ICL 10.10: Fundamentals of Epileptogenesis & Epilepsy Pharmacology

Question 1

what is a seizure?

Answer 1

a clinical (or electrographic) event associated with an abnormal, excessive and hypersynchronous electrical discharge in a group of cortical neurons

the fact that it’s cortical neurons specifically is important because that means epilepsy and seizures are a disfunction of the cerebral cortex – so disorders with the cerebellum or brainstem like Parkinson’s do not cause seizures!

but Alzheimer’s which effects the cerebral cortex can cause seizures!

Question 2

what is epilepsy?

Answer 2

recurrent and unprovoked seizures

seizure = a clinical (or electrographic) event associated with an abnormal, excessive and hypersynchronous electrical discharge in a group of cortical neurons

Question 3

what are the guidelines that would state that someone has epilepsy?

Answer 3

epilepsy is a disease of the brain defined by any of the following conditions:

1. at least two unprovoked seizures occurring more than 24 hours apart.
2. one unprovoked seizure and a probability of further seizures similar to the general recurrence risk after two unprovoked seizures (approximately 60% or more)

people who have had a single seizure but have underlying abnormalities on examination like Alzheimer’s or a cortical dysfunction or a stroke are at a higher risk and would qualify for having epilepsy

3. Epilepsy Syndrome

Question 4

what is epilepsy syndrome?

Answer 4

clinical and EG and MRI findings that signify a particular type of epilepsy

Question 5

how does epilepsy effect the disability and death of those who have it?

Answer 5

of all the neurological problems, people with epilepsy comprise 5% of those who have disability that effects their life and work and 1-3% have shortened life span

Question 6

what age range is more effected by epilepsy?

Answer 6

incidence of epilepsy is high in the neonatal group then it plateaus in young adults and starts to go back up after 50

so epilepsy is most common in older adults in their 80s

as people live longer and develop more neurological insults related to falls, trauma, alzheimer’s, heart disease etc. you’re more likely to see seizures in these older patients

Question 7

what is an aura?

Answer 7

a premonition or an objective/subjective sensation of an impending seizure

they are localizable –> some people get a funny taste or smell which localizes to the frontal/temporal lobe while other people get anxious which localizes to the fight or flight part of the brain

it’s considered a simple partial seizure (focal aware seizure) and not all auras lead to a full blown seizure

Question 8

what is the medical word for seizure?

Answer 8

ictus or ictal event

Question 9

what state are people in after a seizure?

Answer 9

post-ictal state

patients will be sleepy, lethargic, somnolence or confusion due to the excessive release of GABA during the seizure

Question 10

what are the 3 stages of a seizure?

Answer 10

1. aura
2. ictus
3. post-ictual state

Question 11

which types of seizures are not associated with epilepsy?

Answer 11

1. metabolic like people with kidney disease
2. traumatic brain injury
3. drugs
4. medications like penicillin
5. alcohol
6. systemic illness (autoimmune disorders like SLE)

Question 12

what are the causes of epilepsy in children?

Answer 12

1. cryptogenic (68%) aka we don’t know
2. congenital abnormality (20%)
3. trauma (5%) like shaken baby syndrome

babies don’t have generalized seizures because their brains aren’t developed enough yet so they just twitch in on like one side or one area of the body

Question 13

what are absence seizures?

Answer 13

a type of epilepsy that is referred to as a generalized epilepsy and it happens in kids between 4-12 years old

the kids will have staring episodes for a few seconds and then they’re okay

there’s no aura or post-ictus confusion and they can have hundreds of episodes in a day

alkalosis makes the neuronal cells more excitable and it can provoke seizures which is why when you’re trying to catch a seizure on an EG, you ask them to blow on a windmill so they hyperventilate

Question 14

what causes epilepsy in young adults?

Answer 14

1. trauma (29%)
2. congenital (22%)
3. tumor (22%); usually low grade astrocytoma or meningioma
4. infection (16%)

Question 15

what causes epilepsy in adults?

Answer 15

1. CVA (33%) like strokes and hemorrhages
2. tumor (23%)
3. trauma (22%); usually more malignant tumors

Question 16

what are the types of seizures in adults?

Answer 16

1. generalized seizures

2. complex partial seizures/focal seizures with impaired awareness

Question 17

what causes epilepsy in the elderly?

