Drug-Resistant Epilepsy¶

VERSION: 1.0 CREATED: January 31, 2026 STATUS: Approved

DIAGNOSIS: Drug-Resistant Epilepsy

ICD-10: G40.919 (Epilepsy, unspecified, intractable, without status epilepticus), G40.911 (Epilepsy, unspecified, intractable, with status epilepticus), G40.119 (Localization-related epilepsy, intractable), G40.219 (Localization-related symptomatic epilepsy, intractable), G40.319 (Generalized idiopathic epilepsy, intractable), G40.A19 (Absence epileptic syndrome, intractable), G40.B19 (Juvenile myoclonic epilepsy, intractable)

CPT CODES: 95816 (EEG routine), 95819 (EEG with sleep), 95700-95720 (continuous EEG), 95950-95954 (video-EEG monitoring), 70553 (MRI brain with/without contrast), 78816 (PET brain), 78607 (SPECT brain), 95965 (MEG), 61536 (craniotomy for epilepsy surgery), 61210 (VNS implantation), 61850 (DBS implantation), 61863 (RNS implantation), 80201-80299 (therapeutic drug monitoring)

SYNONYMS: Drug-resistant epilepsy, DRE, refractory epilepsy, intractable epilepsy, pharmacoresistant epilepsy, medically refractory seizures, treatment-resistant epilepsy, uncontrolled epilepsy, difficult-to-treat epilepsy, therapy-resistant epilepsy

SCOPE: Management of drug-resistant epilepsy defined as failure of adequate trials of two or more appropriately chosen and tolerated antiseizure medications (ASMs) at adequate doses. Covers advanced pharmacotherapy, presurgical evaluation, surgical options, neuromodulation (VNS, RNS, DBS), dietary therapies, and special populations. Excludes initial seizure workup (see New Onset Seizure), acute breakthrough seizures in known epilepsy (see Breakthrough Seizure), and status epilepticus management (see Status Epilepticus template).

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 (all current ASMs) (CPT 80201-80299)	STAT	STAT	ROUTINE	STAT	Verify therapeutic levels and adherence; subtherapeutic levels are the most common correctable cause of apparent drug resistance	Therapeutic ranges (see Appendix A); document steady-state trough levels
Free (unbound) ASM levels (phenytoin, valproate) (CPT 80186, 80164)	STAT	URGENT	ROUTINE	STAT	Protein-bound drugs require free levels in hypoalbuminemia, renal failure, pregnancy, polypharmacy; free fraction is pharmacologically active	Free phenytoin 1-2 mcg/mL; free valproate 5-15 mcg/mL
CBC with differential (CPT 85025)	STAT	STAT	ROUTINE	STAT	Baseline for ASM hematologic effects; infection as seizure precipitant; monitor for bone marrow suppression (carbamazepine, felbamate)	Normal; leukopenia <3000 → evaluate ASM cause; aplastic anemia screening for felbamate
CMP (BMP + LFTs) (CPT 80053)	STAT	STAT	ROUTINE	STAT	Electrolyte abnormalities; hepatic function (ASM metabolism, toxicity); renal function (ASM dosing); hyponatremia (carbamazepine/oxcarbazepine)	Normal; hyponatremia <130 → provokes seizures; elevated LFTs → ASM hepatotoxicity
Magnesium (CPT 83735)	STAT	STAT	ROUTINE	STAT	Hypomagnesemia lowers seizure threshold; chronic ASM use may deplete magnesium	>2.0 mg/dL; low → replete
Ionized calcium (CPT 82330)	STAT	STAT	ROUTINE	STAT	Hypocalcemia can cause seizures; enzyme-inducing ASMs accelerate vitamin D metabolism	Normal ionized Ca; low → check vitamin D, replete
Blood glucose (CPT 82947)	STAT	STAT	ROUTINE	STAT	Hypoglycemia is reversible seizure cause; GLUT1 deficiency syndrome causes DRE with low CSF glucose	70-180 mg/dL; persistent low → evaluate GLUT1 deficiency
Urinalysis (CPT 81003)	STAT	STAT	-	STAT	UTI as occult seizure precipitant; especially in elderly and institutionalized patients	Normal; pyuria → treat infection
Urine drug screen (CPT 80307)	STAT	STAT	-	STAT	Illicit substances lower seizure threshold; assess adherence and drug interactions	Negative; positive → evaluate contribution to seizure frequency
Pregnancy test (β-hCG) (CPT 84703)	STAT	STAT	ROUTINE	STAT	Pregnancy alters ASM levels; teratogenicity concerns with many ASMs used in DRE (valproate, topiramate, phenobarbital)	Document result; positive → urgent ASM safety review
Ammonia (CPT 82140)	STAT	STAT	-	STAT	Valproate-induced hyperammonemic encephalopathy; can occur with normal LFTs and therapeutic levels	<35 μmol/L; elevated → consider valproate reduction or carnitine supplementation

1B. Extended Workup (Second-line)¶

Test	ED	HOSP	OPD	ICU	Rationale	Target Finding
Vitamin D, 25-OH (CPT 82306)	-	ROUTINE	ROUTINE	-	Enzyme-inducing ASMs (phenytoin, carbamazepine, phenobarbital) accelerate vitamin D metabolism → osteoporosis; long-term DRE patients at high risk	>30 ng/mL; deficient → supplement aggressively
B12 (CPT 82607) / Folate (CPT 82746)	-	ROUTINE	ROUTINE	-	Phenytoin and carbamazepine deplete folate; B12 deficiency neuropathy; critical for women of childbearing potential	Normal; low folate → supplement (5 mg/day with enzyme inducers)
TSH (CPT 84443)	-	ROUTINE	ROUTINE	-	Thyroid dysfunction affects seizure threshold; some ASMs affect thyroid function	Normal; abnormal → treat and reassess seizure frequency
Lipid panel (CPT 80061)	-	ROUTINE	ROUTINE	-	Enzyme-inducing ASMs increase lipid levels; cardiovascular risk in chronic DRE	Normal; elevated → statin if indicated; consider non-enzyme-inducing ASM
Carbamazepine-10,11-epoxide level (CPT 80156)	-	ROUTINE	ROUTINE	-	Active metabolite elevated by valproate co-therapy; toxicity with normal parent drug levels	<9 mcg/mL; elevated → toxicity even with therapeutic carbamazepine level
HLA-B15:02 / HLA-A31:01 (CPT 81374)	-	-	ROUTINE	-	Pharmacogenomic testing before carbamazepine/oxcarbazepine in Asian populations (HLA-B15:02 → SJS/TEN); HLA-A31:01 in Europeans	Negative for risk alleles; positive → avoid associated ASM
Prolactin (CPT 84146)	-	URGENT	-	-	Distinguish epileptic seizure from PNES if diagnostic uncertainty; must draw within 20 min of event	2-3x baseline within 20 min of convulsive seizure; normal in PNES
Cortisol, AM (CPT 82533)	-	ROUTINE	ROUTINE	-	Adrenal insufficiency; chronic ASM use may affect cortisol; consider if fatigue is prominent	Normal
DEXA scan referral (CPT 77080)	-	-	ROUTINE	-	Bone mineral density screening for patients on long-term enzyme-inducing ASMs; fracture risk from seizures	Normal T-score; osteopenia/osteoporosis → treat and modify ASM if possible

