PMCOL 412 > Epilepsy I & II > Flashcards

Epilepsy I & II Flashcards

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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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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)
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Focal seziures
focal (partial) onset with or without secondary generalization to major motor manifestations.
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Continuous seizures
* Generalized (status epilepticus) | * Focal (epilepsia partialis continua)
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Major seizure classifications (6)
1. "Grand Mal" or Generalized tonic-clonic 2. Absence “petit mal” 3. Myoclonic Sporadic 4. Clonic 5. Tonic 6. Atonic
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"Grand Mal" or Generalized tonic-clonic
Unconsciousness, convulsions, muscle rigidity
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Absence “petit mal”
Brief loss of consciousness; generalized; still maintain muscle tone; appear to be daydreaming
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Myoclonic Sporadic
isolated, jerking movements
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Clonic
Repetitive jerking movements
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Tonic
Muscle stiffness, rigidity
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Atonic
Loss of muscle tone
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Typical absence seizure--characterization
petit mal | characterized by 3Hz hyperactivity
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Juventile myoclonic seziure (generalized) EEG
high amplitude spiking; disordered
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Interictal (b/t seizures) EEG of Infantile Spasm (west symdrome)
Hypsarrythmia--lack of brain rhythm (highly disordered)
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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) ```
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Temporal Lobe Epilepsy Symptoms
odd feeling, memory, | sensation
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Frontal Lobe Epilepsy Symptoms
seizure symptoms in the frontal lobes vary widely frontal lobes responsible for executive function; cognitive performance
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Parietal Lobe Epilepsy Symptoms
somatosensory, somatic, | visual, language
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Occipital Lobe Epilepsy Symptoms
visual hallucinations
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Primary Generalized Epilepsy Syndromes
idiopathic, can be myoclonic, grand-mal, or absence
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Reflex Epilepsy
in response to specific | stimuli only
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Epilepsy syndromes in kids
* Benign Rolandic Epilepsy * Juvenile Myoclonic Epilepsy * Infantile Spasms (West Syndrome) * Childhood Absence Epilepsy * Benign Occipital Epilepsy * Landau-Kleffner Syndrome
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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)
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Juvenile Myoclonic Epilepsy
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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Infantile Spasms (West Syndrome)
idiopathic, symptomatic, or cryptogenic, prognosis varies sever neuro-developmental disorder infantile spasms w/ jack-knife convulsions associated w/ interictal hypsarhytmia
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Childhood Absence Epilepsy -
kids 5-9, remission in 80% (mostly benign )
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Benign Occipital Epilepsy
positive (ex. hallucinations) or negative (i.e. lack of visual perception) visual symptoms
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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)
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Non-genetic causes of epilepsy
Vascular malformations; cerebral tumours (structural abnormalities) meningitis, encephalitis (infection) birth asphyxia, cerebrovascular accident (hypoxic-ischemic injury)
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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
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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)
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mTOR good and bad
``` Good= role in learning BAD = likely plays role in epilepsy ```
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mTOR + epilepsy
``` Aberrant activation (overactivation) of mTOR pathway -->altered excitation/inhibition balance --> susceptibility to seizures reverberating circuit --> epileptogenesis ```
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how to decrease mTOR's effect on epilepsy
Rapamycin may reduce | seizure activity by preventing mTOR activity
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Epilepsy and age
Younger (kids) = caused more due to developmental or infection Older = mostly due to cerebrovascular issues or degeneration
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Genetic causes of epilepsy
- KNOWN Genetic diseases ~1% epilepsy cases | But likely much more-but unknown (idiopathic)
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Children born to a parent with epilepsy have ___ chance of developing epilepsy
<10% | normal prevalence is 0.5-1%
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SCN1A mutations
defects in fast inactivation gating, characterized by a persistent, non-inactivating current during membrane depolarization, neuronal hyperexcitability persistent inward current --> increased excitability
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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
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Channelopathese
genetic changes to channel function that increase excitability to increase risk of epilepsy
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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) ```
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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
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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
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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
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GABA-A
GABAA receptors trigger an influx of chloride ions (in the | postnatal brain) that hyperpolarize the neurons
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GABA and epilepsy
mutants GABA-A receptor subunit--> decreased GABA-mediated synaptic inhibition ex. CLCN2
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CLCN2 mutant
CLCN2 = voltage gated chloride channel gene | CLCN2 mutations completely abolish chloride channel function --> less hyperpol --> more excitability --> epilptogenesis
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Genetic causes leading to altered devlepment
Tuberous sclerosis, neuro-fibromatosis, periventricular nodular heterotopi, X-linked lissencephaly
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Tuberous sclerosis –what is it?
