Epilepsy Flashcards
If a patient has at least 2 unprovoked (or reflex) seizures occurring more than 24 hours apart, what could this be?
Epilepsy
If a patient has one unprovoked (or reflex) seizure and a probability of further seizures are similar to the general recurrence risk of after 2 unprovoked seizures (at least 60%), over the next 10 years, what diagnosis is this?
Epilepsy
‘The transient occurrence of signs or symptoms due to abnormal excessive or synchronous neuronal activity in the brain’ - is the definition of what?
A seizure
If a patient has a Seizure that lasts more than give minutes or recurrent one after another with no recovery time in between what is this called?
Status Epilepticus
What can Status Epilepticus be triggered by?
Head injury, metabolic disturbance (hypoglycaemia), cerebrovascular event (stroke) or alcohol withdrawal.
How should Status Epilepticus be managed non-pharmacologically in the community?
1) Note start time of seizure
2) Provide first aid, when stops put in recovery position
If a patient in the community is in ‘status epilepticus’ what and when should drug management be given?
5+ minutes of seizure or 3 seizures in one hour.
First line - Buccal Midazolam or Rectal Diazepam , if continues call 999.
What medications can be given if the patient is still seizing after 5-20 mins?
IV lorazepam (0.1mg/kg MAX 4mg)
NO IV access? - Buccal midazolam
NO response after 10-20 mins *Give second dose = NO MORE THAN TWO DOSES!!
After 20-40 minutes the patient is in established status epilepticus, what medications should be given IV?
AED’s
* Levetiracetam
* Sodium valproate
*Phenytoin or fosphenytoin
If a patient is in refractory Status Epilepticus (40-60 mins), what should be done?
Transfer to ITU.
What is SUDEP?
Sudden unexpected death in epilepsy
What is the cause of Epilepsy?
○ Structural - stroke, trauma, injury
○ Genetic
○ Infectious - TB, Malaria
○ Metabolic
○ Immune - Anti NMDA encephalitis
Idiopathic
What are the risk factors of Epilepsy?
○ Premature birth
○ Febrile seizures (high temp causes!)
○ Brain development malformation
○ Family history of epilepsy or neurological disease
○ Head trauma
○ Infections (meningitis and encephalitis)
○ Tumours ○Cerebrovascular disease/stroke
○ Dementia and neurodegenerative disorders (Alzheimer’s disease)
○Drugs and alcohol withdrawal
What is gold standard for diagnosis of neonates having seizures?
EEG
What testing will be done on a patient who has a new onset of Seizures?
Antibody testing
What are the three seizure types?
1) Focal
2) Generalised
3) Unknown
What are the types of Focal seizures?
Aware/impaired awareness - Motor or Non-motor onset. - Focal or bilateral tonic-clonic
What are the types of Generalised seizures?
Motor (tonic-clonic/other motor)
Nonmotor (absence)
What are the types of unknown seizures?
Motor (tonic-clonic/other motor)
or unclassified
What types of epilepsy are there?
-Focal
-Generalised
-Combined generalised and focal
-Unknown
What is a tonic seizure?
Sustained increased muscle contraction (tense and rigid muscles)
What does ‘motor’ mean during a seizure?
Movement during a seizure
What does ‘non-motor’ mean during a seizure?
No movement during a seizure
What is a myoclonus seizure?
Muscle twitching (can involve single or multiple muscle groups)
What is a Atonic seizure?
Muscles becoming limp (opposite to tonic)
What is a Clonic seizure?
Jerking rhythmic twitching movements
What is a tonic-clonic seizure type?
Starts off in a tonic phase then goes into a clonic phase including loss of control of bladder/bowel.
After a seizure a patient can get a post-ictal phase
What is an absence seizure?
Vacant staring and movement stops.
When is combination therapy used in Epilepsy?
When monotherapy has been tried and the patient is still not seizure free
Blood testing is not routinely recommended and only done if clinically needed and recommended, when might this be done?
- Identify non-adherence
- Investigate suspected toxicity
- Adjustment of phenytoin doses
- Managing interactions with other medication
*For specific clinical conditions - organ failure / pregnancy
When might vitamin D supplementation be given to a patient with epilepsy?
