Epilepsy I & II Flashcards
1
Q
Hippocrates view of Epilepsy
A
- “Sacred disease” - accumulation of phlegm in the veins of the head
- Starts in utero, continues after birth and into adulthood
- Too much - “melted” brain which results in mental illness.
- patient loses speech and chokes causing foam to fall from his or her mouth
2
Q
What Hippocrates got right
A
recognized the symptoms and that they derived from the brain
right about juvenile onset
3
Q
Hippocrates on epilepsy onset
A
Juvenile Onset b/c young children have small veins, not able to accommodate the increased amount of
phlegm
4
Q
Hippocrates on epilepsy symptoms
A
- Shivering
- Loss of speech
- Trouble breathing
- Contraction of the brain
- Blood stops circulating
- Excretion of the phlegm
5
Q
Seizure
A
an abnormal, disorderly discharging of the brain’s nerve cells
• abnormal, excessive or hypersynchronous neuronal spiking
• temporary disturbance of motor, sensory, or mental function
- singular event in 10% of people
6
Q
Epilepsy
A
refers to a continuum of chronic neurological
syndromes in which a person has heightened risk of
recurrent seizures
7
Q
Causes for epilepsy
A
- Causes can be unknown or genetic
* Can result from brain trauma, stroke, brain cancer, drugs
8
Q
Epilepsy vs. Seizure
A
Epilepsy is a disease of RECURRENT seizures
seizures can also be singular events (independent of epilepsy)
9
Q
___ lifetime risk, ___ prevalence
A
~3% lifetime risk, Prevalence 0.5-1%
prevalence is lower than lifetime risk since many epilepsies resolve (ex. juvenile epilepsy)
10
Q
Is prevalence reported exact?
A
No, epilepsy is likely much more prevalent but figures are decreased due to stigma and the heterogenetity of symptoms
11
Q
Most epilepsy is diagnosed before age___
A
18 (75-85%)
44% by age 5; 55% by age 10
12
Q
Children with epilepsy
A
- 1% of children will have recurrent seizures before age 14
* 50% of cases of childhood epilepsy - seizures disappear (juvenile epilepsy often resolves)
13
Q
In ___ % of cases, the cause of epilepsy is unknown
A
50-60%
14
Q
Cryptogenic vs. idoipathic vs. Symptomatic
A
Cryptogenic = cause unknown but has suspected orgins Idiopathic = cause unknown Symptomatic = generated by injury (secondary to another event--stroke, trauma, meningitis)
15
Q
Both cryptogenic and idiopathic epilepsies are thought to be _____
A
Genetic; but the precise gene itself is unknown
16
Q
Common causes of epilepsy
A
- Genetic abnormalities
- brain tumour, stroke, head trauma of any type
- more severe the injury, the greater the chance of developing epilepsy
- aftermath of infection (meningitis, viral encephalitis)
- poisoning, substance abuse (lead, CO, alcohol)
17
Q
Causes for child onset
A
- injury, infection, or systemic illness of the mother during pregnancy
- brain injury to the infant during delivery may lead to epilepsy
18
Q
Seizure’s effect on life expectancy
A
seizures are not typically fatal, they do reduce life expectancy as well as quality of life (e.g. driving, employment)
19
Q
Epileptics have __ times higher mortality; depends on _____
A
3x; depends on control of seizures
If uncontrolled–shorter life expectancy
If controlled–no difference
20
Q
4 conditions that have risk of death
A
- status epilepticus (continual seziures)
- suicide associated with depression
- trauma from seizures (ex. trauma from falls)
- sudden unexpected death in epilepsy (SUDEP, 8-17%)
21
Q
Highest risk of mortality in epilepsy due to
A
Underlying neurological impairment OR poor control of seizures
22
Q
Can categorize epilepsies based on
A
- Seizure types (semiology)
- Etiology
- Electroencephalogram (EEG) findings
- Brain structure
- Age when seizures begin
- Family history of epilepsy or genetic disorder
- Prognosis
23
Q
Major seizure categories
A
GENERAL vs FOCAL onset
general = whole brain
focal/partial = only in one part of the brain
and Continuous
24
Q
General seizure subtypes
A
Grand mal (generalized motor) Petit mal (absence)--loss of consciousness
25
Focal seizures subtypes
• Simple partial (focal) seizures (elementary cortex involvement)--w/o loss of consciousness
• Motor cortex (Jacksonian)--seizures move through body according to homunculus representation
• Complex partial seziures (limbic seziures)--w/ loss of consciousness
• Sensory cortex:
-->Somatosensory
-->Auditory-vestibular
--> Visual
-->Olfactory-gustatory (uncinate)
26
Focal seziures
focal (partial) onset with or
without secondary generalization to major
motor manifestations.
