Scenario	Treatment	Protocol	Rationale
Subtherapeutic level due to non-adherence	Resume current regimen at prescribed doses	Counsel on importance of adherence; identify barriers (cost, side effects, complexity); pill organizer; simplify regimen if possible	Non-adherence is #1 cause; restoring regimen usually sufficient
Subtherapeutic level at maximum dose	Increase current ASM OR add second ASM	Increase dose if tolerated and therapeutic range allows; OR add complementary ASM (e.g., add levetiracetam to lamotrigine)	Some patients require levels above "therapeutic range" for control
Therapeutic level but breakthrough seizure	Add second ASM OR optimize current ASM timing	Consider drug-drug interaction reducing efficacy; add ASM with different mechanism; divide doses more frequently for better coverage	Breakthrough at therapeutic levels may require adjunctive therapy
Subtherapeutic due to drug interaction	Remove interacting drug OR increase ASM dose OR switch ASM	Example: Starting enzyme inducer (rifampin, carbamazepine) reduces lamotrigine level by 50% → double lamotrigine dose	Enzyme inducers and inhibitors significantly affect ASM levels
Pregnancy with subtherapeutic level	Increase dose with frequent monitoring	Pregnancy increases clearance (especially lamotrigine, levetiracetam); monitor levels monthly; anticipate need for increased doses	Seizure risk to mother and fetus outweighs small ASM risk; maintain control
New-onset breakthrough in previously controlled epilepsy	Full re-evaluation	Imaging (new structural lesion?); EEG; consider progressive cause (tumor, autoimmune); assess for PNES	Change in control pattern requires investigation for new etiology

3C. Specific ASM Adjustments

ASM	Therapeutic Range	Adjustment Notes
Phenytoin	Total: 10-20 mcg/mL; Free: 1-2 mcg/mL	Nonlinear kinetics; small dose changes → large level changes; check free level if hypoalbuminemia, renal failure, pregnancy; adjust dose by 25-50 mg increments
Carbamazepine	4-12 mcg/mL	Auto-induction over 2-4 weeks (levels drop); check 4 weeks after initiation; also check epoxide level if toxicity suspected
Valproate	Total: 50-100 mcg/mL; Free: 5-15 mcg/mL	Highly protein-bound; check free level in elderly, hepatic disease, pregnancy; check ammonia if encephalopathy
Levetiracetam	Not routinely monitored (no established range)	Level: 12-46 mcg/mL often cited; renal dosing required; generally well-tolerated dose increases
Lamotrigine	3-14 mcg/mL (varies)	Highly affected by enzyme inducers (carbamazepine, phenytoin, oral contraceptives) and inhibitors (valproate); pregnancy increases clearance; slow titration to avoid rash
Oxcarbazepine	10,11-monohydroxy derivative: 3-35 mcg/mL	Causes hyponatremia (check sodium); less drug interactions than carbamazepine
Lacosamide	10-20 mcg/mL (emerging data)	Check ECG (PR prolongation); dose-dependent side effects; no major drug interactions
Topiramate	5-20 mcg/mL (not well-established)	Renal dosing; causes metabolic acidosis, cognitive effects, kidney stones; enzyme inducer reduces OCP efficacy
Phenobarbital	15-40 mcg/mL	Long half-life (adjust weekly); sedation; enzyme inducer
Brivaracetam	Not routinely monitored	Similar to levetiracetam but may have fewer behavioral side effects; can substitute directly for levetiracetam
Clobazam	0.03-0.3 mcg/mL (+ N-desmethylclobazam metabolite)	Benzodiazepine; tolerance may develop; useful adjunct especially in Lennox-Gastaut

