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PMCOL 412 > Epilepsy I & II > Flashcards

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
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2
Q

What Hippocrates got right

A

recognized the symptoms and that they derived from the brain

right about juvenile onset

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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

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4
Q

Hippocrates on epilepsy symptoms

A
  • Shivering
  • Loss of speech
  • Trouble breathing
  • Contraction of the brain
  • Blood stops circulating
  • Excretion of the phlegm
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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

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6
Q

Epilepsy

A

refers to a continuum of chronic neurological
syndromes in which a person has heightened risk of
recurrent seizures

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7
Q

Causes for epilepsy

A
  • Causes can be unknown or genetic

* Can result from brain trauma, stroke, brain cancer, drugs

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8
Q

Epilepsy vs. Seizure

A

Epilepsy is a disease of RECURRENT seizures

seizures can also be singular events (independent of epilepsy)

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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)

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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

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11
Q

Most epilepsy is diagnosed before age___

A

18 (75-85%)

44% by age 5; 55% by age 10

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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)

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13
Q

In ___ % of cases, the cause of epilepsy is unknown

A

50-60%

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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)
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15
Q

Both cryptogenic and idiopathic epilepsies are thought to be _____

A

Genetic; but the precise gene itself is unknown

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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)
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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
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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)

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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

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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%)
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21
Q

Highest risk of mortality in epilepsy due to

A

Underlying neurological impairment OR poor control of seizures

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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
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23
Q

Major seizure categories

A

GENERAL vs FOCAL onset
general = whole brain
focal/partial = only in one part of the brain
and Continuous

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24
Q

General seizure subtypes

A 
Grand mal (generalized motor)
Petit mal (absence)--loss of consciousness
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25
Q

Focal seizures subtypes

A

• 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)

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26
Q

Focal seziures

A

focal (partial) onset with or
without secondary generalization to major
motor manifestations.

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27
Q

Continuous seizures

A
  • Generalized (status epilepticus)

* Focal (epilepsia partialis continua)

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28
Q

Major seizure classifications (6)

A
  1. “Grand Mal” or Generalized tonic-clonic
  2. Absence “petit mal”
  3. Myoclonic Sporadic
  4. Clonic
  5. Tonic
  6. Atonic
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29
Q

“Grand Mal” or Generalized tonic-clonic

A

Unconsciousness, convulsions, muscle rigidity

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30
Q

Absence “petit mal”

A

Brief loss of consciousness; generalized; still maintain muscle tone; appear to be daydreaming

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31
Q

Myoclonic Sporadic

A

isolated, jerking movements

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32
Q

Clonic

A

Repetitive jerking movements

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33
Q

Tonic

A

Muscle stiffness, rigidity

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34
Q

Atonic

A

Loss of muscle tone

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35
Q

Typical absence seizure–characterization

A

petit mal

characterized by 3Hz hyperactivity

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36
Q

Juventile myoclonic seziure (generalized) EEG

A

high amplitude spiking; disordered

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37
Q

Interictal (b/t seizures) EEG of Infantile Spasm (west symdrome)

A

Hypsarrythmia–lack of brain rhythm (highly disordered)

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38
Q

Ictial and interictal EEG in mesial temporal love epilespy

A 
Interictal = focal temporal discharges (spikes outside of seizure activity)
Ictal = rhythmic theta discharges (5-7 Hz)
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39
Q

Temporal Lobe Epilepsy Symptoms

A

odd feeling, memory,

sensation

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40
Q

Frontal Lobe Epilepsy Symptoms

A

seizure symptoms in the
frontal lobes vary widely
frontal lobes responsible for executive function; cognitive performance

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41
Q

Parietal Lobe Epilepsy Symptoms

A

somatosensory, somatic,

visual, language

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42
Q

Occipital Lobe Epilepsy Symptoms

A

visual hallucinations

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43
Q

Primary Generalized Epilepsy Syndromes

A

idiopathic, can be
myoclonic,
grand-mal, or absence

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44
Q

Reflex Epilepsy

A

in response to specific

stimuli only

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45
Q

Epilepsy syndromes in kids

A
  • Benign Rolandic Epilepsy
  • Juvenile Myoclonic Epilepsy
  • Infantile Spasms (West Syndrome)
  • Childhood Absence Epilepsy
  • Benign Occipital Epilepsy
  • Landau-Kleffner Syndrome
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46
Q

Benign Rolandic Epilepsy

A

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)

