Epilepsy Diagnostic Workup
Epilepsy Diagnostic Workup
What Do You Need to Know?
- EEG is the single most important ancillary test — routine EEG detects IEDs in ~50% on first study; yield increases with sleep deprivation (+20–30%) and repeat studies
- MRI with epilepsy protocol at 3T is the gold standard — 1.5T misses ~20% of lesions (especially FCD, hippocampal sclerosis)
- First seizure labs: glucose, BMP (Na, Ca, Mg), CBC, tox screen — identify provoked causes before committing to ASM therapy
- Surgical evaluation after failure of 2 appropriate ASMs — video-EEG, FDG-PET, ictal SPECT, MEG, neuropsychological testing
- Autoimmune workup when new-onset refractory seizures, FBDS, limbic encephalitis features, or APE2 ≥4 — send serum AND CSF panels
- Genetic testing highest yield in neonatal/infantile seizures and DEEs (Dravet >80%, BFNS ~80%, DEE 30–50%)
- Prolactin elevated post-GTCS and focal impaired awareness (not absence, not PNES) — limited sensitivity; draw within 20 min
First Seizure Evaluation: Children vs. Adults
| Component | Children | Adults |
|---|---|---|
| History | Witness/video; birth hx (HIE, prematurity); developmental milestones; febrile seizure hx; family hx; vaccination timing | Witness/video; prior unrecognized events (staring, morning myoclonus); alcohol/drug use; sleep deprivation; driving/occupational risk |
| Labs | Glucose, BMP (Na, Ca, Mg), CBC; metabolic workup in neonates (lactate, ammonia, amino acids); tox screen in adolescents | Glucose, BMP (Na, Ca, Mg), CBC, LFTs, ammonia, tox screen; prolactin (limited — draw within 20 min) |
| When to CT | Emergent: trauma, focal deficits, persistent AMS, VP shunt; NOT routine for simple febrile seizure | Emergent: focal deficits, persistent AMS, trauma, anticoagulation, cancer hx, immunocompromised, meningeal signs |
| When to MRI | All focal seizures; DD + seizures; abnormal exam; NOT required if classic IGE with typical EEG (e.g., CAE with 3 Hz spike-wave) | ALL adults with unprovoked seizures — epilepsy protocol at 3T; CT alone is insufficient |
| EEG timing | Within 24–48 h; ~50% IED detection on first study; sleep recording essential in children | Within 24–48 h; IED 20–50% on first EEG; sleep-deprived or prolonged EEG if initial nondiagnostic |
| EEG yield | Higher yield than adults; pathognomonic patterns (hypsarrhythmia, 3 Hz spike-wave, centrotemporal spikes) | Yield 80–90% after 3–4 routine EEGs with sleep deprivation and longer recording |
💎 Board Pearl
- EEG within 24–48 h has the HIGHEST yield — IEDs are most likely captured in the early postictal period
- Classic IGE in children (CAE, JAE, JME) with typical EEG may NOT require MRI — any atypical feature mandates imaging
When to Order EEG
Routine EEG (20–40 min)
- First-line test for any suspected seizure or epilepsy
- IED detection: ~50% on first study; increases to 80–90% with repeat studies (3–4 EEGs)
- Should include wakefulness + drowsiness/sleep for maximal yield
- Normal EEG does NOT exclude epilepsy — epilepsy is a clinical diagnosis
Sleep-Deprived EEG
- Increases IED yield by 20–30% over routine EEG
- Activates IEDs during drowsiness and NREM sleep transitions
- Particularly useful for: suspected IGE (JME, CAE), temporal lobe epilepsy, nondiagnostic routine EEG
Prolonged / Ambulatory EEG (24–72 h)
- When routine EEG is nondiagnostic but clinical suspicion remains high
- Captures interictal and potentially ictal events; correlates symptoms with EEG changes
- Home ambulatory EEG is an alternative to inpatient monitoring for selected patients
Continuous EEG (cEEG) — ICU Indications
- Unexplained altered mental status / encephalopathy
- Post-cardiac arrest (detect nonconvulsive SE; prognostication)
- Refractory SE (titrate IV anesthetics to burst suppression)
- Comatose patients with suspected subclinical seizures
- Acute brain injury (TBI, SAH, ICH) — subclinical seizures in 10–30%
- Minimum 24–48 h monitoring; longer in high-risk patients
Activation Procedures
| Procedure | Mechanism | Key Clinical Utility |
|---|---|---|
| Hyperventilation (3–5 min) | Hypocapnia → vasoconstriction → hyperexcitability | Provokes absence seizures >90%; activates 3 Hz spike-wave in CAE |
| Photic stimulation | Intermittent flashing light (1–30 Hz) | PPR: generalized spike-wave; seen in IGE (especially JME). Distinguish from photic driving |
| Sleep | NREM disinhibits cortical networks | NREM activates most IEDs; REM suppresses them. Adds 20–30% yield |
Clinical Pearl
Hyperventilation is the single best activation procedure for absence epilepsy — triggers 3 Hz spike-wave in >90% of untreated CAE. If a board question describes staring spells with a normal interictal EEG, the answer is hyperventilation during the EEG, not a repeat study.