3D. Non-Pharmacologic Considerations

Intervention	Setting	Details
Seizure precautions	HOSP/ICU	Padded side rails; suction at bedside; no sharps within reach; fall risk protocol; 1:1 supervision if frequent seizures
Driving restrictions	OPD/Discharge	State-specific laws; generally 3-12 months seizure-free required; document counseling; patient should NOT drive until cleared
Activity restrictions	OPD/Discharge	Avoid swimming alone; no heights (ladders, scaffolding); avoid dangerous machinery; bathing vs. showers (supervision if frequent seizures)
Sleep hygiene	OPD/Discharge	Sleep deprivation is major trigger; regular sleep schedule; 7-8 hours nightly; avoid shift work if possible
Alcohol / substance avoidance	OPD/Discharge	Alcohol lowers seizure threshold; withdrawal is high risk; cocaine/amphetamines provoke seizures; counsel strongly
Stress management	OPD/Discharge	Stress/anxiety are common triggers; counseling; mindfulness; adequate support
VNS (vagus nerve stimulator) check	OPD	If patient has VNS → check device function; consider adjusting parameters; use magnet during seizure if trained
Ketogenic diet (if on)	OPD	Ensure compliance; check ketosis; dietary counseling
Epilepsy surgery evaluation	OPD	If drug-resistant epilepsy (failure of 2 appropriate ASMs at adequate doses) → refer for surgical evaluation

3E. Medications to AVOID or Use with Caution

Treatment	Route	Indication	Dosing	Contraindications	Monitoring	ED	HOSP	OPD	ICU
Tramadol	-	-	-	-	-	-	-	-	-
Meperidine (Demerol)	-	-	-	-	-	-	-	-	-
Bupropion	-	-	-	-	-	-	-	-	-
Clozapine	-	-	-	-	-	-	-	-	-
Fluoroquinolones	-	-	-	-	-	-	-	-	-
Carbapenems (imipenem > meropenem)	-	-	-	-	-	-	-	-	-
Isoniazid	-	-	-	-	-	-	-	-	-
Theophylline / Aminophylline	-	-	-	-	-	-	-	-	-
Stimulants (amphetamines, methylphenidate)	-	-	-	-	-	-	-	-	-
Alcohol (acute intoxication and withdrawal)	-	-	-	-	-	-	-	-	-
Illicit drugs (cocaine, amphetamines, synthetic cathinones)	-	-	-	-	-	-	-	-	-

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4. OTHER RECOMMENDATIONS

4A. Essential

Recommendation	ED	HOSP	OPD	ICU	Details
Neurology consultation	-	URGENT	ROUTINE	URGENT	For medication adjustments, change in seizure pattern, refractory seizures, presurgical evaluation consideration
ASM level check	STAT	STAT	ROUTINE	STAT	All ASMs with available assays; interpret in clinical context; free levels for protein-bound drugs
Adherence assessment	STAT	STAT	ROUTINE	STAT	Ask directly about missed doses; identify barriers (cost, side effects, complexity, depression); pill counts if available; pharmacy refill records
Precipitant identification	STAT	STAT	ROUTINE	STAT	Infection (UTI most common); sleep deprivation; alcohol; medication changes; stress; menstrual cycle (catamenial epilepsy)
Injury assessment	STAT	STAT	-	STAT	Tongue laceration; posterior shoulder dislocation (classic); vertebral compression fracture; head trauma (if fall)
Safety counseling	-	ROUTINE	ROUTINE	-	Driving restrictions (document!); activity limitations; seizure first aid for family; MedicAlert bracelet; rescue medication prescription (rectal diazepam or intranasal midazolam)
Return to baseline confirmation	STAT	STAT	-	STAT	Document return to neurologic baseline; if not returning → consider ongoing seizures (NCSE), structural lesion, metabolic cause

4B. Extended

Recommendation	ED	HOSP	OPD	ICU	Details
EEG	-	URGENT	ROUTINE	STAT	If change in seizure pattern, prolonged post-ictal state, concern for NCSE, or to characterize epileptiform activity
Imaging	-	URGENT	ROUTINE	URGENT	MRI if change in seizure semiology, new focal findings, or suspicion of progressive lesion; CT acutely if trauma, anticoagulation, or prolonged altered mental status
Pharmacy consultation	-	ROUTINE	ROUTINE	-	Drug interaction review; adherence strategies; cost-effective alternatives; patient education on ASMs
Social work	-	ROUTINE	ROUTINE	-	Insurance/cost barriers to medication; disability resources; driving/employment impact; support services
Psychology / Psychiatry	-	ROUTINE	ROUTINE	-	Depression (common comorbidity; some ASMs worsen depression); anxiety; PNES if suspected; coping strategies
Epilepsy nurse educator	-	ROUTINE	ROUTINE	-	Self-management education; seizure diary; lifestyle modifications; medication management; rescue medication training
Women's health counseling	-	ROUTINE	ROUTINE	-	Contraception (enzyme-inducing ASMs reduce OCP efficacy); pregnancy planning (folic acid, ASM optimization); teratogenicity counseling

