Epilepsy: Pathophysiology and Pharmacology

Question 1

What about the brain makes it inherently susceptible to seizures?

Answer 1

“Recurrent collaterals, feed forward connections”

…a little vague.

Question 2

If you get rid of somebody’s seizures, have you gotten rid of all the problems with their brain?

Answer 2

Typically, no. Seizures are symptom of underlying problem.

Question 3

4 acquired structural etiologies of seizures?

Answer 3

Tumor, stroke, trauma, hemorrhage

Question 4

4 developmental structural etiologies of seizures?

Answer 4

Malformation
Dysplasia
Tuberous sclerosis (TS)
Neurofibromatosis (NF)

Question 5

What are 2 categories of developmental functional alterations that cause seizures?

Answer 5

Channelopathies

Synaptic alterations

Question 6

3 acquired causes of functional alterations that cause seizures?

Answer 6

Drugs, Metabolic, Toxins

Question 7

What are 3 changes increasing excitation that happen in an epileptic brain?

Answer 7

Mossy fiber sprouting.
Changes in EAA (excitatory amino acid) receptors.
Presynaptic changes.

Question 8

What are 3 changes decreasing inhibition that happen in an epileptic brain?

Answer 8

GABA receptor change.
Loss of interneurons.
Change of interneuron activity.

Question 9

What is epileptogenesis?

Answer 9

Processes that happen after insult to brain before patient develops spontaneous seizures. (some sort of progressive damage leading to hyper-excitability)

Question 10

What is the “functional unit” of a seizure? (i.e. What process is occurring in each affected neuron?)

Answer 10

Paroxysmal depolarization shift (PDS).

Question 11

Describe a paraoxysmal depolarization shift (PDS). What ions are used?

Answer 11

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)

Question 12

What hyperpolarizes the cell after PDS?

Answer 12

GABA receptors, Cl- influx, and/or K+ efflux.

Question 13

What happens to EPSPs and IPSPs during seizures?

Answer 13

EPSPs sum with repetitive firing.

IPSPs decrline with repetitive firing

Question 14

What is sustained repetitive firing? How does it contrast from paroxysmal depolarizing shift (PDS)?

Answer 14

Lots of self-sustained spike generation with sustained depolarization.
Unlike PDS, does not require inward Ca++ current. Relies on V-gated Na+ channels.

Question 15

Most simply, what part of the brain does the onset of a generalized seizure involve that a focal seizure does not?

Answer 15

The thalamus

Question 16

What part of the thalamus in particular is important in generalized seizure generation? How does this relate to its normal function?

Answer 16

Intralaminar nuclei - which have “diffuse cortical connections.”
These are normally capable of synchronizing widespread cortical activity.

Question 17

What neurons relevant to generalized seizure generation have T-type Ca++ channels that can lead to generalized bursts?

Answer 17

Some cortical pyramidal neurons (esp. in layer 5).

Intralaminar nuclei of the thalamus.

Question 18

2 clinical characteristics that early-onset epilepsy syndromes tend to have in common?

Answer 18

Myoclonic seizures.

Global developmental delay.

Question 19

2 factors that may make children/infants susceptible to epilepsy?

Answer 19

GABA is excitatory during development.
NMDA receptors develop before AMPA receptors.
(Allows for synaptic formation, brain is in excitatory state)

Question 20

How do GABA receptors that alter Cl- levels work?

Answer 20

They are channels that just allow Cl- to flow down the electrochemical gradient?

Question 21

What are 2 transporters that set up neurons’ Cl- gradient? When are they expressed? Does each increase or decrease intracellular Cl-?

Answer 21

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.

Question 22

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?

Answer 22

Early development: [Cl-] is high. GABA lets Cl- flow out, depolarizing, exciting.
Maturity: [Cl-] is low. GABA lets Cl- flow in, hyperpolarizng, inhibiting.

Question 23

What do NKCC1 and KCC2 stand for? (not actually in the lecture, but useful)

Answer 23

Na+ K+ Cl- Cotransporter 1
K+ Cl- Cotransporter 2
(and 1 is expressed 1st, 2 is expressed 2nd)

Question 24

When does the switch from NKCC1 to KCC2 occur in humans? What affect does this have on the use of benzodiazepines to stop seizures?

Answer 24

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.

Question 25

What other receptors contribute to the hyperexcitability of the developing brain?

Answer 25

``` NMDA receptors (Mg++ block less effective). AMPA receptors (more permeable to Ca++). ```

Question 26

What GABA-mediated effect helps to "synchronize cortical development"?

Answer 26

Giant depolarizing potentials. GABA cells project bilaterally, excitation leads to seizures.

Question 27

Do drugs prevent the development of epilepsy from acquired causes?

Answer 27

No. (i.e. you can't give someone with head trauma prophylactic anti-epileptic drugs to prevent epilepsy)

Question 28

5 mechanisms of action for anti-epileptic drugs?

Answer 28

``` Block repetitive Na+ channel activation GABA enhancers Glutamate modulators Ca++ channel blockers (esp. T-type) Synaptic transmission modulators ```

Question 29

What type of epilepsy are drugs blocking V-gated Na+ channels used for?

Answer 29

Focal epilepsy. (makes sense, as this would prevent the spikes in paroxysmal depolarizing shift (PDS))

Question 30

``` Two mechanism of GABA agonists? What class of drug does each? What type of epilepsy do they work on? ```

Answer 30

Barbituates *prolong* GABA-mediated Cl- channel openings. Benzodiazepines *increased frequency* of GABA-mediated Cl- channel openings. Work on all epilepsy.

Question 31

What are blockers of T-type Ca++ channels used for? How might they work?

Answer 31

Absence seizures. | May act mainly in thalamic neurons to prevent abnormal thalamo-cortical interactions.

Question 32

What are 3 mechanisms by which EAA (excitatory amino acid) transmitter antagonists work?

Answer 32

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.

Question 33

What are the 2 main "excitatory amino acids" that EAA transmitter antagonists affect?

Answer 33

Glutamate and glycine.

Question 34

Big picture of EAA transmitter antagonists' effects?

Answer 34

They reduce excitation.

Question 35

3 mechanisms by which drugs restore inhibitory balance at the synapse?

Answer 35

GABA reuptake inhibition. Increase GAD activity, rate-limiting step in GABA synth . Synaptic vesicle binding.

Question 36

2 resective surgical therapies for epilepsy?

Answer 36

Resection of epileptic zone (you make sure you localize it as finely as possible, first). Corpus callostomy.

Question 37

2 stimulation surgical therapies for epilepsy?

Answer 37

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).

Question 38

3 non-surgical, non-pharmaceutical therapies for epilepsy?

Answer 38

Ketogenic diet (works 30% of time) Low glycemic index diet Vitamin B6 therapy diet (some evidence)

Question 39

3 reasons why a ketogenic diet may help epilepsy?

Answer 39

Increases GABA production Ketones are directly anti-epileptic Acidification alters EAA activity