1C. Rare/Specialized (Refractory or Atypical)¶

Test	ED	HOSP	OPD	ICU	Rationale	Target Finding
Autoimmune encephalitis antibody panel (serum) (CPT 86255)	-	EXT	EXT	-	Autoimmune epilepsy is treatable cause of apparent DRE; anti-LGI1, anti-CASPR2, anti-NMDAR, anti-GABA-B, anti-AMPA	Negative; positive → immunotherapy trial
Autoimmune encephalitis antibody panel (CSF)	-	EXT	EXT	-	CSF more sensitive than serum for some antibodies (NMDAR); paired serum/CSF testing recommended	Negative; positive → immunotherapy
Genetic epilepsy panel / Whole exome sequencing (CPT 81415, 81419)	-	-	EXT	-	Genetic cause suspected if syndromic features, family history, or early onset DRE; may guide targeted therapy (e.g., SCN1A → avoid sodium channel blockers in Dravet)	Pathogenic variants in epilepsy genes (SCN1A, SCN2A, KCNQ2, DEPDC5, TSC1/2, etc.)
Paraneoplastic antibody panel (CPT 86255)	-	EXT	EXT	-	New-onset DRE in adults >40 with cognitive decline or other neurologic symptoms; anti-Hu, anti-CV2, anti-amphiphysin	Negative; positive → malignancy workup
CSF glucose with paired serum glucose (CPT 82950)	-	EXT	EXT	-	GLUT1 deficiency syndrome: CSF glucose <40 mg/dL or CSF/serum glucose ratio <0.4; ketogenic diet is treatment of choice	CSF/serum ratio >0.6; low ratio → GLUT1 deficiency → ketogenic diet
Mitochondrial DNA testing (CPT 81401)	-	-	EXT	-	Mitochondrial epilepsy (MELAS, MERRF) if myoclonus, hearing loss, exercise intolerance, elevated lactate; avoid valproate	Specific mutations (m.3243A>G for MELAS, m.8344A>G for MERRF)
Ceruloplasmin / serum copper (CPT 82390)	-	-	EXT	-	Wilson disease with seizures (rare); treatable cause	Ceruloplasmin >20 mg/dL; low → 24h urine copper, slit lamp exam
Pyruvate dehydrogenase complex assay	-	-	EXT	-	PDC deficiency causes early-onset epilepsy responsive to ketogenic diet	Normal activity; deficient → ketogenic diet
SLC2A1 gene sequencing (GLUT1)	-	-	EXT	-	Confirmatory testing for GLUT1 deficiency if low CSF glucose	No mutation; pathogenic variant → ketogenic diet definitive treatment

2. DIAGNOSTIC IMAGING & STUDIES¶

2A. Essential/First-line¶

Study	ED	HOSP	OPD	ICU	Timing	Target Finding	Contraindications
MRI brain epilepsy protocol (3T preferred) (CPT 70553)	-	URGENT	ROUTINE	-	All DRE patients require dedicated epilepsy protocol MRI if not already done; includes thin-cut coronal T2/FLAIR through temporal lobes, volumetric T1, T2*, post-contrast	Mesial temporal sclerosis (hippocampal atrophy, T2 signal change); focal cortical dysplasia; cavernous malformation; tumor; tuberous sclerosis cortical tubers	MRI-incompatible implants; check VNS/RNS MRI compatibility
EEG (routine) (CPT 95816)	-	URGENT	ROUTINE	-	If not done recently; awake + sleep recording preferred; may capture interictal discharges to guide localization	Epileptiform discharges; focal vs generalized; specific syndrome features	None
Continuous EEG (cEEG) monitoring (CPT 95700)	-	STAT	-	STAT	If frequent seizures, altered mental status, or concern for subclinical seizures; quantify seizure burden	Ictal patterns; NCSE; seizure frequency and duration	None; resource-dependent
CT head without contrast (CPT 70450)	STAT	STAT	-	STAT	Acute presentation: head trauma during seizure, prolonged postictal state, new focal deficit, anticoagulated patient	Acute hemorrhage; mass effect; herniation	None for non-contrast
ECG (12-lead) (CPT 93000)	STAT	STAT	ROUTINE	STAT	Cardiac arrhythmia vs seizure; QTc prolongation (lacosamide, rufinamide); baseline before ASM changes	Normal; prolonged QTc → avoid QT-prolonging ASMs

2B. Extended¶

Study	ED	HOSP	OPD	ICU	Timing	Target Finding	Contraindications
Video-EEG monitoring (EMU admission) (CPT 95711-95720)	-	ROUTINE	ROUTINE	-	Core presurgical evaluation: Capture habitual seizures with scalp EEG + video; confirm epileptic vs non-epileptic; localize seizure onset zone; typically 5-7 day admission	Ictal onset zone; seizure semiology; concordance with MRI lesion; PNES identification	Requires specialized epilepsy monitoring unit
FDG-PET brain (CPT 78816)	-	-	ROUTINE	-	Presurgical localization: Interictal hypometabolism at seizure focus; most useful when MRI is non-lesional; obtain during seizure-free interictal state	Focal hypometabolism concordant with EEG focus; sensitivity 60-90% for temporal lobe epilepsy	Diabetes (may affect uptake); pregnancy
Ictal SPECT (CPT 78607)	-	ROUTINE	-	-	Injection during seizure onset (must have tracer ready at bedside); shows hyperperfusion at seizure focus; requires subtraction with interictal SPECT (SISCOM)	Focal hyperperfusion at seizure onset zone	Requires in-unit injection within 30 sec of seizure onset
Magnetoencephalography (MEG) (CPT 95965)	-	-	EXT	-	Non-invasive source localization of interictal discharges; complementary to EEG; most useful for non-lesional neocortical epilepsy	Dipole cluster concordant with suspected focus	Metallic implants; limited availability
Neuropsychological testing (CPT 96132-96133)	-	-	ROUTINE	-	Required presurgical evaluation: Lateralize and localize cognitive function; predict postoperative cognitive outcome; baseline before surgery	Memory lateralization; language dominance; cognitive profile consistent with seizure focus	Requires cooperation; active seizures may invalidate
Functional MRI (fMRI) (CPT 70555)	-	-	ROUTINE	-	Language and motor cortex mapping for presurgical planning; non-invasive alternative to Wada test for language lateralization	Language dominance (left, right, bilateral); proximity of eloquent cortex to planned resection	Same as standard MRI
Ambulatory EEG (24-72h) (CPT 95711)	-	-	ROUTINE	-	Home monitoring to capture events; useful if EMU admission not yet feasible or for seizure frequency quantification	Ictal events; interictal discharges; seizure frequency	Patient cooperation required
MRI post-processing (morphometric analysis)	-	-	EXT	-	Computer-assisted detection of subtle cortical dysplasia not visible on visual MRI review; voxel-based morphometry	Subtle FCD; gray-white junction blurring	Requires specialized software
Chest X-ray (CPT 71046)	STAT	STAT	-	STAT	Aspiration pneumonia post-seizure; ETT position if intubated	Infiltrate; aspiration	None