4C. Atypical/Refractory

Recommendation	ED	HOSP	OPD	ICU	Details
Epilepsy surgery evaluation	-	-	ROUTINE	-	Drug-resistant epilepsy (failed ≥2 appropriate ASMs); refer to comprehensive epilepsy center for surgical workup (video-EEG, MRI epilepsy protocol, neuropsych, PET, etc.)
VNS / RNS / DBS evaluation	-	-	ROUTINE	-	Neuromodulation for drug-resistant epilepsy not surgical candidates; VNS (vagus nerve stimulator); RNS (responsive neurostimulation); DBS (deep brain stimulation)
Ketogenic diet referral	-	-	ROUTINE	-	Dietary therapy for drug-resistant epilepsy; especially effective in certain epilepsies (Dravet, GLUT1 deficiency); requires dietitian supervision
PNES evaluation	-	-	ROUTINE	-	If clinical features suggest psychogenic non-epileptic seizures (variable semiology, prolonged events, lack of post-ictal state, eyes closed, pelvic thrusting, ictal crying, preserved awareness with bilateral movements); video-EEG confirmation; psychology/psychiatry referral
Autoimmune epilepsy workup	-	ROUTINE	ROUTINE	-	If new-onset refractory seizures, cognitive decline, or change in previously controlled epilepsy → autoimmune antibody panel; LP; MRI; consider immunotherapy trial
Genetic testing	-	-	ROUTINE	-	If suspected genetic epilepsy; may inform ASM selection (e.g., avoid sodium channel blockers in SCN1A/Dravet; valproate effective in SCN2A); family counseling

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═══════════════════════════════════════════════════════════════ SECTION B: SUPPORTING INFORMATION ═══════════════════════════════════════════════════════════════

5. DIFFERENTIAL DIAGNOSIS

Differential for "Breakthrough Seizure"

Diagnosis	Key Distinguishing Features	Evaluation
True breakthrough seizure (epileptic)	Typical semiology for patient; post-ictal state; EEG correlation; identifiable precipitant or subtherapeutic level	ASM levels; EEG; precipitant search
Psychogenic non-epileptic seizure (PNES)	Variable semiology; prolonged duration (>2 min); preserved awareness with bilateral movements; eyes closed; pelvic thrusting; ictal crying; side-to-side head movements; no post-ictal confusion (or prolonged pseudo-post-ictal); normal prolactin; normal EEG during event	Video-EEG (gold standard); prolactin (not elevated); clinical features; psychology evaluation
Syncope (convulsive)	Triggered by standing, hot environment, vagal stimulus; brief LOC (<1 min); myoclonic jerks are common during syncope (not true seizure); rapid recovery; pale before event	ECG; orthostatics; tilt table test; echocardiogram; cardiac history
Cardiac arrhythmia	Sudden LOC without warning or with palpitations; rapid recovery; history of cardiac disease	ECG; Holter/event monitor; echocardiogram; electrophysiology study
Toxic/metabolic	Hypoglycemia; hyponatremia; hypocalcemia; uremia; hepatic encephalopathy; drug intoxication/withdrawal	Glucose; electrolytes; renal/hepatic function; drug screen; specific toxin levels
Transient ischemic attack (TIA)	Negative symptoms (weakness, numbness, aphasia) vs. positive symptoms (convulsion); typically no LOC; vascular risk factors	MRI with DWI; MRA; vascular risk factor assessment
Sleep disorders	REM sleep behavior disorder; parasomnias; cataplexy (narcolepsy)	Sleep history; PSG; MSL
Movement disorders	Dystonia; chorea; myoclonus (non-epileptic); paroxysmal dyskinesia	Preserved awareness; stereotyped movements; neurologic exam; movement disorder evaluation
Migraine with aura	Visual, sensory, or motor aura preceding headache; duration 20-60 min; no LOC	Headache history; migraine features; may have EEG abnormalities but distinct from seizure

