CNS Flashcards
Define seizure
Manifestation of inappropriately raised cortical electrical activity
Power surge of neural activity in the brain
Define epileptic seizure
A transient occurrence of symptoms due to abnormal excessive or synchronous neuronal activity in the brain
Define epilepsy
A disorder of the brain characterised by an enduring predisposition to generate epileptic seizures and by the neurobiologic, cognitive, psychological and social consequences of this condition
Need to have had more than one seizure to have epilepsy
What are some reasons for having a single / first seizure
Head Injury
Alcohol withdrawal
Drugs
Metabolic disturbance
Stroke
Onset of epilepsy
Tumour
Infection
Diabetes complication
What is epileptogenesis
The process by which a brain network that was previously normal is functionally altered toward increased seizure suscpetibility, thus having an enhanced probability to generate spontaneous recurrent seizures
In what ways are epileptics brains more excitable
Structurally:
- tumours
- scars
Congenital
- channelopathies (genes for ion channels)
- abnormal neural networks
What are the 2 main types of seizures
Generalised - spread across whole cerebral cortex
Focal - exist in one hemisphere or part of one hemisphere
How can focal seizures be divided
Simple focal : consciousness spared. Usually in frontal or occipital lobe
Complex focal : consciousness affected. Usually in temporal lobe
How can generalised seizures be divided
Tonic clonic
Myoclonus
Absence
Consciousness always affected
Sometimes simple focal or complex focal can spread to other parts of the brain and manifest as generalised tonic clonic
What to expect with a simple focal seizure
Same as an epileptic aura
No consciousness impairment
Focal epileptic discharge
What are the 3As in terms of complex focal seizures
Aura: may be initially fully conscious
Altered consciousness: usually partially responsive
Automatisms:
- lip smacking
- teeth grinding
- fiddling with clothes and objects
What are some typical characteristics of a complex focal seizure
Wandering, pacing, circing
Absence common but typically not the sole feature
Typically the most bizarre seizure type
Longest in duration (several mins - 1 hr)
Variable disorientation afterwards, amnesia for the event
What are the classic symptoms of a frontal lobe seizure
Thrashing of the arms,
Losing control of the bladder or bowels
Classic symptoms of a temporal lobe seizure
Plucking at clothes
Smacking lips
Classic symptoms of a occipital lobe seizure
Flashes of light
Brief loss of vision
Classic symptoms of a parietal lobe seizure
Tinging / warm feeling down one side of the body
Features of a generalised seizure
Very brief (1sec)
Shock like
Muscle contraction
Usually bilateral
Falls
Full immediate recovery
Loss of consciousness too brief to be appreciated
Features of absence seizures
Brief (<10 sec)
Abrupt loss of consciousness
Vacant stare
Speech arrest
Usually no motor signs
Tone unaffected
Full immediate recovery
Unaware of episode
Often missed / misinterpreted as daydreaming
Features of a generalised tonic clonic seizure
Possible aura
Ictus
Clonic phase:
- jerking limbs
- reducing frequency
- intermittent / suspended breathing
- tongue bitten
- urinary incontinence
Afterwards: drowsy, disoriented, out of sorts
What do anti-epileptic drugs target
Sodium channels
Block the channels when there is excess activity
They prolong the inactivated state of the channel
Block increases with repetitive activation
Reduces burst firing
What are the 3 main anti epileptic drugs that target sodium channels
Carbamazepine and Lamotrigine - can also block pre synaptic calcium channels
Phenytoin
When is carbamazepine used
In focal and generalised tonic clonic seizures
Not used in absence of myoclonic seizures as can exacerbate these
Slow release preparation to avoid plasma peaks in drug of narrow therapeutic range
When is carbamazepine contraindicated
In patients with acute porphyria’s, unplaced AV conduction abnormalities or history of bone marrow depression
Use with caution in patients with cardiac disease or angle closure glaucoma
Increased risk of major congenital malformations in the fetus if taken during pregnancy in 1st trimester
When is Lamotrigine used
Focal and generalised tonic clonic seizures in adults and children
Can cause skin rashes which are occasionally severe
Safer to take in pregnancy than carbamazepine
When is Lamotrigine contraindicated