Answer 17

1. stroke from CVD (40.7%)
2. unknown (33%)
3. degenerative (16.5%)

this is the most common age group to get epilepsy!!

Question 18

how do you classify seizures/epilepsy?

Answer 18

1. based on phenomenology (seizure semiology)

generalized vs. partial/focal onset

2. based on etiology

post-traumatic, post-stroke, tumor associated etc.

3. based on pathophysiology

primary generalized epilepsy vs. secondarily generalized = involves both hemispheres or spreads from one to the other

4. genetics

SCN1A mutation, GABRA1

5. epileptic syndromes

Lennox Gastaut, Juvenile Myoclonic Epilepsy

we care about classification because certain medications only work on certain types of epilepsy

Question 19

what’s the difference between a partial vs. generalized seizure?

Answer 19

FOCAL SEIZURES
1. simple partial seizures –> no alteration of awareness

2. complex partial seizures –> there is alteration of awareness

GENERALIZED
1. primary generalized –> absence and JME seizure

2. secondary generalized

slide 14

Question 20

what are the various etiologies/causes behind epilepsy that are used to classify epilepsy?

Answer 20

1. structural
2. genetic
3. infectious
4. metabolic (inborn errors of metabolism like mitochondrial disorders)
5. immune
6. unknown

whatever the underlying cause may be, the management and treatment are pretty much the same!

Question 21

what is the pathogenesis of a seizure?

Answer 21

first there is an insult and then there is a rapid response with inflammation, glial reaction and gene expression which increases excitability

this causes a decreasing seizure threshold due to epileptogenesis and allows a subthreshold stimulus to cause electrical activation and recurrent seizures

so brain tissues of epilepsy patients have more excitatory neurons than inhibitory neurons whether that be induced by stroke, trauma, infection etc – they all have a change in the cortical circuitry where there’s a group of abnormal neurons that are firing!

teacher explanation = epilepsy can be simplified as three stages: an initial insult, followed by epileptogenesis, and ultimately ending in a state of recurrent, spontaneous seizures(epilepsy). The initial insult can take several forms and is followed by both rapid and slower progressive changes with rapid and slower durations. Rapid changes in animal models include neuronal excitation and calcium influx, triggering a cascade of events that include second messenger and immediate early gene responses, modifications to pre-existing proteins, and protein synthesis. Within days, there can be cell death and proliferation as well as inflammatory, glia, and vascular responses. Slower responses include growth (eg, axon outgrowth, synapto-genesis, angiogenesis), leading to synaptic reorganization, and this may in turn cause other changes. Over time, seizure threshold is lowered by a growing increase in excitability, and the risk of a seizure increases. These changes may be sufficient to cause epilepsy or may stall until a second “hit” occurs. The second hit could be environmental, or it could be due to time-dependent gene expression or co-morbidity. Therefore, genes, development, and the responses to the initial insult are likely to act together to result in a state of chronic seizures.

Question 22

what are the steps that occur building up to, during and after a seizure?

Answer 22

1. epileptogenic lesion like head trauma, stroke, infection, etc. that causes neuronal injury
2. latency period (epileptogenesis)

during this time there is reorganization such as neuronal loss, neurogenesis, gliosis, plasticity, inflammation and molecular reorganization which causes increased excitability

3. seizure
4. recurrent seizures

reorganization continues which allows for continued neuronal loss, neurogenesis, gloss etc.

if there is good seizure control though, there won’t be recurrent seizures and reorganization process will stop

Question 23

which parts of the brain is most involved in focal seizures?

Answer 23

CA1 and CA3 of the hippocampus in the temporal lobe

they produce a lot of electrical activity that spreads to the rest of the cortex; they’re kind of the pacemakers of the brain so when there’s problems with them it can cause focal seizures!

focal epilepsy is the most common type of epilepsy and within that population, temporal and hippocampal are the most common

Question 24

what is ictogenesis?

Answer 24

seizure generation

there are inhibitory neurons that shut down excitatory responses – but if you inhibit the inhibitory neurons then you get excitation and seizures!

if you inhibit multiple neurons, that’s what gives you epilepsy! this can effect many circuits in the brain, specifically the thalamic circuit that usually causes seizures due to abnormal excitation

Question 25

what parts of the brain are involved with a simple vs. complex seizure?

