Week 11 - Epilepsy Flashcards
Epilepsy Background INFO
Seizures occur due to imbalance of excitatory (glutamate) and inihibitory (GABA) n.transmitters
- too much excitation causes seizures
- MOST commonly diagnosed in children and elderly
- Mortality rate is 2-3x higher than general population
- due to SUDEP (sudden unexpected death in epilepsy) - Up to 70% may become seizure free
- others may experience refractory epilepsy (diff. to treat + still have seizures)
NOTE:
- 1 seizure does NOT = epilepsy
- need to have recurrent seizures
What are the potential causes of epilepsy
Many cases have NO identifiable causes
- change occurs causing ABNORMAL neuronal firing
- Genetic (MOST common)
- gene abnormalites - Structural brain abnormalities
- CNS infection
- can cause inflammation of brain = damage brain - Metabolic
- Immune
- autoimmune brain inflammation - Unknown
Seizures CAUSED BY:
- loss of balance between excitation (glutamate) and inhibition (GABA or Na+ channel inactivation)
- glutamate + GABA are major n.transmitters in CNS
What is autoimmune epilepsy
Epilepsy trigger by own body’s immune system which mistakenly attacks components of the brain
- leading to inflammation + damage to the brain
- can occur in pts with underlying immunse disorders
How is autoimmune epilepsy treated
Most pts are already on AEDs (not very beenficial)
- will keep them on this for symptomatic relief but AIM is to taper down + discontinue
TREATMENT:
1. IV corticosteroids (methylprednisolone)
- supresses inflammation + stablises patient
2. IV immunoglobulins (IG)
3. Plasma exchange
- used in critically ill
4. Immunosupressive medication
- e.g. Rituximab or Cyclophosphamide
What is paraneoplastic autoimmune epilepsy
A subtype of autoimmune epilepsy
Epilepsy that occurs due to cancer (tumour in CNS)
- immune system is triggered by presence of tumours = autoantibody production
- antibodies attack neuronal antigens in brain
- antibodies can disrupt normal neuronal function leading to seizures
How is paraneoplastic autoimmune epilepsy treated
FIRSTLY identify and treat cause of tumour
THEN SAME TREATMENT (as autoimmune):
1. IV corticosteroids (methylprednisolone)
- supresses inflammation + stablises patient
2. IV immunoglobulins (IG)
3. Plasma exchange
- used in critically ill
4. Immunosupressive medication
- e.g. Rituximab or Cyclophosphamide
How is epilepsy diagnosed
- Need to identify if patient actually had a seizure of if it was something else
- Diagnosis is made by specialist based on:
- medication history (overdose, illegal drugs, meds. that lower seizure threshold)
- family history (genetic)
- descritpion of attack (video / witness)
- blood tests (infection markers)
- ECG (cardiac cause?)
Misdiagnosis inc:
- acute symptomatic seizure
- seizure is a result of something else
- e.g. head injury, infection
- migraine with aura
- inflammation of brain (enchephalitis)
- non-epileptic attack
What are the different types of seizures
Not 1 type of epilepsy, some can be characterised by diff. seizure types
- Focal seizures
- caused in 1 specific part of brain
- can become focal with secondary generlisation when electrical activity starts at focues then spreads throughout brain - Generalised tonic clonic seizures
- most common
- all muscles tense up = tonic
- broad, repetitive movement = clonic - Absence seizures
- stop and stare into space for few min. then snap back like nothing happened
- common in kids
- gets misdiagnosed as daydreaming - Myoclonic seizures
- limb jerking e.g. involuntary twitch - Atonic and tonic
- atonic = all tone in muscle goes
- tonic = ↑ in muscle tone
NOTE:
- Diff. seizure types are treated with diff. drugs
How is epilepsy drug treatment initiated
Initiated by: Specialist AFTER a diagnosis
- when choosing drug consider: age, gender, lifestyle, co-morbodity, SE profile, fomrulation, interactions
- re-iterate importance of compliane (even when seizure free)
AIMS:
1. Monotherapy
- only add on drugs if tried 2 monotherapies + both failed
2. Use LOWEST dose possible
- start low + titrate up (prevents SE)
3. MIN. side effects (SE)
- AEDs are NOT started after 1st seizure
