Session 13 Flashcards
Define seizure
“Transient occurrence of signs or symptoms
due to abnormal electrical activity in the brain,
leading to a disturbance of consciousness,
behaviour, emotion, motor function or
sensation”
Pathology of seizures
■ The brain is a complicated network of neurones ■ These are either excitatory, inhibitory or interneurons ■ The most important excitatory neurotransmitter is glutamate via the NMDA receptor ■ The most important inhibitory neurotransmitter is GABA, via the GABAa receptor
Glutamate + NMDA Receptor
■ Cation channel- lets in Na and Ca
and lets K out ■ Depolarises membrane ■ More likely to fire action potential • In the normal brain the inhibitory and excitatory sides are
in balance
GABA and GABAa Receptor
■ Cl- channel ■ Hyperpolarise membrane ■ Less likely to fire action potential
■ A seizure is the clinical manifestation of abnormal and excessive excitation and synchronisation of a group of neurones
within the brain ■ Therefore a loss of inhibitory (GABA mediated) signals ■ Or too strong an excitatory (NMDA/Glutamate) one ■ This imbalance can happen in any point in the brain, and local changes can lead to generalised effects
■ This can be caused by genetic differences in brain chemistry/receptor structure – genetic epilepsy syndromes ■ By exogenous activation of receptors- drugs ■ Acquired changes in brain chemistry- drug withdrawal, metabolic changes ■ Damage to any of these networks- strokes, tumours
Time for some ICPP
Image and panopticon
What are the signs and symptoms of a seizure
Not just shaking
For generalised seizures a loss of consciousness often (but not always) with changes in muscle tone, tongue biting
For tonic-clonic seizures initial hypertonic phase, followed by rapid clonus (shaking/jerking)
Post-ictal period present- can last minutes up to hours
Often an aura prior to seizure
May be more varied or subtle depending on type of seizure
How to define epilepsy?
■ Not everyone who has a seizure has epilepsy ■ An epilepsy diagnosis is life changing, and therefore should only be made by a
specialist, in an epilepsy or first fit clinic
■ Note not just a disease of the young, over 60s almost as common and incidence
increases with age
■ Epilepsy is a tendency toward recurrent seizures unprovoked by a systemic or
neurological insult
■ At least two unprovoked (or reflex) seizures occurring more than 24 hours apart ■ One unprovoked (or reflex) seizure and a probability of further seizures similar to the
general recurrence risk after two unprovoked seizures (at least 60% over the next 10
years) ■ Diagnosis of an epilepsy syndrome
Types of Reflex Seizure
■ Seizure brought on by a particular stimulus
■ Photogenic ■ Musicogenic ■ Thinking ■ Eating ■ Hot water immersion ■ Reading ■ Orgasm ■ Movement
What are the classifications of seizure
Images and panopto
Generalized seizures
• Originate at some point within and rapidly engage bilaterally distributed networks • Can include cortical and subcortical structures but not necessarily the entire cortex
Focal seizures
• Originate within networks limited to one hemisphere • May be discretely localized or more widely distributed.…
Older terminology
■ Grand mal= Generalised seizure ■ Petit mal= absence seizure ■ Partial seizure= focal seizure
Provoked Seizures
■ Seizure as a result of another medical condition ■ Examples include: ■ Drug use or withdrawal ■ Alcohol withdrawal ■ Head trauma and intracranial bleeding ■ Metabolic disturbances e.g hyponatraemia, hypoglycaemia ■ CNS Infections: meningitis and encephalitis ■ Febrile seizures in infants ■ Uncontrolled hypertension
■ Key is to treat both the seizure and the underlying condition. Unlikely to need ongoing AED treatment if cause treated
Differential diagnosis of seizures
■ Syncopal episodes e.g vasovagal syncope ■ Cardiac issues including reflex anoxic seizures, arrythmias ■ Movement disorders e.g Parkinsons, Huntingtons ■ TIAs ■ Migraines ■ Non-epileptic attack disorders (formerly pseudo-seizures)
Initial Management of a Seizure
■ Primary Survey/A to E assessment ■ Airway- Is it patent? Can you do anything about it it?/Adjuncts ■ Breathing- Sats reading +/- Oxygen ■ Circulation- Expect a high HR, wary of BP ■ Disability- Will have reduced consciousness in generalised seizures, may be awake in
partial ■ E- May want to get them into recovery position if able ■ Do something for the ABC problems if you can ■ Look at a clock/start a timer ■ Get some help
When to use drugs to treat seizures?
