Lecture 1: Pathophysiology and Principles of Drug Therapy for Epilepsy

PDAT 507

What is defined as a seizure?

• A brief, discrete event that is intermittent, irregular, and unpredictable.

• Results from abnormal, excessive, and synchronous discharge of cortical neurons

What is defined as a convulsion?

Seizure manifested by muscle contractions

Describe the initiation of a seizure:

• Small group of abnormal neurons undergo prolonged depolarizations →

• Recruit adjacent neurons into rapid firing →

• Discharge of large number of neurons become abnormally linked (synchronized) (this is defined as a clinical seizure)

What is a seizure (from a neurochemical perspective)?

A imbalance between excitatory and inhibitory influences in CNS

What are proposed causes of seizures?

• Abnormalities in voltage/ligand gated ion channels

• Reduced inhibitory neurotransmission (GABA)

• Enhanced excitatory neurotransmission (glutamate)

Clinical manifestations of seizures:

• Symptoms may include a change in:

  • Motor activity

  • Sensation

  • Autonomic function

  • Consciousness

  
  

• Symptoms may vary depending on site of origin and spread of abnormal electrical activity

What is epilepsy?

• Neurological condition characterized by recurrent (2 or more) seizures unprovoked by any immediately identifiable cause

• Separated by >24 hours

What are the two mains categories of seizures?

1) Focal (partial) seizures

• a. Simple partial - aware

• b. Complex partial - impaired awareness

2) Generalized seizures

• Involves loss of consciousness

• Focal or partial seizures can develop into secondary generalized tonic clonic seizures (electrical disturbance starts with one side of the brain and spreads to both sides)

What’s the difference between focal and generalized seizures?

• Focal (partial): only part of the brain is affected. The symptoms and level of awareness depend on the area of the brain involved.

• Generalized: Both sides of the brain are affected from the start and the patient will be unconscious, even if only briefly

What is aura?

Subjective phenomenon that, in a given patient, may precede an observable seizure. If alone, it constitutes a sensory seizure (focal aware seizure).

• Can include: flashing lights, blurry visions, strange smell/taste, intense emotions

What is automatism?

a set of unconscious behavior observed during seizures (ie: chewing, swallowing, lip smacking, fumbling movements of hands, mumbling, etc.

What is ictal?

The seizure period or events due to a seizure

What are the antiseizure meds that are important for this lecture?

• Carbamazepine (Tegretol)

• Phenytoin (Dilantin)

• Valproic acid (Depakote)

• Lacosamide (Vimpat)

• Lamotrigine (Lamictal)

• Levetiracetam (Keppra)

• Oxcarbazepine (Trileptal)

• Topiramate (Topamax)

What is the general management strategy for seizures?

• Appropriate diagnostic evaluation

  • Confirm diagnosis of epilepsy

  • Classify seizure type (epilepsy syndrome)

  • Identify underlying cause

• Assess need for ASM therapy

• Institute appropriate ASM therapy

When is antiseizure medication not indicated?

1) If seizure are due to a reversible cause

2) If it is the patient’s first unprovoked seizure

3) For specific types of epilepsies (i.e. febrile seizures)

What are the 4 principles of antiepileptic drug therapy?

1) Match drug to patient:

• seizure type (epilepsy syndrome)

• age, lifestyle, other medical conditions; side effects, administration issues, cost

2) Start low, increase slowly

3) Restrict therapy to one drug (monotherapy) whenever possible

4) Monitor patient for:

• seizures

• drug interactions

• side effects

• compliance

What are the drugs of choice for Focal onset seizures (aware and impaired awareness) and focal to bilateral tonic-clonic seizures?

• Initial: (CLLO)

  • Carbemazepine

  • Lamotrigine

  • Levetiracetam

  • Oxcarbazepine

  • ‘Carb’ and ‘Lamo’ ‘Levet-ated’ to the ‘Ox’

• Other options/alternatives:

  • Lacosamide, Phenytoin, Pregabalin, Valproic acid, Topiramate Zonisamide, Briviracetam, Eslicarbazepine

What are the drugs of choice for generalized onset tonic-clonic seizures?

• Initial:

  • Levetiracetam

  • Lamotrigine

  • Topiramate

  • ‘Leve & Lamo’

• Other options:

  • Phenytoin

  • Valproic acid

What are the drugs of choice for absence seizures?

• Initial:

  • Ethosuximide and Valproic acid

• Others:

  • Lamotrigine

  • Levetiracetam

What are the drugs of choice for atonic or myoclonic seizures?