1) If immobile for long periods of time
2) Inadequate sun exposure
3) Inadequate dietary intake
If a patient displays symptoms of Antiepileptic hypersensitivity syndrome what must happen?
STOP AED’s immediately as this can be fatal
Can a AED cause suicidal behaviours?
YES - med review needed immediately
what AED’s are inhibitors?
Sodium Valproate,
What AED’s are inducers?
Carbamazepine, Phenobarbital, Phenytoin
Primary indication for Sodium Valproate?
First line for: Generalised Tonic-Clonic Seizures, Myoclonic seizures, Tonic or Atonic seizures, Idiopathic.
2nd line for: Absence seizures if other AEDs ae not suitable / not tolerated
Potential 1st line agent for: Dravet’s syndrome, Lennox-Gastaut syndrome
Adjunctive (add-on): to other AEDs in certain epilepsies.
What other than Epilepsy can Sodium Valproate be used for?
Migraine prophylaxis (unlicensed)
Mania in Bipolar disorder (either as sodium valproate or as semi-sodium valproate.
Notable pharmacokinetics for Sodium Valproate?
INHIBITOR
* Crosses into through the placenta
* Half-life 8-20 hours (usually shorter in children)
* Metabolised through the liver via glucuronidation
Monitoring for Sodium Valproate?
Before
LFT’s
FBC
During
LFTs within 6 months
Monitoring of blood dyscrasias
Liver disorders - Jaundice, tiredness, lethargy, drowsiness, loss of strength, anorexia, swelling
Pancreatitis (N&V, Abdo pain)
Primary indication for Carbamazepine?
2nd line for: Focal seizures, other types of epilepsy that include benign epilepsy with centrotemporal spikes.
Considered in: Generalised tonic clonic seizures *beware can exacerbate myoclonic and absence seizures, if these are present this is not suitable.
Adjunctive (add-on): In focal seizures
What other than epilepsy can Carbamazepine be used for?
Prophylaxis in bipolar disorder unresponsive to lithium
Trigeminal neuralgia
Adjunct to acute alcohol withdrawal (unlicensed)
Diabetic neuropathy (unlicensed)
What are the notable pharmacokinetics for Carbamazepine?
INDUCER
* It is metabolised in the liver
*Clearance affected by other drugs causing enzyme induction/inhibition AND by autoinduction of its own metabolism - thus altering the half-life of the drug after continued administration
*Interacts with other AED’s
Monitoring for Carbamazepine?
Before
If Patient is Han Chinese or Thai origin test for allele HLA-B1502 as this increases risk of Steven-Johnson Syndrome
During
1-2 weeks plasma concentration optimum response 4-12mg/L
FBC, LFT, Renal function
Monitor for blood dyscrasias, liver or skin disorders; fever, rash, bruising, mouth ulcers.
Carbamazepine has other formulations what is important when swapping between them?
The other forms aren’t bioequivalent, therefore dose conversions need to be done.
What is the primary indication for Ethosuximide?
First line and adjunctive (add-on) for: Absence seizures, including childhood absence epilepsy.
3rd line for: Epilepsy with myoclonic-atonic seizures (Doose syndrome)
Also: Licensed for myoclonic seizures
What are the notable pharmacokinetics for Ethosuximide?
NON-ENZYME INDUCER
* Metabolised in the liver
What monitoring needs to happen for a patient on Ethosuximide?
Before
Patient counselling on: fever, rash, mouth ulcers, bruising or bleeding development. Also monitoring for suicidal behaviours.
During
FBC
Monitor for any blood dyscrasia’s
What is the primary indication for Lamotrigine?
First line and adjunctive for: Focal seizures, generalised tonic-clonic seizures, absence seizures (If ethosuximide or sodium valproate is not suitable/tolerated), tonic or atonic seizures, idiopathic generalised epilepsy.
Second or third line for: Myoclonic seizures *Caution as can exacerbate these seizures
Also can be an option for: Certain epilepsy syndromes.
What other than epilepsy can Lamotrigine be used for?
Bipolar disorder (monotherapy and as an adjunctive)
Neuropathic pain (unlicensed)
What are the notable pharmacokinetics for Lamotrigine?
Induces own metabolism
* When given with drugs that are hepatic enzyme inducers or inhibitors, the half life of the drug is altered.
