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'B33CNS - Pharmacology & Therapeutics > Epilepsy; Causes and Treatments > Flashcards

Epilepsy; Causes and Treatments Flashcards

1
Q

What goes wrong during a seizure? 11:53

A
  • Abnormal hyper-synchronised activity within a neural network (inc. burst firing)
  • Many different types of epileptic seizure
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2
Q

What are the variable factors WRT seizures?

A
  • Pattern of epileptic discharges
  • Circuits involved
  • Likely cause
  • Drugs used
  • Chance of cure
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3
Q

Why are some people more predisposed to seizures?

A
  • Brain lesions and disorders of channels and receptors

- Many different ‘epilepsies’ (benign vs malignant)

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4
Q

What do anti-epileptic drugs target?

A

Neuronal channels and NT receptors:

  • Na+, K+, Ca2+
  • GABA, Glu
  • SV2a
  • Cannabinergic mechanisms
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5
Q

What is a seizure?

A

The clinical manifestation (symptomatic) of a disordered and hypersynchronised discharge/firing in a network of cerebral neurons

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6
Q

How are seizures clinically studied/assessed?

A
  • Careful history from patient & witness (99% of cases; before, during and after)
  • Home videos of seizures
  • Combined Video-EEG
  • Result > Classification of seizures (of above information)
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7
Q

What is seizure type determined by?

A
  • Location of onset
  • Type of discharge
  • Pattern of spread
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8
Q

What are the two main categories of seizures, and what do they entail?

A

Generalised seizures:
- Starts simultaneously in BOTH hemispheres

Focal seizures:
- Seizure starts in ONE focus (one region), and then spreads

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9
Q

What are the common types of generalised seizures?

A
  • Typical Absence
  • Myoclonic
  • Tonic-Clonic
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10
Q

Describe Absence Seizures.

A

One of three types of generalised seizures:

  • Mainly childhood in onset
  • Frequent brief attacks (1 - 30 secs)
  • Sudden LOSS and then RETURN of consciousness (quick recovery)
  • No aura (warning), no post-ictal state (altered state of consciousness characterised by drowsiness/confusion etc.)
  • Some involuntary movements e.g. eyes
  • Brief spike on EEG (3 Hz spike and wave)
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11
Q

Describe Myoclonus Seizures.

‘Generalised myoclonic seizures’

A

One of three types of generalised seizures:

  • Teenage onset (e.g. juvenile myoclonic epilepsy)
  • Sudden, brief, shock-like muscle contractions “lightning, blink and you’ll miss it”
  • Bilateral arm jerks (upper limbs)
  • Worse in the mornings
  • Precipitated by: sleep deprivation and alcohol
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12
Q

Who does Myoclonus occur in?

A
  • Epilepsy syndromes e.g. JME (Juvenile Myoclonic Epilepsy)

- Non-epileptic causes

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13
Q

Describe Tonic-Clonic Seizures.

A

One of three types of generalised seizures:
- Sudden onset, gasp, fall
- Tonic phase w/cyanosis (stiff phase/seizing of muscles held for 20 seconds, person unconscious; cyanosis = blue discolouration from deoxygenated haemoglobin)
- Clonic phase (jerking phase after initial stiff phase w/cyanosis)
- Post-ictal phase (confusion, drowsiness etc after)
- Tongue bitten and incontinence
- Noisy breathing
- Headache and muscle pain afterwards
- Absence common (myoclonus)
»> Rely on a witness to tell you signs you had a seizure

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14
Q

What are the types of uncommon generalised seizures, and what are they associated with?

A
  • Atypical absence (drop seizure; sudden loss of muscle tone)
  • Tonic
  • Atonic
    »> Usually associated w/severe epilepsy
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15
Q

What does the Focal Seizure (Partial) category entail?

A
  • Focal onset = often an aura (epileptic activity initiating in one part of the brain; e.g. if motor = jerks, light = visual aura
  • As seizures spread, a ‘complex partial seizure’ develops with loss of awareness and automatisms
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16
Q

What are the different manifestations of Focal (Partial) Seizures?

A
  • Simple Partial; awareness present
  • Complex Partial; awareness lost
  • Secondary Generalised; evolves to Tonic-Clonic (final culmination)
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17
Q

What are the subtypes of Focal (Partial) Seizures determined by?

