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EPILEPSY
An overview of Pathogenesis and
Pharmacology
Lecture overview
1) Define seizures and epilepsy
2) Aetiology and Pathogenesis – 1st Q&A round
3) Classification- more def...
What is a seizure?
• Spontaneous
• Sustained discharge
• Group of neurons from a focus in the brain
Then, what is Epilepsy?
• An increased tendency(or decreased
threshold) for seizures
• (even if long time separates attack...
Putting it together
• Both definitions on the grounds of :
a) Spontaneous
b) Sustained
c) Discharge
ANYONE can get a seizu...
The concept of the seizure threshold
And putting it in context
• Epilepsy IS common!
• 2% of population in developed countries
suffers from seizures 2, or more...
Aetiology and Pathogenesis
To have a seizure, you need one or more of
these three:
1) INCREASED excitation
2) DECREASED in...
Increased excitation
• Mesial Temporal Sclerosis: An example of a
mechanism that leads to increased excitation
and tempora...
Simply: Death of inhibitory neurons and
sprouting of excitatory fibers from
dentate granule cells= Reverberant
pathway= in...
• (other stuff like kindling + LTP, important as
experimental models but not in your lecture)
Decreased inhibition
• Chandelier cells: A model of what might be
happening.
• They are GABA- ergic inhibitory
• Inhibit c...
Huh?- No 1
Huh?- No 2
• They can inhibit lots of pyramidal neurons at
once
• They inhibit at the axonal initial segment
• Therefore, ...
Intrinsic neuronal hyperexcitability
• Not to do with neurotransmitters
• Not to do with aberrant connections
• Intrinsic ...
Channelopathies
1) NaV gated channels= eg SCN1B mutation,
DECREASED inactivation and ‘slower’ closing
of NaV channels
2) K...
Aetiology- a very condensed list
1) Genetic
2) Developmental
3) Brain trauma/surgery
4) Pyrexia
5) Brain tumours
6) Vascul...
Summary (so far)
Questions?
Classification: Partial Seizures
One area of the cortex only. Can remain focal or can
spread (and become generalised)
Simp...
Generalized Seizures- from midline(eg
thalamus) to everywhere
1) Absence: or petit mal, CHILDHOOD. Stop and
stare. Few sec...
Absence and Tonic-clonic
Other stuff
• Other types of Generalized eg myoclonic,
tonic, akinetic.
• (Febrile convulsions)
• (Photosensitivity and Po...
Status Epilepticus
• Two or more tonic- clonic (usually) one after
the other without regaining consciousness.
• 10-15% mor...
Pharmacology of anticonvulsant drugs
1) Na+ voltage gated channels
2) GABAergic transmission
3) Ca2+ channels
4) Others
Na channel pharmacology
Use- dependence: Block channels in inactive
state and don’t let them ‘rest’ so they cannot
reactiv...
Phenytoin
Plus, enzyme induction, hirsutism, teratogenic
etc etc etc
Carbamazepine
• Microsomal enzyme inducer, ataxia, bone
marrow suppression etc…
Valproate
• USED IN ALL SEIZURE TYPES
• Active on Ca and GABA as well
• Liver toxicity, kinky hair, teratogenic
GABA- ergic
1) May act at the receptor to increase opening
(eg Barbiturates or Benzo’s)
2) May decrease the re-uptake of G...
CaCh
1) Ethosuximide- inhibits T-type channels.
Specific for absence seizure treatment
2) Gabapentin(pregabalin)- inhibits...
Other stuff
1) Levetiracetam- affects SV2A therefore
decreases release of NTs
2) Lamotrigine works on Na and Ca channels
a...
Special considerations
1) First line for TC or partials: Carbamazepine,
Phenytoin, Valproate
2) Absence: Ethosuximide, Val...
Further considerations
1) Contraception: Induce enzymes and reduce
efficacy of OCP
2) Pregnancy: Teratogenicity of most AE...
Surgery
• For a lesion causing epilepsy
• Resection of medial temporal lobe in MTS
• Corpus callosum-ectomy?
• Only for mi...
Questions?
Other treatments
• Vagal nerve stimulation
• Ketogenic diet
• ?Drugs affecting epilleptogenesis and/or
neurodegeneration
Conclusion
1) What is the difference between a seizure and
epilepsy?
2) What is a simple partial seizure?
3) What is a com...
One more time
Epilepsy
Epilepsy
Epilepsy
Epilepsy
Epilepsy
Epilepsy
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Epilepsy