- only if recurrent OR MRI scan shows have ↑ chance of another seizure
How is epilepsy drug treatment withdrawn
Occurs under guidance of a SPECIALIST
- MUST be SEIZURE FREE for 2 YEARS before its considered
- Do NOT stop abruptly to avoid risk of rebound seizures
- withdrawal occurs slowly over months
- if on comibination therapy remove one drug at a time - Joint decision by patient and family/carers
- Consider SUDEP risk
- Need to have failsafe plan in case seizure re-occur
List the 4 MoA of Anti-epileptic Drugs (AED) and their drugs
GO BACK TO SLIDE 6
- Enhance GABAergic transmission
- Inhibit excitatory neurotransmission (Glutamate)
- Reduce cell memembrane permeability to Na+ channels
- Reduce cell membran permeability yo Ca2+ channels
Explain how drugs that “Enhance GABAergic transmission” work
When GABA is released into synapse it actiavtes diff. GABA receptors on post-synaptic neurone = further inhibition
- passes on inhibitory signal = dampens excitatory firing in post-synaptic neurone
DONE via:
- ↑ synthesis of GABA
- synthesis is mediated by glutamic acid decarboxylased (GAD)
- ↓ breakdown of GABA
- inihibt GABA-T (transaminases) - ↓ re-uptake of GABA (from synapse)
- inhibit GATs (GABA transporters) on pre-synaptic neurone
- GAT-1, GAT-2, GAT-3, GAT-4 - Use GABA agonists
- act straight on GABA receptor
Explain how drugs that “Inhibit excitatory neurotransmission (Glutamate)” work
Inhibits the opening of Na+ and Ca2+ channels on the pre-synaptic neurone = ↓ post-synaptic excitation
- Drug competes with glutumate for binding site on NMDA or AMPA receptors
When drug antagonist binds to:
1. NMDA = ↓ Ca2+ influx (and Na+)
- prevents exocytosis
- usually NMDA channel is blocked by Mg2+
2. AMPA = ↓ Na+ influx (and Ca2+)
- prevents depolarisation
- when glutumate binds to AMPA receptor = Mg2+ is lost from NMDA = NMDA channel opens
Explain how drugs that “Inhibit Na+ channels” work
Inihibiton = NO depolarisation = NO AP fired = NO neurotransmitter (e.g. glutumate) released
- Drug slows down fast ion transmission
- Drug prevents depolarisation
NOTE:
Occurs at pre-synaptic neurone
Explain how drugs that “Inhibit Ca2+ channels” work
Inhibition = NO influx of Ca2+ = NO exocytsosis of vesicles containing n.transmitter (e.g. glutumate) = NO release
- Drug dampens release of n.transmitter
- Drug prevents excitatory signal being passed on
NOTE:
Occurs at pre-synaptic neurone
List the pharmacological treatments for common types of seizures
- Sodium valporate
- Carbamazepine
- Lamotrigine
- Levetiracetam
- Phenytoin
- Medical Cannabis
Explain how Sodium valporate works in treating seizures
1st line in Tonic clonic and Myoclonic seizures
MoA:
- Ca2+ channel blocker
- Acts on GABA
DOSE: twice daily
- due to 8-20hr half life
SE: nausea, diarrhoea, weight gain, hair loss, hyponatraemia
NOTE:
- is an enzyme inhibitor = causes interactions = dose adjustments necessary
- extensive metabolism
- high protein binding = interactions if displaced from protein
Explain how Lamotrigine works in treating seizures
1st line in Focal seizures
MoA:
- Na+ channel blocker
- glutamate inhibitor
Dose: low dose then ↑ slowly due to SE
- can take up to 8 weeks to get to good therpeautic level of drug
SE: N&V, diarrhoea, skin reactions (can be severe), dry mouth
NOTE:
- extensive metabolism + induces its own metabolism
- effectiveness can be reduced by EHC and oral contraceptives
- SAFER in PREGNANCY
-
Explain how Carbamazepine works in treating seizures
2nd / 3rd line in Tonic clonic and Focal seizures
MoA:
- Na+ channel blocker
Dose: MR tablets recommened
SE: headache, N&V, drowsiness, dizziness, rash, hyponatreamia
NOTE:
- Induces its own metabolism (shortens its t1/2 to similar level of valporate)
- CYP3A4 inducer
- If on CONTRACEPTIVE PILL AVOID this AED is an enzyme inducer = pill is less effective
Explain how Levetiracetam works in treating seizures
Used in multiple seizure types
MoA:
- Binds to synaptic vesicle 2A protein
Dose: twice daily
- has 7hr t1/2
SE: fatigue, dizziness, headache, low mood / depression, irritability, mood / behaviour changes
NOTE:
- rapid absorption
