Seizures and epilepsy symposium Flashcards
Definition of epilepsy
- Is defined as recurring, unprovoked(spontaneous) seizures
What are acute symptomatic seizures provoked by
Acute insults such as
- Stroke
- alcohol withdrawal
- Metabolic disturbance
What are most cases of epilepsy caused by?
- Idiopathic causes
What is a generalised onset seizure?
- Electrical discharges appear to start over the whole brain at the same time on EEG
What is a partial/focal onset seizure
- Electrical discharge appears to start in one cortical region and then may remain localised or spread over the whole brain - secondary generalised
How are seizures classified
- Idiopathic (Primary) Generalized Seizures • limited repertoire of seizures • tonic-clonic seizures (“grand mal”) • absences (“petit mal”) • tonic seizures • atonic seizures myoclonic seizures
Features of an idiopathic generalised seizure
- onset in childhood or adolescence
- usually no focal symptoms/signs
- often a number of seizure types cluster
- a polygenic cause is presumed with no identifiable structural lesion on imaging
- generalized (all leads) spike and wave discharges on EEG, photosensitivity may be present
Features of a juvenile myoclonic epilepsy
- 3-12% all epilepsy
- juvenile onset, probably lifelong
- early morning myoclonic jerks (ask)
- photosensitive, sleep deprivation triggers
- +/- absences
- generalized tonic clonic seizures –
- occur without warning
Features of tonic clonic seizures ‘grand mal’
occurs without warning –risk of injury tonic phase • continuous muscle spasm, fall, cyanosis, tongue biting, incontinence clonic phase • rhythmic jerking slows and gets larger in amplitude as attack ends post-ictal (post-seizure) phase • coma, drowsiness, confusion, headache • muscle aching
Features of absences - petit mal
- abrupt
- short, 5-20 seconds
- multiple times/day, can lead to learning difficulties
- unresponsive, amnesia for the gap, rapid recovery
- tone preserved (or mildly reduced)
- eyelid flickering
- absences only, tend to remit in adulthood (childhood absence epilepsy)
What are absences characterised by on an EEG
- A 3 Hz spike and wave
What are the different types of partial seizures - focal onset seizures
- simple partial seizure (SPS)– patient aware - aura
- complex partial seizure (CPS) – aura/warning with a level of reduced awareness
- (patients may call these “absences”, “blanks” – this is medically inaccurate terminology)
- can be secondary generalized- patient may experience a prior warning, either SPS, CPS, or both, before the tonic clonic seizure
Features of secondary generalised tonic clonic seizures(GTCS)
- warning/aura –eg epigastric rising sensation, altered smell, déjà vu, fear
- cannot abort attack
- onset sudden
- duration 1-3 minutes
- then falls , loses consciousness as seizure generalizes
- rigidity/ convulsive jerks/ excess salivation
- incontinence/tongue bite common
- red/blue, wakes in ambulance/A&E
Where do most partial seizures occur and what percentage approx
- Temporal 70%
second most frequent frontal at 25%
What are the psychological symptoms of temporal lobe epilepsy
- Deja vu
- speech arrest(dominant hemisphere)
- formed words during the seizure implies non-dominant hemisphere focus
- Fear, elation, depression, anger
Physical symptoms of temporal lobe epilepsy
- hallucination of taste, speech and/or smell, visual distortion
- Epigastric rising sensation
- Pallor/flushing/heart rate changes(can mimic panic/hyperventilation attacks)
- Automatisms - semi-purposeful movements
- Oral - lip smacking, chewing movements
- Dystonic posturing(limb rises)
How long do frontal lobe seizures last for on avg
10-30 secs
- Rapid recovery, frequent predominantly nocturnal
Features of a frontal lobe seizure
- Forced head/eye deviation to contralateral side
- Motor activity often bizarre, thrashing
- Often misdiagnosed as non-epileptic
- EEG(during the seizure) is often normal
- Jacksonian spread with todd’s paresis
- Automatisms, dystonic posturing(overlap TLE)
Symptoms of parietal epilepsy
- Positive sensory symptoms(unlike TIA/stroke)
- Tingling, pain
- Distortion of body shape/image
- Jacksonian march of positive sensory symptoms
What anti-epileptic drugs can make myoclonic jerks and absences worse
phenytoin, carbamazepine, gabapentin, pregabalin
• (although all treat tonic clonic seizures so safe to use in status epilepticus)
• some syndromes remit, and some don’t, correct advice to patient re medication
Which seizure patients should you prioritise scanning
- Jacksonian motor or sensory seizure are priority as they have a focal neurological deficity
- Alcohol withdrawal seizure should only be scanned if subdural hematoma suspected
What is epileptogenesis
- Process by which parts of the normal brain are converted to a hyperexcitable brain
Physiological definition of a seizure
- An explosion of synchronous activity by lots of neurons at once that has a tendency to spread throughout the cerebral cortex causing an ‘electrical brain-storm’
- A brief change in behaviour caused by the synchronous and rhythmic firing of action potentials by populations of neurons in the CNS
What is epilepsy as a result of?
