Epilepsy I & II Flashcards
Hippocrates view of Epilepsy
- “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
What Hippocrates got right
recognized the symptoms and that they derived from the brain
right about juvenile onset
Hippocrates on epilepsy onset
Juvenile Onset b/c young children have small veins, not able to accommodate the increased amount of
phlegm
Hippocrates on epilepsy symptoms
- Shivering
- Loss of speech
- Trouble breathing
- Contraction of the brain
- Blood stops circulating
- Excretion of the phlegm
Seizure
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
Epilepsy
refers to a continuum of chronic neurological
syndromes in which a person has heightened risk of
recurrent seizures
Causes for epilepsy
- Causes can be unknown or genetic
* Can result from brain trauma, stroke, brain cancer, drugs
Epilepsy vs. Seizure
Epilepsy is a disease of RECURRENT seizures
seizures can also be singular events (independent of epilepsy)
___ lifetime risk, ___ prevalence
~3% lifetime risk, Prevalence 0.5-1%
prevalence is lower than lifetime risk since many epilepsies resolve (ex. juvenile epilepsy)
Is prevalence reported exact?
No, epilepsy is likely much more prevalent but figures are decreased due to stigma and the heterogenetity of symptoms
Most epilepsy is diagnosed before age___
18 (75-85%)
44% by age 5; 55% by age 10
Children with epilepsy
- 1% of children will have recurrent seizures before age 14
* 50% of cases of childhood epilepsy - seizures disappear (juvenile epilepsy often resolves)
In ___ % of cases, the cause of epilepsy is unknown
50-60%
Cryptogenic vs. idoipathic vs. Symptomatic
Cryptogenic = cause unknown but has suspected orgins Idiopathic = cause unknown Symptomatic = generated by injury (secondary to another event--stroke, trauma, meningitis)
Both cryptogenic and idiopathic epilepsies are thought to be _____
Genetic; but the precise gene itself is unknown
Common causes of epilepsy
- 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)
Causes for child onset
- injury, infection, or systemic illness of the mother during pregnancy
- brain injury to the infant during delivery may lead to epilepsy
Seizure’s effect on life expectancy
seizures are not typically fatal, they do reduce life expectancy as well as quality of life (e.g. driving, employment)
Epileptics have __ times higher mortality; depends on _____
3x; depends on control of seizures
If uncontrolled–shorter life expectancy
If controlled–no difference
4 conditions that have risk of death
- status epilepticus (continual seziures)
- suicide associated with depression
- trauma from seizures (ex. trauma from falls)
- sudden unexpected death in epilepsy (SUDEP, 8-17%)
Highest risk of mortality in epilepsy due to
Underlying neurological impairment OR poor control of seizures
Can categorize epilepsies based on
- Seizure types (semiology)
- Etiology
- Electroencephalogram (EEG) findings
- Brain structure
- Age when seizures begin
- Family history of epilepsy or genetic disorder
- Prognosis
Major seizure categories
GENERAL vs FOCAL onset
general = whole brain
focal/partial = only in one part of the brain
and Continuous
General seizure subtypes
Grand mal (generalized motor) Petit mal (absence)--loss of consciousness
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)
Focal seziures
focal (partial) onset with or
without secondary generalization to major
motor manifestations.
Continuous seizures
- Generalized (status epilepticus)
* Focal (epilepsia partialis continua)
Major seizure classifications (6)
- “Grand Mal” or Generalized tonic-clonic
- Absence “petit mal”
- Myoclonic Sporadic
- Clonic
- Tonic
- Atonic
“Grand Mal” or Generalized tonic-clonic
Unconsciousness, convulsions, muscle rigidity
Absence “petit mal”
Brief loss of consciousness; generalized; still maintain muscle tone; appear to be daydreaming
Myoclonic Sporadic
isolated, jerking movements
Clonic
Repetitive jerking movements
Tonic
Muscle stiffness, rigidity
Atonic
Loss of muscle tone
Typical absence seizure–characterization
petit mal
characterized by 3Hz hyperactivity
Juventile myoclonic seziure (generalized) EEG
high amplitude spiking; disordered
Interictal (b/t seizures) EEG of Infantile Spasm (west symdrome)
Hypsarrythmia–lack of brain rhythm (highly disordered)
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)
Temporal Lobe Epilepsy Symptoms
odd feeling, memory,
sensation
Frontal Lobe Epilepsy Symptoms
seizure symptoms in the
frontal lobes vary widely
frontal lobes responsible for executive function; cognitive performance
Parietal Lobe Epilepsy Symptoms
somatosensory, somatic,
visual, language
Occipital Lobe Epilepsy Symptoms
visual hallucinations
Primary Generalized Epilepsy Syndromes
idiopathic, can be
myoclonic,
grand-mal, or absence
Reflex Epilepsy
in response to specific
stimuli only
Epilepsy syndromes in kids
- Benign Rolandic Epilepsy
- Juvenile Myoclonic Epilepsy
- Infantile Spasms (West Syndrome)
- Childhood Absence Epilepsy
- Benign Occipital Epilepsy
- Landau-Kleffner Syndrome
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)
Juvenile Myoclonic Epilepsy
seizures associated with sleep status–often when tired or waking
often diagnosed b/t 12-18; not benign continues into adulthood
Infantile Spasms (West Syndrome)
idiopathic, symptomatic, or cryptogenic, prognosis varies
sever neuro-developmental disorder
infantile spasms w/ jack-knife convulsions
associated w/ interictal hypsarhytmia
Childhood Absence Epilepsy -
kids 5-9, remission in 80% (mostly benign )
Benign Occipital Epilepsy
