Epilepsy Flashcards
Incidence/prevalence of epilepsy?
50 per 100,000 diagnosed each year
approx 1 in 100 people in the UK have it
most commonly presents in children and the elderly
Prognosis of epilespy?
up to 70% can become seizure free
50% can withdraw medicatiom
20-30% will continue to have seizures despite treatment
Mortality of epilepsy?
2-3x higher than general population
can be due to accidents not just the disease (indirect)
sudden unexpected death in epilepsy (more common in generalised tonic clonic and poor seizure control)
How many different types of epilepsy?
over 40
Definition of a seizure?
episode of neurological dysfunction of abnormal firing of neurones manifesting as changes in motor control
Definition of epilepsy?
Condition of recurrent, spontaneous seizures arising from abnormal, synchronus and sustained electrical activity in the brain
Aetiology of epilepsy?
- idiopathic epilepsy: genetic cause
- symptomatic epilepsy: e.g. head injury or stroke
- up to 50% have no apparent cause
What is the first step of epilepsy diagnosis?
establish if paroxysmal event was actually a seizure
acute symptomatic seizure? e.g. head injury, infection, imbalance etc
Non-epileptic attack from syncope, encephalitis, migraine?
witnesses are very helpful
Updated NICE guidelines on diagnosis of epilepsy?
must be made by a specialist (i.e. neurologist) as other doctors had an even worse misdiagnosis rate
What is the clinical decision of epilepsy diagnosis based on?
- desrcription of attack (footage, witness)
- family history (genetic cause)
- blood tests
- ECG (cardiac cause/syncope?)
- Medication history - illegal drugs can cause seizures, overdose of some drugs can cause seizures, many commonly prescribed drugs can lower seizure threshold)
Tongue biting pattern of seizures?
tonic clonic seizures - patients tend to bite the sides of their tongue
tip of tongue - generally non-epileptic attack disorder
Which drugs can lower seizure threshold?
SSRIs, tricyclics, quinolones, tramadol
Importance of imaging in epilepsy diagnosis?
MRI preferrred to CT - can see structural abnormalities
important in <2s and adults who develop seizures (see a treatable cause)
should be performed within 4 weeks
Role of EEGs in epilepsy diagnosis?
should never be used in isolation
main use is to classify the epilepsy for correct treatment
however: 10% epileptics have normal EEGs, and 2-4% healthy people have abnormal EEGs
Principles of classification of seizures?
- depend on the location and focus on the pathway involved
- patients can have more than one type of seizures
- failure to classify correctly can lead to inappropriate treatment and therefore treatment failure
Two main types of seizures?
Partial and generalised seizures
Types of partial seizures?
- simple partial seizures (maintain consciousness)
- complex partial seizures (lose consciousness)
- with secondary generalisation
Types of generalised seizures?
- tonic/clonic (muscles spasm in tonic, then limb shaking in clonic)
- absence
- myoclonic
- atonic
Common seizure triggers?
fatique, lack of sleep, stress, excess alcohol, flashing lights, excitement, menstruation, missing meals, some medications
NICE guidelines for treatment of epilepsy?
- always intiated by a specialist after diagnosis
- monotherapy to start (low and slow)
- adjunctive treamtent only if monotherapy has failed
- AEDs are not usually started after first seizure
Ideal epilepsy therapy aim?
Single drug
lowest possible dose
minimum side effects
Patient factors that contribute to choice of drug for epilepsy?
- epilepsy syndrome
- seizure type
- co-morbidity
- lifestyle
- gender, age
- preferences of individual/carers
Drug factors that contribute to choice of drug epilepsy?
- side effect profile
- dose
- formulation
- treatment schedule
- interactions
First line drugs for tonic-clonic seizures?
carbamazepine, lamotrigine, sodium valproate, oxcarbazepine
Adjunctive drugs for tonic-clonic seizures?
Clobazam, lamotrigine, levetiracetam, sodium valproate, topiramate
Drugs that may worsen tonic-clonic seizures?
Carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin
First line drugs for tonic or atonic seizures?
Sodium valproate
Adjunctive drugs for tonic or atonic seizures?
Lamotrigine
Drugs that may worsen tonic or atonic seizures?