■ The majority of seizures will self terminate without the use of drugs ■ Wait for 5 minutes and if still going then give seizure terminating drugs
Status Epilepticus
A seizure (of any variety) lasting more than 5 minutes or more, or multiple seizures without a complete recovery between them
Status is a medical emergency
It occurs in around 40 out of 100,000 people per year and has a 30 day mortality of around 20%
Pharmacological Treatment for Status
■ Wait 5 minutes ■ Benzodiazepine ■ Benzodiazepines again ■ Phenytoin (or maybe Levetiracetam?) ■ Thiopentone/Anaesthesia (Call intensive care/anaesthetics)
Benzodiazepines
■ Class of drug- GABAa agonists ■ End in –apam, come in various flavours
■ Increased Cl- conductance, = more negative resting
potential, less likely to fire. ■ Work best when membrane positive i.e in seizures ■ No firing neurones=no more seizure
■ Be wary of addiction, cardiovascular collapse, airway
issues ■ Also used as anxiolytics, sleep aids, alcohol
withdrawal
Benzodiazepine Options for Status Epilepticus
■ Intravenous Lorazepam ■ Diazepam rectally- difficult to do ■ Buccal or intranasal Midazolam – Don’t lose a finger
■ IM can also work, and various IM preparations are on different local guidelines
■ The non-guideline answer, get some fast acting benzos into the patient one way or
another. ■ Remember you can always put more in but you can’t take it out so go slowly
How to make a diagnosis of epilepsy?
■ Epilepsy diagnosis should be made by a specialist, in a dedicated first fit or epilepsy
clinic ■ Largely based on history from patient and eyewitnesses to attacks ■ Video can be very helpful in determining this
What investigations should be done for someone who may have epilepsy
■ Electroencephalography:
■ Record of electrical pattern of activity in the brain ■ Can be very useful, especially if an attack is caught while being
recorded- Can make this more likely with sleep deprived EEG ■ But relies on either capturing an episode or an abnormal pattern ■ Many people without epilepsy have an abnormal EEG ■ A single EEG may show abnormalities in as few as 30% of adults
with epilepsy
What imaging can be done for someone with epilepsy
■ MRI is the imaging of choice ■ May detect vascular or structural abnormalities that
can account for epilepsy ■ Generally not required when there is a degree of
confidence that there is a generalised epilepsy
syndrome e.g generalised seizures in a young
person, associated with sleep deprivation
Anti-Epileptic Drugs (AEDs) and why do we use them?
■ There are numerous AEDs, with varying mechanisms of action ■ We will concentrate on 6: ■ Carbamazepine ■ Phenytoin ■ Valproate ■ Lamotrigine ■ Levetiracetam ■ Benzodiazepines for seizure termination (already done)
■ Sudden Unexplained Death in Epilepsy (SUDEP) ■ Occurs in 0.1% adults with epilepsy per year ■ More frequent in people with poor seizure control
■ Massive burden- can impact ability to drive, swim, have a bath, time out of school or
university
How Anti-Epileptic Drugs Work
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■ Lots of potential mechanisms ■ Many drugs act in several ways
Sodium Channel Blockade
■ Blocking of Na channels in central neurones ■ This slows recovery of neurones from inactive
to closed state ■ Reduces neuronal transmission
How does Carbamazepine (Tegretol) work and what are it’s side effects?
■ Sodium channel blocker ■ Also used as a medication for bipolar and sometimes chronic pain
■ Side effects: ■ Suicidal thoughts ■ Joint pain ■ Bone marrow failure
How does Phenytoin work and what are it’s side effects?
■ Sodium channel blocker ■ Use mainly in status epilepticus or as an adjunct in generalised seizures ■ Exhibits zero order kinetics- care when adjusting doses
■ Specific side effects: ■ Bone marrow suppression ■ Hypotension ■ Arrythmias (IV use)
How does Sodium Valproate (Epilim, Depakote)
work and what are it’s side effects?
