Seizure Disorders

Seizure Phases…

1. Prodrome phase

   1. Change in behavior/mood 

   2. AUra 

2. Ictal “Seizure Phase”

3. Postictal phase

   1. Confusion, weakness, behavioral changes

Seizure Classification…

Focal

1. Focal MOTOR

   1. Automatisms

   2. Atonic (loss of muscle tone)

   3. clonic

2. Focal NONMOTOR

   1. Autonomic 

   2. Behavior arrest 

   3. cognitive/emotional/sensory 

Generalized Classifcation…

1. Motor

   1. Tonic-clonic

   2. Myoclonic 

2. NON-Motor

   1. Absence

Causes of Seizures

1. Stroke/CVD - vascular seizure

2. Infection - CNS infection 

3. Metabolic Disorders: 

   1. Hyponametric (low Na+)

   2. Hypoglycermic 

4. Drug withdrawal

   1. Barbituates 

   2. Benzodiazepines 

   3. Alcohol 

5. Hyperventilation, Genetics, Head Trauma, Sleep Deprivation, Dehydration

Drug-Indued Seizures

1. Antibiotics 

   1. Fluoroquinolones

   2. Meropenem/Ertapenem 

2. Chemotx - alkylating agents 

3. Psychostimulants - amphetamines 

4. Meperidine - active excitotoxic metabolite 

5. Antidepressants - TCA, Bupropion

6. Antipsychotics 

7. Xanthine Derivatives 

   1. Theopylline 

   2. Caffeine

Generalized Tonic-Clonic Treatment…

→ first line: sodium valproate 

• CI in women of childbearing potential

  • levetiracetam (KEPPRA) or Lamotrigine for these individuals 

→ second line: topiramate, zonisamide

→ third line: clobazam, perampanel 

Generalized Myoclonic Treatment…

→ first line: sodium valproate 

• CI in women of childbearing potential 

  • Levetiracetam for these individuals 

→ second line: topiramate, levetiracetam

Absence Seizures:

petit-mal seizures

• Blank look/brief staring

• Unresponsive 

• Quick return with no confusion afterwards

Absence Seizure Drug Selection 

1. Ethosuximide 

2. Lamotrigine 

3. Valproic Acid

Focal Seizures:

One hemisphere impacted 

• Patient can be aware (consciousness) 

• Contralateral impact (left, right)

Focal Seizure Drug Selection 

1. Lamotrigine, Levetiracetam (KEPPRA), Oxcarbazepine

2. Second: Carbamazepine, Lacosamide, Topirmate 

3. Gabapentin, Zonismade, Phenobarbital 

Which seizure types do these agents WORSEN?

1. Carbamazepine, Oxcarbazepine,Eslicarbazepine

   1. Worsens absence 

   2. Worsens myoclonic

2. Phenytoin 

   1. Worsens absence

   2. Worsens myoclonic

3. Phenobarbital 

   1. ONLY worsens absence 

Carbamazpeine, phenytoin, and oxcarbazepine can provoke status epilepticus 

Valproate (Depakene/Depakote)

→ stimulates glutamic acid decarboxyclase, blocks Ca++ channel, suppresses Na+ voltage gates

• 90% protein bound there those with low albumin levels have MORE free drug available 

USE: broad spectrum anticonvulsant

ADR: 

• GI (use ENTERIC COATED DEPAKOTE and/or give with food)

• Hematologic: THROMBOCYTOPENIA (therefore CBC baseline needed) 

  • Aspirin use warning 

• Idiosyncratic hair loss 

• Weight gain 

Black box warning: FETAL RISK, pancreatitis, hepatotoxicity 

Valproate Drug Monitoring: 

→ target blood/trough levels 50-100 mcg/mL

DDI: Lamotrigine 

• Carbapenems DECREASE Valproate concentrations (seizure inducing risk)

Lamotrigine (Lamictal)

→ inhibits voltage-dependent Na+ channels 

USE: wide spectrum 

• Focal seizure 

• Lennox-gastaus syndrome 

• Generalized tonic-clonic seizures 

• Absence seizures 

• Bipolar depression 

ADR: 

Black box warning: rash (benign), steven johnsons syndrome

• Best avoided with slow titration up

Lamotrigine Dosing

1. Patients taking valproic acid products 

   1. 25 mg every other day 

2. Patients NOT taking enzyme-inducing

   1. 25 mg/day

   2. 50 mg/day every 1-2 weeks with goal range of 225-375 mg/day

3. Patients taking EIAED monotherapy → estradiol, carbamazepine

   1. 50 mg/day (start at higher dose) 

EIAED stands for Enzyme-Inducing Antiepileptic Drug. These are a specific class of anti-seizure medications that "rev up" or accelerate the liver’s metabolic enzymes. Common examples of EIAEDs include:

• Carbamazepine (Tegretol)

• Phenytoin (Dilantin)

• Phenobarbital

• Primidone (Mysoline) 

Levetiracetam (KEPPRA)

→ common monotx for AED activity 

• Minimal drug-drug interactions 

MOA: binds synaptic vesicle proteins (SV2A)

• 500 mg BID start, 3000 mg/day maintenance, 4500 mg for acute seizure treatment 

PO dose = IV dose

MOOD and Behavorial changes… AVOID IN PSYCHOSIS

Topiramate (TOPAMAX)