In patients with myoclonic seizures or Parkinson’s disease as can exacerbate these
Use with caution in patients with brugada syndrome (heart block)
When is phenytoin used
Focal and generalised tonic clonic seizures
Also used IV to treat status epilepticus
When is phenytoin contraindicated
In patients with acute porphyria’s
IV use contraindicated in patients with heart block, sinus bradycardia and stokes adams syndrome
Use with caution in patients with absence and myoclonic seizures as can exacerbate these
Cross sensitivity with carbamazepine
Can cause antiepileptic hypersensitivity syndrome
Increased risk of congenital malformations in the foetus if taken during pregnancy
Which other anti epileptic drugs promote inhibition
Benzodiazepines such as lorazepam, midazolam, clonazepam and clobazam
- enhance CI- current as GABA receptors
When are midazolam and lorazepam used
In emergency situations such as status epilepticus or febrile convulsions
Buccal administration for midazolam
Slow IV administration for lorazepam
When are midazolam and lorazepam contraindicated
Similar to benzodiazepines
- avoid abrupt withdrawal of drug
Avoid in patients with resp disease
Avoid in patients with history of alcohol or substance misuse
When is clonazepam used
Suitable for all forms of epilepsy in adults and children
NOT the same as clobazam which is an adjunctive therapy in epilepsy.
When is clonazepam contraindicated
Similar to other benzodiazepines
- avoid abrupt withdrawal of drug
- avoid in patients with resp disease
- avoid in patients with history of alcohol or substance misuse
- avoid clonazepam in patients with acute porphyria
What is valproate
An inhibitor of GABA transaminase - ultimately reducing GABA metabolism and increasing GABAergic neurotransmission
Not widely understood - complex pharmacology
When is sodium valproate / valproic acid used
Suitable for all forms of epilepsy in children and adults
- very effective
- good side effect profile
- avoid in hepatic impairment
When is sodium valproate / valproic acid contraindicated
Not used in female patients of childbearing age unless the conditions of the pregnancy prevention programme are met and there is no suitable alternative medication
Highly teratogenic 30-40% risk of neurodevelopmental disorders and 10% risk of major congenital malformation
Also not safe to take while breast feeding
Which anti-epileptic drugs are enzyme inducers and what effects does this have
Carbamazepine, phenytoin and topiramate
They increase the metabolism of oestrogen and progesterone so can make contraceptives less effective by reducing hormone levels up to 50%
Progesterone only contraception is not recommended and patients taking combined pill should be counselled about dosage
Barrier methods also recommended in addition
How can enzyme inducers have affects in ways other than contraceptives
Can interfere with the metabolism of some chemotherapeutic agents resulting in poorer outcomes
Can reduce bone health through their effects on vit D metabolism, leading to reduced bone mineral density and an increased risk of osteoporosis and bone fracture
Can also increase the metabolism of several antidepressants and antipsychotic drugs leading to less effective treatment
How to counsel a patient on anti epileptics about suicidal thoughts
Increased risk with any AED of suicidal thoughts and behaviour
Patients and carers should be advised to seek medical advice if any mood changes, distressing thoughts or feelings about suicide or self harming tendency
Also should be advised not to stop or switch antiepileptic treatment and to seek advice from healthcare professional if concerned
What are the core symptoms of clinical depression
2 weeks of low mood
Loss of interest or pleasure in everything plus 3 or 4 of:
- change in sleep
- change in appetite
- low energy
- poor concentration
- restlessness
- low self worth
- suicidal thoughts / ideas
- concern over impending death
What are 2 recommended screening questions for depression
- During the last month have you often been bothered by feeling down, depressed or hopeless
- During the last month have you often been bothered by having little interest or pleasure in doing things
What are the 4 main strands of evidence underpinning investigations into the causes and treatment of depression
- Anatomical changes in the brain systems involved in mood
- Hyperactivity in the HPA system
- Neurotrophic hypothesis