Carbamazepine, gabapentin, oxcarbazepine, pregabalin
First line drugs for absence seizures?
Ethosuximide, lamotrigine, sodium valproate
Adjunctive drugs for absence seizures?
Ethosuximide, lamotrigine, sodium valproate
Drugs that may worsen absence seizures?
Carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin
First line drugs for myoclonic seizures?
Levetiracetem, sodium valproate, topiramate
Adjunctive drugs for myoclonic seizures?
Levetiracetem, sodium valproate, topiramate
Drugs that may worsen myoclonic seizures?
Carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin
First line drugs for partial seizures?
carbamazepine, lamotrigine, sodium valproate, oxcarbazepine, levetiracetem
Adjunctive drugs for partial seizures?
carbamazepine, lamotrigine, sodium valproate, oxcarbazepine, levetiracetem, clobazam, gabapentin, topiramate
Dosing info for sodium valproate?
600mg/day in 1-2 divided doses gradually increased every 3 days
Dosage forms of sodium valproate?
EC tablets, MR tablets, liquid, granules, IV
IV is equivalent to oral doses
Monitoring requirements for sodium valproate?
signs of liver, blood and pancreatic disorders
Side effects of sodium valproate?
nausea, gastric irritation, diarrhoea, weight gain, hair loss
Who is sodium valproate not suitable for?
Women of childbearing age, risk of serious neurodevelopment effects
Dosing info for carbamazepine?
Initially 100-200mg 1-2 times daily, increased slowly every 2 weeks
Monitoring requirements for carbamazepine?
blood liver and skin disorders
Dosage forms of carbamazapine?
oral and PR
125 suppository is equiv to 100mg orally
How is carbemazepine metabolised?
CYP3A4 - so susceptible to DDIs. potent inducer
Side effects of carbamazepine?
Headache, nausea/vomiting, drowsiness, dizziness, rash, ataxia, hyponatraemia
How can the side effects of carbamazepine be managed?
They are dose related and can be dose limiting
can be reduced using MR tabs
Dosing info for lamotrigine?
Initially, 25mg/day and slowly titrated every 2 weeks
Side effects of lamotrigine?
Nausea/vomiting, diarrhoea, dry mouth, skin reactions
How to manage the skin reactions with lamotrigine?
more common in the first 8 weeks or when also on valproate
increase dose slowly
Use of lamotrigine in pregnancy?
Considered the safest AED for pregnancy
Dosage forms of lamotrigine?
Oral only
Dosing info for levetiracetam?
250mg/day, increased every 1-2 weeks to max 1.5g BD
How is levetiracetam metabolised?
very little, so no CYP450 interaction
Dosage forms of levetiracetam?
oral and IV
good oral bioavailability, so no dose adjustment required between the two
Side effects of levetiracetam?
Nasopharyngitis, somnolence, fatigue, dizziness, headache
Low mood, irritability, depression are common reasons for discontinuation
Dosing info for phenytoin?
Initially 3-4mg/kg/day (usual dose 200-500mg/day)
Dose adjusted according to levels and effect
Place of phenytoin in epilepsy treatment?
Not recommended by NICE for first line
Pharmacokinetics of phenytoin?
- Narrow therapeutic index with saturable kinetics
- Half life 4-72 hours (depends on dose)
- Steady state reached after 7-10days
- Extensive hepatic metabolism
- Strong inducer of CYP450 - interactions
- Highly protein bound – albumin
- Interactions with enteral feeding
Phenytoin dosage forms and how to interchange?
Capsules and IV - phenytoin sodium
Liquid and chewable tablets - phenytoin base
92mg phenytoin = 100mg phenytoin sodium
Side effects of phenytoin?
N+V, constipation, drowsiness, parasthesia, gingival hyperplasia, acne, hirsuitism, coarsening of facial features
Signs of phenytoin overdose?
Nystagmus (involuntary eye movements), ataxia, diplopia (double vision), slurred speech, confusion, hyperglycaemia
What is the desired phenytoin plasma concentration?
10-20mg/L
MHRA categories for antiepileptics for supply - category 1?
Includes phenytoin, carbamazepine, phenobarbital,
Specific measures are necessary to ensure consistent supply of a particular product
MHRA categories for antiepileptics for supply - category 2?