A

Onset zone:

  • Temporal lobe; takes a while to regain consciousness
  • Frontal lobe; wailing, quickly regain consciousness
  • Occipital lobe
  • Parietal lobe
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18
Q

What is the most common Focal (Partial) Seizure? What is it characterised by?

A

Auras (autonomic symptoms):

  • Epigastric rising sensation (butterflies)
  • Olfactory (smell) and gustatory (taste/sense of taste)
  • Deja vu
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19
Q

What are the symptoms of Complex Partial seizures?

A

Type of Focal (Partial) Seizure:

  • Arrest reaction and blank stare
  • Oral automatisms (lip-smacking)
  • Manual automatisms (unconsciously)
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20
Q

What are the symptoms of Secondary Generalised Focal (Partial) seizures?

A
  • Clonic arm movement

- Raspy breathing

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21
Q

What is the EEG hallmark of Generalised Seizures?

A

Bilateral activity from onset

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22
Q

What are the key regulators of neuronal excitability?

A
  • Non-gated ion channels (resting membrane potential)
  • Voltage gated ion channels (Na+, K+, Ca2+, Cl-, dendrite information processing, APs)
  • Ligand gated ion channels
  • Metabotropic receptors
  • Glia; astrocytes (influence environment around neurones)
  • Neuro-modulators e.g. endocannabinoids (long-term excitability), hormones
  • Extracellular ions
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23
Q

How do EPSPs and IPSPs vary WRT the receptor/ligands?

A
  • EPSPs; Na+ channels open, downstream activation of AMPA (by Glu)
  • IPSPs; Cl- channels open, downstream activation of GABAa (hyperpolarisation)
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24
Q

What are the two rhythms of neuronal firing?

A
  • Regular firing

- Burst firing (can be normal in sleep)

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25
Q

What is ictogenesis? Inter-ictal spike vs seizures?

A
  • Mechanism where seizures begin
  • Inter-ictal spike; a short burst of epileptiform activity lasting 200ms
  • A seizure; more prolonged event lasting many seocnds
  • High frequency oscillations (ripples)
  • Micro-domains; possible basis of focal seizures
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26
Q

What does the inter-ictal spike tell us?

A
  • Characteristic EEG signature of focal epilepsy (not a seizure though)
  • Lasts about 200ms; paroxysmal depolarisation shift (PDS)
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27
Q

Describe Epileptic Discharge WRT an AP/PDS.

A

P186 Handbook:

  • Na+ channels open
  • Repetitive firing (paroxysmal depolarisation shift) instead of just single depolarisation
  • Ca2+ channels open during PDS too after AP is initiated by Na+, small plateau
  • Hyperpolarisation of receptors after with K+ channels open (efflux), resulting GABAa and GABAb receptor activation (Cl- activity)
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28
Q

How does neural activity differ from neural in seizures?

A

1) Burst firing of neurons (PDS)
2) Hyper-synchronised firing of networks (neurons shouldn’t be firing together)
»> Taking over activity of a circuit
»> Seizure activity propagates, spreading forward

  • Initiation (burst firing PDS) = AMPA stimulation
  • Slow depolarisation throughout (NMDA)
  • Oscillation (Ca, K)
  • Synchronisation = AMPA stimulation
  • Termination (GABA, AHP, NMDA-Pi; desensitisation)
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29
Q

What are micro-domains?

A

Possible basis of focal seizures:

  • Hyper-sensitive cortex (+, Glu) is balanced by inhibitory signals (-, GABA)
  • When inhibition fades and Glu drive overcomes GABA = seizures
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30
Q

What are cortico-thalamic loops?

A
  • Looped neuronal pathways that connect the thalamus to the cerebral cortex, and connect the cerebral cortex back to the thalamus
  • Thalamus is brain’s sensory switchboard
    • Sensory information > Thalamic relay neurons > cortical neurons (cortex) > thalamic relay neurons > thalamic reticular nucleus > thalamic relay neurons (with lots of interneurons also)
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31
Q

What are the two modes of firing of thalamic (brain’s sensory switchboard) neurons?

A
  • Tonic mode (talking to cerebral cortex)

- Burst mode

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32
Q

What are some observations in Absence Seizures WRT S&W/thalamic neurons?

A
  • Making cortex hyperexcitable w/penicillin = spike & wave
  • Stimulating frontal cortex or intra-laminar thalamic nucleus causes S&W
  • Human S&W discharges recorded in thalamus
  • Thus thalamus + cortex relationship = perturbed in absence seizures
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33
Q

What is the pathophysiology of Absence seizures?

