Academic Half-Day
Treatment of
Epilepsy
Ruba Benini & Abdullah Tawakul
July 25th , 2012
Preamble

Epilepsy is the second most common neurological condition after headache

Worldwide prevalence of 1% with a cumulative incidence of 2-4%.

The incidence of epilepsy is highest in the very young and the very old.
Hauser et al., 1996
Preamble

Epilepsy is not a single disease entity but rather an umbrella term used to denote a variety of
disorders with different etiologies but with seizures as a common denominator
Port Wine Stain (Sturge-Weber)
Mesial Temporal lobe sclerosis
Prosencephaly
Preamble

Treatment of epilepsy can be broadly divided into:
 Medical treatment (anticonvulsants)
 Surgical treatment (Focal resections; Hemispherectomy; Callosotomy)
 Special diets (Ketogenic diet, Atkinson diet)
 Other (Vagal Nerve stimulation, Deep brain stimulation, Transcranial Magnetic
Stimulation)
OUTLINE
 Approach to a first unprovoked seizure – to treat or not to
treat
 Adult versus Child
 Medical Treatment




What anticonvulsants are available to you
Mechanisms of action
Some important pharmacokinetic properties to keep in mind
Some dos and don’ts
 Surgical Treatment
 Brief overview
 Others
 A few words
OUTLINE
 Approach to a first unprovoked seizure – to treat or
not to treat
 Adult versus Child
 Medical Treatment




What anticonvulsants are available to you
Mechanisms of action
Some important pharmacokinetic properties to keep in mind
Some dos and don’ts
 Surgical Treatment
 Brief overview
 Others
 A few words
Scenario
25 year old male, presents to the ER for an episode this
morning where he was found on the bathroom floor by his
girlfriend after she heard a big bang.
Consult says: r/o seizure.
What is a seizure?
What do you want to know?
How do you take a seizure history?
Scenario
25 year old male, presents to the ER for an episode this
morning where he was found on the bathroom floor by his
girlfriend after she heard a big bang.
Consult says: r/o seizure.
What is a seizure?
What do you want to know?
How do you take a seizure history?
Definitions
What is a Seizure:
•Clinical event characterized by transient neurological signs and/or
symptoms (motor, sensory, level of consciousness)
•That arise due to abnormal and excessive discharges from
hyperexcitable, synchronized neuronal networks
Scenario
25 year old male, presents to the ER for an episode this
morning where he was found on the bathroom floor by his
girlfriend after she heard a big bang.
Consult says: r/o seizure.
What is a seizure?
What do you want to know?
How do you take a seizure history?
Approach to a first Seizure
• Is this really an epileptic seizure
HISTORY!
or a seizure mimic?
HISTORY!
• What type of seizure was it?
(Seizure Semiology)
HISTORY!
• Can you identify a particular
epilepsy syndrome?
• What is the etiology of the
seizure?
Approach to a first Seizure
• Is this really an epileptic seizure
or a seizure mimic?
Suggested Reading:
Crompton and Berkovic (2009) The borderland of epilepsy:
clinical and molecular features of phenomena that mimic
epileptic seizures. Lancet Neurology
Approach to a first Seizure
• What type of seizure was it?
Focal (Partial) Seizures
Generalized seizures
•Simple partial
•Complex partial
•Complex partial with
secondary generalization
•Tonic-clonic (Grand mal)
•Absence (Petit mal)
•Myoclonic
•Tonic
•Clonic
•Atonic


Simple partial seizures
No loss of consciousness
May manifest as motor signs,
autonomic symptoms,
somatosensory, special
sensory symptoms or psychic
symptoms




Complex partial seizures
Impairment of consciousness
Usually originate in frontal or
temporal lobe
Maybe preceded by auras
May involve automatisms
Approach to a first Seizure
• What type of seizure was it?
Suggested Reading:
Berg et al. (2010) Revised terminology and
concepts for organization of seizures and
epilepsies: Report of the ILAE Commission
on Classification and Terminology, 2005–
2009. Epilepsia.
Approach to a first Seizure
• Can you identify a particular
epilepsy syndrome?
Suggested Reading:
Berg et al. (2010) Revised terminology and
concepts for organization of seizures and
epilepsies: Report of the ILAE Commission
on Classification and Terminology, 2005–
2009. Epilepsia.
Definitions
What is an Epilepsy Syndrome:
Clinical entity with relatively consistent clinical features that is
defined by seizure semiology, etiology, EEG signature, neurologic
status, prognosis and in some cases response to specific
anticonvulsants
Approach to a first Seizure
• Can you identify a
particular epilepsy
syndrome?
Suggested Reading:
Berg et al. (2010) Revised terminology and
concepts for organization of seizures and
epilepsies: Report of the ILAE Commission
on Classification and Terminology, 2005–
2009. Epilepsia.
Approach to a first Seizure
• What is the etiology?
Back to Scenario
25 year old male, presents to the ER for an episode this
morning where he was found on the bathroom floor by his
girlfriend after she heard a big bang.
Consult says: r/o seizure.
First unprovoked Seizure
Generalized seizure
Patient asks if he has epilepsy?
Do you treat?
Definitions
What is Epilepsy:
 Chronic condition characterized by recurrent, usually spontaneous, epileptic
seizures
 Two or more unprovoked seizures
Back to Scenario
25 year old male, presents to the ER for an episode this
morning where he was found on the bathroom floor by his
girlfriend after she heard a big bang.
Consult says: r/o seizure.
First unprovoked Seizure
Generalized seizure
Patient asks if he has epilepsy?
Do you treat?
Approach to first unprovoked seizure
•Risk of recurrence after first seizure: 30 to 55% over 2 to 5 years
•Treatment of first seizure reduces risk of recurrence by 50% but does
not alter the risk of developing epilepsy
•There is no evidence that delaying treatment alters prognosis (chances
for eventual seizure control are not reduced by delaying AED therapy)
Approach to first unprovoked seizure
First unprovoked epileptic seizure
No treatment
Exceptions: Early treatment is justifiable for
patients in whom recurrence of seizure would
have significant consequences related to
driving, working and general safety
Summary of Guideline
1. Treatment with AED is not indicated for the prevention of the development of epilepsy (Level
B).
2. Treatment with AED may be considered in circumstances where the benefits of reducing the
risk of a second seizure outweigh the risks of pharmacologic and psychosocial side effects
(Level B).
Hirtz et al., 2003
OUTLINE
 Approach to a first unprovoked seizure – to treat or not to
treat
 Adult versus Child
 Medical Treatment




