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EPILEPSY
An overview of Pathogenesis and Pharmacology
Lecture overview
1) Define seizures and epilepsy2) Aetiology and Pathogenesis – 1st Q&A round3) Classification- more definitions!!!4) Pharmacology of AEDs- 2nd Q&A round5) Future treatments6) Last round of Q&As
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 attacks)
Putting it together
• Both definitions on the grounds of :a) Spontaneousb) Sustained c) Discharge
ANYONE can get a seizure, some have epilepsy!
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, times in their lifetime
• In 0.5% epilepsy is an active problem• Roughly 250,000 people on AED in the UK
Aetiology and Pathogenesis
To have a seizure, you need one or more of these three:1) INCREASED excitation2) DECREASED inhibition3) Intrinsic hyperexcitability (jumpy neurons)
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
Simply: Death of inhibitory neurons and sprouting of excitatory fibers from dentate granule cells= Reverberant pathway= increased excitation in that focus
• (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 cortical pyramidal neurons and also
control excitability
Huh?- No 1
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
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?
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.
Aetiology- a very condensed list
1) Genetic2) Developmental 3) Brain trauma/surgery4) Pyrexia5) Brain tumours6) Vascular- eg stroke or AVM7) Drugs and drug withdrawal inl alcohol8) Infection and inflammation- encephalitis, MS9) Metabolic conditions- uraemia, hypocalcaemia etc10) Neurodegeneration- AD
Summary (so far)
Questions?
Classification: Partial Seizures
One area of the cortex only. Can remain focal or can spread (and become generalised)
Simple: Consciousness is not impairedComplex: Consciousness is impaired (usually temporal)
(Might have to take a look what’s causing it)
Generalized Seizures- from midline(eg thalamus) to everywhere
1) Absence: or petit mal, CHILDHOOD. Stop and stare. Few seconds. Some twithces in face.
ÞMay become Tonic- Clonic in adult life. ÞAssociated with T-type Ca-channel problems
2) Tonic-clonic:ÞTonic- LOC, contraction, cyanosis- <1mÞClonic- Convulsive movements, incontinence cyanosis 2-4m
ÞComa- Flaccid, regular breathing, colour back
Absence and Tonic-clonic
Other stuff
• Other types of Generalized eg myoclonic, tonic, akinetic.
• (Febrile convulsions)
• (Photosensitivity and Pokemon)
Status Epilepticus
• Two or more tonic- clonic (usually) one after the other without regaining consciousness.
• 10-15% mortality!!!• A medical emergency
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 reactivate!
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 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)
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.
Other stuff
1) Levetiracetam- affects SV2A therefore decreases release of NTs
2) Lamotrigine works on Na and Ca channels and therefore decreases NT release
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!!!
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.
Surgery
• For a lesion causing epilepsy• Resection of medial temporal lobe in MTS• Corpus callosum-ectomy?• Only for minority of patients!
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 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?
One more time