A

1) Connections between thalamus; cortex contains loops
2) Connections within thalamus contain loops
3) Membrane and synaptic properties of neurons in these loops cause oscillations
4) Disturbances of these oscillations may cause S&W firing

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34
Q

So what goes wrong in absence seizures?

A

Not fully understood:
- Primary abnormality; bursts of abnormal activity from cortex to thalamus
- Thalamus may have a role in synchronising
- Reticular nucleus inhibiting TC relay cells may underlie “absence”
- Low threshold “T” Ca Channel may play a role
»> Like focal but quick af; thalamus role in looking generalised?

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35
Q

What is the pathophysiology of Tonic-clonic seizures?

A
  • Basal ganglia/brainstem involved in seizure

- Substantia nigra has gating function for severity of seizure

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36
Q

What changes occur in epileptogenesis?

A
  • Neuronal channels: Na, K, Ca, Cl, HCO3
  • Receptors, GABA, AMPA, NMDA, ACh
  • NT transporters
  • Neuro-modulators; peptides + endocannabinoids
  • Gap junctions
  • Glia: buffering of extracellular environment
  • BBB and inflammation
  • Loss and reorganisation of synapses
  • Cell loss inhibitory (interneurons) and new neurons
  • Inherited channel defects; GEFS+, Dravet syndrome (Na+ channel mutation)
  • Some acquired epilepsies show changes in dendritic channel functions; becoming more excitable after injury etc.
37
Q

What channelopathies are known to be involved in epilepsy?

A

Na+ (increased):

  • GEFS+ (Generalised epilepsy with febrile seizures plus)
  • SMEI (Severe myoclonic epilepsy of infancy/Dravet’s)

K+:
- Familial neonatal convulsions

Ca2+:
- CAE (Childhood Absence Epilepsy)

Cl-:
- Juvenile Myoclonus Epilepsy

nAChRs:
- Autosomal Dominant frontal lobe epilepsy

GABA gated Cl- channel:
- Families of JME

38
Q

What 3 states do Na+ channels undergo?

A
  • Resting state (closed)
  • Activated state (open)
  • Inactivated state
39
Q

What are Na+ channels involved in?

A
  • APs
  • Transmitter release
  • Sub-threshold neuronal properties
40
Q

How do AEDs manipulate Na+ channels?

A
  • They are use and voltage dependent
  • AEDs prolong inactivated state of channel (e.g. Lamotrigine)
  • Block increases with repetitive activation
  • Reduce burst firing
41
Q

What are the issues with trying to block Na+ channels with AEDs?

A
  • Drugs bind poorly to resting Na+ channel
  • Fast inactivation (normal) not affected
  • Onset of block is slow; allowing some bursting to occur ‘spikes’
  • Main action; stop spread of seizure
  • Binding w/prolonged depolarisations
42
Q

How may persistent Na+ current be of importance in epilepsy? Corresponding AED?

A
  • Some AEDs bind selectively to Nap

- E.g. Lacosamide; enhances slow inactivation of Na channels

43
Q

Which AEDs promote inhibition?

A
  • BZDs
  • Barbiturates
  • Topiramate
    »> Enhance Cl- current at GABA receptors
44
Q

Which AEDs reduce GABA degradation/reuptake?

A
  • Vigabatrin; GABA transaminase inhibitor (like AChr)
  • Tiagabine; GABA reuptake inhibitor (prevents breakdown of GABA into GABAT in supporting astrocytes - can also prolong seizure duration conversely)
    »> Higher GABA levels prevent fading of inhibition
45
Q

Which AED works by augmenting the K+ channel?

A

Retigabine:

- Currently withdrawn due to possible retinal S/Es

46
Q

Which AED works by blocking AMPA? Caveat?

A

Perampanel:
- Highly selective non-competitive AMPA antagonist
»> Targets excitatory activity
»> BUT, some patients are v aggressive on Perampanel

47
Q

Which AEDs have a multiple mode of action/are poorly understood?

A

Valproate
- Na+, K+, Ca2+, GABA, NMDA

Gabapentin, Pregabalin
- Ca2+ (in synapse), GABA, NMDA

Levetiracetam
- SV2a (synaptic vesicle protein 2a; controls excocytosis of vesicles, treats Focal and Myoclonic)

48
Q

What are the implications of having epilepsy?