What anticonvulsants are available to you
Mechanisms of action
Some important pharmacokinetic properties to keep in mind
Some dos and don’ts
 Surgical Treatment
 Brief overview
 Others
 A few words
Treatment of Epilepsy
(Anticonvulsants)
 In epilepsy, there is a pathologic imbalance between inhibitory and excitatory
processes
Excitation
Inhibition
 Anticonvulsants control seizures either by increasing inhibition or decreasing
excitation
•Voltage-gated Na channels
•Voltage-gated Ca channels
•GABAergic transmission
•Glutamatergic excitation
Excitation
Inhibition
Treatment of Epilepsy
(Anticonvulsants)
Treatment of Epilepsy
(Anticonvulsants)
 Mechanism of action
 Important side-effects
 Pharmacokinetics
 How do you choose the first drug
 Special considerations (pregnancy, etc)
Match the following
anticonvulsants
to their mechanism(s) of
action
Anticonvulsants
(Mechanism of Action)
Blocks voltage-gated Na channels
Blocks presynaptic release of neurotransmitter by blocking SV 2A
Blocks presynaptic release of neurotransmitter by N-type Ca channels
Blocks GAT-1 and prevents uptake of GABA from synapse
Phenytoin
(Dilantin)
GABA(A) receptor agonist
Increases intracellular GABA levels
Blocks voltage-gated Ca channels
Blocks T-type Calcium channels
Stabilizes slowly-inactivated voltage-gated Na channels
Blocks NMDA receptors
Blocks AMPA receptors
Blocks metabolism of GABA by inhibiting GABA-T
Anticonvulsants
(Mechanism of Action)
Blocks voltage-gated Na channels
Blocks presynaptic release of neurotransmitter by blocking SV 2A
Blocks presynaptic release of neurotransmitter by N-type Ca channels
Blocks GAT-1 and prevents uptake of GABA from synapse
Phenobarbital
GABA(A) receptor agonist
Increases intracellular GABA levels
Blocks voltage-gated Ca channels
Blocks T-type Calcium channels
Stabilizes slowly-inactivated voltage-gated Na channels
Blocks NMDA receptors
Blocks AMPA receptors
Blocks metabolism of GABA by inhibiting GABA-T
Anticonvulsants
(Mechanism of Action)
Blocks voltage-gated Na channels
Blocks presynaptic release of neurotransmitter by blocking SV 2A
Blocks presynaptic release of neurotransmitter by N-type Ca channels
Blocks GAT-1 and prevents uptake of GABA from synapse
Carbamazepine
(Tegretol)
GABA(A) receptor agonist
Increases intracellular GABA levels
OxCarbamazepine
(Trileptal)
Blocks voltage-gated Ca channels
Blocks T-type Calcium channels
Stabilizes slowly-inactivated voltage-gated Na channels
Blocks NMDA receptors
Blocks AMPA receptors
Blocks metabolism of GABA by inhibiting GABA-T
Anticonvulsants
(Mechanism of Action)
Blocks voltage-gated Na channels
Blocks presynaptic release of neurotransmitter by blocking SV 2A
Blocks presynaptic release of neurotransmitter by N-type Ca channels
Blocks GAT-1 and prevents uptake of GABA from synapse
Clobazam
(Frisium)
GABA(A) receptor agonist
Increases intracellular GABA levels
Diazepam
Lorazepam
Midazolam
Clonazepam
Blocks voltage-gated Ca channels
Blocks T-type Calcium channels
Stabilizes slowly-inactivated voltage-gated Na channels
Blocks NMDA receptors
Blocks AMPA receptors
Blocks metabolism of GABA by inhibiting GABA-T
Anticonvulsants
(Mechanism of Action)
Blocks voltage-gated Na channels
Blocks presynaptic release of neurotransmitter by blocking SV 2A
Blocks presynaptic release of neurotransmitter by N-type Ca channels
Blocks GAT-1 and prevents uptake of GABA from synapse
Lamotrigine
(Lamictal)
GABA(A) receptor agonist
Increases intracellular GABA levels
Blocks voltage-gated Ca channels
Blocks T-type Calcium channels
Stabilizes slowly-inactivated voltage-gated Na channels
Blocks NMDA receptors
Blocks AMPA receptors
Blocks metabolism of GABA by inhibiting GABA-T
Anticonvulsants
(Mechanism of Action)
Blocks voltage-gated Na channels
Blocks presynaptic release of neurotransmitter by blocking SV 2A
Blocks presynaptic release of neurotransmitter by N-type Ca channels
Blocks GAT-1 and prevents uptake of GABA from synapse
Levetiracetam
(Keppra)
GABA(A) receptor agonist
Increases intracellular GABA levels
Blocks voltage-gated Ca channels
Blocks T-type Calcium channels
Stabilizes slowly-inactivated voltage-gated Na channels
Blocks NMDA receptors
Blocks AMPA receptors
Blocks metabolism of GABA by inhibiting GABA-T
Anticonvulsants
(Mechanism of Action)
Blocks voltage-gated Na channels
Blocks presynaptic release of neurotransmitter by blocking SV 2A
Blocks presynaptic release of neurotransmitter by N-type Ca channels
Blocks GAT-1 and prevents uptake of GABA from synapse
Lacosamide
(Vimpat)
GABA(A) receptor agonist
Increases intracellular GABA levels
Blocks voltage-gated Ca channels
Blocks T-type Calcium channels
Stabilizes slowly-inactivated voltage-gated Na channels
Blocks NMDA receptors
Blocks AMPA receptors
Binds to CRMP-2
Anticonvulsants
(Mechanism of Action)
Blocks voltage-gated Na channels
Blocks presynaptic release of neurotransmitter by blocking SV 2A
Blocks presynaptic release of neurotransmitter by N-type Ca channels
Blocks GAT-1 and prevents uptake of GABA from synapse
Valproic Acid
(Epival,
Depakene)
GABA(A) receptor agonist
Increases intracellular GABA levels
Blocks voltage-gated Ca channels
Blocks T-type Calcium channels
Stabilizes slowly-inactivated voltage-gated Na channels
Blocks NMDA receptors
Blocks AMPA receptors
Blocks metabolism of GABA by inhibiting GABA-T
Anticonvulsants
(Mechanism of Action)
Blocks voltage-gated Na channels
Blocks presynaptic release of neurotransmitter by blocking SV 2A
Blocks presynaptic release of neurotransmitter by N-type Ca channels
Blocks GAT-1 and prevents uptake of GABA from synapse
Valproic Acid
(Epival,
Depakene)
GABA(A) receptor agonist
Increases intracellular GABA levels
Blocks voltage-gated Ca channels
Blocks T-type Calcium channels
Stabilizes slowly-inactivated voltage-gated Na channels
Blocks NMDA receptors
