W19 Epilepsy Flashcards
What is epilepsy?
- Anyone can have an isolated seizure – this is NOT the same as having epilepsy
- Epileptic seizures occur when ordinary brain activity is disrupted spontaneously and recurrently
What is the definition of a seizure?
“A transient paroxysm of uncontrolled discharges, beginning at the epileptic focus, causing an event which is discernible* by the person experiencing the seizure and/or an observer”
*able to be seen or understood
Prognosis of Epilepsy:
(chance of treatment success)
- Good
- 70-80% of patients become seizure-free
- About 50% successfully withdraw their medication
- 20-30% have chronic epilepsy
- Usually normal function between seizures
- 5% will not be able to live alone
Mortality in Epilepsy:
Increased by?
- Increased by 2-3 times due to:
- Accidents
- Status epilepticus
- Tumours
- Cerebrovascular disease
- Pneumonia
- Suicide
(SUDEP – sudden unexpected death in epilepsy)
Causes of Epilepsy? (7)
*Cause now identified in ~50% of people globally
*Most common defined causes:
–cerebrovascular disease
–cerebrovascular tumours
–genetic, congenital, or hereditary conditions
–alcohol
–drugs and toxic causes
–head trauma (including neurosurgery)
–post-infective causes (encephalitis/meningitis)
What are the risk factors for Seizures? (9)
*Disturbed levels of water/electrolytes
*Disturbed levels of blood glucose
*Altered blood gases
*Raised body temperature
*Altered sleep patterns
*Hormonal disturbance
*Toxicity
*Heredity
*Tumours
How is epilepsy diagnosed?
- Difficult
- Unpredictable and transient
- Need a reliable account
- Use of EEG, MRI and/or CT
– not conclusive alone - Seizures MUST be recurrent and spontaneous
- EEG records abnormal electrical discharges
- Has limitations
– 5% of people without epilepsy have abnormal EEG
– 40% of people with epilepsy have normal EEG between attacks
Features of Epilepsy:
- Sudden, excessive high frequency neuronal discharge
- Highly synchronous discharges- Not random
- A disorder of the cerebral cortex
- May be loss of consciousness
- Behavioural changes related to site of discharge (focus)
What is an EEG?
What are some other imaging techniques?
Electro-EncephaloGraphy (EEG)
Electroencephalogram - EEG
* Records the activity of populations
(many thousands) of neurones
* reveals synchrony of neuronal activity
- MEG (Magnetoencephalography)
- PET (Positron emission tomography)
- MRI / fMR
Seizure Types
what is it based on?
2 main groups:
- Based on the description of events and EEG
- Classified according to the international scheme:
1. Generalised- whole brain
2. Focal (previously referred to as “partial”)
-involves small part of brain
What are the different types of generalised seizures? (6)
Absence
Tonic-Clonic
Myoclonic
Clonic
Tonic
Atonic
Generalised Seizures
1. Tonic-clonic Convulsions (Grand Mal)
What are the features?
*Most common form
*Patient stiffens, falls and convulses
*Laboured breathing, hyper-salivation
*Cyanosis, tongue biting and incontinence
*Lasts a few minutes
*Followed by headache and drowsiness
Generalised Seizures
Tonic and Clonic seizures:
What are the features of tonic?
What are the features of clonic?
Tonic seizures
* stiffening of body – head, trunk +/- limbs
Clonic seizures
* rhythmic, motor, jerking movements
* +/- impairment of consciousness
* simultaneous involvement of arms and legs
Generalised Seizures
4. Absence Attacks (Petit Mal)
What are the features?
- Rarer; almost exclusively in childhood and early adolescence
- Goes blank, stares, eyelids flutter, head flops
- Last a few seconds
- Child may not be aware of it
Generalised Seizures (5)
Describe a Myoclonic Seizure? (Abrupt)
- Abrupt, brief, involuntary, shock-like jerks
- Involve head, limbs or whole body
- Recovery immediate
- Not always epilepsy
Generalised Seizures
6. Atonic Seizures
- Sudden loss of muscle tone
- Quick recovery
- Very rare
Focal Seizures (also sometimes called Partial Seizures)
1. Simple Focal/Focal Aware Seizures (retains awareness)
What are the Features? (5)
abnormal discharge?