Includes sodium valproate, lamotrigine, oxcarbazepine
The need for continued supply based on clinical judgement
MHRA categories for antiepileptics for supply - category 3?
Includes levetiracetam, lacosamide, gabapentin
No specific measures required
Important points when giving antiepileptics to women?
- Antiepileptics interact with hormonal medications
Can reduce effectiveness as enzyme inducers
E.g. Carbamazepine, phenytoin
Oral contraceptives and EHC can reduce effectiveness of lamotrigine.
May need to increase dose of lamotrigine - Some AEDs are teratogens/can cause birth/developmental defects
- These drugs are to be avoided in women of childbearing potential and pregnant women
- Pharmacokinetics can be altered in pregnancy
- All women on AEDs should be offered folic acid 5mg OD before any possibility of pregnancy
- Some women have increased seizure frequency around menstruation
- Side effects of some AEDs may be undesirable
Risks when giving antiepileptics to the elderly?
Pharmacokinetic and pharmacodynamic issues
- Polypharmacy
- Co-morbidity
Consider using lower doses of AEDs
If on carbamazepine, this should be modified release
What is status epilepticus?
Medical emergency associated with significant morbidity and mortality
Generalised Convulsive Status Epilepticus is defined as a tonic clonic seizure which lasts longer than 30 minutes or repeated tonic clonic seizures within 30 minutes with little or no recovery in between
Treatment aims for status epilepticus?
Efficient and effective treatment is key
Aim of treatment is seizure termination
Treatment for status epilepticus?
- IV Lorazepam 0.1mg/kg (usually 4mg), repeated once after 10-20 minutes if seizure continues
- Give usual AEDs if already on treatment
- Alternatives to lorazepam are IV diazepam or buccal midazolam
- then Phenytoin IV 20mg/kg over 20 minutes (or phenobarbital if already on phenytoin) if still no success
last resort - general anaesthesia
What to check if treatment is failing?
- compliance
- change in brand/formulation?
- diagnosis - wrong drug for their epilepsy type
- brain tumour?
- alcohol/drug misuse
How to change drug in case of treatment failure?
- change to second line therapy
- initiate new drug, titrate up, then wean off old drug
- never abruptly stop AEDs, risk of rebound seizures
What to do if combination therapy doesn’t work?
revert to the regimen that provided the best balance of tolerability and efficacy (could me mono or combination therapy)
What are the issues with combination therapy in epilepsy?
- drug interactions (many are potent inducers)
- increased toxicity
- identifying ADRs
- non-compliance (increased pill burden and side effects)
When is treatment withdrawal suitable?
- seizure free for at least two years
- joint decision by patient, carers and under guidance of specialist
How is treatment withdrawal carried out?
- slowly over months
- one drug at a time if combination therapy
- plan in place if seizures recur: reverse last dose reduction and seek specialist help
What counselling points are important to patients on epilepsy treatment?
- Importance of compliance explained – even when seizure free
- Dosing schedule and dose titration
- Signs and symptoms of adverse effects (Blood disorders, Liver dysfunction, Skin disorders)
- Brands and formulations
What are some of the social impacts of epilepsy?
- Employment: cannot be refused but must consider health and safety
- Driving: must be one year seizure free to drive (also consider side effects)
- Alcohol: interaction with drugs, can trigger seizures
How is childhood epilepsy diagnosed?
Same as adults
- history (description, video, witness)
- exclusion of other causes (cardiac, structural, metabolic)
Non-epileptic causes of childhood seizures?
- febrile seizures
- trauma
- metabolic
Epileptic causes of childhood seizures?
- primary idiopathic (genetic)
- secondary (tumour, structural abnormality)
- neurodegenerative disorders
What are paroxysms?
‘fully turns’
- anoxic tonic-clonic seizures
- breath holding attacks, dramatic tantrums
reflex anoxic seizures arise from cold food, trauma or fright
What are febrile seizures?
NOT EPILEPSY
- often a strong family history
- high incidence (3% of 3 months to 5 years)
- generalise tonic-clonic
- short lived, self resolving, associated with high body temperature
How to treat febrile seizures?