2C. Rare/Advanced¶

Study	ED	HOSP	OPD	ICU	Timing	Target Finding	Contraindications
Intracranial EEG / Stereo-EEG (SEEG) (CPT 61760, 95700)	-	ROUTINE	-	-	When non-invasive data is discordant or non-localizing; depth electrodes placed stereotactically to sample suspected epileptogenic zone; typically 1-3 weeks monitoring	Precise ictal onset zone; propagation pathways; define resection margins	Neurosurgical risks (hemorrhage 1-2%, infection 1-3%)
Wada test (intracarotid amobarbital) (CPT 95958)	-	ROUTINE	-	-	Presurgical memory and language lateralization; largely replaced by fMRI but still used when fMRI inconclusive or discordant; assesses risk of postoperative amnesia	Language lateralization; memory adequacy of contralateral hemisphere	Contrast allergy; carotid stenosis; vascular anomalies
High-density EEG (hdEEG, 256-channel) (CPT 95816)	-	-	EXT	-	Improved source localization with dense array; electrical source imaging (ESI); research and specialized centers	Refined dipole localization; source imaging concordant with other modalities	Limited availability
MRI-guided LITT planning scan	-	-	EXT	-	Pre-operative planning for laser interstitial thermal therapy; volumetric sequences to plan trajectory	Target lesion (MTS, FCD, hypothalamic hamartoma) amenable to LITT	Same as standard MRI

LUMBAR PUNCTURE¶

Indication: Suspected autoimmune epilepsy, CNS infection, or leptomeningeal disease contributing to DRE; CSF glucose for GLUT1 deficiency evaluation Timing: Routine outpatient or inpatient; urgent if infection suspected Volume Required: Standard 10-15 cc

Study	Rationale	Target Finding	ED	HOSP	OPD	ICU
Cell count (tubes 1 and 4)	Infection or inflammation	WBC <5, RBC 0	URGENT	ROUTINE	ROUTINE	URGENT
Protein	Elevated in infection, inflammation	15-45 mg/dL; elevated → infection/inflammation	URGENT	ROUTINE	ROUTINE	URGENT
Glucose with paired serum glucose	GLUT1 deficiency (CSF/serum ratio <0.4); infection (low CSF glucose)	Ratio >0.6; low → GLUT1 deficiency or infection	URGENT	ROUTINE	ROUTINE	URGENT
Autoimmune encephalitis antibody panel (CSF)	More sensitive than serum for NMDAR and some antibodies	Negative; positive → immunotherapy trial	-	EXT	EXT	-
Oligoclonal bands / IgG index	CNS inflammation; MS overlap (rare)	Negative; positive → inflammatory etiology	-	EXT	EXT	-
Cytology	Leptomeningeal malignancy if progressive DRE with other neurologic symptoms	Normal; abnormal → oncology referral	-	EXT	EXT	-

Contraindications: Elevated ICP without imaging clearance; coagulopathy (INR >1.5, platelets <50K); skin infection at LP site

3. TREATMENT¶

3A. Acute/Emergent (Rescue Medications)¶

Treatment	Route	Indication	Dosing	Contraindications	Monitoring	ED	HOSP	OPD	ICU
Midazolam (Nayzilam)	IN	Acute seizure clusters/rescue; first-line outpatient rescue for DRE patients	5 mg single spray :: IN :: once PRN :: 5 mg intranasal single spray into one nostril; may repeat x1 in 10 min if seizure continues; max 10 mg per episode; max 5 episodes/month	Acute narrow-angle glaucoma; severe respiratory depression	Respiratory status; sedation level; oxygen saturation	STAT	STAT	ROUTINE	STAT
Diazepam rectal (Diastat)	PR	Acute seizure clusters/rescue; alternative outpatient rescue	10-20 mg based on weight :: PR :: once PRN :: 0.2 mg/kg PR rounded to available dose (10, 12.5, 15, 17.5, 20 mg); may repeat x1 in 4-12h; max 2 doses per episode; max 5 episodes/month	Acute narrow-angle glaucoma; severe hepatic impairment	Respiratory status; sedation level	STAT	STAT	ROUTINE	STAT
Diazepam nasal (Valtoco)	IN	Acute seizure clusters/rescue; nasal alternative to rectal	5-20 mg based on weight :: IN :: once PRN :: 5 mg, 10 mg, 15 mg, or 20 mg intranasal based on weight; may repeat x1 in 4-12h; max 2 doses per episode	Acute narrow-angle glaucoma	Respiratory status; sedation level	STAT	STAT	ROUTINE	STAT
Lorazepam	IV	Acute prolonged seizure or cluster in ED/hospital setting	4 mg IV push :: IV :: once :: 4 mg IV push over 2 min; may repeat x1 in 5 min; max 8 mg; prepare for airway management	Severe respiratory depression without ventilatory support; acute narrow-angle glaucoma	Respiratory rate; BP; SpO2; sedation; have airway equipment ready	STAT	STAT	-	STAT
Midazolam	IM	Acute seizure when IV access unavailable	10 mg IM :: IM :: once :: 10 mg IM single dose (RAMPART trial); faster onset than IV lorazepam when IV access delayed	Severe respiratory depression; acute narrow-angle glaucoma	Respiratory status; BP; SpO2	STAT	STAT	-	STAT

3B. Symptomatic Treatments¶

Treatment	Route	Indication	Dosing	Contraindications	Monitoring	ED	HOSP	OPD	ICU
Sertraline	PO	Depression/anxiety comorbidity (occurs in 30-50% of DRE patients); does NOT lower seizure threshold	25 mg daily; 50 mg daily; 100 mg daily; 200 mg daily :: PO :: daily :: Start 25 mg daily; increase by 25-50 mg q1-2wk; target 50-200 mg daily	Concurrent MAOIs; caution with serotonergic drugs	Suicidality monitoring first 4 weeks; serotonin syndrome symptoms	-	ROUTINE	ROUTINE	-
Escitalopram	PO	Depression/anxiety comorbidity; well-tolerated in epilepsy; does NOT lower seizure threshold	5 mg daily; 10 mg daily; 20 mg daily :: PO :: daily :: Start 5-10 mg daily; increase to 20 mg after 1 week if needed; max 20 mg	Concurrent MAOIs; QT prolongation	QTc if risk factors; suicidality monitoring	-	ROUTINE	ROUTINE	-
Melatonin	PO	Sleep disturbance (common in DRE); sleep deprivation is major seizure trigger; may have mild anticonvulsant properties	3 mg qHS; 5 mg qHS; 10 mg qHS :: PO :: QHS :: Start 3 mg 30 min before bedtime; may increase to 5-10 mg; use extended-release for sleep maintenance	Few; caution with immunosuppressants	Daytime sedation; sleep quality	-	ROUTINE	ROUTINE	-
Calcium 600 mg + Vitamin D 400 IU	PO	Bone health protection for chronic ASM use; enzyme-inducing ASMs accelerate vitamin D metabolism and increase fracture risk	600 mg calcium + 400 IU vitamin D BID :: PO :: BID :: 600 mg elemental calcium + 400-800 IU vitamin D3 twice daily with meals	Hypercalcemia; kidney stones; sarcoidosis	Serum calcium and vitamin D annually; DEXA every 2 years	-	ROUTINE	ROUTINE	-
Folic acid	PO	Folate depletion by enzyme-inducing ASMs; critical for women of childbearing potential (neural tube defect prevention)	1 mg daily; 4 mg daily :: PO :: daily :: 1 mg daily for all DRE patients on enzyme-inducing ASMs; 4 mg daily for women planning pregnancy	Few contraindications	Serum folate annually	-	ROUTINE	ROUTINE	-
Lorazepam (short-term oral)	PO	Acute anxiety; seizure cluster prophylaxis during high-risk periods (illness, sleep deprivation)	0.5 mg q8h PRN; 1 mg q8h PRN :: PO :: q8h PRN :: 0.5-1 mg PO q8h PRN for anxiety or cluster prophylaxis; limit to 2-4 weeks; chronic use increases tolerance and complicates epilepsy management	Respiratory depression; myasthenia gravis; severe hepatic impairment	Sedation; tolerance; dependence risk; respiratory status	URGENT	ROUTINE	ROUTINE	-