non malignant | tumours in brain and other organs
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Tuberous sclerosis –cause?
Genetic disease that is Autosomal dominant | Altered TSC1/2 (tumour suppressor genes) --> formation of benign tumors in brain
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Tuberous sclerosis –relation to epilepsy
Epilepsy in 80-90%, infantile spasm due to benign tumors
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Neurofibramotosis
<10% epileptic, primarily partial Benign tumours, compression effects
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Benign tumours and epilepsy
ex. Neurofibramotosis and Tuberous sclerosis | space occupying masses lead to altered neuronal activity and recurrent seizures
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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
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X-linked lissencephaly
smooth brain --> altered connnectivity --> epilepsy
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Metabolic disorders and epilepsy
MELAS; inherited metabolic disorders; leigh disease | Altered cerebral metabolism --> cellular stress and injury --> epilepsy
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MELAS
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) Defect in mitchondrial genome, lactic acidosis (which triggers strokes) Progressive and fatal
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Leigh disease
detected in infancy | usually fatal in 6-7 years
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Inherited metabolic disorders | and epilepsy
• Epilepsy an important indicator, but not disorders not necessarily causative • Tend to be focal, related to neurologic damage
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Pharmacotherapy for epilepsy: current approaches
Reduce hyperexcitability; relatively effective
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Downsides of current therapies
* Side effects--excitatbility is tightly regulated causing side effects * Not curative--treats the hyperexcitability not the cause of it
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Major targets of Pharmacotherapies for epilepsy
voltage gated sodium channels (VGSCs) and | GABA signaling
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First line therapies for Generalized tonic clonic
Sodium valproate; lamotrigine
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First line therapies for absence
Sodium valproate; lamotrigine ; ethosuxamide
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First line therapies for Tonic, atonic and myoclonic seizures
Sodium valproate; clonazepam | AVOID: carbamezepine, oxcarbazepine
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First line therapies for partial seziures
carbamezepine; lamotrigine
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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
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Sodium valproate--type of drug
Anticonvulsant and mood stabilizer | • Also treats anxiety disorders, bipolar disorder
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Sodium valproate--what seizure types
Efficacious in all seizures, particularly | generalized
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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)
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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
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Carbamezepine--drug type/other uses
* Anticonvulsant and mood stabilizer | * used for Epilepsy, bipolar disorder
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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
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Carbamezepine--side effects
``` • Sedation, headache, motor impairment • Gastrointestinal • Liver damage • Risk of birth defects Similar to those of sodium valproate (due to similar mechanism) ```
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Oxcarbazepine vs carbazepine
Oxcarbazepine is a carbazepine derivative with same mechanisms BUT Reduced side-effects, liver damage
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Lamotrigine--drug type, other uses
Anticonvulsant and mood stabilizer | •used in Epilepsy, bipolar, off label use in depression
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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
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Lamotrigine--side effects
* rash, fever, and fatigue, life-threatening skin reactions * Loss of coordination, blurred vision * Increased risk of birth defects
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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
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Benzodiazepines--what type of drug, most common one?
