12.3 Epilepsy, Seizure Types, Antiseizure Medications & Neuropathic Pain

Epilepsy, Seizure Types, Antiseizure Medications & Neuropathic Pain

Epilepsy and chronic neuropathic pain are major neurological conditions that share fundamental neurobiological mechanisms, including neuronal hyperexcitability, abnormal voltage-gated ion channel conductance, and blunted inhibitory neurotransmission. Canadian pharmacists frequently evaluate antiseizure medications (ASMs) across acute emergency resuscitation (Status Epilepticus), chronic ambulatory seizure prevention, specialized preconception planning, and peripheral neuropathic pain management.

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International League Against Epilepsy (ILAE) Seizure Classification

The 2017 ILAE operational classification organizes seizures based on three foundational levels: type of seizure onset, awareness level during the seizure, and motor versus non-motor features.

                           ILAE 2017 SEIZURE CLASSIFICATION

                                  TYPE OF SEIZURE ONSET
                                            │
         ┌──────────────────────────────────┴──────────────────────────────────┐
         ▼                                                                     ▼
   FOCAL ONSET                                                           GENERALIZED ONSET
(Originates in one hemisphere)                                        (Engages both hemispheres)
   │                                                                     │
   ├─► Focal Aware                                                       ├─► Motor:
   │   (Consciousness intact; sensory/motor aura)                         │   - Generalized Tonic-Clonic (GTC)
   ├─► Focal Impaired Awareness                                           │   - Atonic ("drop attacks")
   │   (Consciousness altered; automatisms)                               │   - Myoclonic (brief shock-like jerks)
   └─► Focal to Bilateral Tonic-Clonic                                   └─► Non-Motor (Absence):
       (Propagates across both hemispheres)                                  - Typical Absence (3 Hz spike-and-wave;
                                                                               brief 5–15s staring; childhood)

1. Focal Onset Seizures

Originates within neuronal networks limited to one cerebral hemisphere:

• Focal Aware Seizure: Awareness remains fully intact throughout the event. The patient experiences subjective sensory disturbances (auras: epigastric rising sensation, olfactory hallucinations, paresthesias), focal motor jerking, or autonomic symptoms.
• Focal Impaired Awareness Seizure: Awareness is clouded, altered, or lost at any point during the event. The patient often exhibits automatisms (repetitive, involuntary, semi-purposeful motor behaviors such as lip smacking, chewing, swallowing, clothing fumbling, or aimless wandering), followed by post-ictal confusion and amnesia.
• Focal to Bilateral Tonic-Clonic: Begins focally (with or without an aura) and subsequently propagates across both cerebral hemispheres to produce generalized convulsions.

2. Generalized Onset Seizures

Originates at some point within and rapidly engages bilaterally distributed cerebral networks:

• Generalized Tonic-Clonic (GTC): Sustained tonic muscle contraction (ictal cry, extensor rigidity) followed by synchronous bilateral clonic jerking, tongue biting (characteristically lateral tongue borders), urinary incontinence, and prominent post-ictal stupor/stertorous breathing.
• Atonic Seizures ("Drop Attacks"): Sudden loss of postural muscle tone lasting < 2 seconds, causing violent falls and severe head/facial trauma; requires protective helmet use.
• Myoclonic Seizures: Brief, sudden, shock-like involuntary muscle jerks without loss of consciousness. Hallmarking feature of Juvenile Myoclonic Epilepsy (JME), typically occurring in the morning shortly after waking.
• Typical Absence Seizures (Petit Mal): Non-motor generalized seizures primarily affecting children. Characterized by sudden, brief (5 to 15 seconds) behavioral arrest, blank staring, unresponsiveness, and subtle eyelid fluttering, with an immediate return to full baseline consciousness without post-ictal confusion. Classical electroencephalogram (EEG) finding: generalized 3 Hz (cycles per second) spike-and-wave discharges.

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Status Epilepticus (SE) Emergency Management Protocol

Status Epilepticus is defined operationally as continuous seizure activity lasting ≥ 5 minutes, OR ≥ 2 discrete seizures without complete recovery of consciousness between episodes. Prolonged status epilepticus causes progressive neuronal necrosis, excitotoxic cell death, systemic metabolic acidosis, hyperthermia, and pharmacoresistance due to rapid internalization and loss of functional synaptic GABA-A receptors. Management proceeds through four tightly timed phases:

                        STATUS EPILEPTICUS EMERGENCY TIMELINE

 PHASE 1: STABILIZATION           PHASE 2: EMERGENT THERAPY       PHASE 3: URGENT CONTROL         PHASE 4: REFRACTORY SE
       (0–5 min)                       (5–20 min)                      (20–40 min)                      (> 40 min)
┌──────────────────────┐       ┌──────────────────────┐       ┌──────────────────────┐       ┌──────────────────────┐
│ • ABCs, High-flow O₂ │       │ • FIRST-LINE BENZOS: │       │ • IV BROAD-SPECTRUM  │       │ • ICU Admission      │
│ • Point-of-care BG   │───►   │   - IV Lorazepam 4mg │───►   │   NON-SEDATING ASM:  │───►   │ • Intubation & cEEG  │
│   (Dextrose+Thiamine)│       │   - IM Midazolam 10mg│       │   - Levetiracetam IV │       │ • General Anesthesia:│
│ • IV access & timer  │       │   - PR Diazepam gel  │       │   - Fosphenytoin IV  │       │   Propofol / Midaz.  │
└──────────────────────┘       └──────────────────────┘       │   - Valproate IV     │       │   continuous infusion│
                                                              └──────────────────────┘       └──────────────────────┘

Phase 1: Stabilization Phase (0 to 5 Minutes)

• Assess Airway, Breathing, and Circulation (ABCs); administer high-flow oxygen.
• Measure capillary blood glucose immediately: if hypoglycemic (< 4.0 mmol/L), administer 50 mL of Dextrose 50% (D50W) IV. In adults with suspected alcohol use disorder or chronic malnutrition, administer Thiamine 100 mg IV prior to dextrose to prevent precipitating acute Wernicke encephalopathy.
• Establish intravenous access, obtain baseline laboratory tests (electrolytes, complete blood count, venous blood gas, toxicological screen, ASM trough concentrations), and initiate continuous ECG, pulse oximetry, and blood pressure monitoring.

Phase 2: Initial Emergent Therapy / Benzodiazepine Phase (5 to 20 Minutes)

If seizure activity persists beyond 5 minutes, immediately administer a first-line benzodiazepine:

• Option A (Intravenous Access Available): IV Lorazepam 4 mg (0.1 mg/kg) administered at 2 mg/min. May repeat once after 5 to 10 minutes if seizures continue.
• Option B (No Intravenous Access Available): IM Midazolam 10 mg (for body weight > 40 kg; 5 mg for 13–40 kg) administered into the anterior thigh. The landmark RAMPART trial demonstrated that IM midazolam administered by emergency paramedics is non-inferior to IV lorazepam and terminates seizures faster due to avoiding delays associated with establishing IV access in actively seizing patients.
• Option C (Community / Pediatric Setting without IV): Rectal Diazepam gel (0.2–0.5 mg/kg, max 20 mg) or intranasal midazolam (0.2 mg/kg, max 10 mg).

Phase 3: Urgent Control / Second-Line ASM Phase (20 to 40 Minutes)

If seizure activity persists despite adequate benzodiazepine dosing, administer a single loading dose of an intravenous, non-sedating antiseizure medication. The landmark ESETT trial demonstrated statistically equivalent efficacy (~45% to 47% seizure termination) and safety among three primary agents:

1. IV Levetiracetam: 60 mg/kg IV (maximum 4,500 mg) infused over 10 minutes;
2. IV Fosphenytoin: 20 mg PE (phenytoin sodium equivalents)/kg IV (maximum 1,500 mg PE) infused at up to 150 mg PE/min;
3. IV Valproate Sodium: 40 mg/kg IV (maximum 3,000 mg) infused over 10 minutes.

Phase 4: Refractory Status Epilepticus (RSE) Phase (> 40 Minutes)

Seizures that persist despite benzodiazepine administration and a second-line ASM constitute Refractory Status Epilepticus (RSE).

• Mandatory Interventions: Immediate admission to the Intensive Care Unit (ICU), endotracheal intubation, continuous invasive arterial pressure monitoring, and continuous electroencephalography (cEEG).
• Therapeutic Endpoint: Titrate continuous intravenous general anesthetic infusions to achieve electrographic seizure cessation or burst suppression (10 to 15 seconds of flatline between cerebral bursts) maintained for 24 to 48 hours.
• Continuous Infusion Anesthetics: Propofol (loading dose 2 mg/kg, then infusion 2–10 mg/kg/hr; monitor for Propofol Infusion Syndrome [PRIS]: severe refractory metabolic acidosis, hyperkalemia, rhabdomyolysis, hepatomegaly, cardiac failure), Midazolam infusion (0.2 mg/kg load, then 0.05–2 mg/kg/hr), or Ketamine.

