Epilepsy Flashcards
What is a seizure?
Transient occurrence of signs/symptoms due to abnormal activity in the brain, leading to a disturbance of consciousness, behaviour, emotion, motor function or sensation
- clinical manifestation of abnormal and excessive excitation and synchronisation of a group of neurones within the brain
- so a loss of GABA signals or too strong an excitatory Glutamate ions
What can cause seizures?
- genetic differences in brain chemistry/receptor structure: genetic epilepsy syndromes
- by exogenous activation of receptors-drugs (something that normally isnt there, activates the receptors)
- acquired changes in brain chemistry: drug withdrawal, metabolic changes
- damage to any of these networks: strokes, tumours
What are the symptoms and signs of a seizure?
- loss of consciousness often (but not always) with changes in muscle tone, tongue biting
- for tonic-clinic seizures initial hypersonic phase, followed by rapid clonus (shaking/jerking)
- post-ictal period present: can last minutes to hours
- often an aura prior to seizure (like déjà vu)
- may be more varied or subtle depending on type of seizure
What is epilepsy?
- repeated series of seizures that is unprovoked by a systemic or neurological insult
- not only a disease of the young, over 60s almost as common (increases as they age due to cerebrovascular disease)
- must have at least 2 unprovoked seizures occuring more than 24 hours a apart
- one unprovoked seizure and probability of further seizures (at least 60% over the next 10 years)
- diagnosis of epilepsy syndrome
What are the types of reflex seizures?
- brough by a particular stimulius
- photogenic
- musicogenic
- thinking
- eating
- hot water immersion
- reading
- orgasm
- movement
What are the classifications of seizures?
- focal onset: aware and impaired awareness, motor and non motor onset
- Generalised onset: motor (tonic-clinic, myoclonic, atonic) and non motor (absence)
- Unknown onse
What are generalised seizures?
- no consciousness at all
- originate at some point within and rapidly engage bilaterally distributed networks
- can include cortical and subcortical structures but not necessarily the entire cortex
What are focal seizures?
- originate within networks limited to one hemisphere
- may be discretely localized or more widely distributed
- only spread locally, gives unilateral motor symptoms, can be conscious
What are provoked seizures?
- seizures as a result of another medical condition such as:
- drug use or withdrawal
- alcohol withdrawal
- head trauma and intracranial bleeding
- metabolic disturbances
- CNS infections
- febrile seizures in infants
- uncontrolled hypertension
What are the differential diagnoses of seizures?
- syncopal episodes (ex. Vasovagal syncope)
- cardiac issues including reflex anoxia seizures, arrhythmia
- movement disorders (ex. Parkinson’s, Huntington’s)
- TIA
- Migraines
- non-epileptic attack disorder (formerly pseudo-seizures) which often occurs in druggies
What is the initial management of a seizure?
ABCDE Airway Breathing Circulation Disability E: recovery position
When do you give drugs to terminate a seizure?
- wait after 5 minutes
- most seizures will self terminate
What is status epilepticus?
- seizure of any variety lasting 5 min or more, or multiple seizures without a complete recovery between them
- status is a medical emergency
What is the pharmacological treatment for Status?
- wait 5 minutes
- benzodiazepine
- benzodiazepines again
- phenytoin (or maybe Levetiracetam?)
- thiopentone/anaesthesia (call intensive care)
Benzodiazepines as treatment for Status Epilepticus (lorazepam, midazolam, diazepam)
- GABA agonists so work best when membrane positive in order to hyperpolarize (in seizures)
- work best as a preventative measure
- no firing neurones=no more seizures
What inevestigstions can you do for epilepsy?