27
Continuous seizures
* Generalized (status epilepticus)
| * Focal (epilepsia partialis continua)
28
Major seizure classifications (6)
1. "Grand Mal" or Generalized tonic-clonic
2. Absence “petit mal”
3. Myoclonic Sporadic
4. Clonic
5. Tonic
6. Atonic
29
"Grand Mal" or Generalized tonic-clonic
Unconsciousness, convulsions, muscle rigidity
30
Absence “petit mal”
Brief loss of consciousness; generalized; still maintain muscle tone; appear to be daydreaming
31
Myoclonic Sporadic
isolated, jerking movements
32
Clonic
Repetitive jerking movements
33
Tonic
Muscle stiffness, rigidity
34
Atonic
Loss of muscle tone
35
Typical absence seizure--characterization
petit mal
| characterized by 3Hz hyperactivity
36
Juventile myoclonic seziure (generalized) EEG
high amplitude spiking; disordered
37
Interictal (b/t seizures) EEG of Infantile Spasm (west symdrome)
Hypsarrythmia--lack of brain rhythm (highly disordered)
38
Ictial and interictal EEG in mesial temporal love epilespy
```
Interictal = focal temporal discharges (spikes outside of seizure activity)
Ictal = rhythmic theta discharges (5-7 Hz)
```
39
Temporal Lobe Epilepsy Symptoms
odd feeling, memory,
| sensation
40
Frontal Lobe Epilepsy Symptoms
seizure symptoms in the
frontal lobes vary widely
frontal lobes responsible for executive function; cognitive performance
41
Parietal Lobe Epilepsy Symptoms
somatosensory, somatic,
| visual, language
42
Occipital Lobe Epilepsy Symptoms
visual hallucinations
43
Primary Generalized Epilepsy Syndromes
idiopathic, can be
myoclonic,
grand-mal, or absence
44
Reflex Epilepsy
in response to specific
| stimuli only
45
Epilepsy syndromes in kids
* Benign Rolandic Epilepsy
* Juvenile Myoclonic Epilepsy
* Infantile Spasms (West Syndrome)
* Childhood Absence Epilepsy
* Benign Occipital Epilepsy
* Landau-Kleffner Syndrome
46
Benign Rolandic Epilepsy
seizure activity around central sulcus (aka the rolandic fissure)
Outgrown b/t 14-18; peak seizure activity ages ~8-9
Results in infrequent facial seizures and other pharyngal symptoms (ex. hyper salivation)
47
Juvenile Myoclonic Epilepsy
seizures associated with sleep status--often when tired or waking
often diagnosed b/t 12-18; not benign continues into adulthood
48
Infantile Spasms (West Syndrome)
idiopathic, symptomatic, or cryptogenic, prognosis varies
sever neuro-developmental disorder
infantile spasms w/ jack-knife convulsions
associated w/ interictal hypsarhytmia
49
Childhood Absence Epilepsy -
kids 5-9, remission in 80% (mostly benign )
50
Benign Occipital Epilepsy
positive (ex. hallucinations) or negative (i.e. lack of visual perception) visual
symptoms
51
Landau-Kleffner Syndrome
loss of language between 3 and 7 (in kids who had normal language development up until age 3)
Includes seizures but they are rare or at night (and often therefore go unnoticed)
52
Non-genetic causes of epilepsy
Vascular malformations; cerebral tumours (structural abnormalities)
meningitis, encephalitis (infection)
birth asphyxia, cerebrovascular accident (hypoxic-ischemic injury)
53
mTOR (Mammalian target of
| rapamycin)--what is it
protein kinase that regulates cell growth, proliferation, motility, and survival
As well as protein synthesis and transcription
54
mTOR roles in
- Important in excitatory
synaptic neurotransmission
- positive regulator of development, survival and plasticity
- synaptic connectivity (increased spine stability, spine enlargement, role in LTP)
55
mTOR good and bad
```
Good= role in learning
BAD = likely plays role in epilepsy
```
56
mTOR + epilepsy
```
Aberrant activation (overactivation) of mTOR pathway -->altered excitation/inhibition
balance --> susceptibility to seizures reverberating circuit --> epileptogenesis
```
57
how to decrease mTOR's effect on epilepsy
Rapamycin may reduce
| seizure activity by preventing mTOR activity
58
Epilepsy and age
Younger (kids) = caused more due to developmental or infection
Older = mostly due to cerebrovascular issues or degeneration
59
Genetic causes of epilepsy
- KNOWN Genetic diseases ~1% epilepsy cases
| But likely much more-but unknown (idiopathic)
60
Children born to a parent
with epilepsy have ___
chance of developing
epilepsy
<10%
| normal prevalence is 0.5-1%
61
SCN1A mutations
defects in fast inactivation
gating, characterized by a persistent, non-inactivating
current during membrane depolarization, neuronal hyperexcitability
persistent inward current --> increased excitability
62
KCNQ2/3 mutations
altered M currents that modulates
neuronal excitability by dampening repetitive firing
M currents usually dampen excitability but it is altered here to increase repetitive firing due to lack of modulation
altered potassium current
63
Channelopathese
genetic changes to channel function that increase excitability to increase risk of epilepsy
64
3 states of voltage gated Na channel
```
deactivated = closed
activated = open (when threshold is reached)
inactivated = closed, fast inactivation gate (responsible for refractory period--> channel can't open even at threshold)
```
65
NA channel mutants alter...