3C. Second-line/Advanced ASMs¶

Treatment	Route	Indication	Dosing	Contraindications	Monitoring	ED	HOSP	OPD	ICU
Cenobamate (Xcopri)	PO	DRE adjunctive therapy; novel mechanism (sodium channel + GABA-A positive allosteric modulator); demonstrated high responder rates in trials	12.5 mg daily; 25 mg daily; 100 mg daily; 200 mg daily; 400 mg daily :: PO :: daily :: Start 12.5 mg daily x 2 weeks → 25 mg daily x 2 weeks → 50 mg daily x 2 weeks → 100 mg daily x 2 weeks → 150 mg daily x 2 weeks → 200 mg daily; max 400 mg daily; TITRATE SLOWLY (DRESS risk)	DRESS syndrome risk (mandatory slow titration); hypersensitivity; QT shortening with familial short QT	ECG at baseline and after reaching 200 mg; monitor for DRESS (rash, fever, lymphadenopathy, eosinophilia); ASM level interactions (reduce clobazam, phenytoin, phenobarbital)	-	ROUTINE	ROUTINE	-
Brivaracetam (Briviact)	PO, IV	DRE adjunctive therapy; SV2A ligand with higher affinity than levetiracetam; may work when levetiracetam failed; less psychiatric side effects	25 mg BID; 50 mg BID; 100 mg BID :: PO :: BID :: Start 25-50 mg BID; may increase to 100 mg BID; max 200 mg/day; no titration required; IV available for patients unable to take PO	Hypersensitivity to brivaracetam	Psychiatric symptoms (less common than levetiracetam); hepatic function with concurrent hepatotoxic drugs	-	ROUTINE	ROUTINE	-
Clobazam (Onfi)	PO	DRE adjunctive therapy; benzodiazepine with less sedation than clonazepam; approved for Lennox-Gastaut; effective across seizure types	5 mg daily; 10 mg BID; 20 mg BID :: PO :: BID :: Start 5 mg daily; increase by 5 mg/week; target 20-40 mg/day in 2 divided doses; max 40 mg/day; CYP2C19 poor metabolizers need lower doses	Severe hepatic impairment; myasthenia gravis	Sedation; tolerance (less than other benzodiazepines); respiratory depression; CYP2C19 status if excessive sedation; reduce dose if taking cenobamate	-	ROUTINE	ROUTINE	-
Lacosamide (Vimpat)	PO, IV	DRE adjunctive therapy; sodium channel (slow inactivation); well tolerated; IV formulation for acute use	50 mg BID; 100 mg BID; 150 mg BID; 200 mg BID :: PO :: BID :: Start 50 mg BID; increase by 50 mg/dose weekly; target 100-200 mg BID; max 400 mg/day; IV loading 200 mg over 15-60 min if needed	Second/third-degree AV block without pacemaker; known cardiac conduction disorders	ECG at baseline and dose changes; PR interval (prolongation dose-related); dizziness; ataxia	-	ROUTINE	ROUTINE	-
Perampanel (Fycompa)	PO	DRE adjunctive therapy; non-competitive AMPA receptor antagonist; unique mechanism for rational polytherapy	2 mg qHS; 4 mg qHS; 8 mg qHS; 12 mg qHS :: PO :: QHS :: Start 2 mg qHS; increase by 2 mg every 1-2 weeks; target 4-8 mg qHS; max 12 mg qHS (8 mg with enzyme inducers); take at bedtime	Severe hepatic/renal impairment; concurrent enzyme inducers accelerate metabolism	BLACK BOX: Serious psychiatric/behavioral reactions (aggression, hostility, irritability, homicidal ideation); mood monitoring; dizziness; falls (especially elderly)	-	ROUTINE	ROUTINE	-
Zonisamide (Zonegran)	PO	DRE adjunctive therapy; multiple mechanisms (sodium/calcium channels, carbonic anhydrase); broad-spectrum	100 mg daily; 200 mg daily; 300 mg daily; 400 mg daily :: PO :: daily :: Start 100 mg daily; increase by 100 mg q2wk; target 200-400 mg daily; max 600 mg/day	Sulfonamide allergy; severe hepatic/renal impairment	Renal function; bicarbonate (metabolic acidosis); kidney stones; heat intolerance (oligohidrosis); weight (often decreases)	-	ROUTINE	ROUTINE	-
Eslicarbazepine (Aptiom)	PO	DRE adjunctive therapy; voltage-gated sodium channel blocker; once-daily dosing; may work when carbamazepine/oxcarbazepine failed	400 mg daily; 800 mg daily; 1200 mg daily :: PO :: daily :: Start 400 mg daily x 1 week → 800 mg daily; may increase to 1200 mg daily after 1 week; max 1200 mg daily	Third-degree AV block; known HLA-B*15:02 positive; oxcarbazepine hypersensitivity	Sodium (hyponatremia); LFTs; ECG; skin rash (cross-reactivity with carbamazepine/oxcarbazepine in ~25%)	-	ROUTINE	ROUTINE	-
Fenfluramine (Fintepla)	PO	DRE due to Dravet syndrome or Lennox-Gastaut syndrome; serotonin-releasing agent	0.1 mg/kg BID; 0.2 mg/kg BID; 0.35 mg/kg BID :: PO :: BID :: Start 0.1 mg/kg BID (0.2 mg/kg/day); increase after 7 days to 0.2 mg/kg BID; max 0.35 mg/kg BID (26 mg/day) without stiripentol; max 0.2 mg/kg BID with stiripentol	Pulmonary arterial hypertension; valvular heart disease; concurrent MAOIs or serotonergic drugs; aortic/mitral valve disease	REMS PROGRAM REQUIRED: Echocardiogram at baseline, 6 months, then annually; cardiac monitoring mandatory; serotonin syndrome risk	-	ROUTINE	ROUTINE	-
Cannabidiol (Epidiolex)	PO	DRE due to Dravet syndrome, Lennox-Gastaut syndrome, or tuberous sclerosis complex; FDA-approved	2.5 mg/kg BID; 5 mg/kg BID; 10 mg/kg BID :: PO :: BID :: Start 2.5 mg/kg BID; increase after 1 week to 5 mg/kg BID; max 10 mg/kg BID (20 mg/kg/day); take with high-fat meals for absorption	Severe hepatic impairment; hypersensitivity	LFTs at baseline, 1, 3, 6 months then periodically (hepatotoxicity risk, especially with valproate); sedation (potentiated by clobazam — reduce clobazam dose); valproate interaction (hepatotoxicity)	-	ROUTINE	ROUTINE	-
Vigabatrin (Sabril)	PO	DRE refractory to other therapies; infantile spasms (first-line); tuberous sclerosis complex with epilepsy	500 mg BID; 1000 mg BID; 1500 mg BID :: PO :: BID :: Start 500 mg BID; increase by 500 mg/week; target 1000-1500 mg BID; max 3000 mg/day	IRREVERSIBLE VISUAL FIELD DEFECTS (bilateral concentric constriction in 25-50%); retinal toxicity	REMS PROGRAM REQUIRED: Baseline ophthalmologic exam including perimetry; repeat q3 months; discontinue if no benefit by 3 months; OCT monitoring	-	ROUTINE	ROUTINE	-
Rufinamide (Banzel)	PO	DRE due to Lennox-Gastaut syndrome; adjunctive therapy	200 mg BID; 400 mg BID; 800 mg BID; 1600 mg BID :: PO :: BID :: Start 200-400 mg/day in 2 divided doses; increase by 200-400 mg every 2 days; target 1600-3200 mg/day; max 3200 mg/day; take with food	Familial short QT syndrome; severe hepatic impairment	ECG (QT shortening); multi-organ hypersensitivity; drowsiness; vomiting	-	ROUTINE	ROUTINE	-
Felbamate (Felbatol)	PO	DRE refractory to all other options; Lennox-Gastaut syndrome; last-resort due to serious risks	400 mg TID; 600 mg TID; 800 mg TID; 1200 mg TID :: PO :: TID :: Start 400 mg TID (1200 mg/day); increase by 600 mg every 2 weeks; target 2400-3600 mg/day; max 3600 mg/day	BLACK BOX: Aplastic anemia (1:3000-5000) and hepatic failure (1:18,500-25,000); prior hematologic or hepatic disease	CBC with differential q2wk for first year; LFTs q1-2wk for first year; reticulocyte count; informed consent REQUIRED documenting risk discussion	-	-	ROUTINE	-

