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
2
Q
What are the variable factors WRT seizures?
A
- Pattern of epileptic discharges
- Circuits involved
- Likely cause
- Drugs used
- Chance of cure
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)
4
Q
What do anti-epileptic drugs target?
A
Neuronal channels and NT receptors:
- Na+, K+, Ca2+
- GABA, Glu
- SV2a
- Cannabinergic mechanisms
5
Q
What is a seizure?
A
The clinical manifestation (symptomatic) of a disordered and hypersynchronised discharge/firing in a network of cerebral neurons
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)
7
Q
What is seizure type determined by?
A
- Location of onset
- Type of discharge
- Pattern of spread
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
9
Q
What are the common types of generalised seizures?
A
- Typical Absence
- Myoclonic
- Tonic-Clonic
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)
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
12
Q
Who does Myoclonus occur in?
A
- Epilepsy syndromes e.g. JME (Juvenile Myoclonic Epilepsy)
- Non-epileptic causes
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
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
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
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)
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
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
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)
20
Q
What are the symptoms of Secondary Generalised Focal (Partial) seizures?
A
- Clonic arm movement
- Raspy breathing
21
Q
What is the EEG hallmark of Generalised Seizures?
A
Bilateral activity from onset
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
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)
24
Q
What are the two rhythms of neuronal firing?
A
- Regular firing
- Burst firing (can be normal in sleep)
25
What is ictogenesis? Inter-ictal spike vs seizures?
- 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
26
What does the inter-ictal spike tell us?
- Characteristic EEG signature of focal epilepsy (not a seizure though)
- Lasts about 200ms; paroxysmal depolarisation shift (PDS)
27
Describe Epileptic Discharge WRT an AP/PDS.
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)
28
How does neural activity differ from neural in seizures?
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)
29
What are micro-domains?
Possible basis of focal seizures:
- Hyper-sensitive cortex (+, Glu) is balanced by inhibitory signals (-, GABA)
- When inhibition fades and Glu drive overcomes GABA = seizures
30
What are cortico-thalamic loops?
- 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)
31
What are the two modes of firing of thalamic (brain's sensory switchboard) neurons?
- Tonic mode (talking to cerebral cortex)
| - Burst mode
32
What are some observations in Absence Seizures WRT S&W/thalamic neurons?
- 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
33
What is the pathophysiology of Absence seizures?
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
34
So what goes wrong in absence seizures?
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?
35
What is the pathophysiology of Tonic-clonic seizures?
- Basal ganglia/brainstem involved in seizure
| - Substantia nigra has gating function for severity of seizure
36
What changes occur in epileptogenesis?
- 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
What channelopathies are known to be involved in epilepsy?
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
What 3 states do Na+ channels undergo?
- Resting state (closed)
- Activated state (open)
- Inactivated state
39
What are Na+ channels involved in?
- APs
- Transmitter release
- Sub-threshold neuronal properties
40
How do AEDs manipulate Na+ channels?
- They are use and voltage dependent
- AEDs prolong inactivated state of channel (e.g. Lamotrigine)
- Block increases with repetitive activation
- Reduce burst firing
41
What are the issues with trying to block Na+ channels with AEDs?
- 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
How may persistent Na+ current be of importance in epilepsy? Corresponding AED?
- Some AEDs bind selectively to Nap
| - E.g. Lacosamide; enhances slow inactivation of Na channels
43
Which AEDs promote inhibition?
- BZDs
- Barbiturates
- Topiramate
>>> Enhance Cl- current at GABA receptors
44
Which AEDs reduce GABA degradation/reuptake?
- 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
Which AED works by augmenting the K+ channel?
Retigabine:
| - Currently withdrawn due to possible retinal S/Es
46
Which AED works by blocking AMPA? Caveat?
Perampanel:
- Highly selective non-competitive AMPA antagonist
>>> Targets excitatory activity
>>> BUT, some patients are v aggressive on Perampanel
47
Which AEDs have a multiple mode of action/are poorly understood?
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
What are the implications of having epilepsy?
Multiple:
- Physical
- Psychological
- Social
49
How is epilepsy managed?
- Ensuring a correct diagnosis (other causes of fainting etc.?)
- Determining the cause
- Deciding on treatment (tailored)
- Advising on lifestyle issues (e.g. driving)
50
What are some causes blackouts and 'funny turns'?
- Epilepsy
- Fainting
- Cardiac
- Attacks w/psychological cause (10-20%; mental health, unconscious manifestation etc.)
- Rarities
51
What is the epilepsy syndrome?
- Seizure type
- EEG results
- MRI findings
- Family history
- Associated causes
>>> Treatment and prognosis
52
What are the two different types of epilepsies?
- Idiopathic (brain is normal; easier to control)
| - Symptomatic (seizure is symptom of brain lesion; difficult to control)
53
Describe idiopathic epilepsies.