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Epilepsy

  1. 1. EPILEPSY An overview of Pathogenesis and Pharmacology
  2. 2. Lecture overview 1) Define seizures and epilepsy 2) Aetiology and Pathogenesis – 1st Q&A round 3) Classification- more definitions!!! 4) Pharmacology of AEDs- 2nd Q&A round 5) Future treatments 6) Last round of Q&As
  3. 3. What is a seizure? • Spontaneous • Sustained discharge • Group of neurons from a focus in the brain
  4. 4. Then, what is Epilepsy? • An increased tendency(or decreased threshold) for seizures • (even if long time separates attacks)
  5. 5. Putting it together • Both definitions on the grounds of : a) Spontaneous b) Sustained c) Discharge ANYONE can get a seizure, some have epilepsy!
  6. 6. The concept of the seizure threshold
  7. 7. And putting it in context • Epilepsy IS common! • 2% of population in developed countries suffers from seizures 2, or more, times in their lifetime • In 0.5% epilepsy is an active problem • Roughly 250,000 people on AED in the UK
  8. 8. Aetiology and Pathogenesis To have a seizure, you need one or more of these three: 1) INCREASED excitation 2) DECREASED inhibition 3) Intrinsic hyperexcitability (jumpy neurons)
  9. 9. Increased excitation • Mesial Temporal Sclerosis: An example of a mechanism that leads to increased excitation and temporal lobe epilepsy • Specific pattern of neuron loss in the hippocampus
  10. 10. Simply: Death of inhibitory neurons and sprouting of excitatory fibers from dentate granule cells= Reverberant pathway= increased excitation in that focus
  11. 11. • (other stuff like kindling + LTP, important as experimental models but not in your lecture)
  12. 12. Decreased inhibition • Chandelier cells: A model of what might be happening. • They are GABA- ergic inhibitory • Inhibit cortical pyramidal neurons and also control excitability
  13. 13. Huh?- No 1
  14. 14. Huh?- No 2 • They can inhibit lots of pyramidal neurons at once • They inhibit at the axonal initial segment • Therefore, they inhibit where the action potential would have been initiated • Therefore, loss of inhibitory interneurons leads to decreased excitability
  15. 15. Intrinsic neuronal hyperexcitability • Not to do with neurotransmitters • Not to do with aberrant connections • Intrinsic problem= Involves ION CHANNELS • Need to understand action potentials to know how they work • SAY WHAT?
  16. 16. Channelopathies 1) NaV gated channels= eg SCN1B mutation, DECREASED inactivation and ‘slower’ closing of NaV channels 2) K+ channels= eg KCNQ2 mutation leads to ‘faster’ closing of the K+ channels and ‘less’ hyperpolarization 3) Ca2+: Activate at a lower threshold, important in the thalamus.
  17. 17. Aetiology- a very condensed list 1) Genetic 2) Developmental 3) Brain trauma/surgery 4) Pyrexia 5) Brain tumours 6) Vascular- eg stroke or AVM 7) Drugs and drug withdrawal inl alcohol 8) Infection and inflammation- encephalitis, MS 9) Metabolic conditions- uraemia, hypocalcaemia etc 10) Neurodegeneration- AD
  18. 18. Summary (so far)
  19. 19. Questions?
  20. 20. Classification: Partial Seizures One area of the cortex only. Can remain focal or can spread (and become generalised) Simple: Consciousness is not impaired Complex: Consciousness is impaired (usually temporal) (Might have to take a look what’s causing it)
  21. 21. Generalized Seizures- from midline(eg thalamus) to everywhere 1) Absence: or petit mal, CHILDHOOD. Stop and stare. Few seconds. Some twithces in face. May become Tonic- Clonic in adult life. Associated with T-type Ca-channel problems 2) Tonic-clonic: Tonic- LOC, contraction, cyanosis- <1m Clonic- Convulsive movements, incontinence cyanosis 2-4m Coma- Flaccid, regular breathing, colour back
  22. 22. Absence and Tonic-clonic
  23. 23. Other stuff • Other types of Generalized eg myoclonic, tonic, akinetic. • (Febrile convulsions) • (Photosensitivity and Pokemon)
  24. 24. Status Epilepticus • Two or more tonic- clonic (usually) one after the other without regaining consciousness. • 10-15% mortality!!! • A medical emergency
  25. 25. Pharmacology of anticonvulsant drugs 1) Na+ voltage gated channels 2) GABAergic transmission 3) Ca2+ channels 4) Others
  26. 26. Na channel pharmacology Use- dependence: Block channels in inactive state and don’t let them ‘rest’ so they cannot reactivate!
  27. 27. Phenytoin Plus, enzyme induction, hirsutism, teratogenic etc etc etc
  28. 28. Carbamazepine • Microsomal enzyme inducer, ataxia, bone marrow suppression etc…
  29. 29. Valproate • USED IN ALL SEIZURE TYPES • Active on Ca and GABA as well • Liver toxicity, kinky hair, teratogenic
  30. 30. GABA- ergic 1) May act at the receptor to increase opening (eg Barbiturates or Benzo’s) 2) May decrease the re-uptake of GABA from the synapse by inhibiting the transporter GAT-1 (eg Tiagabine) 3) May irreversibly inhibit the breakdown of GABA by GABA transaminase (eg Vigabatrin)
  31. 31. CaCh 1) Ethosuximide- inhibits T-type channels. Specific for absence seizure treatment 2) Gabapentin(pregabalin)- inhibits a specific sub- unit of the CaCh and decreases neurotransmitter release.
  32. 32. Other stuff 1) Levetiracetam- affects SV2A therefore decreases release of NTs 2) Lamotrigine works on Na and Ca channels and therefore decreases NT release
  33. 33. Special considerations 1) First line for TC or partials: Carbamazepine, Phenytoin, Valproate 2) Absence: Ethosuximide, Valproate 3) Status: 1st line is lorazepam (and if it fails phenobarbital) 4) CARBAMAZEPINE AND PHENYTOIN CAN MAKE ABSENCE AND MYOCLONIC SEIZURES WORSE!!!
  34. 34. Further considerations 1) Contraception: Induce enzymes and reduce efficacy of OCP 2) Pregnancy: Teratogenicity of most AEDs. Take folate with them. 3) Also think about driving and social consequences. 4) Use of AEDs in bipolar, anxiety and pain.
  35. 35. Surgery • For a lesion causing epilepsy • Resection of medial temporal lobe in MTS • Corpus callosum-ectomy? • Only for minority of patients!
  36. 36. Questions?
  37. 37. Other treatments • Vagal nerve stimulation • Ketogenic diet • ?Drugs affecting epilleptogenesis and/or neurodegeneration
  38. 38. Conclusion 1) What is the difference between a seizure and epilepsy? 2) What is a simple partial seizure? 3) What is a complex partial seizure? 4) What is status epilepticus? What is the main treatment? 5) Which drugs are 1st line for generalised seizure but can worsen absence seizures?
  39. 39. One more time

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