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