What is epilepsy?
A group of neurological disorders marked by sudden and recurrent episodes of sensory disturbance, loss of conciousness or convulsions associated with abnormal electrical activity in the brain
On this pet scan which areas are coloured blue?(temporal lobe epilepsy)
The area of hypo-metabolism between seizures
How long between seizures in epilepsy?
It varies -> they are usually intermittent
What causes the seizures?
Excessive and abnormal cortical nerve cell activity
What 6 things can precipitate seizures?
- altered blood glucose and pH
- stress (going to dentist)
- flashing lights
- no apparent cause
How is epilepsy diagnosed (2)?
- ruling out other conditions that might cause similar symptoms
- confirmation with an electroencephalogram (EEG)
What are the major causes of epilepsy (10)?
- birth and perinatal injuries
- congenital malformations
- genetic (ion channels)
- idiopathic (unknown)
- Vascular insults
- Head trauma
- Severe metabolic disturbances
- drug/alcohol abuse
What is the treatment when seizures are caused by something else i.e. tumours/infection?
Treat the underlying cause
What can epilepsy be confused with in children?
What are the NICE guidelines for epilepsy?
You must have 2 seizures and investigations prior to treatment
What are the two types of epilepsy?
What are the different categories of localised seizures?
Simple (no loss of conciousness)
Complex (impairment of conciousness)
What are the different categories of Generalised seizures (6)?
What is a localised seizure?
It affects a specific region of a single hemisphere- includes psychomotor epilepsy
What % of seizures are accounted for by localised seizures?
What can cause localised seizures?
Cortical lesions (tumours, developmental malformation, damage due to trauma or stroke)
What are generalised seizures?
Discharges from both hemispheres
What % of seizures are accounted for by generalised seizures?
What are generalised seizures often caused by?
What are Absence seizures?
= look like daydreaming
What are Myclonic seizures?
= muscle twitch
What are Tonic clonic seizures?
= muscle convulsions
What are Tonic seizures?
= becoming stiff
What are Atonic seizures?
= drop seizures
What is Status epilepticus?
epileptic fits follow one another without recovery of conciousness between them
What are the two proposed mechanisms of epilepsy?
- Decreased inhibitory synaptic activity (insufficient GABA/ GABA-A receptor not working)
- increased excitatory synaptic activity (too much Glutamate (NMDA, Kainate or AMPA receptor)
What are the 3 proposed mechanisms for partial seizures?
- Selective loss of (inhibitory) interneurones = decreased feed forward/backward inhibiton of dendate gyrus cells
- Injury = synaptic reorganisation (axonal sprouting of remaining neurones) & recurrent excitatory connections
- Loss of excitatory neurones =usually inhibit dendate granule cells
What is an epileptic focus?
A high frequency burst of action potentials
(n.b. this is not a problem but its also not quite right)
How do epileptic foci develop into a seizure?
Hyper-synchronisation of neuronal populations = paroxysmal depolarising shift (PDS) = seizure
What is paroxysmal depolarising shift?
activation of AMPA (excitatory) receptors
-> e.g. by glutamate= NMDA receptor activation = increased intracellular K, accumulating Ca in pre-synaptic terminal (enhanced neurotransmitter release) & depolarisation induced NMDA receptor activation (increased Ca influx)
What follows the PDS and is used to help localise the brain region where seizures originate:
What is epileptigenesis?
The development of epilepsy (e.g. due to trauma)
What are the 3 stages of epileptigenesis?
- normal network becomes hyper-excitable = not working properly
- often a silent period after injury = gradual change of network
- full blown epilepsy
What is the kindling model?
Animal model of epilepsy produced by electrical stimulation= alters glutamate channel properties, increase neuron loss
What is the general seizure mechanism?
Widespread cortical areas
- genetic (e.g. juvenile myoclonic epilepsy = JME)
- idiopathic gene mutations/change in ion channels (Ca, Na, K, Cl) & GABA/ACh gated channels
What is the seizure mechanism for absence seizures?
- spike wave complexes on EEG
- GABA-B receptors, Ca & K channels within thalamus = oscillations
In which % of patients is the current epilepsy therapy are effective?
Which specific type of epilepsy is not well controlled?
How do anti epilepsy drugs work?
They target the symptoms (they do NOT cure epilepsy!)
The ideal anti-epileptic drug should be able to...(4):
-allow normal function (not sedative) so can still work
- low incidence of interactions with other drugs e.g. NSAIDs
What are the two aims of pharmacological intervention in epilepsy?
- Block activity in the focus
- Block spread of activity (no synchronisation)
What are the actions of pharmacological intervention in epilepsy?
- increase inhibitory influences (decrease neuronal firing rates (Na channels) & increase neurotransmitter release (Ca channels))
- decrease excitatory synaptic transmission (decrease glutamate release & decrease glutamate's actions)
What does AED stand for?
How many generations of AED are there?
3 (the first generation was the first discovered etc. etc.)
Name 3 first generation AEDs:
What is the mechanism of action for Phenytoin?
Inhibits voltage gated Na & Ca channels
What is the mechanism of action for Phenobarbitone?
Potentiates GABA at GABA-A receptors
What is the mechanism of Ethosuximide?