■ Probably a mix of GABAa effects and sodium channel blockade ■ As per guidelines 1st line for generalised epilepsies
■ Specific side effects: ■ Liver failure ■ Pancreatitis ■ Lethargy
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 mechanism of action ■ Synaptic vesicle glycoprotein binder. Stops the release of neurotransmitters into
synapse and reduces neuronal activity ■ Option for focal seizures and generalised seizures ■ Anecdotally being used more frequently, easy dosing and well tolerated ■ Safe in pregnancy
Side Effects of AEDs and the implications of this
■ Largely common across all drugs: ■ Tiredness/drowsiness ■ Nausea and vomiting ■ Mood changes and suicidal ideation ■ Osteoporosis
■ Rashes, including Steven Johnson syndrome can be caused by all. Most likely in
carbamazepine or phenytoin (1 in 1000) ■ Many can cause anaemia, thrombocytopenia or bone marrow failure
■ Patients on anti-epileptics and warfarin will need close monitoring ■ Ideally patients on AEDs should not consume alcohol ■ Carbamazepine and phenytoin may decrease the effectiveness of oral contraceptive
pills ■ Carbamazepine and phenytoin may decrease the effectiveness of some antibiotics ■ Valproate can increase the plasma concentration of other AEDs ■ Newer AEDs have less side effects, or are metabolised in other ways (levetiracetam)
Drug Drug Interaction
Of anti epileptic drugs?
■ AEDs can be both inducers and inhibitors of CYP enzymes ■ They therefore interact with a wide variety of drugs, including each other
Inducers • Phenytoin • Carbamazepine • Barbituates • Rifampicin • Alcohol (chronic) • Sulphonylureas
Inhibitors • Omeprazole • Disulfram • Erythromycin • Valproate • Isoniazd • Ciprofloxacin • Ethanol (acute) • Sulphonamides
How to start someone on AEDs?
■ Pick a drug- There are guidelines for this for various types of epilepsy (they will have
changed by the time you have to know) ■ Start at a low dose and build up ■ Trial of drug and see how patient responds- look for efficacy and tolerable side effects ■ Aim for all anti-epileptic treatment is to be seizure free with minimal or acceptable side
effects ■ Plasma levels can be monitored, but should not necessarily be done regularly without
reason (e.g patient becomes pregnant, loses seizure control, issues with adherence) ■ Transition to a new agent should be done carefully ■ Should be overseen by epilepsy specialist
Family Planning for patients on anti epileptic drugs
■ There is some risk of congenital malformations with all
AEDs ■ The risk is greatest with Valproate (as high as 10% risk of a
major malformation) ■ Valproate should not be prescribed to any woman of
childbearing age unless they meet the conditions of a
pregnancy prevention programme ■ Lamotrigine and particularly Levetiracetam are the safest
Epilepsy and driving
■ Need to ask all patients with seizures about
driving ■ Will temporarily lose license and need to be
seizure free for one year before reapplying ■ For bus lorry or coach drivers you need to be
seizure free for 5 years off medication for a
single seizure, or 10 years if had multiple ■ Patients responsibility to inform DVLA
A) ■ A 26 year old arrives in resus fitting. The ambulance crew state this began 10
minutes ago, she has received a single dose of IV lorazepam.
■ What is the first step in your management?
B)■ You have treated her with further a further dose of lorazepam, and given a loading
dose of phenytoin. It is 30 minutes later and she continues to fit. What do you do
next?
■ A. Give thiopentone ■ B. Wait a further 5 minutes ■ C. Give levetiracetam ■ D. Call intensive care ■ E. Hide in a cupboard and pretend its not happening
C)■ She has now stopped seizing, and you see her in 2 weeks later in the epilepsy clinic. She is not on any contraception. Which of the following drugs should be avoided?