MRI Epilepsy Protocol
- Minimum field strength: 3T — 1.5T misses ~20% of epileptogenic lesions
- Thin slices (1–3 mm); dedicated coronal cuts perpendicular to hippocampal long axis
| Sequence | Key Findings | Primary Targets |
|---|---|---|
| 3D T1 MPRAGE | Volumetric analysis; cortical thickness mapping | FCD (blurred gray-white junction); hippocampal volumetry; VBM post-processing |
| 3D FLAIR | Hyperintense signal in abnormal cortex/hippocampus | HS (FLAIR hyperintensity + atrophy); FCD (transmantle sign); tumors; gliosis |
| Coronal T2 (perp. to hippocampus) | Hippocampal architecture; size/signal asymmetry | HS detection — atrophy + T2 hyperintensity; most sensitive plane |
| SWI / GRE | Blooming from hemosiderin, calcium | Cavernomas; calcified lesions; Sturge-Weber; prior hemorrhage |
| Post-contrast T1 (if indicated) | Enhancement pattern | Tumors (DNET, ganglioglioma); infection; leptomeningeal disease |
💎 Board Pearl
- 3T detects ~20% more lesions than 1.5T — always request 3T for epilepsy; FCD and HS most commonly missed at lower field strength
- Transmantle sign on FLAIR (linear hyperintensity cortex-to-ventricle) = pathognomonic for FCD type IIb (balloon cells)
- MRI-negative epilepsy = 20–30% of drug-resistant cases — advanced post-processing (VBM, HARNESS-MRI) can reveal additional lesions
Specialty Workup Decision Table
| Indication | Workup | Key Tests | When to Order |
|---|---|---|---|
| Surgical Evaluation | Video-EEG | Ictal onset localization; semiology; confirm epileptic vs. nonepileptic | After failure of 2 ASMs (drug-resistant epilepsy); refer early — average delay 15–20 years |
| 3T MRI | Structural lesion (HS, FCD, tumor, vascular malformation) | ||
| FDG-PET | Interictal hypometabolism; 80–90% for mTLE; 45–60% extratemporal | ||
| Ictal SPECT (SISCOM) | Ictal hyperperfusion; inject tracer within 30 sec of onset | ||
| MEG | IED dipole localization; superior for deep/tangential sources | ||
| Neuropsych testing | Cognitive baseline; lateralization; predicts postop outcome | ||
| Wada / fMRI | Language/memory lateralization; fMRI replacing Wada (>90% concordance) | ||
| Autoimmune Workup | Serum antibody panel | NMDAR, LGI1, CASPR2, GABA-B, AMPAR, DPPX, GAD65 | New-onset refractory seizures; FBDS (→ LGI1); limbic encephalitis; APE2 ≥4; subacute cognitive decline |
| CSF antibody panel | NMDAR (CSF > serum sensitivity); OCBs; cytology | ||
| Body CT or PET/CT | Teratoma (NMDAR), thymoma (CASPR2/LGI1), SCLC (GABA-B) | ||
| MRI brain | Mesial temporal FLAIR signal (limbic encephalitis); may be normal early | ||
| Genetic Testing | Epilepsy gene panel | 100–500+ genes; fastest/cheapest first-line genetic test | Neonatal/infantile seizures; DEE; family hx; dysmorphic features; seizures + ID; MRI-negative DRE in young |
| WES (whole exome) | Broader coverage; trio analysis; yield 30–50% in DEE | ||
| WGS (whole genome) | Noncoding variants, structural variants, repeat expansions | ||
| Yield by syndrome | Dravet: >80%; BFNS: ~80%; DEE: 30–50%; focal: 10–20%; IGE: 5–10% | ||
| DD + Seizures | Chromosomal microarray | First-line for ID/DD + epilepsy; CNVs; yield ~15–20% | Seizures + DD/ID; dysmorphic features; autism + epilepsy |
| Fragile X | FMR1 CGG expansion; most common inherited cause of ID in males | ||
| Metabolic screen | Urine organic acids, amino acids, acylcarnitine, lactate | ||
| Metabolic Workup | Lactate / pyruvate | L:P ratio >25 = mitochondrial; MELAS, PDH deficiency | Neonatal/infantile refractory seizures; seizures + FTT; metabolic acidosis; regression |