Common Precipitants of Breakthrough Seizures

Precipitant	Mechanism	Evaluation/Intervention
Non-adherence / missed doses	Subtherapeutic ASM levels	Ask directly; check levels; pharmacy refill records; address barriers
Sleep deprivation	Lowers seizure threshold significantly	Sleep hygiene counseling; regular schedule; treat sleep disorders
Infection (especially UTI)	Fever lowers seizure threshold; metabolic stress	UA/culture; CXR; treat infection
Alcohol use / withdrawal	Both intoxication and withdrawal provoke seizures	Alcohol level; history; withdrawal prophylaxis
Medication changes	Drug interactions; started medication that lowers threshold	Medication reconciliation; check levels; review interactions
Stress / anxiety	Hyperexcitability	Stress management; counseling; anxiolytics if appropriate
Menstrual cycle (catamenial epilepsy)	Perimenstrual or periovulatory clustering	Seizure diary correlation; hormonal treatment; increase ASM perimenstrually
Electrolyte abnormalities	Hyponatremia (carbamazepine, oxcarbazepine); hypocalcemia; hypomagnesemia	Electrolyte panel; correct abnormality
Illicit drugs	Cocaine, amphetamines lower seizure threshold	Drug screen; counseling
Flashing lights / photosensitivity	Photic stimulation triggers seizures in photosensitive epilepsy	EEG with photic stimulation; avoid triggers; blue-tinted lenses

Red Flags Suggesting Alternative Diagnosis

Red Flag	Concern	Action
New focal neurologic deficit	New structural lesion (tumor, stroke, hemorrhage)	STAT imaging (CT then MRI)
Prolonged post-ictal state (>30 min)	Status epilepticus; NCSE; structural lesion; metabolic cause; postictal paralysis (Todd's)	Continuous EEG; imaging; extended metabolic workup
Fever with seizure	Meningitis/encephalitis; febrile seizure in adult is concerning	LP if meningitis suspected; imaging; antibiotics/antivirals empirically if indicated
Change in seizure semiology	New epileptogenic lesion; different seizure type; PNES	EEG; MRI; video-EEG if needed
No return to baseline	Ongoing NCSE; structural lesion; metabolic encephalopathy	Continuous EEG; imaging; metabolic workup
First seizure at this facility	May not be known epilepsy; needs full new-onset seizure workup	Full workup unless confirmed prior epilepsy
Eyes closed during "seizure"	PNES (epileptic seizures typically have eyes open)	Video-EEG; psychology referral
Very prolonged event (>5-10 min)	Status epilepticus; PNES (epileptic seizures typically <2-3 min)	Treat as SE if epileptic; video-EEG for characterization

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6. MONITORING PARAMETERS

ED / Acute Phase

Parameter	Frequency	Target	Action if Abnormal
Mental status (return to baseline)	q15 min until resolved; q1h thereafter	Return to baseline within 30-60 min	Prolonged: consider NCSE → EEG; imaging; extended evaluation
Vital signs	q15-30 min initially; q1h once stable	HR 60-100; BP <180/110; SpO2 >94%; Temp <38°C	Manage accordingly; fever → infection workup
Seizure recurrence	Continuous observation	No further seizures	Repeat seizure: give benzodiazepine; consider additional ASM load; SE protocol if >5 min
Airway / Respiratory status	Continuous; q15 min	Patent airway; no aspiration; adequate ventilation	Position; suction; O2 if needed; intubation if compromised
Blood glucose	Check immediately; repeat if symptomatic	70-180 mg/dL	Hypoglycemia: D50W IV
Cardiac rhythm	Continuous telemetry	Normal sinus; no arrhythmia	Treat arrhythmia; cardiology if indicated

Inpatient Monitoring

Parameter	Frequency	Target	Action if Abnormal
ASM level (repeat)	24-48h after dose adjustment	Therapeutic (per drug)	Adjust dose
Sodium (if on carbamazepine/oxcarbazepine)	Daily during hospitalization	>130 mEq/L	Fluid restriction; consider ASM change if persistent hyponatremia
LFTs (if concern for toxicity)	Q2-3 days if abnormal	AST/ALT <3x ULN	If elevated: consider ASM hepatotoxicity; may need to discontinue
Ammonia (if on valproate with altered mental status)	With any confusion/lethargy	<35 μmol/L	Elevated: consider discontinuing valproate; L-carnitine supplementation
Seizure diary	Continuous	Document all events	Assess frequency and response to treatment
Neurologic exam	Daily	Stable; no new deficits	New deficits: imaging

