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Academic Half-Day Treatment of Epilepsy

Academic Half-Day Treatment of Epilepsy. Ruba Benini & Abdullah Tawakul July 25 th , 2012. Preamble. Epilepsy is the second most common neurological condition after headache Worldwide prevalence of 1% with a cumulative incidence of 2-4%.

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Academic Half-Day Treatment of Epilepsy

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  1. Academic Half-DayTreatment of Epilepsy Ruba Benini & Abdullah Tawakul July 25th , 2012

  2. 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

  3. 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

  4. 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)

  5. 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

  6. 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

  7. 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?

  8. 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?

  9. 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

  10. 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?

  11. Approach to a first Seizure HISTORY! • Is this reallyan epileptic seizure 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?

  12. Approach to a first Seizure • Is this reallyan 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

  13. Approach to a first Seizure • What type of seizure was it? Focal (Partial) Seizures Generalized seizures 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

  14. 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.

  15. 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.

  16. 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

  17. 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.

  18. Approach to a first Seizure • What is the etiology?

  19. 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. Firstunprovoked Seizure Generalized seizure Patient asks if he has epilepsy? Do you treat?

  20. Definitions What is Epilepsy: • Chronic condition characterized by recurrent, usually spontaneous, epileptic seizures • Two or more unprovoked seizures

  21. 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. Firstunprovoked Seizure Generalized seizure Patient asks if he has epilepsy? Do you treat?

  22. 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)

  23. 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

  24. 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

  25. 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

  26. 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 • Glutamatergic excitation • GABAergic transmission Excitation Inhibition

  27. Treatment of Epilepsy(Anticonvulsants)

  28. Treatment of Epilepsy(Anticonvulsants) • Mechanism of action • Important side-effects • Pharmacokinetics • How do you choose the first drug • Special considerations (pregnancy, etc)

  29. Match the following anticonvulsants to their mechanism(s) of action

  30. 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

  31. 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

  32. 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

  33. 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

  34. 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

  35. 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

  36. 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

  37. 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

  38. 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

  39. 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

  40. 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

  41. 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

  42. 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

  43. 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

  44. 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

  45. 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

  46. Summary Panayiotopoulos (2010)

  47. Anticonvulsants: Summary

  48. Anticonvulsants: Summary

  49. Anticonvulsants: Summary

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