| Amino acids / organic acids | NKH, MSUD, propionic/methylmalonic aciduria | ||
| Acylcarnitine profile | Fatty acid oxidation defects; carnitine deficiency | ||
| CSF glucose + lactate | GLUT1: CSF/serum glucose <0.4; responds to ketogenic diet | ||
| Pyridoxine trial | IV pyridoxine 100 mg with EEG; dramatic cessation = ALDH7A1; also trial PLP for PNPO | ||
| Infectious Workup | CSF basic studies | Cell count, protein, glucose, Gram stain, culture | Fever + seizure; immunocompromised; persistent AMS; meningeal signs; suspected encephalitis |
| CSF PCR panel | HSV PCR (start acyclovir empirically); VZV, enterovirus, HHV-6, arboviruses | ||
| Additional CSF | AFB (TB); cryptococcal Ag; cytology; VDRL (neurosyphilis) |
Clinical Pearl
FDG-PET in surgical evaluation: Interictal PET shows hypometabolism at the seizure focus (reduced glucose uptake between seizures). For mTLE, sensitivity is 80–90% — the most useful adjunctive imaging when MRI is negative or equivocal. Extratemporal sensitivity drops to 45–60%. Remember: PET shows HYPOmetabolism interictally, not hypermetabolism.
💎 Board Pearl
- GLUT1 deficiency: CSF/serum glucose ratio <0.4 — LP must be fasting; treat with ketogenic diet (bypasses glucose transporter)
- Pyridoxine-dependent epilepsy (ALDH7A1): Give IV pyridoxine 100 mg to ANY neonate with refractory seizures — dramatic cessation is diagnostic + therapeutic
- NMDAR antibodies are more sensitive in CSF than serum — always send BOTH panels
First-Line Labs for Acute Seizure — Quick Reference
| Test | Purpose | Key Thresholds / Notes |
|---|---|---|
| Glucose | Hypo/hyperglycemia | <40 mg/dL = provoked seizure; nonketotic hyperglycemia → focal seizures |
| Sodium | Hyponatremia | <120 mEq/L = seizure threshold; correct slowly (osmotic demyelination risk) |
| Calcium | Hypocalcemia | <7 mg/dL (total) or low ionized Ca; tetany, QTc prolongation |
| Magnesium | Hypomagnesemia | Lowers seizure threshold; coexists with hypocalcemia; treat Mg first |
| CBC | Infection screening; ASM baseline | Leukocytosis = infection or postictal stress response |
| LFTs | Hepatic encephalopathy; ASM baseline | Baseline before VPA, CBZ, PHT |
| Ammonia | Hepatic encephalopathy; urea cycle; VPA toxicity | Check in encephalopathic patients and those on valproate |
| Tox screen | Drug intoxication / withdrawal | Cocaine, amphetamines, synthetic cannabinoids, PCP; alcohol level |
| BUN/Cr | Uremia | Uremic encephalopathy causes seizures; affects ASM dosing |
Lumbar Puncture Indications
- Fever + seizure (especially new-onset in adults) — rule out meningitis/encephalitis
- Immunocompromised patient — broader infectious differential
- Persistent altered mental status not improving within 30–60 min postictal
- Meningeal signs (nuchal rigidity, Kernig/Brudzinski)
- Suspected autoimmune encephalitis (subacute onset, psychiatric features, movement disorder)
- CT before LP if signs of raised ICP (papilledema, focal deficits, obtundation)
Serum Prolactin
- Elevated (≥2x baseline) after: GTCS (most reliable) and focal impaired awareness
- NOT elevated after: absence seizures, simple partial seizures, PNES
- Draw within 10–20 minutes; peaks at 15–20 min, returns to baseline by 1–2 h
- Sensitivity ~60% for GTCS — normal prolactin does NOT exclude epileptic seizure
- Most useful to distinguish GTCS from PNES; syncope can also transiently elevate prolactin
💎 Board Pearl
- Prolactin is a board favorite: elevated post-GTCS and focal impaired awareness, NOT in absence or PNES, must draw within 20 min