- Abnormal discharge remains localised
- Consciousness not impaired
- What happens depends on area of the brain
- Will vary from person to person
- Will be the same each time in each person
Focal Seizures
Complex Focal/Focal Altered-awareness Seizures (altered awareness)
Features?
- ‘automatic’ behaviours
- confusion
- apparent drunkeness
Focal Seizures:
Secondarily Generalised Seizures
- Simple or complex focal seizures
– then spread to the whole brain
– leads to tonic-clonic attack - May be a warning ‘aura’
– symptoms of the partial seizure
What is Status epilepticus?
- Serious uncontrolled seizure
- Convulsive (tonic-clonic) status epilepticus
- A tonic-clonic seizure lasts for 5 minutes or more, or
- One tonic-clonic seizure follows another without the person regaining consciousness in between
Which areas do seizures arise in the brain?
- Anywhere
- subcortical rare (thalamus: absence)
- mostly cortical
– frontal, parietal, occipital, temporal -
Temporal most prevalent - 30-40%
– Hippocampus, entorhinal cortex,
amygdala
– Most common seizures that are drug refractory
– Surgical resection
Imaging in epilepsy: Susceptible regions and levels of activity
what do PET,MRI and fMRI scans monitor?
MRI- Hippocampus is larger on LHS and smaller on RHS
* PET – monitors local metabolism
* MRI – structure and volume
* fMRI – relates activity to structure
How do seizures arise?
*Cortical activity - dynamic balance between inhibition and excitation
Two levels of control
*Intrinsic or level of individual cell: determined by ion channels (in neurons)
* At a Network level- controlled by synaptic
transmission
Disturbed balance - excessive synchrony and epilepsy
* INC excitation, normal inhibition
* DEC inhibition, normal excitation
* DEC inhibition, INC excitation
WHAT IS THE MAIN CNS…
EXCITATORY NEUROTRANSMITTER?
INHIBITORY NEUROTRANSMITTER?
Glutamate
GABA
Synaptic and cellular factors can initiate and prolong a seizure:
What are these? (4)
Sub-threshold voltage gated Na+ channels
Voltage gated Ca++ channel
NMDA
Glutamate receptors AMPA
Synaptic balance:
What are the roles of excitatory and inhibitory neurones?
- Excitatory neurones recurrently excite each other
- Excitatory recurrently excite inhibitory neurones
- Inhibitory neurones recurrently control excitation
- Loss of inhibition can lead to epilepsy
How do seizures stop (without intervention)? (4)
[Pharmacology]
*Na+ channel inactivation
* K+ channel activation
* Glutamate receptor desensitization
* Glutamate depletion
The pharmacological treatment of epilepsy:
Goal of treatment?
- Antiepileptic drugs (AEDs)/anti-seizure medicines (ASMs) decrease the frequency and/or severity of seizures in people with epilepsy
- Treat the symptoms not the condition
- Goal: maximise quality of life by minimising seizures and adverse drug effects
Mechanism of action of anti-epileptics?
- Antiepileptic drugs inhibit abnormal
neuronal discharge in epilepsy but do not resolve the underlying cause (antiepileptic but not antiepileptogenic!)
Epileptogenetic= brain transforms into long lasting state in which recurrent, spontaneous seizures occur.