positive (ex. hallucinations) or negative (i.e. lack of visual perception) visual
symptoms
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)
Non-genetic causes of epilepsy
Vascular malformations; cerebral tumours (structural abnormalities)
meningitis, encephalitis (infection)
birth asphyxia, cerebrovascular accident (hypoxic-ischemic injury)
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
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)
mTOR good and bad
Good= role in learning BAD = likely plays role in epilepsy
mTOR + epilepsy
Aberrant activation (overactivation) of mTOR pathway -->altered excitation/inhibition balance --> susceptibility to seizures reverberating circuit --> epileptogenesis
how to decrease mTOR’s effect on epilepsy
Rapamycin may reduce
seizure activity by preventing mTOR activity
Epilepsy and age
Younger (kids) = caused more due to developmental or infection
Older = mostly due to cerebrovascular issues or degeneration
Genetic causes of epilepsy
- KNOWN Genetic diseases ~1% epilepsy cases
But likely much more-but unknown (idiopathic)
Children born to a parent
with epilepsy have ___
chance of developing
epilepsy
<10%
normal prevalence is 0.5-1%
SCN1A mutations
defects in fast inactivation
gating, characterized by a persistent, non-inactivating
current during membrane depolarization, neuronal hyperexcitability
persistent inward current –> increased excitability
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
Channelopathese
genetic changes to channel function that increase excitability to increase risk of epilepsy
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)
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
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
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
GABA-A
GABAA receptors trigger an influx of chloride ions (in the
postnatal brain) that hyperpolarize the neurons
GABA and epilepsy
mutants GABA-A receptor subunit–> decreased GABA-mediated synaptic inhibition
ex. CLCN2
CLCN2 mutant
CLCN2 = voltage gated chloride channel gene
CLCN2 mutations completely abolish chloride channel function –> less hyperpol –> more excitability –> epilptogenesis
Genetic causes leading to altered devlepment
Tuberous sclerosis, neuro-fibromatosis, periventricular nodular heterotopi, X-linked lissencephaly
Tuberous sclerosis –what is it?
non malignant
tumours in brain and other organs
Tuberous sclerosis –cause?
Genetic disease that is Autosomal dominant
Altered TSC1/2 (tumour suppressor genes) –> formation of benign tumors in brain
Tuberous sclerosis –relation to epilepsy
Epilepsy in 80-90%, infantile spasm due to benign tumors
Neurofibramotosis
<10% epileptic,
primarily partial
Benign tumours, compression effects
Benign tumours and epilepsy
ex. Neurofibramotosis and Tuberous sclerosis
space occupying masses lead to altered neuronal activity and recurrent seizures
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
X-linked lissencephaly
smooth brain –> altered connnectivity –> epilepsy
Metabolic disorders and epilepsy
MELAS; inherited metabolic disorders; leigh disease
Altered cerebral metabolism –> cellular stress and injury –> epilepsy
MELAS
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like
episodes (MELAS)
Defect in mitchondrial genome, lactic acidosis (which triggers strokes)
Progressive and fatal
Leigh disease
detected in infancy
usually fatal in 6-7 years
Inherited metabolic disorders
and epilepsy
• Epilepsy an important indicator, but not disorders not necessarily
causative
• Tend to be focal, related to neurologic damage
Pharmacotherapy for epilepsy: current approaches
Reduce hyperexcitability; relatively effective
Downsides of current therapies
- Side effects–excitatbility is tightly regulated causing side effects
- Not curative–treats the hyperexcitability not the cause of it
Major targets of Pharmacotherapies for epilepsy
voltage gated sodium channels (VGSCs) and
GABA signaling
First line therapies for Generalized tonic clonic
Sodium valproate; lamotrigine
First line therapies for absence
Sodium valproate; lamotrigine ; ethosuxamide
First line therapies for Tonic, atonic and myoclonic seizures
Sodium valproate; clonazepam
AVOID: carbamezepine, oxcarbazepine
First line therapies for partial seziures
carbamezepine; lamotrigine
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
Sodium valproate–type of drug
Anticonvulsant and mood stabilizer
• Also treats anxiety disorders, bipolar disorder
Sodium valproate–what seizure types
Efficacious in all seizures, particularly
generalized
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)
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
Carbamezepine–drug type/other uses
- Anticonvulsant and mood stabilizer
* used for Epilepsy, bipolar disorder
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
Carbamezepine–side effects
• Sedation, headache, motor impairment • Gastrointestinal • Liver damage • Risk of birth defects Similar to those of sodium valproate (due to similar mechanism)
Oxcarbazepine vs carbazepine
Oxcarbazepine is a carbazepine derivative with same mechanisms
BUT Reduced side-effects, liver damage
Lamotrigine–drug type, other uses
Anticonvulsant and mood stabilizer
•used in Epilepsy, bipolar, off label use in depression
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
Lamotrigine–side effects
- rash, fever, and fatigue, life-threatening skin reactions
- Loss of coordination, blurred vision
- Increased risk of birth defects
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
Benzodiazepines–what type of drug, most common one?