Blocks AMPA receptors
Blocks metabolism of GABA by inhibiting GABA-T
Anticonvulsants
(Mechanism of Action)
Blocks voltage-gated Na channels
Blocks presynaptic release of neurotransmitter by blocking SV 2A
Blocks presynaptic release of neurotransmitter by N-type Ca channels
Blocks GAT-1 and prevents uptake of GABA from synapse
Ethosuximide
(Zarontin)
GABA(A) receptor agonist
Increases intracellular GABA levels
Blocks voltage-gated Ca channels
Blocks T-type Calcium channels
Stabilizes slowly-inactivated voltage-gated Na channels
Blocks NMDA receptors
Blocks AMPA receptors
Blocks metabolism of GABA by inhibiting GABA-T
Anticonvulsants
(Mechanism of Action)
Blocks voltage-gated Na channels
Blocks presynaptic release of neurotransmitter by blocking SV 2A
Blocks presynaptic release of neurotransmitter by N-type Ca channels
Blocks GAT-1 and prevents uptake of GABA from synapse
Topiramate
(Topamax)
GABA(A) receptor agonist
Increases intracellular GABA levels
Blocks voltage-gated Ca channels
Blocks T-type Calcium channels
Stabilizes slowly-inactivated voltage-gated Na channels
Blocks NMDA receptors
Blocks AMPA (non-NMDA) receptors
Blocks metabolism of GABA by inhibiting GABA-T
Anticonvulsants
(Mechanism of Action)
Blocks voltage-gated Na channels
Blocks presynaptic release of neurotransmitter by blocking SV 2A
Blocks presynaptic release of neurotransmitter by N-type Ca channels
Blocks GAT-1 and prevents uptake of GABA from synapse
Vigabatrin
(Sabril)
GABA(A) receptor agonist
Increases intracellular GABA levels
Blocks voltage-gated Ca channels
Blocks T-type Calcium channels
Stabilizes slowly-inactivated voltage-gated Na channels
Blocks NMDA receptors
Blocks AMPA receptors
Blocks metabolism of GABA by inhibiting GABA-T
Anticonvulsants
(Mechanism of Action)
Blocks voltage-gated Na channels
Blocks presynaptic release of neurotransmitter by blocking SV 2A
Blocks presynaptic release of neurotransmitter by N-type Ca channels
Blocks GAT-1 and prevents uptake of GABA from synapse
Tiagabine
GABA(A) receptor agonist
Increases intracellular GABA levels
Blocks voltage-gated Ca channels
Blocks T-type Calcium channels
Stabilizes slowly-inactivated voltage-gated Na channels
Blocks NMDA receptors
Blocks AMPA receptors
Blocks metabolism of GABA by inhibiting GABA-T
Anticonvulsants
(Mechanism of Action)
Blocks voltage-gated Na channels
Blocks presynaptic release of neurotransmitter by blocking SV 2A
Blocks presynaptic release of neurotransmitter by N-type Ca channels
Blocks GAT-1 and prevents uptake of GABA from synapse
Gabapentin
(Neurontin)
GABA(A) receptor agonist
Increases intracellular GABA levels
Pregabalin
(Lyrica)
Blocks voltage-gated Ca channels
Blocks T-type Calcium channels
Stabilizes slowly-inactivated voltage-gated Na channels
Blocks NMDA receptors
Blocks AMPA receptors
Blocks metabolism of GABA by inhibiting GABA-T
Anticonvulsants
(Mechanism of Action)
Blocks voltage-gated Na channels
Blocks presynaptic release of neurotransmitter by blocking SV 2A
Blocks presynaptic release of neurotransmitter by N-type Ca channels
Blocks GAT-1 and prevents uptake of GABA from synapse
Felbamate
GABA(A) receptor agonist
Increases intracellular GABA levels
Blocks voltage-gated Ca channels
Blocks T-type Calcium channels
Stabilizes slowly-inactivated voltage-gated Na channels
Blocks NMDA receptors
Blocks AMPA receptors
Blocks metabolism of GABA by inhibiting GABA-T
Anticonvulsants
(Mechanism of Action)
Blocks voltage-gated Na channels
Blocks presynaptic release of neurotransmitter by blocking SV 2A
Blocks presynaptic release of neurotransmitter by N-type Ca channels
Blocks GAT-1 and prevents uptake of GABA from synapse
Rufinimide
GABA(A) receptor agonist
Increases intracellular GABA levels
Blocks voltage-gated Ca channels
Blocks T-type Calcium channels
Stabilizes slowly-inactivated voltage-gated Na channels
Blocks NMDA receptors
Blocks AMPA receptors
Blocks metabolism of GABA by inhibiting GABA-T
Summary
Panayiotopoulos (2010)
Anticonvulsants: Summary
Drug
Mechanism of Action
Phenobarbital
Agonist of GABA (A) receptors
Antagonist of N- and L-type voltage-gated Ca channels
Phenytoin
Stabilizes inactive state of voltage-gated Na Channels
Inhibit presynaptic release of NT via L-type Ca channels
Carbamazepine
Oxcarbazepine
Stabilizes inactive state of voltage-gated Na Channels
Inhibit presynaptic release of NT via L-type Ca channels
Valproate
Stabilizes inactive state of voltage-gated Na Channels
Increases GABA levels
Blocks NMDA glutamate receptors
Blocks T-type voltage gated Ca channels
Ethosuximide
Antagonist of T-type voltage-gated Calcium channels
Benzodiazepines
(clobazam)
Agonist of GABA (A) receptors
Anticonvulsants: Summary
Drug
Mechanism of Action
Lamotrigine
Stabilizes inactive state of voltage-gated Na Channels
Increases intracellular GABA levels
May act at N, P/Q type voltage-gated Calcium channels
Vigabatrin
Blocks metabolism of GABA through GABA-T
Gabapentin
Pregabalin
Blocks presynaptic release of neurotransmitters via N-type
Calcium channels
Increases intracellular GABA levels
Tiagabine
Blocks GAT-1 and prevents uptake of GABA from synapse
Felbamate
Blocks NMDA glutamate receptors
Enhances GABA(A) receptor transmission
Unclear effect on voltage-gated Na channels
Levetiracetam
Blocks presynaptic vesicle recycling through SV 2A
Anticonvulsants: Summary
Drug
Mechanism of Action
Lacosamide
Stabilizes slowly-inactivated Na channels
Binds to CRMP-2
Topiramate
Blocks AMPA/Kainate glutamate receptors
Blocks L-type voltage gated Ca channels
Unclear effect on voltage-gated Na channels
May enhance GABA(A) receptor transmission
Weak inhibitor of carbonic anhydrase
Anticonvulsants
and side-effects
PART I: What makes nerve cells excitable?
Anticonvulsants: Side-effects
 Which of the following AED can cause somnolence?








