Seizure and epilepsy Flashcards
What is epilepsy?
epilepsy is defined as recurring, unprovoked (spontaneous) seizures
What are acute symptomatic seizures provoked by?
acute symptomatic seizures are provoked by acute insults such as stroke, alcohol withdrawal, metabolic disturbance
What are the causes of epilepsy?
Many causes - idiopathic, mostly caused by genetics
What is generalised onset?
electrical discharges appear to start over the whole brain at the same time on EEG
What is partial/focal onset?
electrical discharge appears to start in one cortical region and then may remain localized or spread over the whole brain - secondary generalized
Describe idiopathic generalized seizures
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
Describe juvenile myoclonic epilepsy
commonest form of primary generalized 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
Describe a tonic clonic seizure
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
Describe absences
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 partial seizures
Focal onset seizures
What is a simple partial seizure?
Patient aware - aura
What is a complex partial seizure?
aura/warning with a level of reduced awareness
patients may call these “absences”, “blanks” – this is medically inaccurate terminology
What is secondary generalized?
patient may experience a prior warning, either SPS, CPS, or both, before the tonic clonic seizure
Describe a secondary generalized tonic seizure ?
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
Which lobe is most affected?
Temporal lobe
List physical symptoms of temporal lobe epilepsy
hallucination of taste, speech and /or smell, visual distortion
epigastric rising sensation (over humpback bridge)
pallor / flushing / heart rate changes (can mimic panic/hyperventilation attacks)
automatisms- semi-purposeful movements
oral- lip smacking, chewing movements
dystonic posturing (limb rises)
List cognitive symptoms of temporal lobe epilepsy
déjà vu / jamais vu speech arrest (dominant hemisphere) formed words during the seizure implies non-dominant hemisphere focus
List the affective symptoms of temporal lobe epilepsy
fear, elation, depression, anger
Describe a frontal lobe seizure
brief 10-30 seconds
rapid recovery, frequent
predominantly nocturnal
forced head /eye deviation to contralateral side
motor activity often bizarre, thrashing
often misdiagnosed as non-epileptic
ictal EEG (during the seizure) is often normal
Jacksonian spread with Todd’s paresis
automatisms, dystonic posturing (overlap TLE)
Describe the symptoms of parietal lobe epilepsy
positive sensory symptoms (unlike TIA/stroke)
tingling, pain
distortion of body shape/image
Jacksonian march of positive sensory symptoms
Describe the occipital lobe epilepsy
typically simple visual hallucinations -balls of coloured or flashing lights
amaurosis (blackout or whiteout) at onset -25%
What anti-epileptic drugs make myoclonic jerks ad absences worse?
phenytoin, carbamazepine, gabapentin, pregabalin
Which patients do you scan?
Jacksonian motor or sensory seizures
Patients with focal neurological deficit
Alcohol withdrawal seizure; only scan if subdural haematoma suspected
What is Epileptogenesis
the process by which parts of a normal brain are converted to a hyperexcitable brain
What is an epileptic 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
Why is the brain prone to seizure activity?
action potentials are regenerative events relying on positive feedback: inherently unstable
a single neuron can fire a train (or trains) of action potentials spontaneously, without any external stimulation (intrinsic excitability)
thus, a network of excitatory neurons connected together in convergent and divergent pathways is potentially explosive:
Stimulation of any one cell can lead to a chain reaction due to the progressive spread of activity over a large area
to avoid this ‘explosion’, the brain requires at least as much inhibition as excitation, by means of inhibitory synapses
Epilepsy represents a failure of inhibitory regulation, either focally (e.g. motor cortex, temporal cortex) or generally (whole cortex at once)
Describe what happens when Na+ channels are too slow to close
e.g., generalized epilepsy with febrile seizures (fever-induced convulsions in infants or small children)
point mutation in part of Na+ channel (β subunit) abnormally slow inactivation
action potential repolarization impaired
Describe the reduction in the number of functional K+
e.g., benign familial neonatal convulsions
defect in KCNQ2 or KCNQ3 K+ channel subunit (K+ channels are tetramers of 4 α subunits) leads to impaired activation
action potential repolarization impaired
What happens to an EEG during epilepsy
rather like an ECG, recording with an array of electrodes attached to the scalp gives information about the electrical activity of very large numbers of neurons in the cerebral cortex
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
when aroused, neuronal activity becomes desynchronized
the hyperexcitation of seizure leads again to synchronous activity on the EEG
EEG can help with determining the localization of a seizure
Where do focal seizures originate and spread to?