• Initial:

  • Lamotrigine (atonic only)

  • Topiramate (atonic only)

  • Valproic acid (both)

• Others:

  • Clobazam, Clonazepam, Levetiracetam, Rufinamide, Zonisamide

Drugs of Choice: Seizure types table

Drugs of choice: Epilepsy Syndromes

What are the drugs of choice for childhood absence epilepsy syndrome?

• First line: Ethosuximide or Valproic acid

• Second line: Lamotrigine or Topiramate

What are the drugs of choice for juvenile absence epilepsy syndrome?

• First line: Lamotrigine or Valproic acid

• Second line: Ethosuximide or Topiramate

What are the drugs of choice for juvenile myoclonic epilepsy syndrome?

• First line: Levetiracetam or Valproic acid

• Second line: Lamotrigine or Topiramate

What are the drugs of choice for infantile myoclonic epilepsy syndrome?

• First line: Valproic acid

• Second line: Clonazepam

What are the drugs of choice for Lennox-Gastaut epilepsy syndrome?

• First line: Valproic acid or Lamotrigine

• Second line: Clobazam, Rufinamide, Topiramate

What are the drugs of choice for Temporal lobe epilepsy syndrome?

• First line: Carbamazepine or Lamotrigine

• Second line: Levetiracetam, Topiramate, or Valproic acid

Are antiseizure medications generally well tolerated?

Yes, little to not side effects.

• What we have to worry about it drug interactions

Carbamazepine: dose-related AEs, interactions, other indications

• Dose-related AEs: sedation, dizziness, ataxia, blurred vision, nystagmus (uncontrolled movement of eyes)

• Interactions: CYP 3A4 inducer

• Other indications: Migraine, depression, bipolar

Lamotrigine: dose-related AEs, interactions, other indications:

• Dose-related AEs: dizziness, drowsiness, double vision

• Interactions: Induced/inhibited by other ASMs and hormonal contraception

• Other indications: Bipolar disorders

Levetiracetam: dose-related AEs, interactions, other indications:

• Dose-related AEs: agitation, dizziness, headache, irritability, anxiety

• Interactions: none!!! (safe to use with everything)

• Other indications: none

Valproic acid: dose-related AEs, interactions, other indications:

• Dose-related AEs: sedation, tremor, dizziness, nausea, ataxia

• Interactions: CYP 2C9, glucuronidation inhibitor

• Other indications: migraine, depression, bipolar

What are the steps to dosing ASMs?

Individualize dosing! Start low and slowly increase until seizures are controlled

• Steps in ASM dosing:

  • Select initial target dose

    • Dependent on age, weight, current drug therapy, other diseases

  • Decide on how to achieve initial target

  • Determine optimal maintenance dosing

How do we determine optimal maintenance dosing?

• Increase dose in small increments assessing seizure control or AEs after each change in dose.

• Allow adequate time to assess response

  • Steady state achieved (PK)?

  • Seizures frequency

• Decide dose adjustment based solely on clinical response (controlled vs uncontrolled)

  • If AEs develop, reduce dose to previous tolerated level and restart with smaller dose increments

What if seizures aren’t controlled at the maximally tolerated dose of the first ASM?

• Reevaluate:

  – Diagnosis of epilepsy

  – Classification of seizure type

  – Adequate dose/duration of therapy

  – Medication compliance (plasma concentration)

What if a patient has failed therapy with a given ASM?

• Consider addition of a second ASM

• Consider if monotherapy with the second ASM a possibility or if patient needs to continue with polytherapy

• Alternative forms of treatment

  • Surgery

  • Vagal nerve stimulator

  • Ketogenic diet

What is Oxcarbazepine (Trileptal) indicated for?

Focal onset seizures (partial seizures)

What are things to note about Oxcarbazepine (Trileptal)?

• It is a pro-drug

  • Immediately metabolized in the liver to active metabolite 10-MHD

• CYP450 enzyme inducer

• Follows linear kinetics

What is Valproic acid (Depakote) indicated for?

Broad spectrum of activity (efficacy for both focal/partial & generalized onset seizures)

What are things to note about Valproic acid (Depakote)?

• Metabolized hepatically

• Is an inhibitor

  • Inhibits 2C9 → which increases phenytoin cncentration

  • Inhibits glucur. → which increases Lamotrigine concentration

  • Inhibits CBZ 10,11 epoxide → which increases CBZ 10,11 epoxide concentration

• Follows linear kinetics

What is Levetiracetam (Keppra) indicated for?

Broad spectrum of activity (both focal/partial & generalized onset seizures)

What are things to note about Levetiracetam (Keppra)?

• Eliminated renally, mainly unchanged

• No enzyme induction/inhibition - meaning, no drug-drug interactions!

• Follows linear kinetics