Phenobarbital
Valproic acid
Topiramate
Vigabatrin
Phenytoin
Lamictal
Primidone
Clobazam
PART I: What makes nerve cells excitable?
Anticonvulsants: Side-effects
 Which of the following AED can cause somnolence?








Phenobarbital
Valproic acid
Topiramate
Vigabatrin
Phenytoin
Lamictal
Primidone
Clobazam
PART I: What makes nerve cells excitable?
Anticonvulsants: Side-effects
 Which of the following are side-effects of Topiramate?
1. Blurry vision
2. Metabolic acidosis
3. Paresthesias
4. Ataxia
5. Renal stones
6. Mental slowing with speech and memory disturbance
7. Psychosis
8. Alopecia
9. Weight gain
10. Glaucoma
PART I: What makes nerve cells excitable?
Anticonvulsants: Side-effects
 Which of the following are side-effects of Topiramate?
1. Blurry vision
2. Metabolic acidosis
3. Paresthesias
4. Ataxia
5. Renal stones
6. Mental slowing with speech and memory disturbance
7. Psychosis
8. Alopecia
9. Weight gain
10. Glaucoma
PART I: What makes nerve cells excitable?
Anticonvulsants: Side-effects
 Which of the following are side-effects of Phenytoin?
1. Blurry vision
2. Metabolic acidosis
3. Paresthesias
4. Ataxia
5. Renal stones
6. Hirsutism
7. Psychosis
8. Osteoporosis
9. Alopecia
10. Weight gain
11. Gum hyperplasia
12. Stevens-Johnson syndrome
13. Blood dyscrasias
PART I: What makes nerve cells excitable?
Anticonvulsants: Side-effects
 Which of the following are side-effects of Phenytoin?
1. Blurry vision
2. Metabolic acidosis
3. Paresthesias
4. Ataxia
5. Renal stones
6. Hirsutism
7. Psychosis
8. Osteoporosis
9. Alopecia
10. Weight gain
11. Gum hyperplasia
12. Stevens-Johnson syndrome
13. Blood dyscrasias
PART I: What makes nerve cells excitable?
Anticonvulsants: Side-effects
 Which of the following are side-effects of Valproic acid?
1. Blurry vision
2. Dysfunctional platelets
3. Paresthesias
4. Ataxia
5. Birth defects
6. Hirsutism
7. Psychosis
8. Abdominal pain and other GI symptoms
9. Alopecia
10. Weight gain
11. Liver failure
12. Stevens-Johnson syndrome
13. Blood dyscrasias
PART I: What makes nerve cells excitable?
Anticonvulsants: Side-effects
 Which of the following are side-effects of Valproic acid?
1. Blurry vision
2. Dysfunctional platelets
3. Paresthesias
4. Ataxia
5. Birth defects
6. Hirsutism
7. Psychosis
8. Abdominal pain and other GI symptoms
9. Alopecia
10. Weight gain
11. Liver failure
12. Stevens-Johnson syndrome
13. Hyperammonemia
PART I: What makes nerve cells excitable?
Anticonvulsants: Side-effects
 Which of the following are side-effects of Carbamazepine?
1.
2.
3.
4.
5.
6.
7.
8.
Ataxia
SJS
Visual field loss
SIADH
Diplopia
Hepatotoxicity
Aplastic anemia
Paresthesias
PART I: What makes nerve cells excitable?
Anticonvulsants: Side-effects
 Which of the following are side-effects of Carbamazepine?
1.
2.
3.
4.
5.
6.
7.
8.
Ataxia
SJS
Visual field loss
SIADH
Diplopia
Hepatotoxicity
Aplastic anemia
Paresthesias
PART I: What makes nerve cells excitable?
Anticonvulsants: Side-effects
 Which of the following anticonvulsants cause peripheral
visual field defects?
1.
2.
3.
4.
5.
6.
Tegretol
Phenobarbital
Vigabatrin
Clobazam
Valproic acid
Dilantin
PART I: What makes nerve cells excitable?
Anticonvulsants: Side-effects
 Which of the following anticonvulsants cause peripheral
visual field defects?
1.
2.
3.
4.
5.
6.
Tegretol
Phenobarbital
Vigabatrin
Clobazam
Valproic acid
Dilantin
Bonus Point: What type of seizures is Vigabatrin used
for?
PART I: What makes nerve cells excitable?
Anticonvulsants: Side-effects
 Which of the following anticonvulsant(s) can be used in
patients with concomitant psychiatric disorders for mood
stabilization?
1.
2.
3.
4.
5.
6.
7.
8.
Levetiracetam
Phenobarbital
Oxcarbazepine
Vigabatrin
Clobazam
Valproic acid
Dilantin
Lamotrigine
PART I: What makes nerve cells excitable?
Anticonvulsants: Side-effects
 Which of the following anticonvulsant(s) can be used in
patients with concomitant psychiatric disorders for mood
stabilization?
1.
2.
3.
4.
5.
6.
7.
8.
Levetiracetam
Phenobarbital
Oxcarbazepine
Vigabatrin
Clobazam
Valproic acid
Dilantin
Lamotrigine
PART I: What makes nerve cells excitable?
Anticonvulsants: Side-effects
 Which of the following anticonvulsant(s) can cause SJS