Focal (partial) seizures originate within a small group of about 1000 neurons: the seizure focus
(temporal lobe seizures, focal motor convulsions)
synchronized ‘paroxysmal depolarizing shift’ (PDS, 20 to 40 mV, 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 the PDS trains of action potentials occur
hippocampal neurons have similar responses under normal conditions, making the hippocampus more prone to seizures than the neocortex
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)
Where do primary generalized seizures spread to?
Primary generalized seizures reach the cerebral cortex via normal neuronal pathways from the thalamus (e.g. tonic clonic seizure; absence; juvenile myoclonic epilepsy)
pathways originate in the brainstem and are normally involved in regulating the sleep/wake cycle and arousal of the cerebral cortex
Ca2+ channels and inhibitory GABA receptors in thalamic neurons have been implicated in ‘spike and wave’ seizures, showing that inhibition (the wave) is preserved
What are the antiepileptic drugs?
AEDs available today are actually not antiepileptic; that is, they 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.
How do drugs work to prevent the spread of epileptic discharges?
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;
Sodium channel blockers and GABA enhancers were the first generation antiepileptic drugs
How do sodium channel blockers work?
Many of the drugs that are used against partial seizures are effective at blocking repetitive firing of neurons by acting at ion channels (especially sodium channels).
Drugs that have selective actions at the channel may control seizures without affecting normal transmission
Normal neuronal firing is not impaired, thus there should be minimal effect on baseline functioning. When neuronal activity increases (as in a seizure), it is inhibited by the drugs, thereby preventing seizure spread.
Name some Na+ channel receptors
Phenytoin
Lamotrogine
Carbamazepine/oxcarbazepine/eslicarbazepine
Zonisamide
Lacosamide enhances slow inactivation of sodium channels
Describe how carbamazepine, oxcarbazepine and eliscarbazipine work?
Carbamazepine, oxcarbazepine and eslicarbazepine 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)
What is perampanel?
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 release of transmitter controlled?
Calcium channels are voltage-activated and require strong membrane depolarization for gating and are largely responsible for the regulation of calcium entry and neurotransmitter release from pre-synaptic nerve terminals.
Several anticonvulsant drugs (e.g. topiramate, gabapentin/pregabalin and probably lamotrigine/zonisamide) work this way. ** narrow vs broad spectrum
List some anticonvulsant drugs
sodium valproate (sodium channels) benzodiazepines (clobazam, lorazepam) barbiturates/primidone tiagabine (inhibits re-uptake) vigabatrin (inhibits GABA -T)
What do anticonvulsant drugs do?
Facilitators of GABAergic transmission
What is 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
What is the ideal antiepileptic drug?
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
Which drugs are used for primary generalized epilepsy
sodium valproate, lamotrigine first line
(also levetiracetam, topiramate, zonisamide)
broad spectrum antiepileptic drugs
Which drugs are used for partial (focal onset) epilepsy
carbamazepine, lamotrigine first line
all other antiepileptic drugs have efficacy (all new antiepileptic drugs are tested first in partial epilepsy)
Which drugs exacerbate generalized seizure types such as myoclonus and absences?
- phenytoin- carbamazepine- gabapentin/pregabalin
List the side effects of benzodiazepines
Dose related - (acute) Drowsiness Ataxia Hyperactivity Personality Change Cognitive impairment
- long term
Tolerance/dependence
List the side effects of phenytoin
Dose related - (acute)
Ataxia
Diplopia
Nystagmus
long term
Gingival hyperplasia
Osteomalacia
Cerebellar atrophy
Which drug interactions are present?
CYP450 liver enzymes most implicated
remember treatment is often long term
but not the only story! Check BNF; some antiepileptic drug blood levels can be measured
consider current and future co-morbidities; digoxin, theophylline, warfarin, OCP, rifampicin (TB), erythromycin, chemotherapy
** bones, heart
