Epilepsy 2 Flashcards
What is epilepsy?
Epilepsy: A disorder of the CNS characterized by recurrent, sudden, large increases in electrical activity (electrical seizures) that may be localized or generalized.
What percentage of children experience one or more seizures (mostly benign febrile convulsions)?
2-5%
What is the prevelance of ‘active’ epilepsy?
- about 0.5 - 1% of the adult population have ‘active’ epilepsy.
- the prevalence is slightly higher in men than in women.
What is the incidence of epilepsy?
about 0.1% of the total population
The incidence of epilepsy is high in children and also in the elderly.
The symptoms/presentation of the epilepsy will depend on what factors?
- The CNS region(s) in which the electrical seizure occurs.
- Whether the seizure is localized or general.
- If localized initially, whether the seizure then spreads to other regions of the CNS.
When is a seizure referred to as partial, primarily generalized and secondarily generalized?
A seizure is said to be PARTIAL (localized, focal) if the seizure is restricted to a limited region
PRIMARILY GENERALIZED if most of the CNS is involved but no focus can be distinguished
SECONDARILY GENERALIZED if most of the CNS is involved eventually but the excitation has spread from an initial focus
What determines whether a partial seizure is described as simple or complex?
A partial seizure is said to be SIMPLE if the subject remains conscious and aware
COMPLEX if consciousness is impaired.
What is an ‘aura’?
Siezures are frequently preceded by an ‘aura’: a feeling or experience that warns the subject of an impending seizure.
What is an absence seizure (old name: petit mal)?
- A primarily generalized seizure that is common in children
- Characterised by sudden loss of awareness lasting up to about 30 sec.
What is a Tonic-clonic seizure (old name: grand mal)?
A generalized seizure lasting 2 - 5 minutes
- characterized by sudden stiffening (‘tonic’) of muscles, a fall, followed by jerking (‘clonic’) movements.
What is a simple partial seizure?
- Simple partial seizure (old name of this example: Jacksonian).
- An example would be a focal cortical seizure characterized by jerking movements that begin in the extremities and spread throughout the body (Jacksonian march)
May be sensory symptoms rather than motor
What is Temporal lobe epilepsy?
- also known as psychomotor epilepsy.
- A partial seizure of the temporal lobe that may be a simple partial seizure characterized by emotional sensory or memory related phenomena or a complex partial seizure where the seizure spreads throughout the temporal lobe impairing consciousness and may be secondarily generalized to provoke a tonic-clonic seizure. This is the commonest form of epilepsy
What is status epilepticus?
When a seizure does not spontaneously stop but continues or repeats for a period of 30 min or more the condition is termed status epilepticus and is life-threatening.
What are epilepsy syndromes?
Epilepsies, especially childhood epilepsies, can sometimes, further classified as ‘syndromes’ which are collections of signs and symptoms that more closely identify the particular conditions. Better definition helps to achieve the optimum therapeutic approach definition helps to achieve the optimum therapeutic approach.
Factors that are considered on defining a syndrome include the type and pattern of seizures their frequency the location of seizures, their frequency, the location of the focus, physical and mental symptoms, the age of onset and gender of the patient and prognosis.
There are at least 40 identified epilepsy syndromes.
What are the causes of epilepsy?
- most cases not known (idiopathic) or cannot be proven (cryptogenic).
About 30% of cases are symptomatic i.e. the seizures occur following:
- head injury (often after a delay)
- stroke
- infection
- tumour growth
- drug abuse.
- 2-3 fold increase in the chances of developing epilepsy if you have a close relative who suffers from the disease but clear genetic links have been difficult to trace suggesting multiple genes or environmental factors are involved.
- ‘Benign febrile epilepsy’ is linked to mutations in KCNQ2 and KCNQ3: genes that encode voltage gated potassium KCNQ3: genes that encode voltage-gated potassium channels.
- Familial generalized epilepsy with febrile seizures plus is linked to mutations in SCN1B, a gene that encodes an accessory subunit of the voltage-gated sodium channel.
Drug-induced: many drugs have pro-convulsant effects.
What animal models are used in epilepsy research?
- Kainic acid (KA) injection.
- Local (e.g. intrahippocampal) or systemic injections of KA can induce seizures in animals and lead to chronic epileptic behaviour. - Kindling.
- Repeated low intensity electrical stimulation (usually in the amydgala or hippocampus) of some brain regions leads after a delay, to development of chronic epileptic behaviour. The frequency of the kindling stimulus is critical.
Studies using these (and many other: pentylenetetrazol injection; electroshock) models suggest that the focal synchronous excitation that occurs to initiate a seizure involves (a) increased synaptic transmission and (b) decreased surround inhibition.
What is the cellular event that initiates a focal seizure?
paroxysmal depolarizing shift (PDS).
Upon what do the rise and curtailment of depolarisation in the PDS depend?
The rise (depolarizing phase) of the cellular PDS depends on: - activation of ionotropic glu receptors (AMPA and NMDA) - opening of voltage gated Ca2+ channels.
Curtailment of the PDS and repolarization depends on:
- opening of voltage-gated K+ channels
- activation of ionotropic GABA receptors
What causes a paroxysmal depolarising shift (PDS)?