• Most often clonazepam
• Widely used sedative – hypnotic,
anxiolytic, anticonvulsant, muscle
relaxant
Benzodiazepines–mechanism
• BZDs bind GABA-A receptors and
increase affinity for GABA ligand
• increases the frequency of channel
opening (increased conductance –> increase inhibition)
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
BZDs–major issue with therapeutic use
Tolerance develops, efficacy declines over weeks–need increasing doses
Dangerous effects when combined with alcohol
Ethosuximide–for what type of seizures
Antiepileptic for Absence seizures
Benefits of Ethosuximide
lacks hepatotoxicity of valproic acid
Ethosuximide–mechanism
- T-type calcium channel blocker
Prevents burst firing often seen –. preventws seizures
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
T-type calcium channels and seizure activity
their tonic bursting activity –> BURST firing = seizures
Ethosuximide–side effects
Drowsiness and gastrointestinal side
effects, can induce psychoses in some
individuals
Leviteracetam–drug type, use for what seziures
Second line therapy Anticonvulsant
Some efficacy alone or in conjunction for multiple syndromes
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)
Leviteracetam-side effects
Generally well tolerated
Drowsiness, coordination
Some association with depression and
suicidal behaviour
Topiramate–drug type
Anticonvulsant with multiple putative
mechanisms of action
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)
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
Prospective treatment–issues
only looking at drugs with same targets as current ones –> not that beneficial need to look at different pathways
New treatments
Acts on sodium channels: Lacosamide, Rufinamide, Eslicarbazepine, Retigabine
AMPA antag: Perampanel
Combination therapy: why
Syngergistic efficacy without additive toxicity
• Supra-additive adverse effects more common with similar mechanism
Combination therapy –downsides
get additive adverse effects when combining drugs with similar mechanisms
- Lack of evidence on synergy, decisions largely based on
adverse effects
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
Experimental therapies – Tau WHY?
Seziures can develop after trauma/injury and Hyperphosphorylated tau associated with neurodegenerative pathology in multiple disorders
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)
Experimental therapies – Inflammation WHY
• Inflammation can contribute to the
development of epilepsy
• and there are Many known anti-inflammatories to try
Anti-inflammatory targets
Cox-2 inhibitors largely ineffective thus far
IL-1beta, IL-6, TNFalpha are upregulated by epilepsy–potential therapeutic targets?
Experimental therapies - Neurosteroids WHAT ARE THEY?
Neurosteroids are positive
modulators of GABA-A activity ex. Allopregnanalone
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
Neurosteroids–endogenous vs. synthetic
Endogenous neurosteroids NOT clinically usable • Synthetic neurosteroids have shown promising results (e.g. ganaxolone, Phase II)
Experimental therapies – P2X7 WHAT IS IT?
P2X7 receptors are purinergic cation channels
• Linked to neuronal excitability
• Also important in microglial activation (i.e. inflammation)
WHY target P2X7
Upregulated after brain damage and seizure
• Agonists potentiate seizure, antagonists reduce seizure
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
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
Optogenetics
use light to control neuronal activity in vivo by shining on different wavelengths of light onto specific inserted light-sensitive channels
Channelrhodopsin
Blue light sensitive
excitatory (increases firing)
Halorhodopsin
reacts to yellow light
turn cells off (reduce firing)
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)
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
DREADDs in epilepsy
Infuse CNO (designer ligand) –> activates inhib DREADD –> decrease seizure
Keto for epilepsy–when to try it
Advocates for the diet recommend that it be seriously
considered after two medications have failed
Keto for epilepsy–mechanism
- Mechanism unknown, not due to hypoglycemia
* Altered metabolism, direct action of ketones?
Keto what is it?
high-fat, moderate-protein, low-carbohydrate diet used to treat refractory juvenile epilepsy and some adults
Keto for epilepsy– response
Effective in 50% of children
