EPI-001
Epilepsy · Seizure Network Engine · EEG Atlas · VIZASL v1
MEBICAL · EOSE Fleet · TRB-MEBICAL-HEALTH-DOMAIN-001 · Day 90 · Real data · Cited · Sorries marked
MEBICAL · NEURO · EEG ← RESEARCH
Hyperexcitable cortical node
Seizure propagation wave
GABA interneuron (inhibitory)
Ion channel (Na/K/Ca)
γ₁ floor anchor
SEIZURES
RX
GENETICS
EEG ATLAS
NPs
Seizure Biology PROVEN
Seizure Definition (ILAE 2014)
Transient occurrence of signs/symptoms due to abnormal, excessive or synchronous neuronal activity in the brain. Epilepsy = ≥2 unprovoked seizures >24h apart, OR 1 unprovoked seizure + ≥60% recurrence risk. 1% population prevalence.
Fisher et al. 2014 Epilepsia (ILAE operational definition)
E/I Imbalance: GABA/Glutamate
Seizure = excessive glutamate excitation OR insufficient GABA inhibition — or both. Fast-spiking parvalbumin interneurons (PV+) are the primary seizure brake. Their loss or dysfunction → runaway excitation → ictal discharge.
Cossart et al. 2001 Science · McCormick & Contreras 2001
Focal vs Generalized Classification
Focal onset: single hemisphere, may or may not spread. Generalized onset: both hemispheres simultaneously — absence, tonic-clonic, myoclonic, atonic. Unknown onset: 3rd category. Classification revised ILAE 2017.
Scheffer et al. 2017 Epilepsia (ILAE 2017 classification)
Post-Ictal State
After ictal discharge: adenosine release, synaptic depression, cortical spreading depression → post-ictal suppression on EEG. Clinical: confusion, weakness (Todd's paresis), sleep. Duration minutes to hours depending on seizure type/duration.
Posner et al. 2007 · Englot et al. 2010
Anti-Seizure Medications — Proven
Sodium Channel Blockers PROVEN
Carbamazepine, lamotrigine, phenytoin, lacosamide. Block voltage-gated Na channels in high-frequency repetitive firing mode. First-line for focal epilepsy. Lamotrigine safe in pregnancy.
Multiple RCTs. Marson et al. 2007 Lancet (SANAD trial — carbamazepine vs others)
Valproate PROVEN
GABA enhancement + Na/Ca channel effects. Broad-spectrum (focal + generalized). MOST EFFECTIVE for generalized epilepsy including JME. Contraindicated in pregnancy (teratogen).
Marson et al. 2007 Lancet (SANAD) — valproate superior for generalized
Levetiracetam (Keppra) PROVEN
SV2A (synaptic vesicle) modulator. Unique mechanism. Broad-spectrum. Favorable safety/interaction profile. First-line in many centers. Psychiatric side effects (irritability) ~10%.
Ben-Menachem et al. 2000 (pivotal trial)
Surgery — Focal Epilepsy PROVEN
Temporal lobe resection: 60–70% seizure-free at 1yr (vs 8% medical). Anterior temporal lobectomy = most evidence. Requires presurgical evaluation (MRI, EEG, neuropsych, fMRI language).
Wiebe et al. 2001 NEJM (first RCT — surgery vs medical, n=80) · Engel et al. 2012 NEJM (early surgery)
Responsive Neurostimulation (RNS) STRONG
Closed-loop device: detects ictal onset EEG → delivers cortical stimulation to abort seizure. 50% responder rate in drug-resistant focal epilepsy. FDA approved 2013.
Nair et al. 2020 Epilepsia (long-term outcomes)
Genetic Epilepsies
SCN1A / Dravet PROVENLoss-of-function SCN1A → Nav1.1 loss in PV+ interneurons → selective interneuron failure → runaway excitation. Paradox: Na channel loss → seizures (not blockade). Most Na blockers worsen Dravet. Claes et al. 2001
KCNQ2/KCNQ3K+ channel. Neonatal seizures. Gain-of-function = LOF alternates. KCNQ2-specific treatments in development.
LGI1 autoimmuneAnti-LGI1 antibody encephalitis. Faciobrachial dystonic seizures (FBDs) — pathognomonic. Immunotherapy responsive. Not a channelopathy.
CDKL5, PCDH19X-linked epileptic encephalopathies. PCDH19 uniquely affects heterozygous females (cellular interference mechanism).
mTOR pathwayTSC1/TSC2 (tuberous sclerosis) → mTOR hyperactivation → cortical tubers → focal epilepsy. Everolimus (mTOR inhibitor) reduces seizures. PROVEN
Dravet gene panelIf first-line drugs fail in child <2yr: SCN1A/KCNQ2/CDKL5/PCDH19 panel. Changes treatment: avoid Na blockers in SCN1A.
EEG Atlas — Canonical Patterns PROVEN
3Hz Spike-WaveAbsence seizure signature. Generalized, symmetric, bisynchronous. Onset/offset abrupt. Correlates with thalamo-cortical loop 3Hz resonance. Hyperventilation provokes. Penfield & Jasper 1954 (original description)
Polyspike + WaveMyoclonic epilepsy signature (JME, PME). Multiple spikes before slow wave. Photoparoxysmal response in JME. Valproate-responsive.
Focal sharp wavesTemporal, frontal, or parietal depending on seizure focus. Interictal epileptiform discharges (IEDs) — guide surgical planning. Spike negativity = cortical hyperexcitability at electrode.
HFOs (80–500Hz)High-frequency oscillations: ripples (80–250Hz) + fast ripples (250–500Hz). Ripples = physiological (memory) OR pathological. Fast ripples = pathological only. HFO resection predicts good surgical outcome. Staba et al. 2002 Science
Ictal onsetLow-voltage fast activity (LVFA) or theta/delta run at seizure onset. Evolves → slows → terminates → post-ictal suppression. Most diagnostic signal in SEEG for surgical planning.
Post-ictal suppress.Diffuse voltage attenuation after GTC seizure. Caused by adenosine release + synaptic depression. Duration correlates with seizure severity. SUDEP risk marker: prolonged suppression.
Thinkbeat Bridge — Most Literal
Epilepsy IS the 4-state classifier in its most literal form:
Interictal = SLOW_MONOTONE (baseline, IEDs present but controlled)
Pre-ictal = OSCILLATING (building synchrony, detectable by RNS)
Ictal = CHAOTIC (hypersynchronous discharge, the seizure itself)
Post-ictal = SLOW_MONOTONE recovery (suppression then return to baseline)
RNS closed-loop device = implemented δ control: detects OSCILLATING → intervenes before CHAOTIC.
Novel Patterns (8)
PROVENNP-EPI-001 · Epilepsy is the most literal EEG disease — every seizure type has a canonical waveform · EEG is both diagnostic AND mechanistic · Fisher 2014 Epilepsia
PROVENNP-EPI-002 · PV+ fast-spiking interneurons are the seizure brake · their selective vulnerability in multiple epilepsy syndromes (Dravet, TLE, post-status) · Cossart 2001 Science
PROVENNP-EPI-003 · SCN1A paradox: Na channel LOSS (not gain) → seizures via selective interneuron failure · Na blockers contraindicated in Dravet · Claes 2001
PROVENNP-EPI-004 · Surgery superiority: 60–70% seizure-free vs 8% medical therapy for drug-resistant TLE · Wiebe 2001 NEJM RCT
PROVENNP-EPI-005 · HFOs (fast ripples 250–500Hz) = most specific biomarker of epileptogenic zone · HFO resection = best surgical outcome predictor · Staba 2002 Science
OPENNP-EPI-006 · RNS closed-loop stimulation = implemented 4-state grammar control: OSCILLATING detected → stimulation before CHAOTIC · 50% responder rate · mechanism unclear
SORRYNP-EPI-007 · 30% drug-resistant — mechanism of pharmacoresistance unknown · multi-drug transporter hypothesis (MDR1/P-gp) vs target hypothesis · no validated biomarker predicts resistance
SORRYNP-EPI-008 · SUDEP (sudden unexpected death) mechanism — post-ictal cardiorespiratory suppression? · incidence 1:1000/yr in controlled, 1:150/yr in drug-resistant · no validated prevention strategy
Open Sorries (5)
SORRY-1: 30% drug-resistant — mechanism unknown. MDR1/P-glycoprotein overexpression vs target hypothesis (altered Na channels). No biomarker predicts who will become drug-resistant.
SORRY-2: SUDEP mechanism — post-ictal cardiac arrhythmia? Central apnea? Spreading depression? Incidence 1:1000–1:150/yr. No validated prevention.
SORRY-3: Surgical outcome prediction — MRI-negative epilepsy surgery success rate drops to 30–40%. Best predictor (HFO resection) still imperfect.
SORRY-4: Status epilepticus second-line treatment — after benzodiazepines fail: valproate vs levetiracetam vs lacosamide. Three head-to-head trials (ESETT) showed equivalent (all bad) efficacy for refractory SE.
SORRY-5: Ketogenic diet mechanism — reduces seizures in 50% of drug-resistant pediatric epilepsy. Why? GABA enhancement? Direct neuronal metabolic shift? Multiple proposed mechanisms, none definitive.
⚠ OPEN SORRIES · EPI-001
SORRY-1 · Drug Resistance Mechanism
30% of epilepsy is drug-resistant (≥2 appropriate ASMs failed). The MDR1/P-glycoprotein hypothesis: drug-efflux pumps upregulated in epileptic tissue → ASMs pumped out. The target hypothesis: altered Nav channels reduce drug binding. Both may operate. No validated biomarker predicts resistance before treatment failure.