- A single neuron can fire a train(or trains) of action potentials spontaneously, without any external stimulation(intrinsic excitability)
- Stimulation of any one cell can lead to a chain reaction due to the progressive spread of activity over a large area
- Epilepsy represents a failure of inhibitory regulation, either focally(eg motor cortex, temporal cortex) or generally(whole cortex at once)
Link between Na+ channel inactivation and epilepsy
- Na+ channel inactivation too slow
- eg generalised epilepsy with febrile seizures(fever-induced convulsions in infants or small children)
- Point mutation in part of Na+ channel(beta subunit) –> abnormally slow inactivation
- Action potential repolarization impaired
Link between number of functional K+ channels and epilepsy
eg. benign familial neonatal convulsions
- defect in KCNQ2 or KCNQ3 k+ channel subunit(K+ channels are tetramers of 4 alpha subunits) –> impaired activation
- Action potential repolarization impaired
When are the largest potentials recorded in an EEG
- Paradoxically, the largest potentials are recorded when the brain is at rest
- When left alone and without sensory inputs the various neural networks feedback upon themselves, leading to rhythmic oscillations
What is seen in an EEG when aroused
- Neuronal activity becomes desynchronised
- The hyperexcitation of seizure again to synchronous activity on the EEG
- EEG can help with determining the localization of a seizure
- EEG can help with determining the localization of a seizure
Where do focal(partial) seizures originate from
- Originate from within a small group of about 1000 neurons: the seizure focus(temporal lobe seizures, focal motor convulsions)
How do focal(partial) seizures start
- Synchronised ‘paroxysmal depolarizing shift’(PDS, 20 to 40mV, lasting 50 to 200 ms) overcomes inhibition
- Increased extracellular K+ due to neuronal damage or reduced uptake by the astrocytes as well as glutamate release from neurons or astrocytes contribute to PDS
- During PDS, trains of action potentials occur
- Hippocampal neurons have similar responses under normal conditions, making the hippocampus more prone to seizures than the neocortex
When do focal seizures spread to other brain regions
- Focal seizures may spread to other brain regions along the normal neuronal pathways and may also show secondary generalization if the activity spreads to the thalamus(tonic clonic seizure)
How do primary generalised seizures reach the cerebral cortex
- Via normal neuronal pathways from the thalamus(eg tonic clonic seizure; absence; juvenile myoclonic epilepsy)
What are pathways that originate in the brainstem normally involved in?
- Regulation of the sleep/wake cycle and arousal of the cerebral cortex
How do we know that inhibition is preserved in epilepsy
- Ca2+ channels and inhibitory GABA receptors in thalamic neurons have been implicated in ‘spike and wave’ seizures, showing that inhibition(the wave) is preserved
How do most antileptic drugs work generally
- AEDs do NOT prevent the development of epilepsy
- Most drugs work to prevent the spread of epileptic discharges
- Thus, they control epilepsy’s major symptom: the seizure, not the cause ;;’
What actions during epileptic seizures do antiepileptic drugs work to counter
Increased activity in the brain may be attributable to:
• Increased membrane excitability
• Increased efficiency of excitatory synaptic transmission - glutamate
• Decreased efficiency of inhibitory synaptic transmission – GABA
• Treatments are be aimed at opposing these actions;
What were the first generation anti-epileptic drugs
- Sodium channel blockers and GABA enhancers
Give examples of anticonvulsant drugs - Na+ channel blockers(just try and remember .a few)
- Phenytoin
- ## LamotrogineCarbamazepine/oxcarbazepine/eslicarbazepine
- Zonsiamide
- Lacosamide
How does lacosamide work as a sodium channel blocker
- Lacosamide enhances slow inactivation of sodium channels
How do drugs such as carbamazepine, oxcarbazepine and eslicarbazepine inhibit voltage gated sodium channels
- Competitively inhibit the voltage gated sodium channel by binding with the receptor in its inactive state, prolonging the period between successive firings(prevents burst firing)
- Blockade increases with repetitive firing
- Drug has greater effect at partially depolarised channel, as a result of facilitated binding
What receptors are targeted by anti-epileptic drugs
- Glutamate receptors
Give an example of a more recently licensed antiepileptic drug