1. Inhibition of voltage gated Na+ channels 

2. Enhances GABA-mediated chloride influx 

3. Glutamate antagonist 

DDIs: CY219 inhibitor, CYP3A4 inducer

Carbazepmine, valproate, and phenytoin all decrease topiramate levels

ADR: 

• Metabolic acidosis risk

  • Acute: hyperventilation, fatigue, anorexia

  • Chronic: nephrolithiasis, osteomalacia

• Difficulty concentrating and word recall

• paresthesia/tingling 

• Weight loss 

Zonisamide (Zonegran)

Inhibition of Na+ channels, Ca++ channels

Similiar to topirmate 

USE: focal (partial) seizures but can be used for absence, myoclonic

• Contains SULFA = avoid in sulfa-allergy patients

Perampanel (Fycompa)

Non competitive antagonist of ionotropic AMPA glutamate receptor (NOVEL)

ADE: CNS effects, behavior changes (hostility agression, BLACK BOX WARNING) 

Narrow Spectrum Antiseizure Medications

Primarily used for focal-onset seizures including ones that evolve to bilateral convulsive seizures

• Carbamazepine 

• Eslicarbazepine 

• Oxcarbazepine 

• Phenobarbital 

• Phenytoin

• Primidone

Phenytoin (Dilantin) 

Various seizure types, status epilepticus, post head trauma/surgery

• Inhibition of voltage Na+ channels 

Pregnancy risk: crosses placenta → fetal hydantoin syndrome increased risk of midline defects 

• Folic acid supplementation necessary for use during pregnancy

Phenytoin ADR:

CNS if dose overshoot…

1. Far lateral nystagmus

2. Ataxia 

3. Stupor 

4. Coma/Death (100 mcg/mL)

Osteomalacia 

Gingival Hyperplasia 

Macrocytic anemia (B12)

Phenytoin Kinetics 

1. Absorption: oral loading doses

2. Distribution: HIGHLY PROTEIN BOUND > 90% bound

   1. Influenced by albumin concentrations 

   2. More FREE drug in those with impaired renal function (decrease dose) 

   3. LESS FREE drug in those with obesity (increase dose) 

3. Metabolism: Parahydroxylation

4. Excretion

ASM Therapeutic Drug Monitoring…Drug Levels 

1. Carbamazepine: 

   1. 4-12 mg/L

2. Phenytoin: 

   1. 10-20 mg/L

3. FREE Phenytoin: 

   1. 1-2 mg/L

4. Valproic Acid: 

   1. 50-100 mg/L

Phenytoin Non-Linear Kinetics

→ at therapeutic serum concentrations elimination is ZERO-ORDER kinetics 

• Enzymatic metabolism 

• Non-linear relationship between serum concentration and drug dose

• Vmax and Km

Small changes in daily dose may result in large changes in serum concentrations 

The closer you are to your target concentration, the smaller your dose adjustment should be

Carbamazepine (Tegretol)

Voltage dependent Na+ channel blockers

• Genearlized tonic-clonic seizures 

• Partial seizures (focal)

• Bipolar mania 

• Trigeminal neuralgia

ADR: CNS, GI, hyponatremia

BBW: agranulocytosism, PREGNANCY FETAL DEFECTS

Autoinduction-Carbamazepine…

Pharmacokinetic cannibal

1. Is substrate of CYP3A4

2. Is inducer of CYP3A4

Will induce its own metabolism at the start

CAN WORSE ABSENCE SEIZURES

Carbamazepine vs. Oxcarbazepine

NARROW SPECTRUM ANTICONVUSLANTS FOR FOCAL onset SEIZURE TX…

Not used as monotherapy for generalized seizures…

1. Gabapentin 

2. Lacosamide

3. Pregabalin

4. Tiagabine

Pregabalin vs Gabapentin…

Pregab does not have increased dose resistance like gabapentin does…

NICHE NOVEL ANTICONVUSLANTS 

1. Ethosuximide-absence seizures 

2. Felbamate; broad spectrum agent of last resort 

Ethosuximide (Zarontin)

Blocks Ca++ channels 

Indicated for absence seizures ONLY 

ADRS:

• Lupus like reaction 

• Aplastic anemia 

• Hepatotoxicity 

Felbamate (Felbatol) 

→ last line for refractory seizures 

NMDA modulation 

ADR: life threatening blood dyscrasia, hepatotoxicity 

Management of Status Epilepticus  

0 - 5 minutes - stabilization phase

5 - 20 minutes - initial therapy

• Parenteral benzodiazepine is initial choice 

  • IM Midazolam 

  • IV Lorazepam 

  • IV Diazepam 

20 - 40 minutes - second therapy phase (IF persisting)

• IV fosphenytoin 

• IV valporic acid 

• IV levetiracetam 

40 - 60 minutes - third therapy, no clear evidence 

• Pentobarbital, propofol (anesthetic agents)

Benzodiazepine Seizure Use:

1. Status epilepticus 

   1. Lorazepam/Diazepam/Midazolam 

2. Refractory seizures

   1. Clobazam (Onfi)

3. Myoclonic seizures 

   1. Conazepam (Klonopin)

Phenobarbital and Primidone

prolonged GABA Cl- channel openings 

→ pheno still used in neonatal seizures

→ primidone is pro-drug of phenobarb

Barbituates…

• CYP450 Inducer 

• HEAVY CNS ADEs