1. Levetiracetam
2. Phenobarbital
3. Oxcarbazepine
4. Vigabatrin
5. Clobazam
6. Carbamazepine
7. Phenytoin
8. Ethosuximide
9. Valproic acid
10. Felbamate
11. Lamotrigine
12. Lacosamide
PART I: What makes nerve cells excitable?
Anticonvulsants: Side-effects
 Which of the following anticonvulsant(s) can cause SJS
1. Levetiracetam
2. Phenobarbital
3. Oxcarbazepine
4. Vigabatrin
5. Clobazam
6. Carbamazepine
7. Phenytoin
8. Ethosuximide
9. Valproic acid
10. Felbamate
11. Lamotrigine
12. Lacosamide
Anticonvulsants: Side-effects
Continuum (2010)
Which of the following anticonvulsants
need to be monitored and why?
1. Phenytoin
2. Phenobarbital
3. Clobazam
4. Topamax
5. Carbamazepine
6. Oxcarbamazepine
7. Levetiracetam
8. Valproic acid
9. Gabapentin
10. Pregabalin
11. Ethosuximide
12. Lacosamide
13. Vigabatrin
Anticonvulsants
and Pharmacokinetics
PART I: What makes nerve cells excitable?
Anticonvulsants: Pharmacokinetics
 All of the following anticonvulsants are hepatically excreted
except:
1.
2.
3.
4.
5.
6.
7.
8.
Phenobarbital
Oxcarbazepine
Carbamazepine
Phenytoin
Levetiracetam
Valproic acid
Lamotrigine
Lacosamide
PART I: What makes nerve cells excitable?
Anticonvulsants: Pharmacokinetics
 All of the following anticonvulsants are hepatically excreted
except:
1.
2.
3.
4.
5.
6.
7.
8.
Phenobarbital
Oxcarbazepine
Carbamazepine
Phenytoin
Levetiracetam
Valproic acid
Lamotrigine
Lacosamide
Anticonvulsants: Pharmacokinetics
Panayiotopoulos (2010)
PART I: What makes nerve cells excitable?
Anticonvulsants: Pharmacokinetics
 Which of the following antoconvulsants decrease
efficacy of OCP?
1.
2.
3.
4.
5.
6.
7.
8.
Carbamazepine/Oxcarbazepine
Phenobarbital
Valproic acid
Topiramate
Vigabatrin
Phenytoin
Lamictal
Primidone
PART I: What makes nerve cells excitable?
Anticonvulsants: Pharmacokinetics
 Which of the following antoconvulsants decrease
efficacy of OCP?
1.
2.
3.
4.
5.
6.
7.
8.
Carbamazepine/Oxcarbazepine
Phenobarbital
Valproic acid
Topiramate
Vigabatrin
Phenytoin
Lamictal (level decreases with OCP use)
Primidone
http://basic-clinical-pharmacology.net/chapter%2024_%20antiseizure%20drugs.htm
PART I: What makes nerve cells excitable?
Anticonvulsants: Pharmacokinetics
Enzyme-Inducers:
•Increase rate of
metabolism of
drugs metabolized
by CYP enzymes
•Results in changes
in sex hormone
levels and
increases clearance
of estrogen and
progesterone in
OCP
•Increase
metabolism of Vit D
(which is
metabolized by
liver) → rickets and
hypocalcemia in
children
Panayiotopoulos (2010)
PART I: What makes nerve cells excitable?
Anticonvulsants: Pharmacokinetics
 Which of the following anticonvulsants will be increased
with the concomitant use of erythromycin or
clarithromycin?
1.
2.
3.
4.
5.
6.
7.
8.
Carbamazepine
Phenobarbital
Valproic acid
Topiramate
Vigabatrin
Phenytoin
Lamictal
Primidone
PART I: What makes nerve cells excitable?
Anticonvulsants: Pharmacokinetics
 Which of the following anticonvulsants will be increased
with the concomitant use of erythromycin or
clarithromycin?
1.
2.
3.
4.
5.
6.
7.
8.
Carbamazepine
Phenobarbital
Valproic acid
Topiramate
Vigabatrin
Phenytoin
Lamictal
Primidone
PART I: What makes nerve cells excitable?
Anticonvulsants: Pharmacokinetics
 A patient who drinks lots of grapefruit juice presents
with toxic levels of which of the following
anticonvulsants:
1.
2.
3.
4.
5.
6.
7.
8.
Carbamazepine
Phenobarbital
Valproic acid
Topiramate
Vigabatrin
Phenytoin
Lamictal
Primidone
PART I: What makes nerve cells excitable?
Anticonvulsants: Pharmacokinetics
 A patient who drinks lots of grapefruit juice presents
with toxic levels of which of the following
anticonvulsants:
1.
2.
3.
4.
5.
6.
7.
8.
Carbamazepine (grapefruit inhibits CYP3A4)
Phenobarbital
Valproic acid
Topiramate
Vigabatrin
Phenytoin
Lamictal
Primidone
PART I: What makes nerve cells excitable?
Anticonvulsants: Pharmacokinetics
 Anticonvulsants (phenytoin, phenobarbital) can
generally have the following effect on warfarin:
1. Increase warfarin level
2. Decrease warfarin level
PART I: What makes nerve cells excitable?
Anticonvulsants: Pharmacokinetics
 Anticonvulsants (phenytoin, phenobarbital) can
generally have the following effect on warfarin:
1. Increase warfarin level