=Dosage of the drug needs to be adjusted to accommodate for this.
What needs monitoring in a patient taking lamotrigine?
Counselling of patients on:
-Skin reactions *Hypersensitivity
-Bone marrow failure - anaemia, bruising or infection *Hb, Pale, Weak, SOB
What is the primary indication for Levetiracetam?
First line for: Generalised tonic-clonic seizures, focal seizures, myoclonic seizures, idiopathic generalised seizures.
Second line for: Absence seizures, myoclonic seizures, idiopathic generalised seizures, other epilepsy syndromes.
Adjunctive for: Focal seizures, generalised tonic-clonic seizures, myoclonic seizures.
What are the notable pharmacokinetics for Levetiracetam?
- Oral bioavailability is almost 100% with linear pharmacokinetic profile
*Plasma levels more predictable = no blood monitoring
*Large proportion is excreted through the kidneys unchanged
*Some of the drug is metabolised through hydrolysis and does not involve the CYP450 hepatic isosforms.
What monitoring do patients require on Levetiracetam?
None except for general counselling of AED’s
What is the primary indication for Phenobarbital?
No first line indications
NICE recommends it’s use as an adjunctive (add-on) 2nd line for: generalised tonic-clonic seizures. 3rd line add-on for: focal seizures and myoclonic seizures.
Licensed for all epilepsy types except: Typical absence seizures but as stated, also used in status epilepticus as IV form.
What are the notable pharmacokinetics for Phenobarbital?
ENZYME INDUCER *POTENT
* Partly metabolised in the liver and some is excreted unchanged from the kidneys.
* Crosses the placenta barrier and is present in breast mild
What does a patient need monitoring when on Phenobarbital?
Optimum plasma concentration levels of phenobarbital are 15-50mg/L, however due to tolerance occurring with phenobarbital, measuring these levels may not be as useful as with other AED’s.
Monitor for suicidal behaviours
Skin reactions - report signs and symptoms of a rash or hypersensitivity syndrome
What is the primary indication for Phenytoin?
First line for: nothing
Adjunctive (add on) for: 3rd line in focal seizures
BNF indications states use in tonic-clonic seizures and focal seizures however NICE guidance states that if myoclonic or absence seizures are present phenytoin should NOT be used.
The BNF also states its use in the prevention of seizures during or following neurosurgery or severe head injury.
What else other than epilepsy can Phenytoin be used for?
Trigeminal neuralgia (unlicensed and often under a specialist)
What are the notable pharmacokinetics for Phenytoin?
ENZYME INDUCER
* Highly protein bound (90%)
* Clearance of the drug is through the liver but follows non-linear kinetics (saturation of the clearance pathway occurs at therapeutic dosages) which can have a knock-on effect on the half-life of the drug.
* Available in various formulations - IV, capsules, tablets, lipid
What needs monitoring when a patient is on Phenytoin?
There are certain groups where protein binding may be reduced including:
* Pregnancy
* Elderly
* When given with other interacting medications
*Free plasma-phenytoin concentration may be more appropriate.
Monitor for blood dyscrasias, or skin disorders.
With IV use monitor ECG and blood pressure.
Are different formulations of phenytoin bioequivalent?
NO!! Dose conversions need to happen!
Category 1 AED’s must be prescribed by brand. BRAND MATTERS. What drugs does this include?
- Carbamazepine
- Phenobarbital
- Phenytoin
- Primidone
Category 2 AED’s can be swapped between brands but clinical and non clinical factors must be considered befroe doing this, what are examples of these drugs?
- Clobazam
- Clonazepam
- Eslicarbazapine
- Lamotrigine
- Oxcarbazepine
- Perampanel
- Rufinamide
- Topiramate
- Sodium Valproate
Zonisamide
Category 3 AED’s can be swapped between brands and only non-clinical factors need to be considered, what medications are in this category?
- Brivacetam
- Ethosuximide
- Gabapentin
- Lacosamide
- Levetiracetam
- Pregabalin
- Tiagabine
Vigabatrin
What non-pharmacological treatments are considered for epileptic patients?
Ketogenic diet as it mimics a state of starvation for the brain, forcing the body to break down fat instead of carbohydrates to produce energy. Ketones are produced which contain anti-convulsive properties.
When can AED treatment be withdrawn in a patient and how?
