Lecture 11

Question 1

Seizure definition

Answer 1

• Seizures are periods of self-sustained neural hyper-excitation. During a seizure, the forebrain neurons in the brain cease their normal activities and begin to fire in massive, synchronized bursts.
• Blood flow to the brain is increased, and there is a greater use of glucose and oxygen.
• After seconds or minutes, when the inhibitory mechanisms of the brain regain control, the seizure ends

Question 2

causes of seizures

Answer 2

• high fever (particularly in children), brain infection, meningitis
• Ingesting alcohol, and these can be pretty bad
• head injury or trauma
  ○ People who have had head trauma are more likely to develop a seizure disorder
• alcohol or benzodiazepine withdrawal
• drug intoxication (cocaine, amphetamine, antidepressants (bupropion))
• stroke or cardiovascular event

Question 3

definition of epilepsy

Answer 3

• The epilepsies are a group of neurological disorders characterized by spontaneous, recurrent seizures.
• Another word for epilepsy is “seizure disorder”

Question 4

people with epilepsy have a

Answer 4

low seizure threshold

Question 5

seizure thresholds

Answer 5

• It is important to note that seizures themselves do not equal epilepsy.
• Every brain has a ‘seizure threshold’, and every brain will generate a seizure if it is subjected to a high enough level of excitatory stimulation.
• Seizures are triggered in non-epileptic people during electroconvulsive therapy (ECT).
  - This used to be a treatment for depression / anxiety

Question 6

prevalence of epilepsy

Answer 6

• About 1% of the population has epilepsy at any given time (point prevalence).
• About 4% of the population will have epilepsy at some point during their lifetimes (lifetime prevalence)

Question 7

causes of epilepsy

Answer 7

• genetic – 70% – due to a mutation in a gene that controls neuron excitability
• structural/metabolic – 30% - a clear structural or metabolic cause
  ○ common structural causes: scar, cancer or benign tumor, vascular malformation
• Idiopathic seizures: we don’t know the exact reason for them
• Also do novo: where a person has a new variation of a gene that controls neuron firing

Question 8

onset of epilepsy

Answer 8

• The onset of epilepsy can occur at any time during life.
  ○ Idiopathic begin in childhood
  ○ Developing brain is more vulnerable to seizures than the adult brain
  § There are more pathways and neurons in a developing brain
  § Adolescence and young adulthood is where the brain decides to keep or terminate certain connections
• In many patients seizures begin in childhood, often before the age of 15 years.
• Children with epilepsy will sometimes “outgrow” seizures or will have reduced frequency of seizures in adulthood.
• In recent years – perhaps because people are living longer – there has been an increased onset of seizures after age 65.
• Many of these are thought to be the result of small strokes

Question 9

Co-morbidities of epilepsy

Answer 9

• People with seizures – especially uncontrolled seizures – often suffer from other disorders
• Cognitive – memory problems
• Psychiatric – anxiety, depression, ADHD, psychosis
• Also co-morbidities for asthma, migraine, stroke, ulcers

Question 10

types of seizures

Answer 10

• Generalized seizures and partial seizures
  ○ Generalized occur throughout the cortex.
  - Partial seizures occur just in one location of the cortex

Question 11

Absence (petit mal)

Answer 11

• generalized
• Briefly unconscious, blank stare, no memory of attack
• Lasts less than 30 seconds
• 3 per second spike and wave throughout whole brain
• The zone out seizure
• Excessive pattern of activity in the brain

Question 12

Tonic Clonic (grand mal)

Answer 12

• generalized
• Unconscious, dramatic convulsions, no memory of attack
• Lasts less than 5 minutes
• Constant spiking throughout the whole brain
• Tonic Clonic is the most severe version of the bad mal generalized seizure
• Tonic Clonic refers to stiffness and shaking
• If it goes beyond 5 mins is called status epilepticus
  § Usually death
• Beyond four minutes is permanent brain damage

Question 13

Simple partial

Answer 13

○ Conscious, memory of attack, sensory/motor/emotion symptoms
○ Duration varies
- Localized spiking in neocortical or limbic area of brain

Question 14

Complex partial (temporal lobe)

Answer 14

○ Conscious but non-responsive, automatisms, no memory of attack
○ Duration varies
- Localized then spreading spiking in one or both temporal lobes