Outpatient Monitoring

Parameter	Frequency	Target	Action if Abnormal
ASM levels	2-4 weeks after dose change; then q6-12 months or PRN	Therapeutic	Adjust dose
CBC, CMP	Q6-12 months or per ASM-specific monitoring	Normal	ASM-specific toxicity management
Bone density (DEXA)	Baseline and q2-5 years if on enzyme-inducing ASMs	T-score >-2.5	Vitamin D, calcium, bisphosphonates if needed
Seizure frequency	Seizure diary; each visit	Reduced or seizure-free	Adjust ASMs; consider surgery evaluation if drug-resistant
Side effects	Each visit	Tolerable; no limiting effects	Dose adjustment; consider alternative ASM
Mood / Cognition	Each visit	No depression; stable cognition	Depression treatment; ASM adjustment if cognitive effects

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7. DISPOSITION CRITERIA

Admission Criteria

Level of Care	Criteria
ICU	Status epilepticus; cluster seizures requiring continuous infusion; severe injuries; need for continuous EEG monitoring; airway compromise; hemodynamic instability
General floor / Observation	Prolonged post-ictal state; multiple seizures in ED; significantly subtherapeutic levels requiring monitoring during adjustment; uncertain diagnosis; new focal deficit; complicating medical illness
Discharge home	Single uncomplicated breakthrough seizure; returned to baseline; identifiable/correctable precipitant; therapeutic or corrected ASM level; no injuries requiring admission; safe home environment; reliable follow-up

Discharge Criteria

Criterion	Details
Return to baseline	Normal mental status and neurologic exam matching patient's baseline
No ongoing seizure activity	Seizure-free since treatment/observation; no concern for subclinical seizures
Precipitant addressed	Infection treated; missed doses restored; electrolytes corrected; adherence barriers addressed
ASM plan established	Levels checked; dose adjustments made if indicated; supply of medications ensured
Safety counseling completed	Driving restrictions documented; activity precautions; seizure first aid for caregivers; when to return
Follow-up arranged	Neurology follow-up within 1-4 weeks; PCP as needed; EEG scheduled if indicated
Rescue medication prescribed	Rectal diazepam or intranasal midazolam prescription if appropriate (cluster seizures, prolonged seizures)

Discharge Checklist

Item	Details
ASM prescriptions	Ensure supply of all ASMs; no gaps in medication
ASM instructions	Dose, frequency, timing; what to do if dose missed; common side effects
Driving restrictions	Document state-specific requirement (typically 3-12 months seizure-free); document counseling
Activity restrictions	No swimming alone; no heights; supervision during bathing if frequent seizures; work restrictions if applicable
Rescue medication	Prescription and training for rectal diazepam or intranasal midazolam
Seizure first aid	Education for patient and family; recovery position; when to call 911
When to return	Return for: repeat seizure, prolonged seizure, status epilepticus, new symptoms, fever with seizure, head injury
Follow-up	Neurology appointment; EEG if scheduled; PCP follow-up
MedicAlert	Encourage bracelet/necklace for epilepsy identification
Seizure diary	Provide or recommend app; track seizures, ASMs, triggers

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8. EVIDENCE & REFERENCES

Key Guidelines

Guideline	Source	Year	Key Recommendation
Practice Guideline Update: Efficacy and Tolerability of ASMs	AAN	2018	Levetiracetam, lamotrigine, oxcarbazepine, topiramate established for monotherapy; choose based on seizure type, side effect profile, comorbidities
Management of Adult Epilepsy	AES/ILAE	Ongoing updates	Drug-resistant epilepsy defined as failure of 2 appropriate ASMs at adequate doses; refer for surgery evaluation; multidisciplinary care
Epilepsy in Women	AAN	2009/Updates	Folic acid 0.4-4 mg daily for all women of childbearing potential; avoid valproate in pregnancy if possible; lamotrigine and levetiracetam generally preferred
SUDEP Prevention	AAN	2017	Counsel on sudden unexpected death in epilepsy; nocturnal supervision reduces risk; seizure control reduces risk