- little metbolism
- less interactions, has less effect on liver enzymes
- SAFER in PREGNANCY
- mainly excreted via urine
Explain how Phenytoin works in treating seizures
NOT 1st line | Used in refractory seizures and status epilepticus
MoA:
Dose:
SE: N&V, consitpation, drowsiness, gingival hyperplasia, acne
- bad SE hnce why not 1st line
NOTE:
- Requires therapeutic monitoring due to NARROW THERAPEUTIC INDEX
- Extensive liver / hepatic metabolism
- Inducer of CYP450 = interactions
- on CONTRACEPTIVE PILL = AVOID this AED = pill is less effective
- Highly protien bound (to albumin)
Explain how Medical Cannabis works in treating seizures
Called “Epidyolex”
Newer drug + ONLY offered if tried 2 other tretaments + failed
MoA: Unknown
- stabilises membrane excitability
Dose:
SE: avoid use in children
NOTE:
- drug contains pure CBD
- treats 2 epilepsy syndromes (dravet and lennox-gastaut)
- extensively metabolised in liver
- need to monitor LFTs
- is an inhibitor AND inducer of CYP3 enzyme
What are side effects associated with commonly used drugs in epilepsy
- GI effects
- N&V
- diarrhoea
- constipation
- Dizziness / drowsiness
- Headaches
- Skin reactions e.g. rash
- Fatigue
- Changes in mood / behaviour
- depression
- low mood - Hyponatremia
- Weight gain
- Hair loss
What is convulsive status epilepticus and its causes
Is a MEDICAL EMERGENCY, if not treated quickly = ↑ morbidity and mortality rates
- seizure lasts longer than 5 minutes OR occur one after the other with no recovery in between
- non-convulisve is NOT and emergency
CAUSE:
- hypoxia
- stroke
- metabolic abnormalities
- poor adherance to AEDs
- alcohol intoxication / withdrawal
How is status epilepticus treated: NICE Guidelines
AIM: stop seizure + manage underlying cause of seizure occurence
- Adminster Lorazepam 4mg (adult)
- or other BDZs
- child = lower dose - IF seizure CONTINUES administer ANOTHER DOSE of Lorazepam
- given after 10-20 mintues - IF seizure CONITUNES administer loading dose of either:
- Sodium valporate
- Levetiracetam
- Phenytoin - IF seizure continues administer another loading dose
- diff. to the one used previously
If this isnt patients 1st experience prescribe:
- rectal diazepam OR buccal midazolam
- non oral as patient cant swallow durign seizure
Women and Epilepsy INFO
Includes: contracpetive, valporate + pregnancy, PPP
- Some AEDs are inducers of enzyme = contrcaeptive pill becomes less effective
- Lamotrigine becomes lees effective due to EHC and oral contraceptives
- Valporate cause ↑ risk of birth defects + development disorders
- ↑ autism and ADHD rate
- need to be on highly effective birth control
- NOT used unless pregnancy prvention programme (PPP) is in place
PPP:- talk to patients about risks if they were to become pregnant
- valpoarte ONLY prescibed if other treatments are ineffective / not tolerated
- if become pregnant treatment must NOT be STOPPED, refer to specialist
- AED doses may need to be altered in pregnancy
- ALL women on AEDs should be OFFERED FOLIC ACID 5mg OD before possibility of pregnancy
NOTE:
- take drug level before pregancny to know their baseline
Valporate and Men
- Causes testicular toxicity + infertility
- infertility is reversible 3 months after stopping treatment - NOT started in men <55 UNLESS 2 specialist agree
- Teratogenic risks = children fathered to men on valporate may have birth defects
Why might epilepsy treatment fail
- Adherance to AED / compliance
- Interactions (inducers / inhibitors)
- Drug is treating wrong seizure type
- Alcohol / drug misuse
How is treatment failure managed
- Change from 1st line to 2nd line treatment
- If both monotherapy failed, then add on a second drug (combination therapy)
- ONLY initiated by specialist
- if combination therapy fails go back to treatment that had best TOLERABILITY and EFFICACY
What are the problems with combination therapy
- Drug interactions
- due to being on many meds
- can be inducers / inhibitors of liver / hepatic enzymes - Increased toxicity
- ↑ SE
-↑ interactions - Difficult to identify what drug is causing what ADRs
- Non-compliance
- ↑ pill burden (more tablets)
- bad SE
