Pathophysiology of Seizures, Sleep, and Insomnia (Dr. Toth)

When a VGSC has a RMP of -70 mV, the activation gate is closed and the inactivation gate is open

resting/deactivated

What is the stimulus for the voltage-gated sodium channels (VGSC) to open?

Depolarization (increasing +15-30 mV)

What are the states of the activation and inactivation gates when the VGSC is activated?

Both gates are open

What membrane potential causes the VGSC to close?

30 mV

What is the state of the activation gate when the VGSC is inactivated?

Open

What is the state of the inactivation gate when the VGSC is inactivated?

Closed

What is the term for the state of the VGSC when it is closed at 30 mV?

Inactivated

What is the process called when membrane potential returns to resting potential?

Repolarization

What type of channels open to help return membrane potential to resting potential?

Voltage-gated K+ channels

What ion efflux contributes to the accumulation of a net negative charge intracellularly during repolarization?

K+ (potassium)

What is the approximate resting membrane potential in mV?

~ -70mV

What is the function of the inactivation gate of VGSCs?

preventi further Na+ conduction/inward currents ('a safety mechanism to avoid over activation/stimulation')

What is epilepsy?

recurrent unprovoked seizures due to an abnormal electrical discharge in the brain

What is the pharmacological target for local anesthetics?

block the Na+ channel at the intracellular end of its conduction pore to stabilize nerve cell membrane in an absolute refractory period (unable to activate).

Glutamate is excitatory or inhibitory?

excitatory

1 multiple choice option

GABA is excitatory or inhibitory?

inhibitory

1 multiple choice option

Glutamate is synthetized in pre-synaptic cells. What is the precursor?

glutamine

Which glutamate receptors are ionotropic?

AMPA & NMDA

Which glutamate receptors are metabotropic (type of GCPR)?

mGlu 1-8

Explain glutamate excitotoxity in seizures, TBI, stroke

Ca2+ enters cells via NMDA-Rs leading to excessively high intracellular Ca2+ concentration that can damage mitochondria and cause Apoptosis

GABA is synthetized in pre-synaptic cells. What is the precursor?

Glutamate

The final step of GABA synthesis is catalyzed by ____

GAD 65/67

What is the function of GABA transaminase?

converts GABA back to glutamate in astrocytes

What happens when GABA transaminase is inhibited?

anticonvulsive effect by increasing GABA

What type of channel GABAa receptors?

Cl-

What type of channel are GABAb receptors?

metabotropic

What clinical effects do GABA receptor Agonists/Positive Allosteric Modulators (PAMs) have

sedative, anxiolytic, anticonvulsant, & muscle relaxant effects

What are seizures?

abnormal electrical discharge in the brain which causes sudden stereotyped episode with change in motor activity, sensation, behavior, and/or consciousness

What are focal seizures (with or without impairment)?

Affects only one hemisphere of the brain. (Secondary generalization possible).

T/F: Symptoms of focal seizures will vary according to where the seizure occurs.

True

1 multiple choice option

What are generalized seizures?

Bilateral hemispheres are involved

What are the subtypes of generalized seizures?

Generalized motor (Grand mal)

Generalized non-motor (Absence or petit mal)

What are Grand mal seizures?

bilateral, convulsive tonic and clonic muscle contractions.

abrupt focal or generalized onset.

with prodrome & extended postictal state

What is prodrome?

In Grand mal seizures, it is the vague sense of impending seizure

may also be present before the seizure begins

What is an extended postictal state?

where the person is unresponsive and commonly sleeping with loud snoring after Grand mal

T/F: After Grand mal seizures, patients are usually very cognizant after waking up

False; confused

1 multiple choice option

What are petit mal seizures?

seizures characterized by a brief loss and return of consciousness, generally not followed by a period of lethargy (i.e. without a notable postictal state)

"day dreaming"

T/F: There is a loss of muscle tone in petit mal seizures?

False

1 multiple choice option

Petit mal seizures can exhibit automatism which are quasi-purposeful movements such as ___

lip licking, aimless walking, rubbing, grunting

Sleep is cyclic. How long is a sleep cycle?

90 min

How many sleep cycles occur during a major sleep episode?

4-6

What are the two types of microarousals during sleep?

NREM & REM

About 75-80% of sleep is NREM. What is NREM?

slow wave sleep (SWS)

What happens in the body during NREM?

decrease in HR. BP, breathing, body temp, muscle tone

About 20-25% of sleep is REM. What is REM?

fast wave sleep (rapid eye movement)

What happens in the body during REM sleep?

increasing HR, BP, breathing, and metabolic rate

When does dreaming (and erections) occur during sleep?

REM

1 multiple choice option

T/F: During REM sleep, the body is paralyzed (muscle-atonia) but myoclonus (jerking movements) still occur

True

1 multiple choice option

Define insomnia

Difficulty in initiating sleep or in staying asleep or waking up earlier.

Insomnia causes all of the following except:

Fatigue, concentration and memory impairment.

Low mood, motivation

Migraine

Daytime sleepiness.

Tension headache.

Migraine