-EEG
-record of electrical pattern of activity in the brain
Imaging
-MRI
-can detect vascular or structural abnormalities
Carbamazepine (Tegretol)
- sodium channel blocker
- also used for bipolar and sometimes chronic pain
- side effects: suicidal thoughts, joint pain, bone marrow failure
Phenytoin
- sodium channel blocker
- used mainly in status epilepticus or as an adjunct in generalised seizures
- has zero order kinetics so no half life (care when adjusting doses)
- specific side effects: bone marrow suppression, hypotension, arrhythmia (give IV)
Sodium Valproate (Epilim, Depakote)
- probably a mix of GABAa effects and sodium channel blockade
- 1st line for GENERALISED epilepsies
- specific side effects: liver failure, pancreatitis, lethargy
- really old and dirty drug
Lamotrigine
- primarily a sodium channel blocker, may also affect calcium channels
- good for focal epilepsy
- used often where valproate contraindicated in generalised epilepsy
Levetiracetam (Keppra)
- novel MOA and is well tolerated
- synaptic vesicle glycoprotein binder, stops the release of neurotransmitters into synapse and reduces neuronal activity
- option for focal seizures and generalized seizures
- anecdotally being use more frequently, easy dosing and well tolerated
- safe in pregnancy
What are the side effects of AEDs?
- tiredness/drowsiness
- nausea and vomiting
- mood changes and suicidal ideation
- osteoporosis
- rashes including Steven Johnson syndrome (most likely caused by carbamazepine or phenytoin)
- many can cause anaemia, thrombocytopenia or bone marrow failure
What should patient do regarding the side effects?
- patients on anti-epileptics and warfarin will need close monitoring
- ideally patients on AEDs shouldn’t consume alcohol
- carbamazepine and phenytoin ay decrease the effectiveness of oral contraceptive pills and some antibiotics
- valproate can increase the plasma conc. Of other AEDS
- newer AEDs have less side effects, or are metabolised in other ways (Levetiracetam)
What are some DDIs with AEDs?
CYP inducers
- phenytoin
- carbamazepine
- barbituates
CYP inhibitors
-valproate
What drug has the greatest risk of congenital malformations?
- valproate
- shouldn’t be prescribed to any woman of child-bearing age
- if prescribed, women must have hysterectomy and on a highly effective contraceptive
- lamotrigine and Levetiracetam are safest
What is the pathology iof Idiopathic Parkinson’s Disease
- neurdegneration
- lewy bodies (synucleinopathy)
- loss of pigment: 50% loss leads to symptoms, increased turnover, upregulate receptors
- reduced dopamine
What are the drug classes in IPD?
- levodopa (L-DOPA)
- dopamine receptor agonists
- MAOI type B inhibitors
- COMT inhibitors
- anticholinergic
- amantidine
Why do we not just use dopamine in IPD??
- dopamine cannot cross BBB
- L—DOPA crosses by active transport and is absorbed by active transport
Levodopa (L-DOPAMINE)
- must be taken up by dopaminergic cells in substantia nigra to be converted to dopamine
- fewer remaining cells means less reliable effect of l-dopa
- given oral
- absorbed by active transport
- 90% inactivated in intestinal wall by monoamine oxidase and DOPA decarboxylase
- half life of 2 hours so must be given frequently
- 9% converted to dopamine in peripheral tissues by DOPA decarboxylase
- <1% enters CNS
What are the formulations of L-DOPA?
- used in combo with PERIPHERAL DOPA decarboxylase inhibitor:
- co-careldopa (Sinemet)
- co-beneldopa (Madopar)
- reduced dose required
- reduced side effects
- increased L-DOPA reaching brain
- given in tablet formulations only
- standard dosage-variable strengths
- controlled released preparations
- dispersible Madopar (not soluble)
What are the advantages and disadvantages of L-DOPA?
Advantages
- highly efficacious
- low side effects: nausea/anorexia, hypotension, psychosis, tachycardia
Disadvantages
- precursor: needs enzyme conversion
- long term: loss of efficacy, involuntary movements, motor complications
What are the interactions of L-DOPA?
- pyridoxine (vitamin B6) increases peripheral breakdown of L-DOPA
- MAOIs risk hypertensive crisis
- many antipsychotic drugs block dopamine receptors and Parkinsonism is a side effects (newer, “atypical” antipsychotics less so)
Dopamine Receptor Agonists
- non ergot: ropinirole, pramipexole
- patch: rotigotine
- subcutaneous: apomorphine
- first line therapy
- add on therapy
- apomorphine: only for patients with severe motor fluctuations
What are the advantages and disadvantages of dopamine receptor agonists?