- AED treatment can be discontinued in patients that have been seizure free for at least 2 years
○ The AED needs to be slowly withdrawn over 3 months
○ Patients who are on barbiturates and bezodiazepines, their withdrawal must be much slower (over 6 months) due to withdrawal symptoms and potential seizure recurrence.
If patients are on multiple AED’s one drug must be withdrawn at a time
What type of drug is Carbamazepine?
Enzyme Inducer
What type of drug is Esiclarbazepine?
Enzyme inducer
What type of drug is Oxcarbazepine?
Enzyme inducer
What type of drug is Perampanel at doses 12mg and upwards?
Enzyme inducer
What type of drug is Phenobarbital?
Enzyme inducer
What type of drug is Phenytoin?
Enzyme inducer
What type of drug is Primidone?
Enzyme inducer
What type of drug is Rufinamide?
Enzyme inducer
What type of drug is Topiramate?
Enzyme inducer
What type of drug is Acetazolamide?
Non-enzyme inducer
What type of drug is Clobazam?
Non-enzyme inducer
What type of drug is Clonazepam?
Non-enzyme inducer
What type of drug is Ethosuximide?
Non-enzyme inhibitor
What type of drug is Gabapentin?
Non-enzyme inhibitor
What type of drug is Lacosamide?
Non-enzyme inhibitor
What type of drug is Perampanel at doses of under 12mg daily?
Non-enzyme inhibitor
What type of drug is Lamotrigine?
Non-enzyme inhibitor
What type of drug is Levetiracetam?
Non-enzyme inhibitor
What type of drug is Pregabalin?
Non-enzyme inhibitor
What type of drug is Sodium Valproate?
Non-enzyme inhibitor
What type of drug is Tiagabine?
Non-enzyme inhibitor
What type of frug is Topiramate?
Non-enzyme inhibitor
What type of drug is Vigabatrin?
Non-enzyme inhibitor
What type of drug is Zonisamide?
Non-enzyme inhibitor
What contraceptive methods should be used for non-enzyme inducers? Except Lamotrigine
Normal contraception methods can be used as if they were not on a AED
What contraception must NOT be used for Lamotrigine?
Combined oral contraceptive as it decreases the effectiveness of lamotrigine!
What contraception can be used when a patient is taking enzyme inducers?
- Progesterone only depot injection
- Levonorgestrel intrauterine device
- Copper intrauterine device
- Exceptional circumstances: combined oral contraceptive with a specific regime.
Anything with ethinylestradial needs to have 50mcg++ daily and use of an extended or tricycling regimen followed by a 4 day break instead of 7 days, this option is unlicensed.
What contraception must NOT be used on enzyme inducers?
NOT APPROPRIATE CONTRACEPTION:
* Oral progesterone only pills
* Progesterone only implants
Combined oral contraceptives with less than 50mcg of ethinylestridiol
How long does an enzyme inducing AED continue to have its effect once withdrawn?
4 weeks, contraceptive methods must be continued during this time!
If a patient is on enzyme inducing AEDs and they need emergency contraception, what should be done?
1st copper IUD
2nd Levonorgestrel 1.5mg tablets, the dose should be doubled to provide cover if the Copper IUD is not suitable or acceptable for the patient
What AEDs are safe in pregnancy?
Lamotrigine and Levetiracetam
What AEDs are NOT safe in pregnancy?
Carbamazepine, Phenobarbital, Phenytoin or Topiramate
What can taking Phenytoin or Phenobarbital during pregnancy increase the risk of?
Difficulty with leading and thinking ability *Neurodevelopmental adverse effects.
What medications can cause a baby to be born smaller than expected compared to the general population?
Phenobarbital, Topiramate or Zonisamide
What can long term AEDs have an effect on?
-Bone loss, reduced bone density and risk of osteoporosis and fractures.
If on multiple AEDs, for long periods of time bone health issues are increased!!
What AED’s need vitamin D levels monitoring?
Carbamazepine, Primidone, Sodium Valproate, Phenytoin.
What are seizures caused by?
Unregulated neuronal discharge in the brain. -Action potentials firing within neurons in an uncontrolled manner.
What type of seizure is caused by localised structural abnormalities (lesions)?