A

Multiple:

  • Physical
  • Psychological
  • Social
49
Q

How is epilepsy managed?

A
  • Ensuring a correct diagnosis (other causes of fainting etc.?)
  • Determining the cause
  • Deciding on treatment (tailored)
  • Advising on lifestyle issues (e.g. driving)
50
Q

What are some causes blackouts and ‘funny turns’?

A
  • Epilepsy
  • Fainting
  • Cardiac
  • Attacks w/psychological cause (10-20%; mental health, unconscious manifestation etc.)
  • Rarities
51
Q

What is the epilepsy syndrome?

A
  • Seizure type
  • EEG results
  • MRI findings
  • Family history
  • Associated causes
    »> Treatment and prognosis
52
Q

What are the two different types of epilepsies?

A
  • Idiopathic (brain is normal; easier to control)

- Symptomatic (seizure is symptom of brain lesion; difficult to control)

53
Q

Describe idiopathic epilepsies.

A
  • No associated neurological damage
  • Often responds well to treatment
  • Genetic component suspected
    »> Often generalised
54
Q

Describe symptomatic epilepsies.

A
  • More treatment resistant
  • May have associated neurological deficits
    »> Often focal
55
Q

What are the different causes of symptomatic epilepsy?

A
  • Cortical malformations (hypoxic birth?)
  • Cerebral palsy
  • Genetic and metabolic disorders
  • Hippocampal sclerosis (febrile convulsions as an infant)
  • Trauma and infection
  • Tumours
  • Stroke
56
Q

What are the aetiology of epilepsies?

A
  • Genetic
  • Structural
  • Metabolic
  • Unknown cause
57
Q

What are the general principles of epilepsy treatment WRT the disorder, the patient and the drug?

A

Disorder:

  • Diagnosis certain
  • What type of epilepsy?

Patient:
- Wants treatment and counselled appropriately

Drug:

  • Appropriate for syndrome
  • Low dose initially, titrate up
  • S/Es and interactions explained (compliance)
58
Q

Which period of time after the first seizure carries the greatest risk of a second seizure? Who are more prone?

A
  • Max risk in first 6 months

- Juvenile Myoclonus certain to have another

59
Q

What are the initial treatment options for generalised and focal epilepsy respectively?

A

Generalised:

  • Sodium Valproate (CI in women of child-bearing age)
  • Lamotrigine

Focal:
- Lamotrigine

60
Q

What are ‘petit mal seizures’ also known as?

A

Complex partial (focal) seizures

61
Q

Describe lamotrigine’s place as an AED.

A
  • Broad spectrum (but Valproate preferred for Absence)
  • First line (for most tings)
  • Focal and generalised seizures
  • May be helpful in: myoclonus, absences
  • Well tolerated
62
Q

What common medicine interact with Lamotrigine?

A
  • Combined oral contraceptives (and pregnancy in general)
  • Results in serum level drop
  • Due to high estrogen levels
63
Q

How does carbamazepine work?

A
  • Acts on Na+ channels

- Suppresses nirst activity and spread of seizures

64
Q

Describe carbamazepine’s place as an AED.

A
  • (Was? Now lamotrigine) First line for: partial (focal) and generalised seizures
    »> NOT helpful for myoclonus and absences (can make generalised absences worst)
  • Relatively well tolerated
65
Q

What are drug interactions w/carbamazepine as a result of?

A

Enzyme induction

  • Warfarin
  • Combined oral contraceptives
  • Erythromycins
66
Q

How does Valproate work?

A
  • Uncertain mode of action

- GABA, inhibits excitatory transmission, Ca2+, K+?

67
Q

Describe Valproate’s place as an AED. Important CI?

A
  • 1st line (along w/Lamotrigine) for partial/focal and generalised seizures
  • Powerful against: myoclonus, absences, photosensitive seizures
  • Important S/Es, especially in women:
    • Weight gain
    • Polycystic ovaries
    • Teratogenicity (6-10% malformation rates)
    • Affects fertility
    »> Recommend lamotrigine in women
68
Q

What is valproate use in pregnancy associated with?

A
  • Low IQ
  • Autism
  • Subtle facial abnormalities
69
Q

Describe Phenytoin’s place as an AED.