conductance
Conductance is different, but AP is the same --> activation gate isn't closed --> allows persistent inward current --> cell closer to threshold --> increased excitability
66
M current and epilepsy
Blocking M currents (ex. in KCNQ2/3 mutants) increases
probability of repetitive firing
potassium channels that usually dampen repetitive firing --> when blocked --> repetitive firing
67
nAchR mutations and epilepsy
Neuronal nicotinic acetylcholine receptors (nAChRs) are nonselective cation channels
Pre-synaptic receptors--may enhance transmitter release
Mutuation --> greater current/conductance w/ smaller amounts of Ach --> enhanced transmitter release --> enhancing excitability
68
GABA-A
GABAA receptors trigger an influx of chloride ions (in the
| postnatal brain) that hyperpolarize the neurons
69
GABA and epilepsy
mutants GABA-A receptor subunit--> decreased GABA-mediated synaptic inhibition
ex. CLCN2
70
CLCN2 mutant
CLCN2 = voltage gated chloride channel gene
| CLCN2 mutations completely abolish chloride channel function --> less hyperpol --> more excitability --> epilptogenesis
71
Genetic causes leading to altered devlepment
Tuberous sclerosis, neuro-fibromatosis, periventricular nodular heterotopi, X-linked lissencephaly
72
Tuberous sclerosis –what is it?
non malignant
| tumours in brain and other organs
73
Tuberous sclerosis –cause?
Genetic disease that is Autosomal dominant
| Altered TSC1/2 (tumour suppressor genes) --> formation of benign tumors in brain
74
Tuberous sclerosis –relation to epilepsy
Epilepsy in 80-90%, infantile spasm due to benign tumors
75
Neurofibramotosis
<10% epileptic,
primarily partial
Benign tumours, compression effects
76
Benign tumours and epilepsy
ex. Neurofibramotosis and Tuberous sclerosis
| space occupying masses lead to altered neuronal activity and recurrent seizures
77
Periventricular nodular heterotopia
Dysfunction in cortical neuron migration
• Mild or no intellectual disability, seizures in teens
(80%)--usually diagnosed due to the seziures rather than cog. impairment
78
X-linked lissencephaly
smooth brain --> altered connnectivity --> epilepsy
79
Metabolic disorders and epilepsy
MELAS; inherited metabolic disorders; leigh disease
| Altered cerebral metabolism --> cellular stress and injury --> epilepsy
80
MELAS
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like
episodes (MELAS)
Defect in mitchondrial genome, lactic acidosis (which triggers strokes)
Progressive and fatal
81
Leigh disease
detected in infancy
| usually fatal in 6-7 years
82
Inherited metabolic disorders
| and epilepsy
• Epilepsy an important indicator, but not disorders not necessarily
causative
• Tend to be focal, related to neurologic damage
83
Pharmacotherapy for epilepsy: current approaches
Reduce hyperexcitability; relatively effective
84
Downsides of current therapies
* Side effects--excitatbility is tightly regulated causing side effects
* Not curative--treats the hyperexcitability not the cause of it
85
Major targets of Pharmacotherapies for epilepsy
voltage gated sodium channels (VGSCs) and
| GABA signaling
86
First line therapies for Generalized tonic clonic
Sodium valproate; lamotrigine
87
First line therapies for absence
Sodium valproate; lamotrigine ; ethosuxamide
88
First line therapies for Tonic, atonic and myoclonic seizures
Sodium valproate; clonazepam
| AVOID: carbamezepine, oxcarbazepine
89
First line therapies for partial seziures
carbamezepine; lamotrigine
90
First line therapies are often
Similar; although epilepsy is a syndrome associated with many different causes the treatments focus on decreasing excitability--using the same drugs rather than treating the causes of the indivdual syndromes
91
Sodium valproate--type of drug