Answer 25

just hippocampal involvement = focal seizure without impairment, might include aura

if the cortex is involved too and the thalamus it can lead to a generalized seizure and might even cause impaired awareness as well

Question 26

what kinds of inflammation or autoimmune diseases can cause epilepsy?

Answer 26

1. systemic illnesses like sepsis
2. paraneoplastic syndromes = antigens in tumor cells are similar to brain antigens so the body attacks the brain

these things don’t reply to epilepsy medications they require immune modulation with steroids

Question 27

A 33-year-old woman presents with 3-month history of bizarre behavior, confusion and hallucinations. Multiple seizures are recorded on EEG. She has NMDA-R antibodies in CSF. Immunosuppressive therapy renders her seizure and symptom free

diagnosis?

Answer 27

ovarian teratoma = paraneoplastic syndrome!

even though she has epilepsy you had to treat it with immunosuppressive therapy instead of epilepsy medications

Question 28

what is genetic epilepsy?

Answer 28

most genetic epilepsy have single gene mutations or complex inheritance

these can lead to defects in ion channels that lead to hyperexcitability of neurons such as SCN1A mutations involving sodium channels underlying severe myoclonic epilepsy of infancy

note: there’s always an interplay between genetic and acquired factors

Question 29

what is Dravet’s syndome?

Answer 29

aka severe myoclonic epilepsy of infancy (SMEI)

SCN1A gene nonsense mutation that leads to Na+ channel mutation and causes epilepsy

frequent generalized tonic-clonic seizures along with focal clonic seizures

may present after vaccination due to interplay between genetic and acquired factors

Question 30

what is cortical dysplasia?

Answer 30

abnormal cortical neurons that never migrated out to the cortex

due to a gene defect that prevents the neurons from traveling to the cortex so it’s usually a neurofilament issue

Question 31

how do you diagnose epilepsy?

Answer 31

clinically!!!

do a history and PE, maybe do an MRI too

only do a PET, SPECT, functional MRI, or EEG if you’re planning on doing surgery

it’s not based on tests or anything, those are just supplementary to what we already know and they have limitations

Question 32

what is the role of an EEG in epilepsy?

Answer 32

1. confirms diagnosis
2. helps classify seizure type and epilepsy syndrome
3. helps guide therapy

Question 33

what are the 2 monitoring strategies used to monitor seizures?

Answer 33

1. synchronized video EEG monitory –> help differentiate non-epileptic events from seizures
2. intracranial recordings in the subdural brain regions during surgery only

Question 34

how does an EEG work?

Answer 34

EEG picks up cortical electrical activity from a large cortical area

Question 35

what types of brain patterns are there on an EEG?

Answer 35

1. alpha = awake, seen posteriorly
2. beta = awake, frontally predominant
3. theta = during drowsiness
4. delta = during sleep
5. gamma = fast and ultra fast

Question 36

what is status epilepticus?

Answer 36

a single seizure or repetitive seizures without return to baseline for more than 5 minutes

this is considered a medical emergency because there’s a period of time that you can interfere with benzodiazepine before you get damage

the first few minutes there’s normal cardiac output, BP and brain lactate levels but as the seizure goes on blood flow drops, glucose and oxygen levels drop and then ATP production stops so as a result you get metabolic changes that are harmful to the brain –> this leads to changes in the receptors where there is decreased GABA and increased NMDA which causes more excitation and as a result you have more cell death

so seizures that go on for a long time can cause lots of cell death

Question 37

the incidence of epilepsy is highest in which age group?

Answer 37

elderly

Question 38

what is the most common cause of epilepsy in the elderly?

Answer 38

cerebrovascular disease

Question 39

a man with a new diagnosis wants a confirmation of his epilepsy diagnosis. what modality would you use?

Answer 39

EEG

Question 40

37 year old man is admitted for frequent seizures. he was recently diagnosed with testicular cancer. what is the most likely cause for his seizures?

Answer 40

autoimmune condition

paraneoplastic syndrome!

Question 41

23 year old women has facal epilepsy with impaired awareness. what structure is most likely involved?

Answer 41

hippocampus