Neurological Treatment of Epilepsy Flashcards
What is epilepsy?
The tendency to have recurrent epileptic seizures (not one disease process)
What are epileptic seizures?
Abnormal, synchronous firing of a large number of cortical neurons, causing symptoms
(Fundamentally abnormal as most actions use spare coding = strong activation from small set of neurons)
What poorer outcomes are associated with epilepsy?
▪️ Education
▪️ Employment
▪️ Mental health
▪️ Stigma
▪️ Injury and mortality
▪️ Unplanned hospital admissions
What are the eight steps of the NICE neurological management pathway for epilepsy?
- Patient presents with suspected seizure(s)
- History, examination, and investigations
- Diagnosis and classification
- Explanation, discussion, provision of info
- Decision to treat
- Ongoing treatment
- Possible referral to tertiary service depending on response/outcome
- Stopping treatment
What usually happens after an individual presents to their GP/A&E with suspected seizure(s)?
They are referred to a specialist for diagnosis and decision to start treatment, ideally within 2 weeks
Why is the aim to get patients with suspected seizure(s) seen by a specialist within 2 weeks?
This follows the cancer pathway due to the possibility of a tumour
What investigations might be ordered by an epilepsy specialist?
▪️ EEG
▪️ ECG
▪️ Neuroimaging
▪️ Neuropsychological assessment
▪️ Blood test
What information does the NICE guidelines say should be provided to people with epilepsy?
▪️ Epilepsy in general (incl. treatment options, types and triggers, SUDEP, status epilepticus)
▪️ Risk management
▪️ Psychological issues
▪️ Education and employment
▪️ Road safety and driving
▪️ Lifestyle (incl. alcohol, sleep deprivation)
▪️ Issues relevant to women
▪️ Voluntary organisations
What should drug treatment for epilepsy be individualised to?
▪️ Seizure type
▪️ Epilepsy syndrome
▪️ Co-medication
▪️ Co-morbidity
▪️ Lifestyle
▪️ Preferences
What should be tried if a single AED is not successful in controlling seizures?
Another drug should be tried as monotherapy
When should combination therapy (polytherapy) be considered?
When monotherapy with more than one AED has not resulted in seizure freedom
What risk should be considered when prescribing sodium valproate to a woman?
Risk of malformation and neurodevelopmental impairments in an unborn child
When is SUDEP most likely to occur and why?
During sleep likely due to suppression of brain stem autonomic processes (e.g., decreased HR and breathing)
How many antiepileptic drugs are currently available in the UK?
25
What are the main issues with the evidence base for which AED to prescribe?
▪️ Only “newer” drugs have gone through RCTs in comparison to placebos
▪️ Trials mostly in difficult-to-treat, chronic patients in addition to current therapy
▪️ Very few comparative trials, mostly in new-onset treatment naïve epilepsy
▪️ Very little evidence for polytherapy
What did Kwan and Brodie (2000) find when comparing monotherapy to polytherapy?
▪️ Most people become seizure free with monotherapy, usually with the first drug tried
▪️ No evidence that any particular drug was preferable
▪️ Outcome predicted by “idiopathic” aetiology and fewer seizures before treatment
What was the SANAD trial?
A large RCT investigating the effectiveness of standard and new epileptic drugs in partial (focal-onset) seizures and generalised/unclassifiable seizures
(Sodium valproate vs topiramate, lamotrigine, carbamazepine, and gabapentin)
What did the SANAD trial find in regards to generalised or unclassifiable seizures?
▪️ Valproate was better tolerated than topiramate and more efficacious than lamotrigine
▪️ BUT must not adverse effects in pregnancy
What did the SANAD trial find in regards to patial (focal) seizures?
▪️ Lamotrigine = better tolerated than carbamazepine and equally efficacious
▪️ Lamotrigine = better tolerated than topiramate but both better than gabapentin
What were the two arms of the SANAD II trial?
A) Lamotrigine vs levetiracetam vs zonisamide in untreated focal onset seizures
B) Levetiracetam vs valproate in untreated generalised onset/unclassifiable seizures
What did Arm B of the SANAD II trial conclude?
Valproate = best 12 months remission for generalised onset seizures (and cheaper)
What did Arm A of the SANAD II trial conclude?
Lamotrigine = best 12 month remission for focal onset seizures (and cheaper)
What did Nevitt et al., (2017) find when comparing ‘time to withdrawal of allocated treatment’ of different AEDs for partial seizures?
▪️ Best = levetiracetam (best combination of efficacy and tolerability)
▪️ Second best = lamotrigine
▪️ Third best = carbamazepine
What did Nevitt et al., (2017) find when comparing ‘time to withdrawal of allocated treatment’ of different AEDs for generalised seizures?