3D. Disease-Modifying / Non-Pharmacologic Therapies¶

Treatment	Route	Indication	Dosing	Pre-Treatment Requirements	Contraindications	Monitoring	ED	HOSP	OPD	ICU
Anterior temporal lobectomy	Surgical	Mesial temporal lobe epilepsy (MTS) with concordant data; 60-80% seizure-free rate; most evidence-based epilepsy surgery	N/A — surgical procedure :: Surgical :: once :: Resection of anterior temporal lobe including mesial structures; standard anterior temporal lobectomy or selective amygdalohippocampectomy	Complete presurgical evaluation: video-EEG, epilepsy protocol MRI, neuropsych, fMRI/Wada; multidisciplinary epilepsy surgery conference	Bilateral independent seizure foci; eloquent cortex involvement; patient unable to tolerate craniotomy	Post-op MRI; EEG; neuropsych at 6 months; monitor for ASM withdrawal if seizure-free	-	ROUTINE	ROUTINE	-
Focal cortical resection	Surgical	Neocortical epilepsy with identifiable lesion (FCD, cavernoma, tumor) concordant with EEG	N/A — surgical procedure :: Surgical :: once :: Resection of epileptogenic zone with intraoperative monitoring; extent guided by intracranial EEG and functional mapping	Same as ATL; may require SEEG for lesion delineation	Multifocal or generalized epilepsy; lesion in eloquent cortex without safe resection margins	Post-op MRI; EEG; neuropsych; monitor new deficits	-	ROUTINE	ROUTINE	-
Laser interstitial thermal therapy (LITT)	Surgical	MTS, hypothalamic hamartoma, small FCD; minimally invasive MRI-guided thermal ablation; lower morbidity than open surgery	N/A — MRI-guided percutaneous procedure :: Surgical :: once :: Stereotactic placement of laser fiber; real-time MRI thermometry; ablation of target	MRI with epilepsy protocol; concordant presurgical data; target amenable to ablation	Lesion too large or poorly defined; proximity to critical structures without safe thermal margins	Post-ablation MRI; EEG monitoring; neuropsych follow-up	-	ROUTINE	ROUTINE	-
Vagus nerve stimulation (VNS)	Surgical implant	Palliative neuromodulation for DRE when surgery not feasible; reduces seizure frequency by ~50% in ~50% of patients; efficacy improves over years	N/A — device implantation :: Surgical :: once :: Generator implanted subcutaneously in left chest; lead wrapped around left vagus nerve; standard parameters: 30 sec on/5 min off; 0.25 mA titrated up over weeks	MRI compatibility confirmed for specific VNS model; baseline voice evaluation; cardiac evaluation	Prior left vagotomy; caution with OSA; bradycardia/asystole during lead impedance testing	VNS interrogation q6 months; voice changes; dyspnea; magnet use training; battery life monitoring	-	ROUTINE	ROUTINE	-
Responsive neurostimulation (RNS)	Surgical implant	DRE with 1-2 identifiable seizure foci; closed-loop stimulation triggered by detected seizure activity; seizure reduction ~50-70% at 5 years	N/A — device implantation :: Surgical :: once :: Cranial neurostimulator + cortical/depth leads at seizure focus; device detects abnormal ECoG patterns and delivers stimulation	Localized seizure focus (1-2 foci); completed presurgical evaluation; cognitive ability to manage device	Multifocal epilepsy >2 foci; poor surgical candidacy; MRI after implant restricted	Remote device interrogation; seizure diary correlation; electrocorticography data review; battery replacement ~8 years	-	ROUTINE	ROUTINE	-
Deep brain stimulation (DBS) of anterior nucleus of thalamus	Surgical implant	DRE with focal epilepsy when resection/RNS not feasible; SANTE trial showed ~69% seizure reduction at 5 years	N/A — device implantation :: Surgical :: once :: Bilateral electrodes in anterior nucleus of thalamus; parameters optimized over months; typically cycling stimulation	MRI targeting of anterior thalamic nucleus; completed presurgical workup; confirmed DRE	Depression risk (15%); caution in patients with pre-existing psychiatric disorders; MRI restrictions post-implant	Device interrogation q3-6 months; psychiatric monitoring (depression, memory); stimulation parameter optimization; battery monitoring	-	ROUTINE	ROUTINE	-
Ketogenic diet (classic 4:1)	Dietary	DRE, especially GLUT1 deficiency and PDC deficiency (first-line); 50% seizure reduction in ~50% of adults; mechanism involves ketone bodies as alternative fuel	4:1 fat-to-carbohydrate+protein ratio :: Dietary :: daily :: Initiate under dietitian supervision; 4:1 ratio (4g fat per 1g carb+protein); caloric restriction not required in adults; monitor ketosis with urine/serum ketones; 3-month trial minimum	Baseline metabolic panel, lipids, urinalysis, renal ultrasound, carnitine level; dietitian consultation REQUIRED	Pyruvate carboxylase deficiency; fatty acid oxidation disorders; porphyria; severe liver disease	Serum ketones, lipids, CMP q3 months; growth parameters; kidney stones (supplement citrate); cardiac monitoring if prolonged	-	ROUTINE	ROUTINE	-
Modified Atkins diet	Dietary	More tolerable alternative to classic ketogenic diet for adult DRE; 20 g/day net carb limit; less restrictive	20 g net carbs/day :: Dietary :: daily :: Limit net carbohydrates to 20 g/day; high-fat intake encouraged; no caloric restriction; no protein restriction; less dietitian oversight needed than classic KD	Same baseline labs as ketogenic diet; dietitian consultation recommended	Same as ketogenic diet	Same as ketogenic diet; better compliance and quality of life in adults	-	ROUTINE	ROUTINE	-
Low glycemic index treatment (LGIT)	Dietary	Least restrictive dietary therapy for DRE; glycemic index <50 for all carbohydrates; may be sufficient for some patients	40-60 g low-GI carbs/day :: Dietary :: daily :: Restrict to 40-60 g carbohydrate/day; all carbs must have glycemic index <50; liberal fat and protein; most flexible dietary option	Same baseline labs as ketogenic diet	Same as ketogenic diet	Same as ketogenic diet; monitor glucose and lipids	-	-	ROUTINE	-