Landmark Studies

Study	Finding	Impact
Kwan & Brodie (2000)	47% of newly diagnosed epilepsy patients became seizure-free on first ASM; 13% on second; 4% on third; after failure of 2 appropriate ASMs, chance of seizure freedom with additional ASMs is <5%	Defined drug-resistant epilepsy; established rationale for early surgery referral
SANAD I & II (2007, 2021)	Lamotrigine best for focal epilepsy; valproate best for generalized/unclassified (but teratogenic); levetiracetam non-inferior to lamotrigine for focal	Guide first-line ASM selection by seizure type
Standard and New Antiepileptic Drugs (SNAED) Trial	Levetiracetam and zonisamide non-inferior to lamotrigine for focal epilepsy	Expanded first-line options
Early Randomized Surgical Epilepsy Trial (ERSET, 2012)	Early surgery superior to continued medical therapy for drug-resistant temporal lobe epilepsy; 73% vs. 0% seizure-free at 2 years	Surgery is highly effective; early referral improves outcomes
SUDEP Risk Factors	Convulsive seizures, especially nocturnal; living alone; poor seizure control	Counsel patients; nocturnal monitoring devices; optimize seizure control

ASM Therapeutic Ranges (Reference)

ASM	Total Level	Free Level	Notes
Phenytoin	10-20 mcg/mL	1-2 mcg/mL	Free level essential if hypoalbuminemia, renal failure, pregnancy; nonlinear kinetics
Carbamazepine	4-12 mcg/mL	N/A	Check epoxide if toxicity; auto-induction
Valproate	50-100 mcg/mL	5-15 mcg/mL	Free level in pregnancy, elderly, hepatic disease; check ammonia if encephalopathy
Phenobarbital	15-40 mcg/mL	N/A	Long half-life; steady-state takes weeks
Levetiracetam	12-46 mcg/mL (suggested)	N/A	Not routinely monitored; wide therapeutic range; renal dosing
Lamotrigine	3-14 mcg/mL (varies)	N/A	Highly variable; affected by estrogen, enzyme inducers/inhibitors
Oxcarbazepine (MHD)	3-35 mcg/mL	N/A	MHD is active metabolite; monitor sodium
Topiramate	5-20 mcg/mL (suggested)	N/A	Not routinely monitored
Lacosamide	10-20 mcg/mL (emerging)	N/A	Check ECG for PR prolongation
Clobazam	0.03-0.3 mcg/mL	N/A	Also measure N-desmethylclobazam metabolite
Brivaracetam	Not established	N/A	Similar to levetiracetam; not routinely monitored
Perampanel	Not established	N/A	Long half-life; steady-state takes weeks

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APPENDICES

Appendix A: Breakthrough Seizure Evaluation Algorithm

BREAKTHROUGH SEIZURE IN KNOWN EPILEPSY
                │
    IMMEDIATE MANAGEMENT (if still seizing):
    • Benzodiazepine per protocol
    • Protect patient; do not restrain
    • Time seizure; SE protocol if >5 min
                │
    POST-ICTAL ASSESSMENT:
    • Return to baseline? (typically 5-30 min)
    • Injury assessment
    • Vital signs
                │
    NOT RETURNING TO BASELINE (>30-60 min)?
         │
    YES → Consider:
         • Ongoing NCSE (continuous EEG)
         • Structural lesion (CT/MRI)
         • Metabolic cause
         • Prolonged post-ictal (can be >1h in some patients)
                │
    RETURNED TO BASELINE:
                │
    EVALUATE PRECIPITANT:
    • Non-adherence? (ask directly; levels)
    • Infection? (UTI, pneumonia)
    • Sleep deprivation?
    • Alcohol/drugs?
    • Medication change?
    • Menstrual cycle?
    • Stress?
    • Electrolyte abnormality?
                │
    CHECK ASM LEVELS:
    • Subtherapeutic → Restore/adjust doses
    • Therapeutic → Consider adding ASM or
                    evaluate for change in epilepsy
                │
    IMAGING (NOT routinely needed if):
    • Typical seizure for this patient
    • Returned to baseline
    • No trauma, no new focal signs
    │
    CONSIDER IMAGING IF:
    • New seizure semiology
    • New focal deficit
    • Prolonged post-ictal
    • Head trauma
    • Anticoagulation
    • Immunocompromised
                │
    DISPOSITION:
    • Discharge if: single seizure, baseline, precipitant addressed,
      ASM plan, safe environment, follow-up
    • Admit if: multiple seizures, prolonged post-ictal,
      uncertain diagnosis, injuries, unsafe home