• Most often clonazepam • Widely used sedative – hypnotic, anxiolytic, anticonvulsant, muscle relaxant
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Benzodiazepines--mechanism
• BZDs bind GABA-A receptors and increase affinity for GABA ligand • increases the frequency of channel opening (increased conductance --> increase inhibition)
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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
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BZDs--major issue with therapeutic use
Tolerance develops, efficacy declines over weeks--need increasing doses Dangerous effects when combined with alcohol
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Ethosuximide--for what type of seizures
Antiepileptic for Absence seizures
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Benefits of Ethosuximide
lacks hepatotoxicity of valproic acid
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Ethosuximide--mechanism
- T-type calcium channel blocker | Prevents burst firing often seen --. preventws seizures
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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
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T-type calcium channels and seizure activity
their tonic bursting activity --> BURST firing = seizures
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Ethosuximide--side effects
Drowsiness and gastrointestinal side effects, can induce psychoses in some individuals
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Leviteracetam--drug type, use for what seziures
Second line therapy Anticonvulsant | Some efficacy alone or in conjunction for multiple syndromes
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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)
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Leviteracetam-side effects
Generally well tolerated Drowsiness, coordination Some association with depression and suicidal behaviour
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Topiramate--drug type
Anticonvulsant with multiple putative | mechanisms of action
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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)
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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
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Prospective treatment--issues
only looking at drugs with same targets as current ones --> not that beneficial need to look at different pathways
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New treatments
Acts on sodium channels: Lacosamide, Rufinamide, Eslicarbazepine, Retigabine AMPA antag: Perampanel
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Combination therapy: why
Syngergistic efficacy without additive toxicity | • Supra-additive adverse effects more common with similar mechanism
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Combination therapy --downsides
get additive adverse effects when combining drugs with similar mechanisms - Lack of evidence on synergy, decisions largely based on adverse effects
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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
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Experimental therapies – Tau WHY?
Seziures can develop after trauma/injury and Hyperphosphorylated tau associated with neurodegenerative pathology in multiple disorders
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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)
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Experimental therapies – Inflammation WHY
• Inflammation can contribute to the development of epilepsy • and there are Many known anti-inflammatories to try
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Anti-inflammatory targets
Cox-2 inhibitors largely ineffective thus far | IL-1beta, IL-6, TNFalpha are upregulated by epilepsy--potential therapeutic targets?
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Experimental therapies - Neurosteroids WHAT ARE THEY?
Neurosteroids are positive | modulators of GABA-A activity ex. Allopregnanalone
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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
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Neurosteroids--endogenous vs. synthetic
``` Endogenous neurosteroids NOT clinically usable • Synthetic neurosteroids have shown promising results (e.g. ganaxolone, Phase II) ```
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Experimental therapies – P2X7 WHAT IS IT?
P2X7 receptors are purinergic cation channels • Linked to neuronal excitability • Also important in microglial activation (i.e. inflammation)
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WHY target P2X7
Upregulated after brain damage and seizure | • Agonists potentiate seizure, antagonists reduce seizure
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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
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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
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Optogenetics
use light to control neuronal activity in vivo by shining on different wavelengths of light onto specific inserted light-sensitive channels
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Channelrhodopsin
Blue light sensitive | excitatory (increases firing)
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Halorhodopsin
reacts to yellow light | turn cells off (reduce firing)
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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)
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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
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DREADDs in epilepsy
Infuse CNO (designer ligand) --> activates inhib DREADD --> decrease seizure
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Keto for epilepsy--when to try it
Advocates for the diet recommend that it be seriously | considered after two medications have failed
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Keto for epilepsy--mechanism
* Mechanism unknown, not due to hypoglycemia | * Altered metabolism, direct action of ketones?
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Keto what is it?
high-fat, moderate-protein, low-carbohydrate diet used to treat refractory juvenile epilepsy and some adults
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Keto for epilepsy-- response
Effective in 50% of children
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