- Perampanel
- AMPA receptor antagonist
How does perampanel work
- non-competitive blockade of AMPA glutamate receptor
- reduce spread / generalisation of seizure
- well tolerated with improved alertness
- role in LD with multiple seizure types not established for perampanel (or lacosamide)
How is neurotransmitter release controlled
- Calcium channels are voltage-gated and require strong membrane depolarization for gating
- They are largely responsible for the regulation of calcium entry and neurotransmitter release from pre-synaptic nerve terminals
Which anticonvulsant drugs work by affecting Ca2+ channels
- Topiramate
- Gabapentin/pregablin
- Lamotrigine/zonisamide
What are the type of calcium channels involved in action potentials
- T-type calcium channels involved in bursting and intrinsic oscillations
What part of the calcium channels are targeted by
- Act at a1G subunits containing channels heavily represented in thalamic neurones
- Thalamic neurones from knockout mice missing a1G fail to fire in burst mode and are resistant to chemical induction of absence-like events
- A rat model of ‘absence’ increased expression of T-type channels
Effect of ethosuximide
- Highly effective in absence epilepsy, but not other seizure types blocks T-channels in thalamus
(zonisamide also acts on T-type channels)
How does GABA increase efficiency of inhibitory synaptic transmission?
- Focal epilepsy characterised by intermittent high amplitude discharges at site of epileptic focus during inter-ictal (seizure) periods
- Two phases, - synchronous depolarisation (caused by strong excitatory inputs to the region of the focus), followed by a period of hyperpolarisation, reflecting activation of GABA inhibition.
- Transition from inter-ictal discharges to full-blown seizure is a decrease in the hyper-polarisation phase (failure of inhibition to kick in)
Give examples of anticonvulsant drugs
- Sodium valporate(sodium channels)
- Benzodiazepines(clobazam, lorazepam)
- Barbiturates/primidone
- Tiagabine(inhibits re-uptake)
- Vigabatrin(inhibits GABA-T)
Features of levetiracetam
• high-affinity synaptic vesicle protein-2A ligand • modulates neurotransmitter release • rapidly titrated and is effective • Keeps patients alert but… mood lowering/agitation side-effects
Features of an ideal antieplieptic agent
- good efficacy, easy and rapid to titrate
- no drug-drug interactions/liver enzyme induction
- no cognitive side-effects/low sodium
- no bone marrow suppression
- no affective (mood)/drowsy side-effects
- different routes of administration
- cost effective
Features of established anti-epileptics
- single mode of action
- less selective effects
- more side effects in cognition, sedation
- more drug interactions
- kinetics/narrow therapeutic range
- much cheaper
Features of modern anti-epileptics
- Act in broad spectrum
- More selective actions
- Less sedating side effects but have many psychiatric/behavioural effects
- Less long term toxicity
- Fewer or no drug interactions
- Easier titration
- 10X expensive
Drugs used to treat primary generalized epilepsy
- Sodium valporate, lamotrigine first line
- Also levetiracetam, topiramate, zonisamide)
- Broad spectrum antiepileptic drugs
Drugs used to treat partial(focal onset) epilepsy
- carbamazepine, lamotrigine first line
* all other antiepileptic drugs have efficacy (all new antiepileptic drugs are tested first in partial epilepsy)
Give examples of drugs that exacerbate generalized seizure types such as myoclonus and absences
- Phenytoin
- Carbamazepine
- Gabapentin/pregablin
What is a teratogen
A teratogen is an agent that can disturb the development of the embryo or fetus. Teratogens halt the pregnancy or produce a congenital malformation (a birth defect)
What are the teratogenic effects that anticonvulsants can have
- most anticonvulsants implicated in congenital
- birth defects - less data for newer agents
- sodium valproate –affects cognitive development; reduced IQ in infant by 9-10 points, and has a higher rate (3-4% vs 2% of major congenital malformations - dose related). Commoner in mums with a LD
- epilepsy pregnancy register – voluntary, not randomised or controlled. Risk increased > 1 AED
What percentage of patients remain refractory to pharmacological treatment(AEDs)
- 30-40%
What set of enzymes are most implicated in drug-drug interactions
- CYP450 liver enzymes
What is the most common type of generalised primary epilepsy
- Juvenile myoclonic epilepsy