- reassure and comfort parents
- cool the child (remove clothing, bedding, reduce heaitng)
- antipyretics don’t prevent them, cold swabbing no longer recommended
- maintenance AEDs are not appropriate as will resolve by age 5
- management of prolonged seizures should follow status epilepticus pathway
What is Dravets Syndrome?
80% have a mutation in SCN1A gene
Characteristics of Dravets Syndrome?
- Intractable seizures
- developmental delay
- failure to thrive
- dysregulated autonomic nervous system (thermoregulation, sweating)
15-20% mortality - as it doesn’t respond to any AEDs
Management of Dravets Syndrome?
- Sodium valproate, plus clobazam, plus stiripentol if the first two doesn’t work
Treatment goals for Dravets Syndrome?
Reduce frequency and severity of seizures
Reduce doses of valproate and clobazam
What must we do to valproate and clobazam if steripentol is initiated?
Reduce dose - potent inhibitors of CYP2C19, 2D6 and 3A4
Mode of action of Stiripentol?
- increase amount of GABA, inhibit metabolism of other AEDs
Who is stiripentol licensed in?
> 3 years with Dravets Syndrome
Formulations fo stiripentol?
Oral suspension (sachet) and capsule
sachet has greater bioavailability, so not bioequivalent
Starting dose for stiripentol?
10mg/kg BD for a week
then 15mg/kg BD for a week
Max dose for stiripentol <6 years?
increase over three weeks to max 25mg/kg BD
Max dose for stiripentol 6-12 years?
increase over four weeks to max 25mg/kg BD
Max dose for stiripentol >12 years?
increase slowly to maximum tolerated dose
Why can we increase stiripentol dose quicker in under 6s than 6-12s?
Different pharmacokinetics in children
How does drug absorption vary between children and adults, and relate to AEDs?
- children have higher gastric pH (5-6 vs 2-3)
- lower bioavailability of phenytoin than adults (<75% vs 95%)
- slower gastric motility (reduced peak levels of phenobarbitone, which is rapidly absorbed through the GI tract - increase dose). also slower time to reach peak levels of carbemazepine
- milk based diets react with AEDs (phenytoin absorption reduced by 35% if administered with enteral feed)
How does drug metabolism vary between children and adults, and relate to AEDs?
- Hepatic extraction ratio is much higher - liver surface area is larger relative to their size
- increased first pass metabolism
- higher mg/kg dose for carbemazepine and sodium valproate required compared to adults
- higher expression of 1A2, 2C9 and 3A4 so lower F of substrates of these
Results of varying pharmacokinetics on dosing in children of AEDs?
Usually higher doses mg/kg than adults
Child vs adult dose of valproate?
10mg/kg for BD childen
300mg BD for adults - approx 3.8mg/kg
Child vs adult dose of clobazam?
5mg/kg daily for child
100mg BD for adult - approx 1.3mg/kg
Child vs adult dose of phenytoin?
5mg/kg/day child
3mg/kg/day adult
What is Lennox-Gastaut syndrome?
- most common form of intractable epilepsy
- characterised by ‘drop attacks’ - generalised absense seizures, atypical focal absence seizures (floppy and unresponsive), tonic seizures (jerking)
- developmental delays
Why does epilepsy cause development delays?
large amount of calorie expenditure on seizures
Treatment options for Lennox-Gastaut syndrome?
1st line: valproate
2nd line: lamotrigine, topiramate, clobazam, phenytoin
corticosteroids to reduce inflammation and neuronal damage
surgery to remove the affected area of the brain
Properties of valproate?
short chain fatty acid that inhibits uptake of GABA in the CNS
Why is valproate so commonly used in epilepsy?
- broad spectrum
- well tolerated
- cheap
- range of formulations
Toxicity profile of valproate?
- Liver (monitor LFTs, bilirubin, ALT etc) - fatty liver
- Pancreatitis (10% of patients)
- Haemotological (pancytopaenia, thrombocytopoenia)
- Metabolic derangement (urea cycle disorders)
Pharmacokinetics of valproate?
- half life 4-8 hours (8-20 hours in adults)
- 90% protein bound
- 65% renally cleared
- therapeutic level 40-100mg/L
concentration not correlated with therapeutic efficacy, only useful if concerned about toxicity
Valproate and teratogenicity?