How do we treat epilepsy? (3)
(pharmacological mechanisms)
- Block destabilizing (depolarizing) currents (1)
- Increase stabilizing currents (hyperpolarizing)
- Reduce synaptic excitation
- Block glutamate release (2)
- Block glutamate receptors
- Increase synaptic inhibition (3)
- Increase GABA release
- Potentiate GABA receptor
Bold: most common approaches
Main Mechanisms of AEDs? (summary)
excitatory mechanisms? (3)
Decrease excitatory mechanisms
* Inhibition of sodium channel function (1)
* Inhibition of calcium channel function (1)
* Directly inhibit glutamate neurotransmission (2)
Increase inhibitory brain mechanisms
* Enhancement of GABA action (3)
Many AEDs are pleiotropic – multiple modes of action
Reducing excitability: Inhibition of
sodium channels
- Many anti-epileptic drugs block voltage-dependent sodium channels to reduce cell membrane excitability
- Their blocking action is use-dependent
- This allows the drugs to preferentially block the excitation of cells that are firing repetitively, so can block the high-frequency discharge that occurs in an epileptic fit, without interfering with the low-frequency firing when neurons are in the normal state
3 states: Closed, Open and Inactivated
Blocking voltage gated Na-channels:
What are the CNS Drugs that block Na-channels? (4)
phenytoin (++)
carbamazepine (++)
lamotrigine (++)
sodium valproate (+)
What is meant by drugs that have a
‘Use-dependent blocking action’?
- Depolarisation of a neuron increases the proportion of sodium channels in an inactivated state
- The drugs bind preferentially to the inactivated state of sodium channels, preventing them from returning to the resting state
- This reduces the number of sodium channels available to generate action potentials
Blocking voltage gated Ca-channels
Drugs that block Ca-channels
ethosuximide (++)
gabapentin
phenytoin (?)
Blocking glutamate release
What is the rule?
Drugs that reduce glutamate release?
Drugs that block Na and Ca channels will
block glutamate release.
* Na-channel block
-phenytoin (++)
-carbamazepine (++)
-lamotrigine (++)
-sodium valproate (+)
* Ca-channel block
-gabapentin
-pregabalin
* Reducing vesicle fusion
-levetiracetam
How might we regulate GABA transmission? (3)
- Inhibition of GABA breakdown: increase GABA levels/ increase release
- Reuptake inhibition: decrease GABA inactivation
- Activation/regulate the GABA receptor
Drugs acting at GABA synapses:
Which drugs:
Increase GABA levels? (2) MoA?
Decrease GABA inactivation? MoA?
Enhance postsynaptic response? MoA?
Increase GABA levels
* vigabatrin (++)
* sodium valproate (+)
=GABA transaminase inhibitor blocks GABA breakdown
= increases GABA levels
= increases GABA release
Decrease GABA inactivation
=tiagabine
=Blocks GABA reuptake increases GABA in cleft
Enhance postsynaptic response
=benzodiazepines
=barbiturates
=prolong channel open time
Alternative anticonvulsants? (3)
1.felbamate
blocks NMDA receptors
2.topiramate
blocks AMPA/kainate receptors
3.retigabine
activates K-currents
Carbamazepine must be prescribed by Brand
=Category 1
Epilepsy
What are the Non-drug Treatments? (4)
Surgery
Vagus Nerve Stimulation (VNS)
Deep Brain Stimulation (DBS)
Ketogenic Diets (various types)
(Epilepsy- Non-drug Treatments)
What are the different surgeries? (4)
- Resection
– removes damaged area of brain - Multiple subpial transection
– separates damaged area from rest of brain - Corpus callosotomy
– separates the two hemispheres of the brain - Hemispherectcomy
– removes outer layer of one hemisphere
Non-pharmacological treatments –
What is Vagus Nerve Stimulation? (VNS)
- Stimulation with a pacemaker-type device
- May intercept abnormal brain activity
Non-pharmacological treatments –
Deep Brain Stimulation (DBS)
stimulates area of brain where seizures originate
Non-pharmacological treatments –
Ketogenic Diets (various types)
What is the effect as it allows the brain to do what?
- very high fat diet
- alters metabolism in the brain
- brain forced to use ketones for energy rather than
glucose (and increased presence of decanoic acid
thought to be a factor) - must be medically supervised
Epilepsy in Pregnancy
Pre-conception
- folic acid supplementation
- specialist advice essential
discontinue therapy?
change drug?
Change to m/r if not already taking?
Establish seizure control with the lowest possible dose of a single drug?