4. OTHER RECOMMENDATIONS¶

4A. Referrals & Consults¶

Recommendation	ED	HOSP	OPD	ICU
Comprehensive epilepsy center referral for presurgical evaluation if seizures persist despite two or more appropriately chosen ASMs (ILAE definition of DRE met)	-	URGENT	ROUTINE	-
Epileptologist consultation for ASM optimization, rational polytherapy, and candidacy assessment for surgery/neuromodulation	URGENT	URGENT	ROUTINE	URGENT
Neuropsychological testing for baseline cognitive assessment and presurgical lateralization of memory and language	-	ROUTINE	ROUTINE	-
Psychiatry referral for depression, anxiety, or psychiatric comorbidity management (affects 30-50% of DRE patients)	-	ROUTINE	ROUTINE	-
Neurosurgery consultation when presurgical workup supports surgical candidacy (concordant localization data)	-	ROUTINE	ROUTINE	-
Registered dietitian for ketogenic diet or modified Atkins diet initiation and monitoring if pharmacotherapy insufficient	-	ROUTINE	ROUTINE	-
Social work referral for disability assistance, vocational rehabilitation, and community resources for patients with functional limitations from DRE	-	ROUTINE	ROUTINE	-
Reproductive endocrinology or OB/GYN referral for women of childbearing potential for preconception planning, ASM teratogenicity counseling, and contraception optimization	-	-	ROUTINE	-
Physical therapy for fall prevention, injury management, and exercise program given recurrent seizure-related falls	-	ROUTINE	ROUTINE	-
Palliative care or supportive care team for patients with severe refractory epilepsy significantly impacting quality of life	-	ROUTINE	ROUTINE	-

4B. Patient Instructions¶

Recommendation	ED	HOSP	OPD
Take all antiseizure medications exactly as prescribed; even one missed dose can trigger breakthrough seizures in DRE — use pill organizers and alarms	ROUTINE	ROUTINE	ROUTINE
Ensure rescue medication (nasal midazolam or rectal diazepam) is available at all times; train household members and caregivers on administration technique	ROUTINE	ROUTINE	ROUTINE
Return to ED immediately if seizure lasts >5 minutes, multiple seizures without recovery between them, seizure in water, significant head injury during seizure, or first seizure during pregnancy	STAT	STAT	ROUTINE
Do not drive until seizure-free for state-mandated period (varies by state, typically 3-12 months); discuss driving restrictions with neurologist at each visit	-	ROUTINE	ROUTINE
Avoid swimming alone or unsupervised bathing; use showers instead of baths; avoid heights and open water without supervision due to drowning risk (leading cause of seizure-related death)	-	ROUTINE	ROUTINE
Keep a seizure diary (paper or app such as Seizure Tracker, EpiFinder) documenting date, time, duration, type, triggers, and medications taken — bring to all neurology visits	-	ROUTINE	ROUTINE
Wear a medical alert bracelet or necklace identifying epilepsy diagnosis and current medications for emergency responders	-	ROUTINE	ROUTINE
Inform prescribing physicians about all ASMs before starting any new medication; many common drugs (antibiotics, psychiatric medications) interact with ASMs and can lower seizure threshold or affect ASM levels	-	ROUTINE	ROUTINE

4C. Lifestyle & Prevention¶

Recommendation	ED	HOSP	OPD
Prioritize consistent sleep schedule with 7-9 hours nightly; sleep deprivation is the most potent modifiable seizure trigger — avoid shift work if possible	-	ROUTINE	ROUTINE
Avoid alcohol use; alcohol withdrawal lowers seizure threshold and alcohol interacts with ASMs; if unable to abstain, limit to ≤1 drink with food and never binge drink	-	ROUTINE	ROUTINE
Implement stress reduction techniques (mindfulness, cognitive behavioral therapy) as chronic stress increases seizure frequency through cortisol-mediated excitotoxicity	-	-	ROUTINE
SUDEP risk reduction: optimize seizure control, ensure nocturnal supervision if possible, avoid prone sleeping position, consider seizure detection devices (watches, bed monitors)	-	ROUTINE	ROUTINE
Use reliable contraception for women of childbearing potential; enzyme-inducing ASMs (phenytoin, carbamazepine, phenobarbital) reduce efficacy of hormonal contraceptives — use IUD or barrier methods	-	-	ROUTINE
Home safety modifications: remove sharp furniture edges, install stove guards, use microwave instead of stovetop, shower instead of bath, avoid locked bathroom doors	-	ROUTINE	ROUTINE
Consider protective headgear (SeizureGuard, Ribcap) for patients with frequent tonic or drop seizures to prevent head injury	-	ROUTINE	ROUTINE

═══════════════════════════════════════════════════════════════ SECTION B: REFERENCE (Expand as Needed) ═══════════════════════════════════════════════════════════════