Anticonvulsant and mood stabilizer
| • Also treats anxiety disorders, bipolar disorder
92
Sodium valproate--what seizure types
Efficacious in all seizures, particularly
| generalized
93
Sodium valproate--mechanism
Relatively weak blocker of voltage gated sodium channels (weak is good because don't want to completely stop neuronal firing but modulate it-reduce likelihood of AP)
• also weakly inhibits GABA transaminase (prevent GABA breakdown --> more GABA --> more inhibition)
94
Sodium valproate--side effects
* Risk of severe liver damage
* Tiredness, sedation
* Gastrointestinal issues
* Birth defects – highest risk among antiepileptics
* However, seizures can also be harmful to baby
95
Carbamezepine--drug type/other uses
* Anticonvulsant and mood stabilizer
| * used for Epilepsy, bipolar disorder
96
Carbamezepine--mechanism
Stabilizes the inactivated state of voltage gated sodium channels (prevents recurrent firing)
• Potentiates GABA receptors (increase inhibitory actions when ligands are bound) similar to Sodium valproate targets but diff mechanism
97
Carbamezepine--side effects
```
• Sedation, headache, motor impairment
• Gastrointestinal
• Liver damage
• Risk of birth defects
Similar to those of sodium valproate (due to similar mechanism)
```
98
Oxcarbazepine vs carbazepine
Oxcarbazepine is a carbazepine derivative with same mechanisms
BUT Reduced side-effects, liver damage
99
Lamotrigine--drug type, other uses
Anticonvulsant and mood stabilizer
| •used in Epilepsy, bipolar, off label use in depression
100
Lamotrigine--mechanism
Not precisely defined, presumed action on sodium channels (confirmed in vitro)
Found to be helpful for epilepsy despite having been created for other things
101
Lamotrigine--side effects
* rash, fever, and fatigue, life-threatening skin reactions
* Loss of coordination, blurred vision
* Increased risk of birth defects
102
Lamotrigine--what we learn from its side effects
- side effects different from other sodium channel blockers--maybe due to being a 'dirty' drug and be effects unrelated to therapeutic actions
- May also suggest a different mechanism of action than other sodium channel blockers
103
Benzodiazepines--what type of drug, most common one?
• Most often clonazepam
• Widely used sedative – hypnotic,
anxiolytic, anticonvulsant, muscle
relaxant
104
Benzodiazepines--mechanism
• BZDs bind GABA-A receptors and
increase affinity for GABA ligand
• increases the frequency of channel
opening (increased conductance --> increase inhibition)
105
Benzodiazepines--side effects
• Not major teratogens, some association with cleft palate
• Well tolerated but sedation, dizziness,decreased alertness common
• Tolerance develops, efficacy declines
over weeks
106
BZDs--major issue with therapeutic use
Tolerance develops, efficacy declines over weeks--need increasing doses
Dangerous effects when combined with alcohol
107
Ethosuximide--for what type of seizures
Antiepileptic for Absence seizures
108
Benefits of Ethosuximide
lacks hepatotoxicity of valproic acid
109
Ethosuximide--mechanism
- T-type calcium channel blocker
| Prevents burst firing often seen --. preventws seizures
110
T-type calcium channels role
T-type calcium channels contribute to tonic bursting activity, responsible for low threshold spikes when cell is at negative, membrane depolarizations
111
T-type calcium channels and seizure activity
their tonic bursting activity --> BURST firing = seizures
112
Ethosuximide--side effects
Drowsiness and gastrointestinal side
effects, can induce psychoses in some
individuals
113
Leviteracetam--drug type, use for what seziures
Second line therapy Anticonvulsant
| Some efficacy alone or in conjunction for multiple syndromes
114
Leviteracetam--Mechanism
- Exact mechanism unknown.