2. Decrease warfarin level
PART I: What makes nerve cells excitable?
Anticonvulsants: Pharmacokinetics
 The pharmacokinetics of phenytoin can be described
as:
1.
2.
3.
4.
Non-linear
Linear
First-order
Zero-order
PART I: What makes nerve cells excitable?
Anticonvulsants: Pharmacokinetics
 The pharmacokinetics of phenytoin can be described
as:
1.
2.
3.
4.
Non-linear
Linear
First-order
Zero-order
PART I: What makes nerve cells excitable?
Anticonvulsants: Pharmacokinetics
 An ICU patient with multiple medical problems is on IV
dilantin for the treatment of status epilepticus. What lab
variable do you need to order to ascertain the correct
dilantin level?
1.
2.
3.
4.
5.
Liver enzymes
Albumin
CBC
Urea
Ammonia
PART I: What makes nerve cells excitable?
Anticonvulsants: Pharmacokinetics
 An ICU patient with multiple medical problems is on IV
dilantin for the treatment of status epilepticus. What lab
variable do you need to order to ascertain the correct
dilantin level?
1.
2.
3.
4.
5.
Liver enzymes
Albumin
CBC
Urea
Ammonia
Special considerations
PART I: What makes nerve cells excitable?
Anticonvulsants: Special Considerations
 You just diagnosed a 16 year old girl with JME. Which
of the following drugs would you not prescibe?
1. Lamictal
2. Levetiracetam
3. Valproic acid
PART I: What makes nerve cells excitable?
Anticonvulsants: Special Considerations
 You just diagnosed a 16 year old girl with JME. Which
of the following drugs would you not prescibe?
1. Lamictal
2. Levetiracetam
3. Valproic acid
PART I: What makes nerve cells excitable?
Anticonvulsants: Special Considerations
Choosing among
anticonvulsants
Anticonvulsants: Choosing AEDs
 Which of the following are important to consider when
choosing an anticonvulsant
1.
2.
3.
4.
5.
6.
Age
Type of seizure (partial versus generalized)
Patient characteristics
Co-morbid conditions
Cost
Side-effect profile
Anticonvulsants: Choosing AEDs
 Which of the following are important to consider when
choosing an anticonvulsant
1.
2.
3.
4.
5.
6.
Age
Type of seizure (partial versus generalized)
Patient characteristics
Co-morbid conditions
Cost
Side-effect profile
Anticonvulsants: Choosing AEDs
 High-level evidence for the efficacy for initial
monotherapy of partial seizures exists for which of the
following drugs:
1.
2.
3.
4.
5.
6.
7.
Phenytoin
Lamotrigine
Phenobarbital
Carbamazepine
Oxcarbazepine
Topiramate
Valproic acid
Anticonvulsants: Choosing AEDs
 High-level evidence for the efficacy for initial
monotherapy of partial seizures exists for which of the
following drugs:
1.
2.
3.
4.
5.
6.
7.
Phenytoin
Lamotrigine
Phenobarbital
Carbamazepine
Oxcarbazepine
Topiramate
Valproic acid
Anticonvulsants: Choosing AEDs
 High-level evidence for the efficacy for initial
monotherapy of generalized seizures exists for which
of the following drugs:
1.
2.
3.
4.
5.
6.
7.
Phenytoin
Lamotrigine
Phenobarbital
Carbamazepine
Oxcarbazepine
Topiramate
Valproic acid
Anticonvulsants: Choosing AEDs
 High-level evidence for the efficacy for initial
monotherapy of generalized seizures exists for which
of the following drugs:
1.
2.
3.
4.
5.
6.
7.
Phenytoin
Lamotrigine
Phenobarbital
Carbamazepine
Oxcarbazepine
Topiramate
Valproic acid
Anticonvulsants: Choosing AEDs
 8 year old girl with childhood absence epilepsy, your
choice(s) include:
1.
2.
3.
4.
5.
6.
7.
Phenytoin
Ethosuximide
Phenobarbital
Lamictal
Oxcarbazepine
Topiramate
Valproic acid
Anticonvulsants: Choosing AEDs
 8 year old girl with childhood absence epilepsy, your
choice(s) include:
1.
2.
3.
4.
5.
6.
7.
Phenytoin
Ethosuximide
Phenobarbital
Lamictal
Oxcarbazepine
Topiramate
Valproic acid
Anticonvulsants: Choosing AEDs
 16 year old boy with JME, your choice(s) include all of
the following except:
1.
2.
3.
4.
Lamictal
Carbamazepine
Valproic acid
Levetiracetam
Anticonvulsants: Choosing AEDs
 16 year old boy with JME, your choice(s) include all of
the following except:
1.
2.
3.
4.
Lamictal
Carbamazepine
Valproic acid
Levetiracetam
PART I: What makes nerve cells excitable?
Anticonvulsants: Summary
Panayiotopoulos (2010)
OUTLINE
 Approach to a first unprovoked seizure – to treat or not to
treat
 Adult versus Child
 Medical Treatment