5. DIFFERENTIAL DIAGNOSIS¶

Alternative Diagnosis	Key Distinguishing Features	Tests to Differentiate
Pseudo-resistance (non-adherence)	Subtherapeutic ASM levels; missed doses; inconsistent refills; social/financial barriers	ASM trough levels; pharmacy refill records; pill counts; direct questioning
Pseudo-resistance (incorrect ASM for syndrome)	Wrong ASM for epilepsy syndrome (e.g., sodium channel blocker worsening absence or myoclonic epilepsy); diagnostic re-evaluation needed	Detailed seizure semiology; EEG classification (focal vs generalized); syndrome-appropriate ASM selection
Psychogenic non-epileptic seizures (PNES)	Waxing/waning movements; eyes closed; pelvic thrusting; prolonged duration; out-of-phase limb movements; lack of postictal confusion	Video-EEG monitoring (gold standard); postictal prolactin (normal in PNES); PNES may coexist with epilepsy in 10-20%
Autoimmune epilepsy	New seizure onset or acceleration in previously controlled patient; cognitive decline; psychiatric symptoms; faciobrachial dystonic seizures (LGI1)	Autoimmune encephalitis antibody panel (serum + CSF); MRI (medial temporal T2/FLAIR signal); CSF pleocytosis
Progressive structural lesion	Gradual increase in seizure frequency; new neurologic deficits; papilledema	MRI with contrast; compare to prior imaging; consider tumor, vascular malformation, or progressive cortical dysplasia
Mitochondrial epilepsy (MELAS, MERRF)	Myoclonus; hearing loss; exercise intolerance; stroke-like episodes; elevated lactate; maternal inheritance	Serum/CSF lactate; genetic testing (m.3243A>G, m.8344A>G); muscle biopsy (ragged red fibers)
Drug interactions reducing ASM efficacy	New medication started (enzyme inducer/inhibitor); herbal supplements; grapefruit juice	Detailed medication reconciliation; ASM levels before and after new drug; pharmacokinetic interaction review
Catamenial epilepsy	Seizure clustering around menstruation (perimenstrual C1, periovulatory C2, luteal C3 patterns); may respond to hormonal therapy	Seizure diary with menstrual cycle mapping (3+ months); progesterone challenge; neurosteroid levels
Neurodegenerative disease with seizures	Progressive cognitive decline; parkinsonian features; seizures as late manifestation (Alzheimer's, frontotemporal dementia)	Neuropsychological testing; MRI volumetrics; FDG-PET; biomarkers (amyloid, tau)
FIRES (Febrile Infection-Related Epilepsy Syndrome)	Preceding febrile illness → explosive onset of refractory status epilepticus; typically in children/young adults; devastatingly refractory	EEG (super-refractory SE); MRI (initially normal, later hippocampal/cortical changes); extensive infectious/autoimmune workup negative

Red Flags Requiring Urgent Investigation¶

Red Flag	Concern	Immediate Action
Sudden increase in seizure frequency with no medication change	New structural lesion; autoimmune process; metabolic derangement	Urgent MRI; expanded labs; consider autoimmune workup
New focal neurologic deficit	Progressive structural lesion; stroke; post-ictal Todd paralysis (resolves)	Urgent neuroimaging; if Todd paralysis, should resolve within 24-48h
Cognitive decline beyond expected ASM effects	Autoimmune encephalitis; NCSE; neurodegenerative disease; ASM toxicity	Autoimmune panel; continuous EEG; neuropsychological testing; ASM levels
Seizures immediately after medication change	ASM interaction; paradoxical seizure aggravation; withdrawal effect	ASM levels; review interaction profile; consider reverting change
Psychiatric symptoms (psychosis, aggression) with seizure change	Forced normalization; ASM psychiatric effects (perampanel, levetiracetam); autoimmune process	Psychiatric evaluation; EEG (forced normalization shows EEG improvement with psychiatric worsening); ASM review
Weight loss, night sweats, new neurologic symptoms	Paraneoplastic syndrome; occult malignancy	Paraneoplastic antibody panel; CT chest/abdomen/pelvis; whole-body PET

6. MONITORING PARAMETERS¶

Parameter	Frequency	Target/Threshold	Action if Abnormal	ED	HOSP	OPD	ICU
ASM trough levels (all current ASMs)	Each visit; 2 weeks after dose change; with breakthrough seizures	Therapeutic range (see Appendix A); individual target based on seizure control and tolerability	Adjust dose; assess adherence; check interactions	STAT	STAT	ROUTINE	STAT
CBC with differential	Baseline; q3 months x 1 year for felbamate; q6 months for carbamazepine; annually otherwise	WBC >3500; ANC >1500; platelets >100K	WBC <3000 → consider ASM change; felbamate: any cytopenia → discontinue	-	ROUTINE	ROUTINE	-
CMP (hepatic and renal function)	Baseline; q3-6 months first year; annually thereafter	Normal LFTs; normal creatinine	Elevated LFTs >3x ULN → evaluate ASM hepatotoxicity; dose adjust for renal impairment	-	ROUTINE	ROUTINE	-
Sodium	Baseline; q3 months for carbamazepine/oxcarbazepine/eslicarbazepine; with symptoms	>130 mEq/L	<130 → fluid restrict, consider ASM change; <125 → urgent correction	STAT	ROUTINE	ROUTINE	STAT
Vitamin D, 25-OH	Baseline; annually for enzyme-inducing ASMs	>30 ng/mL	Deficient → supplement 2000-5000 IU daily; recheck in 3 months	-	-	ROUTINE	-
DEXA bone density scan	Baseline if on enzyme-inducing ASMs >2 years; repeat q2 years	Normal T-score (>-1.0)	Osteopenia → supplement calcium/D, weight-bearing exercise; osteoporosis → bisphosphonate, consider ASM change	-	-	ROUTINE	-
ECG	Baseline; after lacosamide/rufinamide initiation; with dose changes	Normal PR interval; normal QTc	PR >220 ms on lacosamide → dose reduce or discontinue; QT shortening on rufinamide → cardiology consult	STAT	ROUTINE	ROUTINE	STAT
Seizure frequency (diary)	Every visit	Decreasing or stable; >50% reduction = responder	No improvement after adequate trial → re-evaluate; consider surgical evaluation	-	ROUTINE	ROUTINE	-
Echocardiogram (fenfluramine patients)	Baseline; 6 months; then annually	No valvular regurgitation or pulmonary hypertension	New regurgitation → cardiology referral; consider fenfluramine discontinuation	-	-	ROUTINE	-
Visual field testing (vigabatrin patients)	Baseline; q3 months while on vigabatrin	Full visual fields	Any field constriction → discontinue vigabatrin (irreversible)	-	-	ROUTINE	-
Pregnancy test (women of childbearing potential)	Annually; before ASM changes; if sexually active and menstrual irregularity	Negative	Positive → immediate ASM safety review; high-risk OB referral; folic acid 4 mg/day	-	ROUTINE	ROUTINE	-
Psychiatric screening (PHQ-9, GAD-7)	Every visit	PHQ-9 <5; GAD-7 <5	Score ≥10 → psychiatric referral; adjust ASM if contributing (levetiracetam, perampanel, phenobarbital)	-	ROUTINE	ROUTINE	-

