Epilepsy Syndromes, Seizure Mimics & Drug-Resistant Epilepsy

Recognizing the Classic Epilepsy Syndromes

An epilepsy syndrome bundles age at onset, seizure types, EEG pattern and prognosis. Naming it dictates drug choice, because several common drugs worsen the generalized epilepsies.

Childhood absence epilepsy. Onset at ages 4–10. Dozens of daily behavioral arrests, usually under 20 seconds, start and stop abruptly with no aura and no postictal confusion — often reported as "daydreaming." Three minutes of hyperventilation reproduces a spell and the generalized 3-Hz spike-and-wave. Ethosuximide (a thalamic T-type calcium channel blocker) is first-line; valproate is used if tonic-clonic seizures coexist. Most children outgrow it.

Juvenile myoclonic epilepsy (JME). Onset at 12–18 years with bilateral arm jerks shortly after waking (awareness preserved), generalized tonic-clonic seizures after sleep deprivation or alcohol, and sometimes absences. EEG shows 4–6 Hz polyspike-and-wave with photosensitivity; exam and MRI are normal. Valproate works best, but because it is teratogenic, levetiracetam or lamotrigine is preferred in anyone who could become pregnant. Relapse after withdrawal is the rule, so therapy is usually lifelong.

Carbamazepine, oxcarbazepine, phenytoin and gabapentin can aggravate absence and myoclonic seizures; a teenager who worsens on carbamazepine probably has unrecognized JME.

Mesial temporal lobe epilepsy (MTLE). The most common focal — and most common drug-resistant — epilepsy of adults. An aura (rising epigastric sensation, déjà vu, fear, odd smell or taste) is followed by 1–2 minutes of impaired awareness with lip-smacking, hand fumbling and contralateral arm dystonia, then postictal confusion. A history of prolonged febrile seizures in early childhood is common. Epilepsy-protocol MRI shows hippocampal sclerosis: atrophy with T2/FLAIR hyperintensity from neuronal loss and gliosis, worst in CA1.

Lennox-Gastaut syndrome (LGS). An epileptic encephalopathy starting at ages 1–8, sometimes evolving from infantile spasms or caused by tuberous sclerosis or hypoxic brain injury. Its triad is multiple seizure types (tonic seizures in sleep, atonic drop attacks, atypical absences), slow spike-and-wave below 2.5 Hz with fast bursts in sleep, and intellectual disability. It is nearly always drug resistant: valproate, lamotrigine, rufinamide, clobazam, felbamate, cannabidiol or fenfluramine, with helmets, corpus callosotomy, VNS or the ketogenic diet for drop attacks.

Seizure Mimics

Convulsive syncope. Cerebral hypoperfusion can cause a few irregular jerks once the patient is limp. Clues are a trigger (prolonged standing, pain, venipuncture, micturition), a prodrome (lightheadedness, sweating, tunnel vision, pallor), jerks lasting seconds, and full orientation within about a minute. Incontinence does not discriminate; a lateral tongue bite, head version and prolonged confusion favor a seizure.

Psychogenic nonepileptic seizures (PNES). Functional events without epileptiform activity, most common in young women with trauma, depression or PTSD. Clues are eyes closed and resisting opening, asynchronous limb movements, pelvic thrusting, side-to-side head movements, gradual onset, a waxing-waning course often longer than 2 minutes, ictal crying and recall of the event. Video-EEG capturing a typical event with no ictal change is the gold standard. Prolactin drawn 10–20 minutes after a generalized or focal impaired-awareness seizure is usually raised but stays normal after PNES; a normal value does not exclude a seizure, and syncope can raise it. Management is a clear, non-judgmental explanation, CBT, treatment of psychiatric comorbidity and tapering of unneeded drugs — though a minority have both PNES and epilepsy.

Hypermotor frontal lobe seizures can include pelvic thrusting, but they are brief, stereotyped and cluster out of sleep.

Migraine aura and TIA. Migraine aura is positive (zigzags, tingling), spreads over at least 5 minutes, lasts 5–60 minutes and is usually followed by headache; seizure auras spread in seconds. TIA gives sudden negative symptoms (weakness, numbness, visual loss) without a march. Postictal Todd paralysis follows a witnessed seizure and resolves within hours to 2 days.

Parasomnias. NREM arousal disorders (sleepwalking, sleep terrors) are childhood events from slow-wave sleep in the first third of the night, with amnesia. REM sleep behavior disorder is dream enactment later in the night in older adults and may herald a synucleinopathy. Nocturnal frontal lobe seizures are brief, stereotyped and cluster several times a night; video-polysomnography with EEG separates them.

Drug-Resistant Epilepsy

Definition. The ILAE defines drug resistance as failure of two tolerated, appropriately chosen and used drug schedules, alone or combined, to achieve sustained seizure freedom; about one-third of patients qualify. Roughly half are controlled by the first drug and about 13% more by the second, but each later drug adds only a few percent — so two failures should trigger referral, not endless drug rotation.

Neuromodulation and diet. Vagus nerve stimulation targets the left vagus (the right carries more fibers to the SA node) and reduces rather than abolishes seizures; hoarseness, cough and dyspnea occur during stimulation. Responsive neurostimulation and anterior thalamic deep brain stimulation are alternatives. The high-fat, low-carbohydrate ketogenic diet helps children with drug-resistant epilepsy, including LGS, and is first-line for GLUT1 deficiency; watch for kidney stones, acidosis and hyperlipidemia.

SUDEP and Drug Interactions

SUDEP. Sudden unexpected death in epilepsy occurs in about 1 per 1,000 adults with epilepsy per year, usually at night after an unwitnessed convulsion, with the patient found prone in bed. Frequent generalized tonic-clonic seizures are the dominant risk factor, along with nocturnal seizures, sleeping alone, drug resistance and nonadherence. Counsel every patient that seizure control is the main prevention.

Enzyme inducers. Carbamazepine, phenytoin, phenobarbital and primidone strongly induce CYP3A4 (oxcarbazepine and topiramate above 200 mg/day weakly). Combined pills, progestin-only pills and the implant become unreliable, so an IUD (copper or levonorgestrel) or DMPA is preferred. Inducers also blunt warfarin (the INR falls, then rebounds when the inducer stops), lower DOAC levels and accelerate vitamin D breakdown.

Levetiracetam and lacosamide have minimal hepatic enzyme interactions, making them convenient when a patient also relies on hormonal contraception or an anticoagulant.