• maybe GABA agonism (increase inhibitory tone)
- Binds to a synaptic vesicle glycoprotein, SV2A --> inhibits presynaptic calcium channels --> less Ca influx --> less NT (Presynaptic inhibition of neurotransmission)
115
Leviteracetam-side effects
Generally well tolerated
Drowsiness, coordination
Some association with depression and
suicidal behaviour
116
Topiramate--drug type
Anticonvulsant with multiple putative
| mechanisms of action
117
Topiramate--mechanism
• blockage of voltage-dependent sodium channels
• augmentation of GABA-A receptors --> potentiates Cl- influx --> decreased excitatory drive
• AMPA/kainate antagonist (reduced
excitatory transmission by glutamate)
• inhibition of carbonic anhydrase (less important)
118
Topiramate-side effects
* cognitive side effects including short term memory loss and word-finding difficulty (due to AMPA-effects; ampa important for memory)
* Numbness, tingling
119
Prospective treatment--issues
only looking at drugs with same targets as current ones --> not that beneficial need to look at different pathways
120
New treatments
Acts on sodium channels: Lacosamide, Rufinamide, Eslicarbazepine, Retigabine
AMPA antag: Perampanel
121
Combination therapy: why
Syngergistic efficacy without additive toxicity
| • Supra-additive adverse effects more common with similar mechanism
122
Combination therapy --downsides
get additive adverse effects when combining drugs with similar mechanisms
- Lack of evidence on synergy, decisions largely based on
adverse effects
123
Best human evidence of Combo Therapy
Lamotrigine-valproate
• Best human evidence for synergy
• Efficacy in patients refractory to monotherapy
• Adverse effects – severe and disabling tremor, rash
124
Experimental therapies – Tau WHY?
Seziures can develop after trauma/injury and Hyperphosphorylated tau associated with neurodegenerative pathology in multiple disorders
125
Experimental therapies – Tau HOW?
PP2A accounts for over 70% of tau phosphatase activity in the human brain
• Activating PP2A with Sodium Selenate significantly reduced the
frequency and severity of seizure activity in a rodent mode (parents neurodegenerative pathology)
126
Experimental therapies – Inflammation WHY
• Inflammation can contribute to the
development of epilepsy
• and there are Many known anti-inflammatories to try
127
Anti-inflammatory targets
Cox-2 inhibitors largely ineffective thus far
| IL-1beta, IL-6, TNFalpha are upregulated by epilepsy--potential therapeutic targets?
128
Experimental therapies - Neurosteroids WHAT ARE THEY?
Neurosteroids are positive
| modulators of GABA-A activity ex. Allopregnanalone
129
Allopregnanalone
Neurosteroid; Progesterone metabolite
• Potent positive modulator of GABA-A
• Varies inversely with seizure frequency
• Effective in treatment of refractory status epilepticus in animal models
130
Neurosteroids--endogenous vs. synthetic
```
Endogenous neurosteroids NOT
clinically usable
• Synthetic neurosteroids have
shown promising results (e.g.
ganaxolone, Phase II)
```
131
Experimental therapies – P2X7 WHAT IS IT?
P2X7 receptors are purinergic cation channels
• Linked to neuronal excitability
• Also important in microglial activation (i.e. inflammation)
132
WHY target P2X7
Upregulated after brain damage and seizure
| • Agonists potentiate seizure, antagonists reduce seizure
133
Experimental therapies – Gene therapy HOW
Lenti-virus, adeno-associated virus (AAV), and herpes simplex virus (HSV)–based vectors have all been used in clinical trials for long tern manipulation of brain activity and possibly optogenetics
134
Prefered viral vectors for gene therapy
• Viral vectors with preferential CNS-targeting properties, such as variants of AAV vectors and SV40 recombinant vectors have been developed
135
Optogenetics
use light to control neuronal activity in vivo by shining on different wavelengths of light onto specific inserted light-sensitive channels
136
Channelrhodopsin
Blue light sensitive
| excitatory (increases firing)
137
Halorhodopsin
reacts to yellow light
| turn cells off (reduce firing)
138
How to use optogenetics for epilepsy in animal models
Put Halorhodopsin on excitatory cells in cortex (can turn off excitatory cells with yellow light )
OR
Put Channelrhodopsin on inhibitory cells in cortex (can turn on inhibitory cells with blue light)
139
DREADDs
chemogenetics; designer receptors to be activated by designer drugs
DREADDs not activated by endogenous compounds and designer drugs will not cause any side effects
140
DREADDs in epilepsy
Infuse CNO (designer ligand) --> activates inhib DREADD --> decrease seizure
141
Keto for epilepsy--when to try it
Advocates for the diet recommend that it be seriously
| considered after two medications have failed
142
Keto for epilepsy--mechanism
* Mechanism unknown, not due to hypoglycemia
| * Altered metabolism, direct action of ketones?
143
Keto what is it?
high-fat, moderate-protein, low-carbohydrate diet used to treat refractory juvenile epilepsy and some adults
144
Keto for epilepsy-- response
Effective in 50% of children