Inhibits Ca channels (T-type)
Name 3 second generation AEDs:
What is the mechanism of action of Carbamazepine?
Inhibits Na channels
What is the mechanism of action for Valproate?
- Potentiates GABA at GABA-A receptors
- Inhibits GABA-T, SSA dehydrogenase & Na channels
What is the mechanism of action of Diazepam?
Potentiates GABA at GABA-A receptors
Name 4 third generation AEDs:
What is the mechanism of action of Lamotrigine?
Inhibits Na channel
Inhibits Ca channels
What is the mechanism of action of gabapentin?
Initially synthesised to be a GABA-mimetic
Inhibits voltage-gated Ca channels
Modulates action of GAD
What is the mechanism of action of Vigabatrin?
Inhibition of GABA-T
What is the mechanism of action of Tiagabine?
Inhibits GABA reuptake by blocking the GABA transporter
What is the mechanism of action of Talampenel and Tezampanel?
Which anti-epileptic drug is not used for epilepsy as it does not work in the way expected?
- instead it binds Ca channel subunit = used for neuropathic pain and other disorders= INCREASE INHIBITORY INFLUENCES
Which drugs potentiate GABA at GABA-A receptors (3)?
= INCREASE INHIBITORY INFLUENCES
Which drugs inhibit GABA break down (2)?
& which enzymes do they inhibit?
= vigabatrin & valproate
Inhibit SSA dehydrogenase
= INCREASE INHIBITORY INFLUENCES
Which drugs inhibit GABA reuptake (in both neurones & glial cells)?
Tagabine= INCREASE INHIBITORY INFLUENCES
Which 4 antiepileptic drugs work by blocking volatge-activated sodium channels?
= INCREASE INHIBITORY INFLUENCES
What are the three main conformations of sodium channels?
Which conformation of sodium channels does phenytoin preferentially bind?
Inactive form (once bound it holds the channel in the inactivated form)
How does blocking voltage gated sodium channels are used to treat epilepsy?
Reduces the amplitude of sodium-dependent action potentials
-> has a greater block of rapidly firing neurons (e.g. high frequency firing = stops synchronicity)
= works along side GABA= INCREASE INHIBITORY INFLUENCES
Name three drugs used to treat epilepsy that block voltage gated calcium channels:
How does Ethosuximide work?
Binds T-Type voltage gated Ca channel = low threshold Ca currents = modulates firing patterns of neurons= INCREASE INHIBITORY INFLUENCES
How does Lamotrigine work?
Inhibits voltage sensitive Na and/or Ca channels = modulates glutamate release= INCREASE INHIBITORY INFLUENCES
How does Gabapentin work?
Binds α2δ subunit of Ca channel (prevents trafficking to plasma membrane)= increases synaptic GABA = enhanced GABA response at non-synaptic sites of neuronal tissue & reduces release of mono amine neurotransmitters)= INCREASE INHIBITORY INFLUENCES
Which antiepileptic drugs are used to increase inhibitory influences (10)?
- Benzodiazepines (Diazepam)
Which anti-epileptic drugs are used to reduce Glutamate actions?
AMPA antagonists (talampanel & tezamapanel)
Kainate or NMDA receptor antagonist
What is Glutamate?
Major fast excitatory neurotransmitter
Which neurones does Glutamate act at?
AMPA, kainate & NMDA receptors
Metabotropic glutamate receptors
Which 5 drug treatments are preferred in Partial seizures?
Sodium valproate (often not used as teratogenic)
Which type of epilepsy is poorly treated with current drugs?
Which 5 drug treatments are preferred in General seizures?
- Lamotrigene (not in myclonic)
Which 7 drugs can NOT be used in myoclonic or absence seizures?
Which 2 drug treaments are used to treat status epilepticus/ seixures in children?
Which 3 drug treatments are used to treat absence seizures?
Which 3 drug treatments are used to treat myclonic seizures?
Which 3 antiepileptic drugs can also be used to for migraines and neuropathic pain?
Which antiepileptic drug can also be used for trigeminal neuralgia?
Which 3 antiepileptic drugs can also be used to treat bipolar disorders and anxiety?
2 Key things that should be taken into account with an epileptic patient:
- falls increase risk of dental injuries, soft tissue damage and misalignment of TMJ
- fixed dental replacements (e.g. tooth implants) are recommended to reduce the risk of aspiration
Which dental side effects does Phenytoin have?
Causes gingival hyperplasia in 50% -60% of patients
Which 4 dental side effects does carbamazepine have?
Which dental side effects does sodium valproate have?
reduce blood clotting mechanism
Which dental side effects does phenytoin and phenobarbital have?
Accelerates the excretion and metabolism of Vitamin D = increased risk of fractures (recommend vitamin D + Ca supplements)
Which other drugs affect the metabolism of Carbamazepine, sodium valproate and phenytoin negatively?
NSAIDs and some antifungals (metronidiazole, fluconazole & miconazole)
Which types of local anaesthetic should be used in an epileptic patient?
NO ADDED ADRENALINE!!
e.g. Mepivacain & Articain
Which local anaesthetic possess both proconvulsant & anticonvulsant properties (3)?
High dose opioids