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Antiseizure Medications (ASMs): Clinical Pharmacology & Spectrum

Antiseizure medications are broadly divided into broad-spectrum and narrow-spectrum agents based on their clinical efficacy across different seizure types:

                           ASM SPECTRUM COMPARISON

          BROAD-SPECTRUM ASMs                           NARROW-SPECTRUM ASMs
  (Effective in Focal + ALL Generalized)           (Effective ONLY in Focal Seizures)
┌────────────────────────────────────────┐       ┌────────────────────────────────────────┐
│ • Levetiracetam (Keppra)               │       │ • Carbamazepine (Tegretol)             │
│ • Valproic Acid / Divalproex (Epival)  │  vs   │ • Phenytoin (Dilantin)                 │
│ • Lamotrigine (Lamictal)               │       │ • Oxcarbazepine (Trileptal)            │
│ • Topiramate (Topamax)                 │       │ • Gabapentin / Pregabalin              │
│ SAFE in Absence & Myoclonic Seizures   │       │ CONTRAINDICATED in Absence & Myoclonic │
│                                        │       │ (Paradoxically Worsens Seizures!)      │
└────────────────────────────────────────┘       └────────────────────────────────────────┘

1. Broad-Spectrum ASMs

• Levetiracetam: Binds synaptic vesicle protein 2A (SV2A), modulating calcium-dependent exocytosis. 100% bioavailable, < 10% protein bound, 66% excreted unchanged by kidneys (adjust for CrCl). Zero CYP metabolism; virtually zero drug interactions. Key Toxicity: Neuropsychiatric and behavioral adverse effects in up to 15% of patients (irritability, agitation, hostility, depression, aggression).
• Valproic Acid / Divalproex Sodium: Multi-mechanistic: blocks Na+ channels, blocks T-type Ca2+ channels, increases brain GABA. Broadest spectrum available (drug of choice for Juvenile Myoclonic Epilepsy). Boxed Warnings: Severe teratogenicity (neural tube defects ~1–2%, lower IQ), fatal hepatotoxicity (highest in children < 2 years with POLG mutations), hemorrhagic pancreatitis, and hyperammonemic encephalopathy. Common: weight gain, alopecia, fine tremor, thrombocytopenia. Potent enzyme inhibitor (doubles lamotrigine levels!).
• Lamotrigine: Voltage-gated Na+ channel blocker. Broad-spectrum. Boxed warning for SJS/TEN; requires strict slow titration. Glucuronidated via UGT; cleared rapidly in the presence of enzyme inducers or estrogen oral contraceptives.
• Topiramate: Blocks Na+ channels, potentiates GABA-A, blocks AMPA/kainate, weak carbonic anhydrase inhibitor. Adverse effects: cognitive slowing and word-finding difficulty ("Dopamax"), anorexia and weight loss, nephrolithiasis (calcium phosphate kidney stones; counsel to drink 2–3 L fluids daily), oligohidrosis with hyperthermia (reduced sweating, especially in children), secondary angle-closure glaucoma, and oral cleft teratogenicity.

2. Narrow-Spectrum ASMs

• Carbamazepine: Voltage-gated Na+ channel blocker. First-line for focal seizures and trigeminal neuralgia.
  • Autoinhibition Kinetics: Carbamazepine is a potent inducer of CYP3A4, which metabolizes carbamazepine itself (autoinduction). Elimination half-life drops from 36 hours down to 12 to 17 hours after 2 to 4 weeks of continuous therapy. Titration must account for this clearance surge.
  • Adverse Effects: Diplopia, ataxia, hyponatremia / SIADH (monitor serum Na+), aplastic anemia, agranulocytosis.
  • Pharmacogenomics (HLA-B*1502): The Canadian carbamazepine monograph recommends testing for the HLA-B*1502 allele before starting carbamazepine in patients with ancestry in populations where it is common (for example, many East and Southeast Asian groups), because carriers have a greatly increased risk of Stevens-Johnson syndrome and toxic epidermal necrolysis. If positive, avoid carbamazepine unless the benefit clearly outweighs the risk.
• Phenytoin: Non-linear Michaelis-Menten saturation pharmacokinetics:
  • At therapeutic levels, hepatic metabolizing enzymes (CYP2C9/2C19) become saturated (zero-order kinetics). Small dose increases cause disproportionate, exponential surges in serum concentrations and neurotoxicity.
  • Therapeutic Range: Total serum phenytoin 10 to 20 mg/L (40 to 80 µmol/L).
  • Protein Binding & Hypoalbuminemia: Phenytoin is 90% bound to serum albumin. Only unbound (free) drug is active (target free phenytoin: 1 to 2 mg/L). In hypoalbuminemia or renal failure, the total level appears falsely low while the active free level may be toxic.
  • Winter-Tozer Equation: $\text{Adjusted Phenytoin (mg/L)} = \frac{\text{Measured Total Phenytoin}}{\left(0.2 \times \text{Albumin in g/dL}\right) + 0.1}$ (or with Albumin in g/L: $\frac{\text{Measured}}{\left(0.02 \times \text{Albumin}\right) + 0.1}$).
  • Toxicities: Acute: nystagmus (> 20 mg/L), ataxia (> 30 mg/L), lethargy/coma (> 40 mg/L). Chronic: gingival hyperplasia, hirsutism, coarsening of facial features, osteomalacia / osteoporosis, peripheral neuropathy.
• Ethosuximide: Selectively blocks low-threshold T-type Ca2+ channels in thalamic neurons. First-line drug of choice for pure childhood absence seizures. Zero efficacy in focal or generalized tonic-clonic seizures.