■ A. Levetiracetam ■ B. Valproate ■ C. Lamotrigine ■ D. Carbamazepine ■ E. I’m still hiding in the cupboard from question 2
A)
B)
C)
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Idiopathic Parkinson’s Disease (IPD)
• Neurodegenerative disorder • Progressive clinical course • Motor symptoms improve with levodopa • Non motor symptoms
Clinical Features of Parkinsonism: • Tremor* • Rigidity* • Bradykinesia** • Postural instability
*low dopamine and disturbance
other neurotransmitter levels **low dopamine
Non motor manifestations PD
• Mood changes • Pain • Cognitive change • Urinary symptoms • Sleep disorder • Sweating
Prognosis in PD
• 94% Dyskinesia • 81% Falls • 84% Cognitive decline (50%
hallucinations) • 80% Somnolence • 50% Swallowing difficulty • 27% Severe speech problems
How to make a diagnosis of Parkinson’s disease?
- Clinical Features • Exclude other causes of Parkinsonism
- Drug Induced Parkinsonism • Vascular Parkinsonism • Progressive Supranuclear Palsy • Multiple Systems Atrophy • Corticobasal Degeneration
- Response to Treatment • Structural neuro imaging is normal • Functional neuro imaging - SPECT, PET
Pathology of IPD
• Neurodegeneration • Lewy bodies – synucleinopathy
• Loss of pigment
– 50% loss->symptoms – Increased turnover – Upregulate receptors
• Reduced dopamine
Basal ganglia and the basal ganglia circuit
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Dopamine
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Catecholamine Synthesis
Image
Dopamine Degradation
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Neurons and Neurotransmitters
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DAT Scan
• Labelled tracer • Presynaptic uptake • Abnormal in PD • Not diagnostic • Tremor • Neuroleptic • Vascular
Treatment of Parkinson’s Disease
Drug Classes in IPD • Levodopa (L-DOPA) • Dopamine receptor agonists • MAOI type B inhibitors • COMT inhibitors • Anticholinergics • Amantidine
Why not use dopamine to treat Parkinson’s disease
Dopamine can not cross blood brain barrier but L-DOPA can and then can be used to make dopamine
Levodopa (L-DOPA)
Levodopa (L-DOPA)
Levodopa must be taken up by dopaminergic cells in the substantia nigra to be converted to dopamine. Fewer remaining cells - less reliable effect of levodopa- motor fluctuations
(Pharmacokinetics)
• Oral administration • Absorbed by active transport
• In competition with amino acids (NB high protein meals) • 90% inactivated in intestinal wall
• monoamine oxidase & DOPA decarboxylase
•T
1/2 2 hours
• short dose interval
• fluctuations in blood levels and symptoms
• (physiologically dopamine is produced tonically)
• 9% converted to dopamine in peripheral tissues • DOPA decarboxylase
• <1% enters CNS
O again competes with amino acids for active transport across blood brain barrier
Formulations of L-DOPA
L-DOPA is used in combination with a peripheral DOPA decarboxylase inhibitor :
• Co-careldopa Sinemet • Co-beneldopa Madopar
• Reduced dose required • Reduced side effects • Increased L-DOPA reaching brain
• Tablet formulations only
– Standard dosage – variable strengths
– Controlled release preparations (CR)
– Dispersible Madopar (not soluble)
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Advantages and disadvantages of L-DOPA
Advantages • Highly efficacious • Low side effects • Nausea/ anorexia
– Vomiting centres • Hypotension
– central and peripheral • Psychosis
– Schizophrenia-like
effects. Hallucination/ delusion/ paranoia
O Tachycardia
Disadvantages • Precursor • needs enzyme conversion • Long term • Loss of efficacy (Only effective in presence of dopaminergic neurones) • Involuntary movements • Motor Complications – On / off – Wearing off – Dyskinesias – Dystonia – Freezing
Drug drug interactions of levodopa
• Pyridoxine (vitamin B6) increases peripheral
breakdown of L-DOPA • MAOIs risk hypertensive crisis
• (not MOABIs at normal dose-lose specificity at high dose)
• Many antipsychotic drugs block dopamine receptors
and parkinsonism is a side effect (newer, ‘atypical’