- should not be used in women of childbearing age
- 1 in 10 risk of birth defects
- 4 in 10 risk of developmental delays (memory impairment, lower IQ, delay in walking/talking)
Why is valproate still on the market despite the risks?
Patient centred assessment, risk vs benefit
Counselling for children on valproate
Make parents/carers aware of risk of valproate and epilepsy in pregnancy
At a suitable time for the patient, discuss suitable contraception
When the child reaches child bearing age, review valproate and consider a change
What to do in unplanned pregnancy whilst taking valproate?
- review treatment and risk assess
- remind her to continue therapy until a decision is made
- use smallest dose possible, consider prolonged release formulation
- check understanding of risks and consider further counselling
- refer to specialist obstetrician for specialist guidance
Mode of action of carbemazepine?
- dose dependent voltage gated sodium channel antagonist: prevents repetitive action potentials, downregulates seizureactivity at the nerve
- also a GABA agonist
When is carbemazepine contraindicated?
Epilepsy seizures with sodium channel involvement, as it makes them worse
- Dravets Syndrome
- Myoclonic seizure disorders
Pharmacokinetic information on carbamazepine?
- half life 30 hours after a single dose (15 hours after repeated dosing) (2-12 hours if with phenytoin)
- 65% protein bound
- hepatically metabolised by CYP3A4
- therapeutic level 4-12mg/L - seldom correlates with efficacy
Mode of action of lamotrigine?
Direct effect on voltage gated sodium channels
- interacts with other AEDs (valproate, increased level. carbemazepine, decreased level)
-
Uses for lamotrigine?
1st line for focal seizures
1st line for generalised tonic clonics (good alternative to valproate)
What is the dynamic target of seizure control?
Balance between factors that influence excitatory and inhibitory post synaptic potentials
What factors influence excitatory post synaptic potential?
- sodium influx
- calcium influx
- paroxysmal depolarisation
What factors influence inhibitory post synaptic potential?
- potassium efflux
- chloride influx
- low pH
At what levels does physiological protection against repetitive firing occur?
cellular (e.g. sodium channel inactivation)
network (e.g. GABA mediated inhibition)
What are the main categories of anticonvulsants?
- drugs that inhibit sodium channels
- drugs that inhibit calcium channels
- drugs that enhance GABA mediated inhibition
- drugs that inhibit glutamate
How do the drugs that inhibit the sodium channels work?
prevent the return of these channels to active state by stabilising them in the inactive state
How do the drugs that inihibit the calcium channels work?
inhibit T-calcium channels (particularly useful in absence seizures)
high voltage activated channels - involved in neurotransmitter release
How is GABA synthesised?
mediated by glutamic acid decarboxylase (GAD)
How is GABA stored?
GABA is packaged into presynaptic vesicles by a transporter (VGAT)
How is GABA released?
In response to an action potential and the presynaptic elevation of intracellular Ca2+, GABA is released into the synaptic cleft by fusion of GABA-containing vesicles with the presynaptic membrane
Reuptake of GABA?
Neurons and glia take up GABA via specific GABA transporters (GATs). Four GATs have been identified, GAT-1, GAT-2, GAT-3 and GAT-4, each with a characteristic distribution in the CNS
How is GABA broken down?
widely distributed mitochondrial enzyme GABA-transaminase (GABA-T) metabolises GABA
Types of drugs that enhance GABA mediated inhibition?
GABA receptor agonists, GABA reuptake inhibitors, GABA-transaminase inhibitors
What do glutamate receptors do?
glutamate is a major excitatory neurotransmitter in the brain
What are the sites on ionotropic glutamate receptors?
AMPA, kainate, NMDA
How do AMPA and Kainate receptor sites regulate glutamate response?
oopen a channel that allows small amounts of sodium and calcium ions through
How do NMDA receptor sites regulate glutamate response?
open a channel that allows large amounts of calcium to enter alongside the sodium
What facilitates the opening of the NMDA rececptor channel?
Glycine
What mediates and regulates the metaobtropic receptors?
Regulated by complex reactions and response mediated by second messengers
Why do NMDA receptor agonists have limited use?
produce psychosis and hallucinations
can also impair learning and memory