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47
Q

Juvenile Myoclonic Epilepsy

A

seizures associated with sleep status–often when tired or waking
often diagnosed b/t 12-18; not benign continues into adulthood

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48
Q

Infantile Spasms (West Syndrome)

A

idiopathic, symptomatic, or cryptogenic, prognosis varies
sever neuro-developmental disorder
infantile spasms w/ jack-knife convulsions
associated w/ interictal hypsarhytmia

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49
Q

Childhood Absence Epilepsy -

A

kids 5-9, remission in 80% (mostly benign )

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50
Q

Benign Occipital Epilepsy

A

positive (ex. hallucinations) or negative (i.e. lack of visual perception) visual
symptoms

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51
Q

Landau-Kleffner Syndrome

A

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)

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52
Q

Non-genetic causes of epilepsy

A

Vascular malformations; cerebral tumours (structural abnormalities)
meningitis, encephalitis (infection)
birth asphyxia, cerebrovascular accident (hypoxic-ischemic injury)

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53
Q

mTOR (Mammalian target of

rapamycin)–what is it

A

protein kinase that regulates cell growth, proliferation, motility, and survival
As well as protein synthesis and transcription

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54
Q

mTOR roles in

A
  • Important in excitatory
    synaptic neurotransmission
  • positive regulator of development, survival and plasticity
  • synaptic connectivity (increased spine stability, spine enlargement, role in LTP)
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55
Q

mTOR good and bad

A 
Good= role in learning 
BAD = likely plays role in epilepsy
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56
Q

mTOR + epilepsy

A 
Aberrant activation (overactivation) of mTOR pathway -->altered excitation/inhibition
balance -->  susceptibility to seizures reverberating circuit --> epileptogenesis
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57
Q

how to decrease mTOR’s effect on epilepsy

A

Rapamycin may reduce

seizure activity by preventing mTOR activity

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58
Q

Epilepsy and age

A

Younger (kids) = caused more due to developmental or infection
Older = mostly due to cerebrovascular issues or degeneration

59
Q

Genetic causes of epilepsy

A
  • KNOWN Genetic diseases ~1% epilepsy cases

But likely much more-but unknown (idiopathic)

60
Q

Children born to a parent
with epilepsy have ___
chance of developing
epilepsy

A

<10%

normal prevalence is 0.5-1%

61
Q

SCN1A mutations

A

defects in fast inactivation
gating, characterized by a persistent, non-inactivating
current during membrane depolarization, neuronal hyperexcitability
persistent inward current –> increased excitability

62
Q

KCNQ2/3 mutations

A

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
Q

Channelopathese

A

genetic changes to channel function that increase excitability to increase risk of epilepsy

64
Q

3 states of voltage gated Na channel

A 
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
Q

NA channel mutants alter…

A

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
Q

M current and epilepsy

A

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
Q

nAchR mutations and epilepsy

A

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
Q

GABA-A

A

GABAA receptors trigger an influx of chloride ions (in the

postnatal brain) that hyperpolarize the neurons

69
Q

GABA and epilepsy

A

mutants GABA-A receptor subunit–> decreased GABA-mediated synaptic inhibition
ex. CLCN2

70
Q

CLCN2 mutant

A

CLCN2 = voltage gated chloride channel gene

CLCN2 mutations completely abolish chloride channel function –> less hyperpol –> more excitability –> epilptogenesis

71
Q

Genetic causes leading to altered devlepment

A

Tuberous sclerosis, neuro-fibromatosis, periventricular nodular heterotopi, X-linked lissencephaly

72
Q

Tuberous sclerosis –what is it?

A

non malignant

tumours in brain and other organs

73
Q

Tuberous sclerosis –cause?

A

Genetic disease that is Autosomal dominant

Altered TSC1/2 (tumour suppressor genes) –> formation of benign tumors in brain

74
Q

Tuberous sclerosis –relation to epilepsy

A

Epilepsy in 80-90%, infantile spasm due to benign tumors

75
Q

Neurofibramotosis

A

<10% epileptic,
primarily partial
Benign tumours, compression effects

76
Q

Benign tumours and epilepsy

A

ex. Neurofibramotosis and Tuberous sclerosis

space occupying masses lead to altered neuronal activity and recurrent seizures

77
Q

Periventricular nodular heterotopia

A

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
Q

X-linked lissencephaly

A

smooth brain –> altered connnectivity –> epilepsy

79
Q

Metabolic disorders and epilepsy

A

MELAS; inherited metabolic disorders; leigh disease

Altered cerebral metabolism –> cellular stress and injury –> epilepsy

80
Q

MELAS

A

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like
episodes (MELAS)
Defect in mitchondrial genome, lactic acidosis (which triggers strokes)
Progressive and fatal