Advantages
- direct acting
- less dyskinesia/motor complications
- possible neuroprotection
Disadvantages
- less efficacy than L-DOPA
- impulse control disorders
- more psychiatric s/e (dose limiting)
- expensive
What are some impulse control disorders (dopamine dysregulation syndrome)
- pathological gambling
- hypersexuality
- compulsive shopping
- desire to increase dosage
- punding
What are the side effects of dopamine receptor agonists?
- sedation
- hallucinations
- confusion
- nausea
- hypotension
- secondary narcolepsy
MAOI type B inhibitors (selegiline, rasagaline)
Monoamine oxidase B
- metabolised dopamine
- predominates in dopamine containing regions in brain
- MAOB inhibitors enhance dopamine
Monoamine Oxidase B inhibitors
- can be used alone
- prolonged action of L-DOPA
- smooths out motor response
- may be neuroprotective
What are COMT inhibitors
- reduces the breakdown of L-DOPA
- but has no therapeutic effect on its own
- entacapone: doesnt cross BBB
- reduce peripheral breakdown of L-DOPA to 3-O-methyldopa since 3-O-methyldopa competes with L-DOPA active transport into CNS
- no therapeutic effect alone
- can use combination tablets COMT inhibitor and L-DOPA and peripheral dopa decarboxylase inhibitor (Stalevo)
- have L-DOPA “sparing” effect
- prolongs motor response to L-DOPA (reduces symptoms of “wearing off”)
What are anticholinergics?
- may have antagonistic effects to dopamine
- trihexyphenidydyl
- orphenadrine
- procyclidine
- minor role in treatment of pD
- not very useful because it doesnt solve the main problems in PD: Bradykinesia and PD
What are the advantages and disadvantages of anticholinergics?
Advantages -treat tremor -not acting via dopamine systems Disadvtanges -no effect on bradykinesia -side effects: confusion, drowsiness, usual anticholinergic s/e, blurred vision, urinary retention
Amantadine
- MOA uncertain
- possibly enhances dopamine release or anticholinergic NMDA inhibition
- poorly effective
- few side effects
- little effect on tremor
- not used as much anymore
Surgery for IPD
- carried out stereotactically
- of value in highly selected cases: must be dopamine responsive, significant side effects with L-DOPA, no psychiatric illness
- controlled trials
- Lesion: thalamus for tremor, GPi for dyskinesia
- deep brain stimulation: subthalamic nucleus
What is Myasthenia Gravis?
- fluctuation, fatiguable, weakness in skeletal muscle
- commonly presents in extraocular muscle (get double vision and ptosis)
- bulbar involvement: dysphagia, dysphagia, dysarthria
- limb weakness: proximal symmetric
- respiratory muscle involvement: will get type 2 resp failre
What are the drugs affecting neuromuscular transmission which exacerbates Myasthenia Gravis?
- aminoglycosides
- beta-blockers
- CCBs
- quinidine
- procainamide
- chloroquine, penicillamine
- succinylcholine
- magnesium
- ACE inhibitors
What is the therapeutic management of myasthenia gravis?
Acetylcholinesterase inhibitors
- enhance neuromuscular transmission
- skeletal and smooth muscle
- excess dose can cause depolarizing block: cholinergic crisis
- cholinergic side effects
Pyridostigmine-oral
Neostigmine- oral and IV preparations (ITU)
- quicker action, duration up to 4 hours
- significant cholinergic side effects
Pyridostigmine
-prevents breakdown of ACh in NMJ
-ACh more likely to engage with remaining receptors
-onset 30min; peak 60-120min; duration 3-6hours
-dose interval and timing crucial
-give several times a day
Cholinergic side effects: miosis and the SSLUDGE syndrome
Salivation
Sweating
Lacrimation
Urinary incontinence
Diarrhoea
GI upset and hypermotility
Emesis
What is a DAT scan?
- labelled tracer
- presynaptic uptake
- abnormal in PD
- not diagnostic
- tremor
- neuroleptic
- vascular