Sodium valproate was better than all others
What did Nevitt et al., (2017) find was the best AED for achieving 12-month remission?
Phenobarbital and phenytoin
BUT not the best adherence, which is more important?
What is the best medication for treating partial (focal) seizures?
▪️ Levetiracetam (no interactions and well tolerated)
▪️ Lamotrigine or carbamazepine
What is the best medication for treating generalised seizures in men?
▪️ Sodium valproate
▪️ Lamotrigine or levetiracetam
What is the best medication for treating generalised seizures in women?
Lamotrigine or levetiracetam
What could be considered for frequent absence seizures that are uncontrolled by the usual drugs?
Ethosuximide
How might topiramate be used for epilepsy?
Start at very low dose and escalate slowly, aiming for low continuing dose is better tolerated despite the contrary evidence
What is rational polytherapy?
Combining drugs known to have different mechanisms of action
What is the evidence for polytherapy in epilepsy?
▪️ Weak
▪️ Kwan & Brodie - 3% seizure free
▪️ Some anecdotal evidence for rational polytherapy
What do the NICE guidelines say about continuing pharmacological treatment in epilepsy?
▪️ Monitor for adverse effects
▪️ Continuation should be planned by the specialist
▪️ If straightforward, can be prescribed in primary care
How can we optimise adherence to treatment in epilepsy?
▪️ Information on their condition and rationale of treatment
▪️ Reduced stigma
▪️ Simple medication regimens
▪️ Positive relationships with healthcare professionals
Should regular blood tests be carried out in adults taking AEDs?
Not necessarily
When might regular blood tests be necessary for adults taking AEDs?
▪️ Detection of non-adherence
▪️ Suspected toxicity
▪️ Adjustment of phenytoin dose
▪️ Management of drug interactions
▪️ Clinical conditions such as status epilepticus, organ failure, or pregnancy
How can we tell if epilepsy has stopped and treatment can be discontinued?
▪️ Just have to stop medication and see
▪️ Not test, can still see abnormalities on EEG when seizure-free
According to the MRC Antiepileptic Drug Withdrawal Study Group (1991), what percentage of people withdrawn from treatment remained seizure-free 2 years later?
59% (compared to 78% continuing treatment)
The difference decreased after this
In the recent meta-analysis by Lamberink (2017), what percentage of people relapsed after AED withdrawal?
46%
What predictors are associated with increased risk of seizure recurrence following withdrawal of AEDs?
▪️ Longer epilepsy duration before remission
▪️ Shorter seizure-free interval before withdrawal
▪️ Younger age at onset
▪️ History of febrile seizures
▪️ Higher number of seizures before remission
▪️ Absence of self-limiting syndrome
▪️ Developmental delay
▪️ Epileptiform abnormality on EEG before withdrawal
▪️ >1 AED
▪️ History tonic-clonic seizures
What can be used for the emergency treatment of seizure clusters or prolonged seizures (status epilepticus)?
Benzodiazepines:
▪️ Rectal diazepam (in US)
▪️ Intranasal midazolam and diazepam
▪️ Buccal midazolam (in EU)
▪️ Sublingual or intranasal lorazepam
▪️ Oral benzos (e.g., clobazam) (but lack evidence)
How does levetiracetam work?
SV2A modulation, preventing release of NT such as glutamate from presynaptic vesicles
(synaptic vesicle protein, regulating neurotransmitters)
How do lamotrigine, carbamazepine, and oxcarbazepine work?
Na+ channel blocker, preventing depolarisation
How does sodium valproate work?
▪️ GABA potentiation
▪️ Glutamate (NMDA) inhibition
▪️ Na+ and calcium channel blockade
What are the main mechanisms of action of AEDs?
▪️ GABA potentiation (reduce rate of GABA removal, enhance inhibition)
▪️ Na+ channel blockade (prevent depolarisation)
▪️ T-type Ca2+ channel blockade (prevent NT release)
▪️ Glutamate (NMDA/AMPA) inhibition
▪️ SV2A modulation
Anything that stops synchronous and excessive neuronal transmission/firing!
How does phenobarbital work?
GABA potentiation
How does phenytoin work?
Na+ channel blockade
What medication is recommended for absence seizures and how does it work?
Ethosuximide - Ca2+ channel blocker
What is the main mechanism of action of benzodiazepines?
Hold open GABA receptors for longer, reducing the likelihood of excitatory synapse firing, and increasing likelihood of GABA action
When might a tertiary referral for epilepsy be considered?
▪️ Child under 2 years old
▪️ Epilepsy is not controlled with meds within 2 years and/or after two drugs
▪️ Diagnostic doubt
▪️ Unacceptable side effects
▪️ Psychological/psychiatric co-morbidity
▪️ Unilateral structural lesion
▪️ Specific rare syndromes