- Monoamine hypothesis; based on actions of antidepressant drugs
How do anatomical changes cause depression
Reduced volume of thalamus, amygdala and hippocampus result in patients suffering from severe depression
How do changes to the HPA pathway cause depression
HPA pathway promotes the release of cortisol from the adrenal gland
In depression levels of cortisol are elevated and the size and activity of the pituitary gland and adrenal glands are elevated
How do antidepressants act on the HPA pathway
Enhance negative feedback and decrease the HPA axis hyperactivity
What is BDNF
Brain derived neurotrophic factor
Is responsible for regulating neurogenesis, development, dendritic growth, survival and maturation
What is the neurotrophic hypothesis of depression
Depression is associated with reduced brain BDNF levels
Antidepressants can increase BDNF levels
What is the monoamine hypothesis
Depression is the result of reduced monoamine signalling
- the antihypertensive drug reserpine caused depression in some patients. Reserpine depletes NA and 5-HT vesicles
CSF in suicidal depressed patients contains reduced levels of 5-HT; implies reduced levels of 5-HT in the brain
Most antidepressants elevate 5-HT and / or NA signalling
Mechanism and examples of SSRIs
Fluoxetine and sertraline
Is a serotonin (5-HT) selective reuptake inhibitor
Examples of and mechanism of SNRIs
Duloxetine and venlafaxine
Serotonin-noradrenaline reuptake inhibitors
Examples and mechanism of tricyclic antidepressants
Lofepramine
Non selective reuptake inhibitors (5-HT and NA)
Examples and mechanism of MAOIs
Moclobemide
Blocks breakdown of 5HT and NA
Examples and mechanism of NASSAs
Mirtazepine
Selective receptor block that enhances NA and 5-HT signalling
What are the first and second line antidepressant treatments
1st line = SSRI
2nd line = tricyclic
Side effects of SSRIs
Generally mild and better than other classes
- GI disturbance: nausea, indigestion, diarrhoea or constipation
- psychiatric: sleep disorders, anxiety, agitation
- sexual: loss of libido, impotence
Increased risk of gastric bleeding
High likelihood of drug interactions
Most improve over time except sexual
Describe the side effect profile of SNRIs
Similar mechanism of action and side effects to SSRIs
Venlafaxine reported to have a higher risk of death from overdose and should be avoided in patients at significant risk of suicide
Describe the side effects of TCAs
Effects histamine H1 so can cause sedation and cholinergic (dry mouth, blurred vision)
Possible cardiovascular effects can be fatal in overdose
Lofepramine has the lowest risks in overdose
MOA of NASSAs
Selectively block NA and 5-HT by MAO
Block a2 receptors
Block 5-HT2 and 5-HT3 receptors
This enhances signalling at certain NA and 5-HT synapses
Side effects of NASSAs
Fewer sexual problems but can cause more drowsiness
Headaches, nausea, anxiety, postural hypotension, constipation, diarrhoea
Recommend to stop treatment if bipolar patient enters a manic episode
Why are MAOIs only prescribed by mental health specialists
Because they have serious and fatal side effects including the cheese reaction which is an interaction with tyramine from certain foods that can lead to a hypertensive crisis
What are the NICE recommendations for mild depression
Use non pharmacological interventions
If these are ineffective offer an SSRI
What does NICE recommend for moderate to severe depression (or depression with a chronic health problem)
First use a generic SSRI as have a more favourable side effect profile and are safer in overdose
What are the hypothesised causes of psychosis
- Dysfunctional development of the frontal cortex with early environmental factors important
- Over activity of subcortical dopamine neurones (affects D2 and D3 receptors)
- Cortical glutamate hypofunction and loss of GABA interneurones
Describe the 2 dopamine receptor subtypes
D1 and D2
D1 subtype comprises D1 and D5 subunits
D2 subtype comprises D2, D3 and D4 subunits
It is receptors in the D2 subtype that are targeted by antipsychotics
All antipsychotics are D2 antagonists
What are the positive symptoms of psychosis
Delusions
Hallucinations
Disorganised speech
What are the negative symptoms of psychosis
Flat affect
Reduced speech
Lack of initiative
What are the 1st generation antipsychotics
Typical antipsychotics (1950s and 60s)
What are the 2nd generation antipsychotics
Atypical antipsychotics 1970s and 80s