A
  • Second line for partial (focal) and generalised seizures
  • Not helpful in myoclonus or absences (like carbamazepine)
  • COMPLEX kinetics and interactions
  • Some important S/Es
  • Useful in emergencies; can be given IV
70
Q

How does Phenytoin work?

A
  • Acts on Na+ channels

- Suppresses burst activity and spread of seizures

71
Q

What are the causes of phenytoin complexity?

A
  • Variable absorption
  • Rate limiting para-hydroxylation
  • High protein binding
  • Some co-medications both induce and inhibit enzyme activity
  • Age variability in metabolism (non-linear, follows zero-order kinetics)
72
Q

Describe Levetiracetam’s place as an AED.

A
  • Targets synaptic vesicle protein 2a (SV2a)
  • Potent broad spectrum agent
  • Good for partial/focal, some myoclonic
  • Well tolerated
  • No interactions
  • Mood S/Es in 10-20%
73
Q

Describe Topiramate’s place as an AED.

A
  • Broad spectrum action
  • Multiple mechanisms
  • BUT, prone to S/Es (sedation, psychiatric, weight loss)
74
Q

Describe Clobazam/Clonazepam’s place in epilepsy treatment.

A
  • Useful add-on/occasional use agents
  • Tendency to tolerance
  • Sedative
  • Particularly good against absence + myoclonus
75
Q

Describe Gabapentin’s place in epilepsy treatment.

A
  • Weak add-on agent for partial/focal seizures

- High doses may be required

76
Q

Describe Ethosuximide’s place in epilepsy treatment.

A
  • Potent anti-absence agent
  • Not useful for other seizures
  • S/Es common; GI upset, headache, psychiatric disturabance
77
Q

What are the main interactions associated with AEDs?

A 
Enzyme inducing drugs:
- Combined oral contraceptive
- Antimicrobials
- Antivirals
- Analgesics
- Oncology drugs
- Warfarin
>>> Decrease plasma levels of carbamazepine, phenytoin

Immunosuppressants, psychotropics:
- Estrogens
»> Decrease lamotrigine plasma level

CYP inhibitors:
- Erythromycin
- Antifungals
»> Increase carbamazepine plasma level

78
Q

What other issues surround AED therapy?

A
  • When to start
  • When to stop
  • Bone health; many enzyme inducers lower Vit D (prescribe supplements)
  • Improving compliance
  • SUDEP (sudden unexpected death)
79
Q

Why is slow withdrawal of AED treatment important?

A
  • No withdrawal = same seizure lapsing of those carrying on treatment anyway
  • Myoclonic; guaranteed to relapse (as well as brain tumours)
80
Q

What is status epilepticus?

A

A medical emergency:

  • Seizures w/o recovery
  • Tonic clonic lethal if untreated
  • Stopped AEDs? Encephalitis?
81
Q

What is the treatment for status epilepticus?

A

1) IV benzodiazepine + phenytoin
2) IV levetiracetam or valproate or lacosamide
3) General anaesthesia

82
Q

What non pharmacological treatments are availible for epilepsy?

A
  • Resection of epileptic focus (surgical removal)
  • Vagal nerve stimulation (suppressing effect)
  • Ketogenic diet; relevant in children
83
Q

What future treatments are proposed for epilepsy?

A
  • Gene therapy; delivering adenosine, NPY using viral vectors
  • Deep brain stimulation
  • Optogenetics; harnessing the power of light (light probes in brain to influence channels)
84
Q

What is the general AED hierarchy for Absence-based epilepsy?

A
  • Valproate
  • Ethosuximide
  • Lamotrigine
  • BZDs
85
Q

What is the general AED hierarchy for Myoclonus-based epilepsy?

A
  • Valproate
  • BZDs
  • Levetiracetam
86
Q

What is the general AED hierarchy for Generalised Tonic-Clonic based epilepsy?

A
  • Carbamazepine
  • Lamotrigine
  • Valproate
  • Phenytoin
  • Topiramate
    (Ethosuximide ineffective)
87
Q

What is the general AED hierarchy for Focal (Partial) epilepsy?

A
  • Carbamazepine
  • Lamotrigine (low S/Es)
  • Topiramate
  • Levetiracetam
88
Q

What are the main consequences of epilepsy?

A
  • Loss of driving license
  • Loss of employment
  • Stigmatisation and anxiety
  • Needing AEDs
  • Problems with contraception and conception
  • Injuries and mortality

'B33CNS - Pharmacology & Therapeutics (13 decks)

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