Focal
What type of seizure are caused by a chain reactions of depolarisations and synaptic activity, affecting the whole brain? *Waves of activity spready from the focal centre.
Generalised seizures
If a seizure cased Autonomic responses to occur such as incontinence, what part of the brain could be affected?
Hypothalamus
If consciousness is lost within a seizure, what part of the brain is affected?
Reticular system
What inhibitory neurotransmitter when imbalanced causes a seizure?
GABA
What excitatory neurotransmitter when imbalanced causes a seizure?
Glutamate
When GABA is released what happens?
Release of GABA, meaning action potential at GABA a preventing convulsions
Where do neurons display a sudden depolarisation?
In the focal area
Where does hyperexcitability occur, which can cause seizures?
Focal area
What type of Seizures are caused by Oscillatory feedback between cortical and thalamic neurons and involve activity of T-type voltage-gated Ca2+ channels?
Absence Seizures
Can epilepsy be genetic?
About 2% of cases are due to specific mutations
Why do the medications used for epilepsy have different modes of actions?
The drugs were found by luck
What are the most common mechanisms for epilepsy drugs?
- Enhanced GABA transmission
-Inhibition of Na+ channels
-Inhibition of Ca2+ channels
What does the release of GABA do in the brain?
STOPS excitatory in the brain
What happens if GABA is inhibited?
Convulsions
if GABA is blocked in the pre-synaptic terminal what happens?
Enhance the amount of GABA
What drug group is this the MOA for
‘Potentiate oping, GABA ad Benzo together increase the time they are open, = Increase the amount of Cl, facilitating the inhibitory effect.’
Benzodiazepam’s
What drug group is this MOA for?
‘Act at separate site, channel modulator, channel open for longer, enhancing the Cl_ influx, hyperpolarisation is enhanced, inhibitory action is enhanced on the post synaptic neuron.
Barbiturates
What drug, despite the name doesn’t act at GABA?
Gabapentin - it acts at P/Q-type Ca2+ channels
What drug is a GABA transaminase inhibitor, therefore increasing the amount of GABA available for release?
Vigabatrin
What drug increases the amount of GABA in the brain? but the exact mechanism is unclear?
Valproate
What drug blocks GAT1, therefore GABA remains in the synapse longer and the stimulation of downstream GABA receptors therefore can have inhibitory effects in the post synaptic cell?= More GABA
Tiagabine
Several antiepileptic drugs inhibit voltage-gated sodium channels, therefore stopping action potentials and therefore the spread of neuronal activity across the brain, what are examples of these?
Valproate, Phenytoin, Carbamazepine, Lamotrigine, Rufinamide, Lacosamide,
What does exhibiting use-dependency mean?
You need action potentials, which STOP the high frequency of action potentials blocking sodium.
What does a slow recovery from inactivation mean?
Inactivated = closed channel, drugs can bind and remain in an inactivated state for longer
What drugs inhibit the T-type calcium channels?
Ethosuximide, Valproate, Clonazepam
What type of seizure are drugs that inhibit T-type calcium channels?
Absence seizures
What drug, binds to the synaptic vesicle protein SV2A, affecting the release of neurotransmitters?
Levetiracetam
What drug inhibits glutamate receptors, as well as enhancing GABA receptors and blocking Na+ channels?
Phenobarbital
What drug blocks AMPA receptors (as well as blocking Na+ and Ca2+ channels and enhancing action of GABA?
Topiramate
What drug was designed as an AMPA antagonist and is one of the most recently introduced antiepileptic drugs?
Perampanel
The balance of what neurotransmitter is most associated with the pathophysiology of epilepsy?
Glutamate and GABA
Seizures that involve loss of consciousness affect which part of the brain?
The reticular system
What AED’s exhibits use-dependency?
AED’s which act at voltage-gated Na+ channels
What AED’s preferentially act at neurons that are repetively firing?
AED’s which act at voltage-gated Na+ channels
What AED has action at voltage-gated Na+ channels?
Valproate
What is the pharmacological target of Vigabatrin?
GABA Transaminase
What is the pharmacological target of Tiagabine?
GAT1 Transporters
What are EPSE side effects?
acute dyskinesias and dystonic reactions, tardive dyskinesia, Parkinsonism, akinesia, akathisia, and neuroleptic malignant syndrome