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Teratogenicity, Preconception Planning & Women's Health

Managing epilepsy in women of childbearing potential requires balancing maternal seizure control against teratogenic risks:

• Teratogenic Risk Hierarchy:
  • Valproate carries the highest teratogenic risk (major congenital malformations in ~10% of infants, neural tube defects [spina bifida] in 1% to 2%, and dose-dependent reductions in offspring IQ of 7 to 10 points with elevated autism spectrum risk). Valproate is strictly contraindicated in women of childbearing potential unless all other treatments fail.
  • Topiramate carries elevated risks of oral clefts (cleft lip/palate) and low birth weight.
  • Lamotrigine and Levetiracetam exhibit the lowest malformation rates (2% to 3%), comparable to baseline unexposed populations, and represent preferred first-line agents.
• Canadian Preconception Planning Guidelines:
  1. Optimize seizure control on monotherapy at the lowest effective dose prior to conception;
  2. High-Dose Folic Acid: Administer folic acid 4 to 5 mg PO daily starting at least 3 months prior to conception and continuing through the first trimester (then 0.4–1 mg daily) to prevent neural tube defects;
  3. Therapeutic Drug Monitoring in Pregnancy: Maternal clearance of lamotrigine surges by 200% to 300% (and levetiracetam by 50%) due to gestational estrogen-induced UGT glucuronidation, precipitating breakthrough seizures; measure monthly serum trough levels and titrate doses upward;
  4. Neonatal Vitamin K: Administer standard 1 mg IM vitamin K to the infant at delivery to prevent neonatal hemorrhagic disease.

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Neuropathic Pain Management (Canadian Pain Society Guidelines)

Neuropathic pain arises from a primary lesion or disease affecting the somatosensory nervous system, characterized by burning pain, hyperalgesia (exaggerated pain from mild painful stimuli), and allodynia (pain provoked by innocuous stimuli like clothing contact).

                       FIRST-LINE SYSTEMIC NEUROPATHIC PAIN AGENTS

          GABAPENTINOIDS                           DUAL SNRIs                           TRICYCLICS (TCAs)
┌────────────────────────────────┐       ┌────────────────────────────────┐       ┌────────────────────────────────┐
│ • Gabapentin (900–3600 mg/day) │       │ • Duloxetine (60–120 mg/day)   │       │ • Nortriptyline (10–75 mg/day) │
│ • Pregabalin (150–600 mg/day)  │  and  │ • Venlafaxine XR (150–225 mg)  │  and  │ • Amitriptyline (10–75 mg/day) │
│ • Alpha-2-delta calcium ligand │       │ • Boost descending spinal      │       │ • SNRI + Na+ channel block     │
│ • 100% Renal excretion (CrCl)  │       │   noradrenergic inhibition     │       │ • Nortriptyline preferred in   │
│ • Dizziness, edema, sedation   │       │ • Pain + depression coverage   │       │   elderly (less anticholinergic)│
└────────────────────────────────┘       └────────────────────────────────┘       └────────────────────────────────┘

1. Gabapentinoids (Gabapentin, Pregabalin)

• Mechanism: Bind with high affinity to the auxiliary alpha-2-delta-1 subunit of voltage-gated calcium channels in the CNS, decreasing calcium influx into presynaptic nociceptive terminals and reducing the release of excitatory neurotransmitters (glutamate, substance P, CGRP).
• Pharmacokinetics: Eliminated 100% unchanged by the kidneys. Mandatory dosage reduction based on calculated Creatinine Clearance (Cockcroft-Gault).
• Dosing & Titration:
  • Gabapentin: Saturable L-amino acid transport absorption (bioavailability drops at higher doses). Start 100–300 mg at bedtime, titrate upwards by 300 mg every 3 to 7 days to target 900–1,800 mg/day in 3 divided doses (max 3,600 mg/day).
  • Pregabalin: Linear, predictable absorption. Start 25–75 mg BID, titrate to 150–300 mg/day in 2 divided doses (max 600 mg/day).
• Adverse Effects: Somnolence, dizziness, peripheral edema, weight gain, ataxia. Caution regarding physical dependence and misuse.

2. Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

• Duloxetine: 60 mg once daily (max 120 mg/day). Established Level 1 evidence in diabetic peripheral neuropathic pain, fibromyalgia, and chronic musculoskeletal pain. Contraindicated in severe hepatic impairment or chronic alcoholism.
• Venlafaxine XR: 150 to 225 mg daily. Doses ≥ 150 mg are required to engage noradrenergic descending pain inhibition.

3. Tricyclic Antidepressants (TCAs)

• Agents: Amitriptyline and Nortriptyline (10–25 mg at bedtime, titrate to 50–75 mg at bedtime; doses are substantially lower than for depression).
• Nortriptyline Preference in Geriatrics: Nortriptyline (a secondary amine) is clinically preferred over amitriptyline (a tertiary amine), especially in older adults, because it causes significantly less anticholinergic toxicity (dry mouth, urinary retention, blurred vision, constipation, confusion) and less alpha-1 adrenergic orthostatic hypotension.
• Cardiac Safety: TCAs block cardiac sodium channels, causing QTc prolongation, conduction delays, and arrhythmogenic risk. Contraindicated in recent myocardial infarction, heart failure, and cardiac conduction blocks; obtain a baseline ECG in patients aged ≥ 40.

4. Special Neuropathic Pain Indications

• Trigeminal Neuralgia: The first-line drug of choice is Carbamazepine (200–1,200 mg/day) or Oxcarbazepine (600–1,800 mg/day). Standard gabapentinoids and TCAs are second-line.
• Topical Lidocaine 5% (Patches or Ointment): In the Canadian Pain Society neuropathic pain guideline, topical lidocaine is a later-line option (behind gabapentinoids, TCAs, SNRIs, then tramadol or opioids). It is most useful for small, well-localized areas such as post-herpetic neuralgia (PHN), especially in frail patients who cannot tolerate systemic agents. PEBC's sample items likewise pick pregabalin, not topical lidocaine, for new burning, shooting leg pain. Apply patches for a maximum of 12 hours on, followed by 12 hours off per 24-hour period to prevent systemic toxicity. Negligible systemic absorption; ideal for frail elderly patients.
• Topical Capsaicin (0.075% cream or 8% patch): TRPV1 receptor agonist; depletes substance P from nociceptive fibers.

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Clinical Case Scenario: Managing Status Epilepticus and Transitioning to Chronic ASM Therapy

A 54-year-old male with a history of alcohol use disorder is brought by EMS to the emergency department in continuous convulsive status epilepticus. Paramedics administered IM midazolam 10 mg into the anterior thigh at minute 8 of the seizure. Upon arrival in the ED (minute 16), the patient continues to experience generalized tonic-clonic convulsions. Peripheral IV access is established.

Resuscitation & Care Plan:

1. Phase 1 Bedside Testing: Bedside capillary blood glucose shows 3.1 mmol/L (hypoglycemia). Because of his alcohol use history, immediately administer Thiamine 100 mg IV followed by Dextrose 50% (D50W) 50 mL IV to treat hypoglycemia and prevent acute Wernicke encephalopathy.
2. Phase 2 Benzodiazepine Evaluation: The patient received IM midazolam 8 minutes ago and continues to seize. Administer IV Lorazepam 4 mg over 2 minutes.
3. Phase 3 Urgent ASM Selection: Prepare a second-line intravenous ASM immediately without waiting to see if lorazepam halts the seizure, as the seizure duration has exceeded 20 minutes. Select IV Levetiracetam 60 mg/kg (max 4,500 mg) infused over 10 minutes (preferred over fosphenytoin due to zero cardiac arrhythmogenic risk and no hepatic metabolism in an alcoholic patient).
4. Post-Resuscitation Maintenance: Once convulsions cease, continue levetiracetam 1,000 mg IV/PO BID as maintenance antiepileptic therapy, monitor renal function, and assess for post-ictal cognitive changes.