7. DISPOSITION CRITERIA¶

Disposition	Criteria
Discharge home from ED	Single breakthrough seizure with return to baseline; identified precipitant corrected (non-adherence, illness); subtherapeutic level corrected with loading dose; rescue medication education provided; reliable follow-up with epileptologist
Admit to floor	Seizure cluster (≥3 seizures in 24h); prolonged postictal state (>1h); new neurologic deficit; medication change requiring monitoring; social concerns about safety
Admit to ICU	Status epilepticus or refractory seizure activity; respiratory compromise; significant head injury during seizure; hemodynamic instability
Admit to EMU	Presurgical evaluation; seizure characterization (epileptic vs PNES); ASM taper for surgery
Transfer to comprehensive epilepsy center	Meets DRE criteria and has not been evaluated for surgical options; intracranial monitoring needed; complex neuromodulation candidacy assessment
Outpatient follow-up	Epileptologist q3 months (or more frequently during ASM changes); presurgical evaluation clinic if surgical candidate; dietitian if on dietary therapy

8. EVIDENCE & REFERENCES¶

Recommendation	Evidence Level	Source
Definition of DRE: failure of 2 appropriately chosen and tolerated ASMs	ILAE Consensus Definition	Kwan et al. Epilepsia 2010
Only ~5% of patients failing 2 ASMs achieve seizure freedom with further medication trials	Class II evidence	Kwan & Brodie. NEJM 2000
Temporal lobectomy superior to medical therapy for mesial TLE	Class I, Level A (RCT)	Wiebe et al. NEJM 2001
Delayed surgical referral worsens outcomes; early surgery recommended	Class II evidence	Engel et al. JAMA 2012 (ERSET)
VNS reduces seizure frequency ~50% in responders; efficacy improves over years	Class I evidence	Morris & Mueller. Epilepsy Behav 2017
RNS achieves median 53% seizure reduction at 2 years, improving over time (long-term data)	Class I evidence (pivotal trial)	Nair et al. Neurology 2020
DBS of anterior nucleus of thalamus: 69% median seizure reduction at 5 years (SANTE trial)	Class I evidence (RCT)	Fisher et al. Epilepsia 2010 (SANTE)
Cenobamate: high responder rate (21% seizure-free) in treatment-resistant focal epilepsy	Class I evidence (RCT)	Krauss et al. Lancet Neurol 2020 (C017 study)
Ketogenic diet effective in adult DRE; ~50% achieve >50% seizure reduction	Class II evidence (systematic review)	Liu et al. Seizure 2018
Cannabidiol (Epidiolex) reduces seizures in Dravet and LGS	Class I evidence (RCTs)	Devinsky et al. NEJM 2017
SUDEP risk increases with DRE; risk reduction strategies recommended	Professional society guideline	Harden et al. Neurology 2017 (AAN Practice Guideline)
Presurgical evaluation should be offered to all patients meeting DRE criteria	AAN/AES Guideline	Engel et al. Neurology 2003
PNES coexists with epilepsy in 10-20% of DRE patients; video-EEG essential	Class III evidence	LaFrance et al. Epilepsia 2013

CHANGE LOG¶

v1.0 (January 31, 2026) - Initial template creation - Comprehensive DRE management covering pharmacotherapy, presurgical evaluation, surgery, neuromodulation, and dietary therapy - Structured dosing format for all medications - Includes rescue medications, advanced ASMs (cenobamate, brivaracetam, fenfluramine, cannabidiol), surgical options (ATL, LITT, VNS, RNS, DBS), and dietary therapies

APPENDIX A: ASM Therapeutic Level Ranges¶

ASM	Therapeutic Range	Notes
Carbamazepine	4-12 mcg/mL	Check epoxide level if on valproate
Clobazam	30-300 ng/mL (N-desmethyl: 300-3000 ng/mL)	Active metabolite important
Eslicarbazepine	3-35 mcg/mL (licarbazepine)	Measured as active metabolite
Lacosamide	1-10 mcg/mL	PR interval correlates with level
Lamotrigine	2.5-15 mcg/mL	Drops ~50% in pregnancy; increases with valproate
Levetiracetam	12-46 mcg/mL	Wide therapeutic index
Oxcarbazepine	3-35 mcg/mL (MHD)	Measured as MHD metabolite
Perampanel	100-1000 ng/mL	Limited clinical utility; dose by response
Phenobarbital	15-40 mcg/mL	Sedation common at higher levels
Phenytoin (total)	10-20 mcg/mL	Adjust for albumin; check free level
Phenytoin (free)	1-2 mcg/mL	Use in hypoalbuminemia, renal failure, pregnancy
Topiramate	5-20 mcg/mL	Metabolic acidosis at higher levels
Valproate (total)	50-100 mcg/mL	Free level needed if low albumin
Valproate (free)	5-15 mcg/mL	Active fraction
Zonisamide	10-40 mcg/mL	Long half-life
Brivaracetam	0.2-2.0 mcg/mL	Emerging data; clinical response primary guide

APPENDIX B: DRE Evaluation Algorithm¶

Confirm DRE diagnosis → Failed ≥2 appropriately chosen ASMs at adequate doses with adequate adherence
Rule out pseudo-resistance → Check ASM levels, assess adherence, review seizure classification, consider PNES (video-EEG)
Optimize current therapy → Maximize current ASM doses; rational polytherapy; consider newer agents (cenobamate)
Refer to comprehensive epilepsy center → All DRE patients should be evaluated for surgical candidacy
Presurgical evaluation → Video-EEG, epilepsy protocol MRI, neuropsych, fMRI, PET; multidisciplinary conference
Surgical candidate?
YES → Resective surgery (ATL, focal resection, LITT) or RNS if focal
NO → VNS, DBS (focal/multifocal), dietary therapy, clinical trials
Long-term management → ASM optimization, comorbidity treatment, SUDEP risk reduction, quality of life

APPENDIX C: Rational Polytherapy Guide¶

Mechanism Class	Example ASMs	Preferred Combinations
Sodium channel blockers	Carbamazepine, oxcarbazepine, lacosamide, phenytoin, eslicarbazepine, cenobamate	Combine with non-sodium channel mechanism
SV2A ligands	Levetiracetam, brivaracetam	Combine with sodium channel blocker or GABA modulator
GABA modulators	Clobazam, phenobarbital, vigabatrin	Combine with sodium channel or SV2A mechanism
Glutamate antagonists	Perampanel	Combine with sodium channel or SV2A mechanism
Mixed/multiple mechanisms	Valproate, topiramate, zonisamide, cenobamate	Broad-spectrum; useful as backbone
Calcium channel (T-type)	Ethosuximide (absence only)	Combine with broad-spectrum for mixed seizures

Preferred Combinations: - Lamotrigine + valproate (synergistic but monitor LTG levels — VPA doubles LTG level) - Lacosamide + levetiracetam (complementary mechanisms, well tolerated) - Cenobamate + non-sodium channel ASM (avoid stacking sodium blockers) - Clobazam + any non-benzodiazepine ASM (broad augmentation) - Perampanel + sodium channel blocker (different mechanisms)