81
Q

Leigh disease

A

detected in infancy

usually fatal in 6-7 years

82
Q

Inherited metabolic disorders

and epilepsy

A

• Epilepsy an important indicator, but not disorders not necessarily
causative
• Tend to be focal, related to neurologic damage

83
Q

Pharmacotherapy for epilepsy: current approaches

A

Reduce hyperexcitability; relatively effective

84
Q

Downsides of current therapies

A
  • Side effects–excitatbility is tightly regulated causing side effects
  • Not curative–treats the hyperexcitability not the cause of it
85
Q

Major targets of Pharmacotherapies for epilepsy

A

voltage gated sodium channels (VGSCs) and

GABA signaling

86
Q

First line therapies for Generalized tonic clonic

A

Sodium valproate; lamotrigine

87
Q

First line therapies for absence

A

Sodium valproate; lamotrigine ; ethosuxamide

88
Q

First line therapies for Tonic, atonic and myoclonic seizures

A

Sodium valproate; clonazepam

AVOID: carbamezepine, oxcarbazepine

89
Q

First line therapies for partial seziures

A

carbamezepine; lamotrigine

90
Q

First line therapies are often

A

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
Q

Sodium valproate–type of drug

A

Anticonvulsant and mood stabilizer

• Also treats anxiety disorders, bipolar disorder

92
Q

Sodium valproate–what seizure types

A

Efficacious in all seizures, particularly

generalized

93
Q

Sodium valproate–mechanism

A

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
Q

Sodium valproate–side effects

A
  • Risk of severe liver damage
  • Tiredness, sedation
  • Gastrointestinal issues
  • Birth defects – highest risk among antiepileptics
  • However, seizures can also be harmful to baby
95
Q

Carbamezepine–drug type/other uses

A
  • Anticonvulsant and mood stabilizer

* used for Epilepsy, bipolar disorder

96
Q

Carbamezepine–mechanism

A

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
Q

Carbamezepine–side effects

A 
• Sedation, headache, motor impairment
• Gastrointestinal
• Liver damage
• Risk of birth defects
Similar to those of sodium valproate (due to similar mechanism)
98
Q

Oxcarbazepine vs carbazepine

A

Oxcarbazepine is a carbazepine derivative with same mechanisms
BUT Reduced side-effects, liver damage

99
Q

Lamotrigine–drug type, other uses

A

Anticonvulsant and mood stabilizer

•used in Epilepsy, bipolar, off label use in depression

100
Q

Lamotrigine–mechanism

A

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
Q

Lamotrigine–side effects

A
  • rash, fever, and fatigue, life-threatening skin reactions
  • Loss of coordination, blurred vision
  • Increased risk of birth defects
102
Q

Lamotrigine–what we learn from its side effects

A
  • 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
Q

Benzodiazepines–what type of drug, most common one?

A

• Most often clonazepam
• Widely used sedative – hypnotic,
anxiolytic, anticonvulsant, muscle
relaxant

104
Q

Benzodiazepines–mechanism

A

• BZDs bind GABA-A receptors and
increase affinity for GABA ligand
• increases the frequency of channel
opening (increased conductance –> increase inhibition)

105
Q

Benzodiazepines–side effects

A

• Not major teratogens, some association with cleft palate
• Well tolerated but sedation, dizziness,decreased alertness common
• Tolerance develops, efficacy declines
over weeks

106
Q

BZDs–major issue with therapeutic use

A

Tolerance develops, efficacy declines over weeks–need increasing doses
Dangerous effects when combined with alcohol

107
Q

Ethosuximide–for what type of seizures

A

Antiepileptic for Absence seizures

108
Q

Benefits of Ethosuximide

A

lacks hepatotoxicity of valproic acid

109
Q

Ethosuximide–mechanism

A
  • T-type calcium channel blocker

Prevents burst firing often seen –. preventws seizures

110
Q

T-type calcium channels role

A

T-type calcium channels contribute to tonic bursting activity, responsible for low threshold spikes when cell is at negative, membrane depolarizations