What anticonvulsants are available to you
Mechanisms of action
Some important pharmacokinetic properties to keep in mind
Some dos and don’ts
 Surgical Treatment
 Brief overview
 Others
 A few words
Introduction
 Approximately 20% to 30% of all patients with epilepsy
will have physically, socially, and medically refractory
seizure disorders.
 Patients with intractable epilepsy are at increased risk
for serious morbidity and mortality.
Introduction
 The goals of therapy in patients with medically
refractory seizures include:
 significantly reducing seizure tendency.
 avoiding adverse effects.
 permitting the individual to become a participating and
productive member of society.
WHEN TO DECIDE DRUG THERAPY HAS
FAILED
 DRE is now defined as ‘failure of adequate trials of two tolerated,
appropriately chosen and used AED schedules (whether as monotherapy
or in combination) to achieve sustained seizure freedom.
 less than 5% to 10%, who have not responded to monotherapy with two
appropriate antiepileptic drugs (AEDs) or a combination of two drugs will
respond to a third drug.

after treatment with multiple AEDS, 11% and 16% became seizure free. It
is interesting that 52% of patients treated surgically in one of these studies
became seizure free.
Who should be referred for surgery
Surgery outcome
Pre-surgical evaluation
Conclusion
 Epilepsy surgery is highly effective and has durable
benefits, and improves quality of life.
 Despite class I evidence and Clinical Practice
Guidelines, epilepsy surgery remains underutilized.
 The spectrum of patients who may benefit from
epilepsy surgery has expanded considerably including
younger and older patients and those without apparent
MRI lesions.
Electronic Devices
 VNS.
 Direct Cortical Stimulation.
 Responsive Neurostimulation System.
 Stimulation of the Anterior Nucleus of the Thalamus for
Epilepsy Trial.
VNS
 Vagus nerve stimulation(VNS) is an approved
treatment for intractable partial epilepsy.
 A VNS is a palliative procedure that may reduce
seizure tendency.
 In clinical trials, seizure frequency was reduced by 25%
to 30%, an outcome similar to new AED trials.
 Day surgery procedure.
 The left vagus nerve is stimulated rather than the right
because the right plays a role in cardiac function, and
stimulating it could have negative cardiac effects.
 Mechanism : Unknown , affect blood flow to different
parts of the brain and to affect neurotransmitters,
including serotonin and norepinephrine, which are
implicated in depression.
 common side effects include hoarseness, throat pain,
cough, dyspnea and paresthesia.
THE KETOGENIC DIET
 The ketogenic diet was developed before all of the
anticonvulsants in current use except phenobarbital.
 It fell out of favor with the introduction of phenytoin.
 Since 1990 ,the ketogenic diet has resurfaced as it is
often very effective in patients who have failed
numerous drug trials.
 patients on the diet often require lower doses of
anticonvulsants and become more alert and less dizzy.
Description and Mechanism
 The classic diet consists of 4 grams of fat for each
gram of protein and carbohydrate consumed.
 Mechanism : Unknown ,overall changes in brain
protein phosphorylation state and particular examples
of altered gene expression have been documented.
 Early proposals suggesting that cerebral acidosis or
changes in electrolyte concentrations are responsible
for the diet’s anti seizure effects
Efficacy
 The ketogenic diet is a first-line therapy for patients
with seizures associated with certain metabolic
disorders.
 A number of studies have shown the ketogenic diet to
be an effective treatment for medically intractable
epilepsy in children.
 One of the prospective studies included 51 children
from 1 to 8 years of age. At the 12-month follow-up,
10% of the children were seizure free, 22% had a
greater than 90% reduction in seizure frequency, and
40% had a greater than 50% reduction.
 With adolescents , 45 patients aged 12 to 19 years, 20
patients remained on the diet at 1 year. Seven had a
50% to 90% reduction in seizure frequency, while six
had a greater than 90% reduction.
 One recent adult study. This study included 11 adults
between age of 32 -45.
 At 8 months follow-up, three patients had a 90%
decrease in seizure frequency, three patients had a
50% to 89% decrease ,and one patient had a less than
50%decrease. 6 patients discontinued the diet. 2 had
no change in their seizure frequency .
Side Effects and Precaution
 Common adverse effects in adolescent and adult trials
Included constipation, hypercholesterolemia, Menstrual
irregularities, and weight loss.
 Kidney stones occur in 6% to7% of children on the diet.
 Because valproate is an inhibitor of fatty acid oxidation
and decreases hepatic ketogenesis, Valproate is not
recommended.
PART I: What makes nerve cells excitable?
References:

Deckers et al. Conference Report. Current limitations of antiepileptic drug therapy:a
conference review. Epilepsy Research 53 (2003) 1–17.

Joana Guimara˜es, and Jose´ Augusto Mendes Ribeiro. Pharmacology of Antiepileptic
Drugs in Clinical Practice. The Neurologist 2010;16:353–357.

Johannessen SI, Landmark CJ. Antiepileptic drug interactions - principles and clinical
implications. Curr Neuropharmacol. 2010 Sep;8(3):254-67.

Panayiotopoulos CP. A Clinical Guide to Epileptic Syndromes and Their treatment. Second
Edition. 2010.

Continuum. Epilepsy. 2010.

http://basic-clinical-pharmacology.net/chapter%2024_%20antiseizure%20drugs.htm
PART I: What makes nerve cells excitable?
Questions??
Figure 1. Focal seizures result from a limited group of neurons
that fire abnormally because of intrinsic or extrinsic factors.
(a) In this simplified diagram, II and III represent epileptic neurons.
Because of extensive cell-to-cell connections, termed 'recurrent
collaterals', aberrant activity in cells II and III can fire synchronously,
resulting in a prolonged depolarization of the neurons. (b) This
intense depolarization of epileptic neurons is termed the
paroxysmal depolarization shift. The prolonged depolarization
results in action potentials and propagation of electrical discharges to
other cells. The paroxysmal depolarization shift is largely dependent
Anticonvulsants: Voltage-gated Na channels
•Blockade/modulation of Voltage-gated Na channels is the most common mechanism of
action of most of the AEDs
•Bind and stabilize inactive forms of channel → prevent repetitive neuronal firing
CBZ
PHT
VPA
Oxcarbazepine
?
Eslicarbazepine
Felbamate
LTG
Topiramate
Zonisamide
Lacosamide
Rufinamide
Approach to Epilepsy
(When to stop treatment)
•Seizure control is possible for most patients with epilepsy
•In a recent study by Brodie et al. (2012, Neurology)
•69% seizure-freedom over 2 years
•61% seizure-freedom over 5 years
•52% seizure-freedom over 10 years
•After many years of seizure-freedom, patient begin to question whether
therapy is still necessary
•Desire to discontinue medications:
•Side-effects
•Cost
•Inconvenience
•Fear of long-term side-effects
•Risk of recurrence after anticonvulsant discontinuation: 12% to 63% over 2 to
5 years follow-up (majority: 41% or less relapse rate)
Approach to Epilepsy
(When to stop treatment)
Approach to Epilepsy
(When to stop treatment)