SORRY-2 · SUDEP
Sudden unexpected death in epilepsy. Incidence 1:1000/yr in controlled, 1:150/yr in drug-resistant. Most occur after generalized tonic-clonic seizures during sleep. Post-ictal cardiac arrhythmia, central apnea, and cortical spreading depression are all proposed. No single mechanism proven. No validated prevention except seizure control.

SORRY-3 · MRI-Negative Surgery
MRI-positive focal epilepsy: surgery 60–70% seizure-free. MRI-negative: 30–40%. HFO resection improves prediction but is still imperfect. We cannot reliably predict surgical outcome for MRI-negative patients.

SORRY-4 · Refractory Status Epilepticus
ESETT trial (2019 NEJM): valproate vs levetiracetam vs fosphenytoin for benzodiazepine-refractory SE. All three equally effective (~50% response) and equally ineffective. No winner. Second-line SE treatment remains an unsolved problem.

SORRY-5 · Ketogenic Diet Mechanism
50% of drug-resistant pediatric epilepsy respond to ketogenic diet. Proposed mechanisms: direct GABA-ergic effects, neuronal metabolic shift (ketone bodies vs glucose), reduced mTOR, altered gut microbiome. Multiple mechanisms active — none definitively primary.
EPI-001 · SEIZURE NETWORK ENGINE · 70% CONTROLLED · 30% DRUG-RESISTANT · SURGERY = BEST OPTION
γ₁ = 14.134725141734693