Session 13 Flashcards

1
Q

Define seizure

A

“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”

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Pathology of seizures

A

■ 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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Time for some ICPP

A

Image and panopticon

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What are the signs and symptoms of a seizure

A

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 well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

How to define epilepsy?

A

■ 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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Types of Reflex Seizure

A

■ Seizure brought on by a particular stimulus

■ Photogenic ■ Musicogenic ■ Thinking ■ Eating ■ Hot water immersion ■ Reading ■ Orgasm ■ Movement

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What are the classifications of seizure

A

Images and panopto

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Generalized seizures

A
• Originate at some point
within and rapidly
engage bilaterally
distributed networks • Can include cortical and
subcortical structures
but not necessarily the
entire cortex
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Focal seizures

A
• Originate within
networks limited
to one
hemisphere • May be discretely
localized
or more widely
distributed.…
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Older terminology

A

■ Grand mal= Generalised seizure ■ Petit mal= absence seizure ■ Partial seizure= focal seizure

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Provoked Seizures

A

■ 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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Differential diagnosis of seizures

A

■ 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)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Initial Management of a Seizure

A

■ 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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

When to use drugs to treat seizures?

A

■ 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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Status Epilepticus

A

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%

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Pharmacological Treatment for Status

A

■ Wait 5 minutes ■ Benzodiazepine ■ Benzodiazepines again ■ Phenytoin (or maybe Levetiracetam?) ■ Thiopentone/Anaesthesia (Call intensive care/anaesthetics)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Benzodiazepines

A

■ 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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

Benzodiazepine Options for Status Epilepticus

A

■ 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 well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

How to make a diagnosis of epilepsy?

A

■ 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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

What investigations should be done for someone who may have epilepsy

A

■ 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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

What imaging can be done for someone with epilepsy

A

■ 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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

Anti-Epileptic Drugs (AEDs) and why do we use them?

A

■ 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 well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

How Anti-Epileptic Drugs Work

A

Panopto

■ Lots of potential mechanisms ■ Many drugs act in several ways

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

Sodium Channel Blockade

A

■ Blocking of Na channels in central neurones ■ This slows recovery of neurones from inactive
to closed state ■ Reduces neuronal transmission

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
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
26
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)
27
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
28
Lamotrigine
■ Primarily a sodium channel blocker, may also affect calcium channels ■ Good for focal epilepsy ■ Used often where valproate contraindicated in generalised epilepsy
29
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
30
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)
31
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
32
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
33
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
34
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
35
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)
36
Extra
Extra
37
Extra
Extra
38
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
39
Prognosis in PD
• 94% Dyskinesia • 81% Falls • 84% Cognitive decline (50% hallucinations) • 80% Somnolence • 50% Swallowing difficulty • 27% Severe speech problems
40
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
41
Pathology of IPD
• Neurodegeneration • Lewy bodies – synucleinopathy • Loss of pigment – 50% loss->symptoms – Increased turnover – Upregulate receptors • Reduced dopamine
42
Basal ganglia and the basal ganglia circuit
Panopto and image
43
Dopamine
Panopto
44
Catecholamine Synthesis
Image
45
Dopamine Degradation
Image
46
Neurons and Neurotransmitters
Insert image
47
DAT Scan
• Labelled tracer • Presynaptic uptake • Abnormal in PD • Not diagnostic • Tremor • Neuroleptic • Vascular
48
Treatment of Parkinson’s Disease
Drug Classes in IPD • Levodopa (L-DOPA) • Dopamine receptor agonists • MAOI type B inhibitors • COMT inhibitors • Anticholinergics • Amantidine
49
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
50
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
51
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) Add image
52
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 ```
53
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)
54
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
55
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
56
Impulse Control Disorders
(also called Dopamine Dysregulation Syndrome) | • Pathological Gambling • Hypersexuality • Compulsive Shopping • Desire to increase dosage • Punding
57
Dopamine Receptor Agonists -side effects
• Sedation • Hallucinations • Confusion • Nausea • Hypotension
58
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
59
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’ Insert image
60
Anticholinergics
• Acetyl Choline may have antagonistic effects to dopamine • Trihexyphenidydyl • Orphenadrine • Procyclidine • Minor role in treatment of PD
61
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
62
Amantadine
* Mechanism action uncertain – possibly * enhanced dopamine release • Anticholinergic NMDA inhibition * Poorly effective • Few side effects • Little effect on tremor
63
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
64
Algorithm
Panopto
65
Post Synaptic Membrane of Neuromuscular Junction
Insert image and panopto
66
Myasthenia Gravis
• Fluctuating, fatiguable, weakness skeletal muscle – Extraocular muscles – commonest presentation – Bulbar involvement – dysphagia, dysphonia, dysarthria – Limb weakness – proximal symmetric – Respiratory muscle involvement
67
Drug affecting neuromuscular transmission exacerbate Myasthenia Gravis
• Aminoglycosides • Beta-blockers, CCBs, quinidine, | procainamide • Chloroquine, penicillamine • Succinylcholine • Magnesium • ACE inhibitors
68
Complications Of myasthenia Gravis
• Acute exacerbation – Myasthenic crisis • Overtreatment – Cholinergic crisis
69
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)
70
DAT Scan | For myasthenia Gravis
• Labelled tracer • Presynaptic uptake • Abnormal in PD • Not diagnostic • Tremor • Neuroleptic • Vascular