antipsychotics less so)
Dopamine Receptor Agonists
• Ergot derived Bromocryptine
Pergolide Cabergoline
• Non Ergot
Ropinirole Pramipexole
• Patch Rotigotine • Subcutaneous Apomorphine
•De Novo therapy •Add on therapy
•Apomorphine
• only for patients with severe motor fluctuations
Dopamine Receptor Agonists
Advantages and disadvantages
Advantages • Direct acting • Less dyskinesias/
motor complications • Possible
neuroprotection
Disadvantages • Less efficacy than
L-DOPA • Impulse control
disorders • More psychiatric s/e • Dose limiting
O Expensive
Impulse Control Disorders
(also called Dopamine Dysregulation Syndrome)
• Pathological Gambling • Hypersexuality • Compulsive Shopping • Desire to increase dosage • Punding
Dopamine Receptor Agonists -side effects
• Sedation • Hallucinations • Confusion • Nausea • Hypotension
Monoamine oxidase B Inhibitors
- Monoamine oxidase B
- Metabolises dopamine • Predominates in dopamine containing regions in brain • MAOB inhibitors enhance dopamine
- Monoamine oxidase B inhibitors
- Selegiline • Rasagaline
- Can be used alone • Prolong action of L-DOPA • Smooths out motor response • May be neuroprotective
Catechol-O-methyl Transferase (COMT) Inhibitors
• Catechol-O-methyl Transferase (COMT)
Inhibitors
• Entacapone – doesn’t cross BBB • Tolcapone – crosses BBB but main effect peripheral
» Monitor liver function
• Reduce peripheral breakdown of L-DOPA to 3-O-methyldopa » 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’
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Anticholinergics
• Acetyl Choline may have antagonistic effects to
dopamine
• Trihexyphenidydyl • Orphenadrine • Procyclidine
• Minor role in treatment of PD
Advantages and disadvantages of anticholinergics
Advantages • Treat tremor • Not acting via
dopamine systems
Disadvantages • No effect on
bradykinesia • Side effects
• Confusion • Drowsiness • Usual anticholinergic s/e
Amantadine
- Mechanism action uncertain – possibly
- enhanced dopamine release • Anticholinergic NMDA inhibition
- Poorly effective • Few side effects • Little effect on tremor
Surgery For Parkinson’s disease
- Carried out stereotactically • Of value in highly selected cases
- Dopamine responsive • Significant side effects with L-DOPA • No psychiatric illness
- Controlled trials • Lesion
- Thalamus for tremor • Globus Pallidus Interna for dyskinesias
- Deep brain stimulation
- Subthalamic nucleus
Algorithm
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Post Synaptic Membrane of Neuromuscular Junction
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Myasthenia Gravis
• Fluctuating, fatiguable, weakness skeletal
muscle
– Extraocular muscles – commonest presentation – Bulbar involvement – dysphagia, dysphonia, dysarthria – Limb weakness – proximal symmetric – Respiratory muscle involvement
Drug affecting neuromuscular transmission exacerbate Myasthenia Gravis
• Aminoglycosides • Beta-blockers, CCBs, quinidine,
procainamide • Chloroquine, penicillamine • Succinylcholine • Magnesium • ACE inhibitors
Complications Of myasthenia Gravis
• Acute exacerbation
– Myasthenic crisis • Overtreatment
– Cholinergic crisis
Therapeutic management
Of myasthenia Gravis
• Acetylcholinesterase inhibitors • Corticosteroids
– Decrease immune response • Steroid sparing
– Azathioprine • IV immunoglobulin Acute decline or crisis – 60% will respond after 7-10 days • Plasmapheresis
– Removes AChR antibodies and short-term improvement
• Acetylcholinesterase inhibitors
– Enhance neuromuscular transmission
– Skeletal and smooth muscle
– Excess dose can cause depolarising 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 3-6hr • Dose interval and timing crucial • Cholinergic side effect –
– miosis and the SSLUDGE syndrome:
» Salivation, » Sweating, » Lacrimation » Urinary incontinence » Diarrhea, » GI upset and hypermotility » Emesis)
DAT Scan
For myasthenia Gravis
• Labelled tracer • Presynaptic uptake • Abnormal in PD • Not diagnostic • Tremor • Neuroleptic • Vascular
