Epilepsy: Pathophysiology and Pharmacology Flashcards
What about the brain makes it inherently susceptible to seizures?
“Recurrent collaterals, feed forward connections”
…a little vague.
If you get rid of somebody’s seizures, have you gotten rid of all the problems with their brain?
Typically, no. Seizures are symptom of underlying problem.
4 acquired structural etiologies of seizures?
Tumor, stroke, trauma, hemorrhage
4 developmental structural etiologies of seizures?
Malformation
Dysplasia
Tuberous sclerosis (TS)
Neurofibromatosis (NF)
What are 2 categories of developmental functional alterations that cause seizures?
Channelopathies
Synaptic alterations
3 acquired causes of functional alterations that cause seizures?
Drugs, Metabolic, Toxins
What are 3 changes increasing excitation that happen in an epileptic brain?
Mossy fiber sprouting.
Changes in EAA (excitatory amino acid) receptors.
Presynaptic changes.
What are 3 changes decreasing inhibition that happen in an epileptic brain?
GABA receptor change.
Loss of interneurons.
Change of interneuron activity.
What is epileptogenesis?
Processes that happen after insult to brain before patient develops spontaneous seizures. (some sort of progressive damage leading to hyper-excitability)
What is the “functional unit” of a seizure? (i.e. What process is occurring in each affected neuron?)
Paroxysmal depolarization shift (PDS).
Describe a paraoxysmal depolarization shift (PDS). What ions are used?
Sustained depolarization with a large number of rapid depolarizing spikes. “Plateau-like” depolarization caused by T-type Ca++ channels, Na+ channels open cause burst of depolarization. (recall that this resembles what happens to a sleeping thalamus)
What hyperpolarizes the cell after PDS?
GABA receptors, Cl- influx, and/or K+ efflux.
What happens to EPSPs and IPSPs during seizures?
EPSPs sum with repetitive firing.
IPSPs decrline with repetitive firing
What is sustained repetitive firing? How does it contrast from paroxysmal depolarizing shift (PDS)?
Lots of self-sustained spike generation with sustained depolarization.
Unlike PDS, does not require inward Ca++ current. Relies on V-gated Na+ channels.
Most simply, what part of the brain does the onset of a generalized seizure involve that a focal seizure does not?
The thalamus
What part of the thalamus in particular is important in generalized seizure generation? How does this relate to its normal function?
Intralaminar nuclei - which have “diffuse cortical connections.”
These are normally capable of synchronizing widespread cortical activity.
What neurons relevant to generalized seizure generation have T-type Ca++ channels that can lead to generalized bursts?
Some cortical pyramidal neurons (esp. in layer 5).
Intralaminar nuclei of the thalamus.
2 clinical characteristics that early-onset epilepsy syndromes tend to have in common?
Myoclonic seizures.
Global developmental delay.
2 factors that may make children/infants susceptible to epilepsy?
GABA is excitatory during development.
NMDA receptors develop before AMPA receptors.
(Allows for synaptic formation, brain is in excitatory state)
How do GABA receptors that alter Cl- levels work?
They are channels that just allow Cl- to flow down the electrochemical gradient?
What are 2 transporters that set up neurons’ Cl- gradient? When are they expressed? Does each increase or decrease intracellular Cl-?
NKCC1: cotransporter for Na+/K+ and Cl-, increasing Cl- intracellularly. Expressed early in development.
KCC2: cotransporter for K+ and Cl-, bringing Cl- out of the cell, decreasing Cl- intracellular. Expressed later in development.
What’s effect of Cl- cotransporters on neuronal intracellar [Cl-] in early development vs. maturity? What effect does GABA have on neurons in each cause?
Early development: [Cl-] is high. GABA lets Cl- flow out, depolarizing, exciting.
Maturity: [Cl-] is low. GABA lets Cl- flow in, hyperpolarizng, inhibiting.
What do NKCC1 and KCC2 stand for? (not actually in the lecture, but useful)
Na+ K+ Cl- Cotransporter 1
K+ Cl- Cotransporter 2
(and 1 is expressed 1st, 2 is expressed 2nd)
When does the switch from NKCC1 to KCC2 occur in humans? What affect does this have on the use of benzodiazepines to stop seizures?
We don’t really know. Maybe in the 3rd trimester.
GABA agonists such as benzos are NOT LESS EFFECTIVE for stopping seizures in babies, as the switch already has happened.
What other receptors contribute to the hyperexcitability of the developing brain?
NMDA receptors (Mg++ block less effective). AMPA receptors (more permeable to Ca++).
What GABA-mediated effect helps to “synchronize cortical development”?
Giant depolarizing potentials. GABA cells project bilaterally, excitation leads to seizures.
Do drugs prevent the development of epilepsy from acquired causes?
No. (i.e. you can’t give someone with head trauma prophylactic anti-epileptic drugs to prevent epilepsy)
5 mechanisms of action for anti-epileptic drugs?
Block repetitive Na+ channel activation GABA enhancers Glutamate modulators Ca++ channel blockers (esp. T-type) Synaptic transmission modulators
What type of epilepsy are drugs blocking V-gated Na+ channels used for?
Focal epilepsy. (makes sense, as this would prevent the spikes in paroxysmal depolarizing shift (PDS))
Two mechanism of GABA agonists? What class of drug does each? What type of epilepsy do they work on?
Barbituates prolong GABA-mediated Cl- channel openings.
Benzodiazepines increased frequency of GABA-mediated Cl- channel openings.
Work on all epilepsy.
What are blockers of T-type Ca++ channels used for? How might they work?
Absence seizures.
May act mainly in thalamic neurons to prevent abnormal thalamo-cortical interactions.
What are 3 mechanisms by which EAA (excitatory amino acid) transmitter antagonists work?
Antagonize glutamate at AMPA/kainate receptor.
Block V-gated T-type Ca++ and Na+ channel (It makes no sense to me why he put this on this list.)
Modulation of NMDA receptor via strychnine-insensitive glycine receptor.
What are the 2 main “excitatory amino acids” that EAA transmitter antagonists affect?
Glutamate and glycine.
Big picture of EAA transmitter antagonists’ effects?
They reduce excitation.
3 mechanisms by which drugs restore inhibitory balance at the synapse?
GABA reuptake inhibition.
Increase GAD activity, rate-limiting step in GABA synth .
Synaptic vesicle binding.
2 resective surgical therapies for epilepsy?
Resection of epileptic zone (you make sure you localize it as finely as possible, first).
Corpus callostomy.
2 stimulation surgical therapies for epilepsy?
Vagal nerve stimulation (we don’t know why this works).
Brain stimulation of ant. nucleus of thalamus / cortex in response to seizure activity (analogous to internal defibrillator).
3 non-surgical, non-pharmaceutical therapies for epilepsy?
Ketogenic diet (works 30% of time)
Low glycemic index diet
Vitamin B6 therapy diet (some evidence)
3 reasons why a ketogenic diet may help epilepsy?
Increases GABA production
Ketones are directly anti-epileptic
Acidification alters EAA activity