Question 15

seizures are detected by

Answer 15

electroencephalogram (EEG) – the more that neurons fire, the higher the peaks and valleys

Question 16

are there consequences if epilepsy is not managed

Answer 16

• Difficulty learning
• Breathing in food or saliva into the lungs during a seizure, which can cause aspiration pneumonia
• Injury from falls, bumps, self-inflicted bites, driving or operating machinery during a seizure
• Permanent brain damage
• Seizure worsening - death from seizures
  ○ Could also cause SUDEP death, where everything could be fine, but then someone dies during their sleep
  § Leading cause of death for people with uncontrolled seizures
• Death from suicide

Question 17

Excitotoxicity

Answer 17

excessive neuron firing leading to cell death
- When neurons are overexcited, there are a number of sources of calcium coming into the neuron, and it eventually leads to the mitochondria breaking down and then neuron death
- Stroke outcomes are a lot better by preventing the secondary neuron death

Question 18

Treatment for Epilepsy

Answer 18

• Many forms of childhood and adult epilepsies are improved with a ketogenic diet. A diet low in carbohydrates causes the body to metabolize fats into ketones (beta-hydroxybutyrate), which the brain uses as an alternate energy source.
  ○ Discovered during periods of famine
  ○ When people were starving they had fewer seizures
• Anti-seizure medications generally act by promoting GABA signaling or reducing the function of voltage- gated ion channels. - Many antiseizure medications have more than one mechanism of action

Question 19

Common side effects of anti-seizure medications

Answer 19

• sleepiness, memory impairment, nausea/GI upset, dependence/withdrawal
• Have to wean off the drug otherwise it could cause other seizures

Question 20

how many classic drugs are there for epilepsy

Answer 20

five

Question 21

Phenobarbital (Luminal)

Answer 21

• First drug discovered for tonic-clonic and partial seizures
• Oldest drug still in use
• Cheap and safe, long half-life
• Side effects: sedation/sleepiness, memory impairment, GI upset
  Mechanism: A barbiturate: enhances GABA-A system – keeps the GABA channel open longer – increases the inhibitory effect of GABA

Question 22

Phenytoin (Dilantin)

Answer 22

• Second drug for tonic-clonic and partial seizures
• Second oldest drug still in use
• Less sedating than phenobarbital, also has long half-life
• Side effects: headache, nausea, dizziness, sleepiness, acne, gingival hyperplasia, hirsutism (growing facial hair)
• Mechanism: Blocks voltage dependent sodium channels (antagonist) – these are the channels that allow the action potential to travel down the axon. Phenytoin blocks the channels and reduces the number of action potentials that a neuron can fire.

Question 23

Ethosuximide (Zarontin)

Answer 23

• The drug of choice for absence seizures.
• Side effects: upset stomach, diarrhea, weight loss, hiccups
• Mechanism: Blocks voltage dependent calcium channels (antagonist) – these are the channels that trigger the release of neurotransmitter when the action potential reaches the axon terminal. Ethosuximide blocks one specific type of these calcium channels that is found in the thalamus and reduces the amount of glutamate neurotransmitter that is released in that brain region.

Question 24

Carbamazepine (Tegretol)

Answer 24

• A treatment for tonic-clonic and partial seizures.
• Side effects: dizziness, nausea, problems with coordination, reduces numbers of white blood cells
• Mechanism: Blocks voltage dependent sodium channels (antagonist) – these are the channels that allow the action potential to travel down the axon.
• Carbamazepine blocks the channels and reduces the number of action potentials that a neuron can fire. It has a mechanism of action similar to phenytoin but they have different side effects.

Question 25

Valproate (Valproic Acid) (Depakene)

Answer 25

• The first broad-spectrum drug – effective for absence, tonic-clonic, and partial seizures.
• Side effects: tremor, weight gain, hair loss, bruising and bleeding. Valproate is a teratogen – should not be used during pregnancy.
• Mechanism: Multiple and not fully understood.
• 1st MOA - Blocks voltage dependent sodium channels (antagonist). In this way it is similar to phenytoin and carbamazepine.
• 2nd MOA – opens up chromatin/DNA structure to allow more gene expression = epigenetics. One of genes that is expressed is for enzyme that makes GABA
• more GABA = more inhibition of neuron firing.