- The ONLY lab that may help distinguish seizure types acutely — but do NOT rely on it to rule out seizures
Board Pearls — Epilepsy Diagnostic Workup
💎 Board Pearl
- EEG within 24–48 hours has highest yield — IEDs on first routine EEG increase recurrence risk to ≥60% (meets ILAE epilepsy definition after a single seizure)
- Hyperventilation provokes absence seizures >90% of the time — the single best activation procedure for CAE
- 3T MRI detects ~20% more lesions than 1.5T — FCD and HS are most commonly missed at lower field strength
- FDG-PET = interictal hypometabolism (not hypermetabolism) at the seizure focus; 80–90% sensitivity for mTLE, 45–60% extratemporal
- GLUT1 = low CSF glucose, normal serum glucose (ratio <0.4) — treat with ketogenic diet
- Drug-resistant epilepsy = failure of 2 ASMs — refer for surgical evaluation; average delay is 15–20 years (far too long)
- APE2 score ≥4 triggers autoimmune testing — components: new-onset seizures, drug resistance, autonomic features, viral prodrome, inflammatory CSF, autoimmune MRI, psychiatric/cognitive features, malignancy hx
Clinical Pearls
Clinical Pearl
Ictal SPECT timing is critical: Radiotracer (Tc-99m HMPAO or ECD) must be injected within 30 seconds of seizure onset for reliable localization. Late injection captures postictal hypoperfusion instead of ictal hyperperfusion, leading to mislocalization. SISCOM (subtraction ictal SPECT co-registered to MRI) improves accuracy by subtracting interictal from ictal SPECT and overlaying the difference on MRI.
Clinical Pearl
Wada vs. fMRI: fMRI is increasingly replacing the Wada test for language lateralization (>90% concordance). Wada remains necessary when fMRI is inconclusive or when memory lateralization is critical — particularly before dominant-hemisphere mesial temporal resection where postoperative memory decline is a concern.
Clinical Pearl
APE2 score for autoimmune epilepsy: A score ≥4 has reasonable sensitivity and should trigger antibody testing. Components include new-onset seizures, drug resistance, autonomic dysfunction, viral prodrome, inflammatory CSF, MRI suggesting autoimmune etiology, psychiatric/cognitive features, and malignancy history. This prevents unnecessary antibody testing in all epilepsy patients while capturing those most likely to have an autoimmune etiology.
References
- Krumholz A, Wiebe S, Gronseth GS, et al. Evidence-based guideline: management of an unprovoked first seizure in adults. Neurology. 2015;84(16):1705–1713.
- Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia. 2014;55(4):475–482.
- Bernasconi A, Cendes F, Theodore WH, et al. Recommendations for the use of structural MRI in epilepsy: ILAE Neuroimaging Task Force consensus. Epilepsia. 2019;60(6):1054–1068.
- Rosenow F, Lueders H. Presurgical evaluation of epilepsy. Brain. 2001;124(Pt 9):1683–1700.
- Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15(4):391–404.
- Helbig I, Riggs ER, Barry CA, et al. ClinGen Epilepsy Gene Curation Expert Panel. Hum Mutat. 2018;39(11):1476–1484.
- Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: ILAE consensus proposal. Epilepsia. 2010;51(6):1069–1077.
- Skidmore CT. Neuroimaging in epilepsy. Continuum (Minneap Minn). 2025;31(1, Epilepsy):61–80.
- Dubey D, Pittock SJ, Kelly CR, et al. Autoimmune encephalitis epidemiology and comparison to infectious encephalitis. Ann Neurol. 2018;83(1):166–177.
- Chen Z, Brodie MJ, Liew D, Kwan P. Treatment outcomes in newly diagnosed epilepsy: a 30-year longitudinal cohort study. JAMA Neurol. 2018;75(3):279–286.