Appendix B: Common Drug Interactions Affecting ASM Levels

Interacting Drug	Effect on ASM	Affected ASMs	Action
Enzyme Inducers (rifampin, phenytoin, carbamazepine, phenobarbital, St. John's Wort)	↓ ASM levels	Lamotrigine (↓50%), valproate, topiramate, levetiracetam (mild), clobazam, perampanel	Increase ASM dose; monitor levels
Enzyme Inhibitors (valproate, fluoxetine, erythromycin)	↑ ASM levels	Lamotrigine (valproate doubles level), carbamazepine, phenobarbital, phenytoin	Decrease ASM dose; lamotrigine titration much slower when adding to valproate
Oral Contraceptives (estrogen)	↓ Lamotrigine levels	Lamotrigine (↓50%)	Increase lamotrigine dose; may need to decrease during pill-free week
Carbapenems (imipenem, meropenem)	↓ Valproate levels dramatically	Valproate (↓60-90%)	Avoid combination if possible; if used, significantly increase valproate or use alternative ASM
Antacids	↓ Absorption of some ASMs	Gabapentin, phenytoin	Separate administration by 2 hours
Protein-binding displacement	↑ Free ASM fraction	Phenytoin, valproate (with aspirin, warfarin, other highly bound drugs)	Check free levels

Appendix C: ASM Selection by Seizure Type

Seizure Type	First-Line Options	Avoid
Focal (aware or impaired awareness)	Lamotrigine, levetiracetam, oxcarbazepine, carbamazepine	Ethosuximide (not effective)
Focal to bilateral tonic-clonic	Same as focal	Same as focal
Generalized tonic-clonic	Valproate (if not woman of childbearing potential), lamotrigine, levetiracetam	Carbamazepine, oxcarbazepine, phenytoin (may worsen)
Absence (typical)	Ethosuximide (first-line for absence only), valproate, lamotrigine	Carbamazepine, oxcarbazepine, phenytoin (can worsen)
Myoclonic	Valproate, levetiracetam, clonazepam	Carbamazepine, oxcarbazepine, phenytoin, gabapentin (can worsen)
Juvenile myoclonic epilepsy (JME)	Valproate (most effective but avoid in women), lamotrigine (may worsen myoclonus), levetiracetam	Carbamazepine, oxcarbazepine, phenytoin
Lennox-Gastaut syndrome	Lamotrigine, valproate, clobazam, rufinamide, felbamate, cannabidiol	N/A (polytherapy usually required)
Dravet syndrome (SCN1A)	Valproate, clobazam, stiripentol, cannabidiol, fenfluramine	AVOID sodium channel blockers (carbamazepine, oxcarbazepine, phenytoin, lamotrigine) — can worsen seizures

Appendix D: Special Populations

Population	Considerations
Pregnancy	Folic acid 0.4-4 mg daily (start preconception); avoid valproate if possible (highest teratogenicity); lamotrigine and levetiracetam generally preferred; levels drop in pregnancy (especially lamotrigine) — monitor monthly and increase doses; valproate level may be falsely reassuring (protein binding changes)
Women of childbearing potential	Counsel all on teratogenicity; contraception counseling (enzyme inducers reduce OCP efficacy); preconception planning; folic acid; prefer lamotrigine, levetiracetam over valproate
Elderly	Increased sensitivity to ASM side effects; cognitive effects; falls; start low, go slow; drug interactions (polypharmacy); lamotrigine, levetiracetam, lacosamide generally well-tolerated; avoid phenobarbital, high-dose phenytoin
Renal impairment	Reduce doses of renally-cleared ASMs: levetiracetam, gabapentin, pregabalin, topiramate, lacosamide; phenytoin, carbamazepine, valproate less affected
Hepatic impairment	Reduce doses of hepatically-metabolized ASMs: phenytoin, carbamazepine, valproate, lamotrigine; levetiracetam, gabapentin safer
Cardiac disease	Avoid lacosamide if significant AV block (PR prolongation); carbamazepine has cardiac conduction effects; check ECG
Psychiatric comorbidity	Depression common in epilepsy; levetiracetam can cause behavioral side effects (irritability, aggression) — consider brivaracetam instead; valproate may worsen depression; lamotrigine has mood-stabilizing properties

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