1. EPILEPSY
An overview of Pathogenesis and
Pharmacology

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. What is a seizure?
• Spontaneous
• Sustained discharge
• Group of neurons from a focus in the brain

4. Then, what is Epilepsy?
• An increased tendency(or decreased
threshold) for seizures
• (even if long time separates attacks)

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. The concept of the seizure threshold

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. 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)

10. 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

11. Simply: Death of inhibitory neurons and
sprouting of excitatory fibers from
dentate granule cells= Reverberant
pathway= increased excitation in that
focus

12. • (other stuff like kindling + LTP, important as
experimental models but not in your lecture)

13. Decreased inhibition
• Chandelier cells: A model of what might be
happening.
• They are GABA- ergic inhibitory
• Inhibit cortical pyramidal neurons and also
control excitability

14. Huh?- No 1

15. 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

16. 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?

19. 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.

20. 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

21. Summary (so far)

22. Questions?

23. 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)

26. 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

27. Absence and Tonic-clonic

28. Other stuff
• Other types of Generalized eg myoclonic,
tonic, akinetic.
• (Febrile convulsions)
• (Photosensitivity and Pokemon)

29. Status Epilepticus
• Two or more tonic- clonic (usually) one after
the other without regaining consciousness.
• 10-15% mortality!!!
• A medical emergency

31. Pharmacology of anticonvulsant drugs
1) Na+ voltage gated channels
2) GABAergic transmission
3) Ca2+ channels
4) Others

32. Na channel pharmacology
Use- dependence: Block channels in inactive
state and don’t let them ‘rest’ so they cannot
reactivate!

33. Phenytoin
Plus, enzyme induction, hirsutism, teratogenic
etc etc etc

34. Carbamazepine
• Microsomal enzyme inducer, ataxia, bone
marrow suppression etc…

35. Valproate
• USED IN ALL SEIZURE TYPES
• Active on Ca and GABA as well
• Liver toxicity, kinky hair, teratogenic

36. 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)

37. 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.

38. Other stuff
1) Levetiracetam- affects SV2A therefore
decreases release of NTs
2) Lamotrigine works on Na and Ca channels
and therefore decreases NT release

39. 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!!!

40. 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.

41. Surgery
• For a lesion causing epilepsy
• Resection of medial temporal lobe in MTS
• Corpus callosum-ectomy?
• Only for minority of patients!

42. Questions?

43. Other treatments
• Vagal nerve stimulation
• Ketogenic diet
• ?Drugs affecting epilleptogenesis and/or
neurodegeneration

44. 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?

45. One more time