Epilepsy Treatment

1. Antiseizure Medications (ASMs)

General Principles

• Start with a single agent (monotherapy) at a low dose and titrate upward
• Approximately 70% of patients achieve complete or near-complete seizure control with medications; an additional 20-25% show significant reduction
• About 50% respond to the first agent, ~15% respond to a second as monotherapy; the remainder are considered treatment-resistant
• The simultaneous use of multiple ASMs presents special problems, and seizure suppression rates with each additional drug are low
• Choice depends on seizure type, sex, age, comorbidities, other medications, and renal/hepatic function

Drug Selection by Seizure Type

Mechanisms of Action (Overview)

1. Blocking voltage-gated Na+ channels - most common mechanism (phenytoin, carbamazepine, lamotrigine, lacosamide, oxcarbazepine). These drugs bind preferentially to channels in the inactivated state, providing "use-dependent block" - they preferentially suppress high-frequency epileptiform firing while sparing normal activity.
2. Enhancing GABA-mediated inhibition - benzodiazepines, barbiturates act as GABA-A positive allosteric modulators; vigabatrin/tiagabine increase GABA availability.
3. Blocking Ca2+ channels - ethosuximide blocks T-type Ca2+ channels (responsible for absence seizures); gabapentin/pregabalin bind alpha-2-delta subunits.
4. Modifying synaptic release - levetiracetam/brivaracetam bind SV2A on synaptic vesicles, reducing neurotransmitter release.
5. Blocking glutamate receptors - perampanel blocks AMPA receptors.

Special Considerations

• HLA-B*1502 genotype: Asians have a ~10x higher risk of carbamazepine-induced Stevens-Johnson syndrome; genetic testing is recommended before starting carbamazepine in this population
• Tuberous sclerosis: Everolimus (an mTOR inhibitor) targets the disease mechanism directly and reduces seizures, particularly infantile spasms
• Pregnancy: Valproate is strongly teratogenic; prefer lamotrigine or levetiracetam when possible
• Older ASDs (phenytoin, phenobarbital, ethosuximide) have long half-lives and can often be dosed once daily at bedtime; valproate and carbamazepine require divided dosing

2. Surgical Treatment

Surgical Procedures

• Temporal lobectomy or amygdalohippocampectomy: Most common; used for temporal lobe epilepsy. About 70% of patients achieve significant or complete seizure reduction.
• Focal neocortical resection (lesionectomy): For extratemporal focal epilepsy with an identifiable lesion on MRI
• Multiple subpial transection: Disrupts intracortical connections when the seizure focus is in eloquent cortex and cannot be resected
• Hemispherectomy / multilobar resection: For hemispheric abnormalities (hemimegalencephaly, dysplasia)
• Corpus callosotomy: For disabling tonic or atonic seizures, especially in Lennox-Gastaut syndrome

Presurgical Evaluation

• Inpatient video-EEG monitoring to correlate electrophysiology with behavior
• High-resolution MRI for structural identification of the epileptogenic focus
• Functional imaging (SPECT, PET, MEG) as adjuncts
• Stereo-EEG (SEEG): Robot-assisted stereotactic depth electrode placement - less invasive than open subdural electrode grids, shorter hospital stays, lower complication rates; allows both cortical and deep structure recording
• Wada test / functional MRI: To lateralize language and memory before temporal lobe surgery
• Clinically significant surgical complications occur in <5% of cases

3. Dietary Therapy

Ketogenic Diet

• High-fat, low-carbohydrate, low-protein diet that induces a state of ketosis
• Indicated for drug-resistant epilepsy of any classification
• In children with drug-resistant epilepsy: ~3% seizure-free at 3 months, ~7% at 12 months, ~27% had a >50% seizure reduction
• Particularly beneficial (may be first-line) in:
  • GLUT1 deficiency and pyruvate dehydrogenase deficiency
  • Dravet syndrome, myoclonic-atatic epilepsy, tuberous sclerosis, Rett syndrome, infantile spasms
• Onset of action can be very rapid (median 5 days in one study)
• Absolute contraindications: Mitochondrial disorders, pyruvate carboxylase deficiency, beta-oxidation defects
• Adverse effects: constipation, acidosis, renal calculi (5-6%), hyperlipidemia, decreased growth in young children

Modified Atkins Diet

• More palatable, only restricts carbohydrates (10 g/day children, 15 g/day adults)
• 65% of children had >50% seizure reduction in one prospective study; 47% of adults at 3 months
• Easier to initiate outpatient, fewer side effects than classical ketogenic diet

4. Status Epilepticus - Emergency Treatment

Step-by-Step Management

• Attend to airway, breathing, circulation and hyperthermia
• Establish IV access; send labs (glucose, electrolytes, toxicology, ASM levels)
• Intubate for apnea or persistent hypoxia; if paralytic used, arrange continuous EEG monitoring

• Administer a benzodiazepine immediately (IV lorazepam, IV/IM midazolam, rectal/IV diazepam)
• Route choice depends on IV access availability
• Two doses without response = benzodiazepines unlikely to work; further doses risk respiratory depression

• Fosphenytoin, levetiracetam, or valproic acid (all are preferred second-line options)
• Note: phenobarbital is generally not preferred second-line (shares GABA mechanism with benzodiazepines), except in neonates

• Requires ICU admission; options include propofol, midazolam infusion, pentobarbital, or ketamine

5. Other Management Considerations

• Comorbidities: Depression occurs in ~20-30% of patients; anxiety and psychosis are also common. These must be actively managed. Some ASMs (valproate, lamotrigine) have mood-stabilizing properties.
• Driving restrictions: Patients must be seizure-free for a legally defined period (varies by jurisdiction) before driving
• SUDEP (Sudden Unexpected Death in Epilepsy): Risk increases with uncontrolled seizures; optimizing seizure control reduces this risk
• Neuromodulation (vagus nerve stimulation, responsive neurostimulation, deep brain stimulation): Options for drug-resistant patients not amenable to resective surgery
• First unprovoked seizure: Treatment reduces subsequent seizure risk modestly (18% vs 26% at 6 months in MESS trial) but long-term differences narrow; treatment decisions must balance medication side effects, patient preferences, and occupation