The mechanism by which the PDS is initiated is not known but the ability of the PDS to spread to neighboring cells to generate a synchronous focus implies a failure of inhibitory feedback through local interneurons focus implies a failure of inhibitory feedback through local interneurons. (Poor surround inhibition)
Epilepsy is often described as being due to an “imbalance” between glutamate mediated excitation and GABA mediated inhibition which has led to attempts to develop drugs that inhibit glutamate or enhance GABA as potential therapeutic agents.
What are the differences in nervous transmission when surround inhibition is present or not present?
No surround inhibition:
- diverging synaptic connections of neurones in a ‘relay’ nucleus can lead to spreading as well as blending of information flowing out
Surround inhibition present:
‘surround inhibition’ mediated by interneurons through feedback pathways has the effect of limiting spread of the ‘input’ signalling i.e. it has a focusing effect.
surround inhibition will localize discharges (e.g. due to PDS) and prevent their spread but reduction or loss of surround inhibition will allow spread of excitation.
What drugs which enhance the activity of GABAergic systems do we use or tonic-clonic, partial, temporal lobe seizures – may provoke absences?
Benzodiazepines (e.g. diazepam, clonazepam)
- enhance the activity of GABA.
- bind to a regulatory site on the GABA receptor
- increase the affinity of the receptor for GABA.
Barbiturates (phenobarbitone)
- prolong the time that GABA-activated Cl channels stay open when the GABA receptor is occupied.
Vigabatrin
- inhibits GABA transaminase (decreases metabolism of GABA).
Tiagabin
- inhibits GABA uptake (increases the concentration of GABA in the extracellular space)
Benzodiazepines are given intravenously to treat status epiliepticus but are usually too sedative for prophylactic use in other epilepsies although oral BDZs are used sometimes in patients who do not respond well to other treatments.
What drugs which involve Use-dependent block of voltage-gated sodium channels do we use or tonic-clonic, partial, temporal lobe seizures – may provoke absences?
Carbamazepine, phenytoin, lacosamide:
These drugs will reduce the likelihood of action potentials firing g p g at high frequencies but have relatively little effect at low frequencies. (Increase refractory period?)
Their binding (and hence blocking action) to the voltage-gated sodium channels is state-dependent.
(Use-dependent blockers of sodium channels bind to and stabilize the inactivated state of the channel which increases the refractoriness of the cell and limits the maximum frequency at which the cell can fire. Some drugs may also have affinity for the open state of the channel and combine an open-channel blocking action with prolongation of inactivation.)
Which drug is used to treat absense seizures only?
Ethosuximide:
- Mechanism uncertain.
- Thought to work by blocking T-type voltage-gated Ca2+ channels in thalamic neurons.
- These channels are important for the generation of rhythmic activity in the neurones.
- Not useful for tonic-clonic seizures
Which drugs are useful for both tonic-clonic and absence seizures?
Lamotrigine:
- Use-dependent blocker of sodium channels.
Sodium valproate
- Mechanism uncertain.
- Combines a weak blocking action on voltage-gated sodium channels with a weak inhibition of GABA transaminase.
How do Gabapentin and pregabalin work?
Mechanism is uncertain but the molecular target is known to be the alpha2delta-subunit of voltage-gated Ca2+ channels so they probably work by compromising neurotransmitter release.
How does Retigabine (Ezogabine in USA) work?
Acts by provoking the opening of K+ channels of the KCNQ type so the anticonvulsant effect is probably due to stabilization of the resting membrane potential of neurones.
How does Perampanel (approved in EU not USA @2012, felbamate) work?
Thought to act as antagonists of AMPA receptors (ionotropic glutamate receptors).
How do Levetiracetam, topiramate and zonisamide work?
Mechanism(s) uncertain - levetiracetam binds to a synaptic
vesicle protein called SV2A so it may affect neurotransmission.
How do you know what drug to give in epilepsy?
The usefulness of individual agents for different epileptic conditions is varied and based on clinical experience
- general rules are difficult to define or apply.
Many drugs are useful given alone (monotherapy e.g. carbamazepine, phenobarbitone, ethosuximide, sodium valproate, topiramate) whilst others are recommended for adjunctive therapy (e.g. tiagabine, vigabatrine, gabapentin, retigabine).
Drugs that are useful for tonic clonic seizures are not always useful for absence seizures and may even make them worse (carbamazepine, phenobarbitone, phenytion). Conversely, ethosuximide is useful for absence seizures but is not effective for tonic-clonic seizures. Sodium valproate and lamotrigine are potentially useful for both classes of seizure.
Monitoring dose and the potential for drug interactions is very important
What role might kerogen if diet play in epilepsy treatment?
It is argued that a high fat, low carbohydrate diet (normal protein) is beneficial for the control of epileptic seizures in children (at least). Sometimes used when conventional therap is not sufficiently effective.
What is the role of vagus nerve stimulation (VNS) in the treatment of epilepsy and how is it though to work?
A surgically implanted device stimulates the vagus nerve by applying regular electrical stimuli. The device can also be activated by a magnet to deliver a predefined program of stimuli to abort an ongoing or impending attack. The device is effective but the mechanism by which it works is not known.
- thought to be by NA release through brain from locus sorelius
What role can surgery play in the treatment of epilepsy?
Removal of tissue that harbours a recurrent focus or to limit spread of excitation.
(Only if all else fails
- may even cut corpus callosum to localise the focus.)