- No associated neurological damage
- Often responds well to treatment
- Genetic component suspected
>>> Often generalised
54
Describe symptomatic epilepsies.
- More treatment resistant
- May have associated neurological deficits
>>> Often focal
55
What are the different causes of symptomatic epilepsy?
- Cortical malformations (hypoxic birth?)
- Cerebral palsy
- Genetic and metabolic disorders
- Hippocampal sclerosis (febrile convulsions as an infant)
- Trauma and infection
- Tumours
- Stroke
56
What are the aetiology of epilepsies?
- Genetic
- Structural
- Metabolic
- Unknown cause
57
What are the general principles of epilepsy treatment WRT the disorder, the patient and the drug?
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
Which period of time after the first seizure carries the greatest risk of a second seizure? Who are more prone?
- Max risk in first 6 months
| - Juvenile Myoclonus certain to have another
59
What are the initial treatment options for generalised and focal epilepsy respectively?
Generalised:
- Sodium Valproate (CI in women of child-bearing age)
- Lamotrigine
Focal:
- Lamotrigine
60
What are 'petit mal seizures' also known as?
Complex partial (focal) seizures
61
Describe lamotrigine's place as an AED.
- 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
What common medicine interact with Lamotrigine?
- Combined oral contraceptives (and pregnancy in general)
- Results in serum level drop
- Due to high estrogen levels
63
How does carbamazepine work?
- Acts on Na+ channels
| - Suppresses nirst activity and spread of seizures
64
Describe carbamazepine's place as an AED.
- (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
What are drug interactions w/carbamazepine as a result of?
Enzyme induction
- Warfarin
- Combined oral contraceptives
- Erythromycins
66
How does Valproate work?
- Uncertain mode of action
| - GABA, inhibits excitatory transmission, Ca2+, K+?
67
Describe Valproate's place as an AED. Important CI?
- 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
What is valproate use in pregnancy associated with?
- Low IQ
- Autism
- Subtle facial abnormalities
69
Describe Phenytoin's place as an AED.
- 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
How does Phenytoin work?
- Acts on Na+ channels
| - Suppresses burst activity and spread of seizures
71
What are the causes of phenytoin complexity?
- 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
Describe Levetiracetam's place as an AED.
- 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
Describe Topiramate's place as an AED.
- Broad spectrum action
- Multiple mechanisms
- BUT, prone to S/Es (sedation, psychiatric, weight loss)
74
Describe Clobazam/Clonazepam's place in epilepsy treatment.
- Useful add-on/occasional use agents
- Tendency to tolerance
- Sedative
- Particularly good against absence + myoclonus
75
Describe Gabapentin's place in epilepsy treatment.
- Weak add-on agent for partial/focal seizures
| - High doses may be required
76
Describe Ethosuximide's place in epilepsy treatment.
- Potent anti-absence agent
- Not useful for other seizures
- S/Es common; GI upset, headache, psychiatric disturabance
77
What are the main interactions associated with AEDs?
```
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
What other issues surround AED therapy?
- When to start
- When to stop
- Bone health; many enzyme inducers lower Vit D (prescribe supplements)
- Improving compliance
- SUDEP (sudden unexpected death)
79
Why is slow withdrawal of AED treatment important?
- No withdrawal = same seizure lapsing of those carrying on treatment anyway
- Myoclonic; guaranteed to relapse (as well as brain tumours)
80
What is status epilepticus?
A medical emergency:
- Seizures w/o recovery
- Tonic clonic lethal if untreated
- Stopped AEDs? Encephalitis?
81
What is the treatment for status epilepticus?
1) IV benzodiazepine + phenytoin
2) IV levetiracetam or valproate or lacosamide
3) General anaesthesia
82
What non pharmacological treatments are availible for epilepsy?
- Resection of epileptic focus (surgical removal)
- Vagal nerve stimulation (suppressing effect)
- Ketogenic diet; relevant in children
83
What future treatments are proposed for epilepsy?
- 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
What is the general AED hierarchy for Absence-based epilepsy?
- Valproate
- Ethosuximide
- Lamotrigine
- BZDs
85
What is the general AED hierarchy for Myoclonus-based epilepsy?
- Valproate
- BZDs
- Levetiracetam
86
What is the general AED hierarchy for Generalised Tonic-Clonic based epilepsy?
- Carbamazepine
- Lamotrigine
- Valproate
- Phenytoin
- Topiramate
(Ethosuximide ineffective)
87
What is the general AED hierarchy for Focal (Partial) epilepsy?
- Carbamazepine
- Lamotrigine (low S/Es)
- Topiramate
- Levetiracetam
88
What are the main consequences of epilepsy?
- Loss of driving license
- Loss of employment
- Stigmatisation and anxiety
- Needing AEDs
- Problems with contraception and conception
- Injuries and mortality