What are the 3rd generation antipsychotics
3rd generation atypical
What is d2 antagonism
D2 antagonism in the Mesolimbic pathway is believed to be responsible for antipsychotic effect but this takes weeks to have an effect
The drugs block the D2, d3 or D4 subunit
What side effects does D2 antagonism in other dopamine systems cause
- Nigrostriatal - extrapyramidal side effects
- Tuberoinfundibular- raised prolactin
- Mesolimbic - worsening cognitive function
What are the extra pyramidal side effects that can be caused by D2 antagonism
Acute dystonia : neck or spine spasms or rigidity and oculogyric crisis
Pseudo-Parkinsonism: rigidity, tremor and Bradykinesia
Akathisia: inability to sit still, restlessness and agitation
Tardive dyskinesia: abnormal movement of the face, mouth or jaw, lip smacking, tongue protrusion, grimacing, bodily writhing
What are some specific side effects of chlorpromazine
Sedation (H1 antagonism)
Weight gain (5HT2c antagonism)
Skin and eye effects (urticaria, photosensitivity, lens and corneal granulation)
Autonomic effects
What autonomic side effects are caused by chlorpromazine
Muscarinic antagonism: atropine like- dry mouth, constipation, failure to ejaculate, urinary retention
Alpha adrenergic antagonism: miosis, cutaneous flushes, postural hypotension
What are atypical antipsychotics
Effective against positive symptoms in the same way as typical
Partially effective against negative symptoms (unlike typical)
Minimal effect on cognitive deficit
Recommended in conjunction with CBT
How do the pharmacodynamics vary between risperidone and olanzapine
Risperidone: D2 and 5HT2 antagonist
Olanzapine: weak D2 and 5-HT2 antagonist
What are the side effects of atypical antipsychotics
Fewer Extrapyramidal side effects - limbic selective D2/D3 antagonism
Hyperprolactineamia
Weight gain due to 5-HT2c antagonism
There are additional side effects specific to individual drugs
What is the order of what quetiapine blocks
H1 > a1 > 5-HT2 > a2 > D2
When is clozapine used
In treatment resistant schizophrenia
- unsatisfactory clinical improvement following at least 2 different antipsychotic agents
- also used for patients with severe, untreatable neurological adverse reactions to other antipsychotics
Why does clozapine have an unusual receptor pharmacology
High 5-HT2A and moderate D4 affinity but low D2 affinity
Very low risk of EPSE but constipation and salivation side effects (M1 and a1 antagonism)
Regular blood tests due to risk of agranulocytosis (consultant only prescribing)
What is aripiprazole
3rd generation atypical antipsychotic
Partial agonist at D2 and 5-HT1A; 5-HT2A antagonist
EPSE similar to placebo but akathisia more common that expected
Common side effects include: insomnia, nausea, restlessness
Outline 3 prescribing principles in antipsychotics
- Use the lowest possible dose - dose increase should only take place after 2 weeks of assessment, showing poor or no response
- Use of a single antipsychotic is recommended - except for short periods eg changing medication or in exceptional circumstances eg clozapine augmentation
Increased risk of prolonged QTc and sudden death - Response to drug treatment should be regularly assessed
What causes weight gain with antipsychotics
Reduced metabolism
Increased appetite and endocrine effects
Increased leptin levels
Fluid retention
Which drugs caused QT prolongation and what are the risks associated with this
Antipsychotic, antidepressants, antibiotics
Cause an increased risk of ventricular arrhythmias, syncope and sudden death syndrome
What can you do if compliance to antipsychotics becomes an issue
Long acting injections
Sustained release formulation indicated for poor compliance
Injected into large muscle every 1-4 weeks (buttock, thigh, deltoid)
Same side effects as oral equivalent
What supplements are recommended for people who are pregnant and on anti epileptics
Folic acid prior to conception and during pregnancy to reduce the chances of neural tube defects
Are people on anti epileptic drugs for their whole life
No
If you have been seizure free for 2-4 years then the aim is to gradually withdraw therapy
Which anti epileptic drug requires extensive drug monitoring
Phenytoin
Does carbamazepine require extensive monitoring
No only phenytoin does as it demonstrates zero order pharmacokinetics
If started on an AED are you on it for the rest of life
No the aim would be to withdraw therapy gradually after 2-4 years if seizure free