111
Q

T-type calcium channels and seizure activity

A

their tonic bursting activity –> BURST firing = seizures

112
Q

Ethosuximide–side effects

A

Drowsiness and gastrointestinal side
effects, can induce psychoses in some
individuals

113
Q

Leviteracetam–drug type, use for what seziures

A

Second line therapy Anticonvulsant

Some efficacy alone or in conjunction for multiple syndromes

114
Q

Leviteracetam–Mechanism

A
  • 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
Q

Leviteracetam-side effects

A

Generally well tolerated
Drowsiness, coordination
Some association with depression and
suicidal behaviour

116
Q

Topiramate–drug type

A

Anticonvulsant with multiple putative

mechanisms of action

117
Q

Topiramate–mechanism

A

• 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
Q

Topiramate-side effects

A
  • cognitive side effects including short term memory loss and word-finding difficulty (due to AMPA-effects; ampa important for memory)
  • Numbness, tingling
119
Q

Prospective treatment–issues

A

only looking at drugs with same targets as current ones –> not that beneficial need to look at different pathways

120
Q

New treatments

A

Acts on sodium channels: Lacosamide, Rufinamide, Eslicarbazepine, Retigabine
AMPA antag: Perampanel

121
Q

Combination therapy: why

A

Syngergistic efficacy without additive toxicity

• Supra-additive adverse effects more common with similar mechanism

122
Q

Combination therapy –downsides

A

get additive adverse effects when combining drugs with similar mechanisms
- Lack of evidence on synergy, decisions largely based on
adverse effects

123
Q

Best human evidence of Combo Therapy

A

Lamotrigine-valproate
• Best human evidence for synergy
• Efficacy in patients refractory to monotherapy
• Adverse effects – severe and disabling tremor, rash

124
Q

Experimental therapies – Tau WHY?

A

Seziures can develop after trauma/injury and Hyperphosphorylated tau associated with neurodegenerative pathology in multiple disorders

125
Q

Experimental therapies – Tau HOW?

A

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
Q

Experimental therapies – Inflammation WHY

A

• Inflammation can contribute to the
development of epilepsy
• and there are Many known anti-inflammatories to try

127
Q

Anti-inflammatory targets

A

Cox-2 inhibitors largely ineffective thus far

IL-1beta, IL-6, TNFalpha are upregulated by epilepsy–potential therapeutic targets?

128
Q

Experimental therapies - Neurosteroids WHAT ARE THEY?

A

Neurosteroids are positive

modulators of GABA-A activity ex. Allopregnanalone

129
Q

Allopregnanalone

A

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
Q

Neurosteroids–endogenous vs. synthetic

A 
Endogenous neurosteroids NOT
clinically usable
• Synthetic neurosteroids have
shown promising results (e.g.
ganaxolone, Phase II)
131
Q

Experimental therapies – P2X7 WHAT IS IT?

A

P2X7 receptors are purinergic cation channels
• Linked to neuronal excitability
• Also important in microglial activation (i.e. inflammation)

132
Q

WHY target P2X7

A

Upregulated after brain damage and seizure

• Agonists potentiate seizure, antagonists reduce seizure

133
Q

Experimental therapies – Gene therapy HOW

A

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
Q

Prefered viral vectors for gene therapy

A

• Viral vectors with preferential CNS-targeting properties, such as variants of AAV vectors and SV40 recombinant vectors have been developed

135
Q

Optogenetics

A

use light to control neuronal activity in vivo by shining on different wavelengths of light onto specific inserted light-sensitive channels

136
Q

Channelrhodopsin

A

Blue light sensitive

excitatory (increases firing)

137
Q

Halorhodopsin

A

reacts to yellow light

turn cells off (reduce firing)

138
Q

How to use optogenetics for epilepsy in animal models

A

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
Q

DREADDs

A

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
Q

DREADDs in epilepsy

A

Infuse CNO (designer ligand) –> activates inhib DREADD –> decrease seizure

141
Q

Keto for epilepsy–when to try it

A

Advocates for the diet recommend that it be seriously

considered after two medications have failed

142
Q

Keto for epilepsy–mechanism

A
  • Mechanism unknown, not due to hypoglycemia

* Altered metabolism, direct action of ketones?

143
Q

Keto what is it?

A

high-fat, moderate-protein, low-carbohydrate diet used to treat refractory juvenile epilepsy and some adults

144
Q

Keto for epilepsy– response

A

Effective in 50% of children

PMCOL 412 (35 decks)

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