L7 - Epilepsy: Addressing Current Treatment Gaps

Question 1

True or false

Epilepsy is the most common serious chronic neurological condition worldwide

Answer 1

True

Question 2

What is the impact of epilepsy?

Answer 2

Physical morbidity - injury, cognitive, medical

Psychiatric morbidity

Social morbidity

Medication side effects

Mortality

Question 3

what is the mortality ratio of epilepsy?

Answer 3

3.0

die from a variety of causes - accidental injury, drowning, asphyxia, suicide

Question 4

What is SUDEP?

Answer 4

Sudden unexpected death in epilepsy

non-traumatic, non-drowning, with or without evidence for a seizure

Question 5

The risk of SUDEP is ____x higher than in the general population

Answer 5

24-40x higher

Question 6

There are estimated to be __-__ deaths by SUDEP a year in Australia

Answer 6

50-100

Question 7

What are the current epilepsy ‘‘treatment gaps’’

Answer 7

1. Drug resistant epilepsy
2. medication tolerability
3. No anti-epileptogenic or disease modifying treatments
4. No treatments for co-mordbidities

Question 8

1. What does drug resistant epilepsy cause?

Answer 8

increased incidence of injury, death, psychiatric co-morbidities, socio-economic disadvantage, reduced QOL

Question 9

2. How many patients report adverse drug reactions (medication tolerability gap)?

Answer 9

up to 90%

cause of discontinuation in 20-40% of patients treated with any AED

Question 10

3. Explain how the lack of anti-epileptogenic or disease modifying treatments is a treatment gap?

Answer 10

We need a sustained symptomatic treatment

poor treatment adherence is common and a major cause of seizure recurrence

The long term effects of AEDs include bone disease, gait imbalance, dermatological

Big risk in pregnant women - birth defects

Question 11

4. explain the bilateral relationship between Psychiatric co-morbidities and seizure control

Answer 11

neurocognitive co-morbidities have prevalence rates between 44-88% - depression, anxiety etc…

No treatment proven to reduce psychiatric or neurocognitive co-morbidities

Question 12

What is the holy grail of epilepsy therapy development?

Answer 12

Disease modifying treatments

Question 13

What are the benefits of an effective Disease modifying treatment?

Answer 13

Prevention/cure of epilepsy

Less drug resistance

Lesser AED dose and number required = less side effects

less psychiatric and neurocognitive comorbidities

Question 14

True or false

There are no current successful disease modifying therapies for epilepsy?

Answer 14

False - Epilepsy surgery

Can result in cure,
resolution of drug resistance and medication burden

Improved QOL, patient satisfaction, employment, independence, injury, mortality

Question 15

What are the problems with the tradition approach to AED discovery and pre-clinical development?

Answer 15

same formula for over 70 years

limited rodent models

NOT using Gold standard comparison - ‘‘Head-to-head’’ animal model studies not performed to demonstrate efficacy and tolerability advantages over standard AED in animal models

Few preclinical studies addressed endpoints related to the ‘‘gaps in care’’, e.g comorbidities

Question 16

What are the molecular, cellular and network changes during epileptogenesis?

Answer 16

neuronal loss and degeneration (cumulation of Tau, B-amyloid)

Axonal sprouting

Changes in voltage gated ion channel expression

Changes in NT release and uptake

Changes in receptor response

Changes in Glial number

Inflammatory processes

Question 17

True or false

Any of the molecular, cellular and network changes during epileptogenesis could be related to epilepsy or the comorbidities

Answer 17

true

Question 18

What is Tau?

Answer 18

Exists in two primary states
- dephosphorylated on the microtubule

• phosphorylated - precipitates out of solution and forms TANGLED CLUMPS - neurotoxicity

Question 19

What does Sodium Selenate do?

Answer 19

stimulates PP2A phosphatase (the enzyme that specifically dephosphrylates Tau)

if you can push tau back into the dephosphorylated state you can prevent build up of clumps

Question 20

What is the epileptic mouse model?

Answer 20

post-Kanic Acid status epilepticus model of MTLE

offers an opportunity to test - histolopathology resembles that seen in human Temporal lobe epilepsy

Question 21

True or false

The epileptogeneis decrease in PP2A activity in the Post-KA mouse model is reversed by selenate treatment

Answer 21

true

increase in Hyperphos-tau reversed

Question 22

What does selenate treatment do to spontanous seizures?

Answer 22

reduces them - less seizures per day

Question 23

Does selenate treatment reduce neurodegeneration?

Answer 23

Yes

Question 24

What does the water maze test show about selenate treatment?

Answer 24

Selenate reduces cognitive memory decline`

Question 25

Why are T-type calcium channels important in acquired epilepsy?

Answer 25

Important for burst firing properties that lead to the development of epilepsy

Question 26

Ca3.2 expression and T-type Ca2+ currents are ______ in the hippocampus after spontanous epilepsy in a mouse model of acquired epilepsy

Answer 26

Ca3.2 expression and T-type Ca2+ currents are increased in the hippocampus after spontanous epilepsy in a mouse model of acquired epilepsy

Question 27

What does treatment of T-channel drug ESX do in GAERS rat?

Answer 27

persistent decrease of seizure expression

Question 28

Z944, a novel _____ calcium blocker suppresses seizures in GAERS

Answer 28

Z944, a novel T-type calcium blocker suppresses seizures in GAERS

an anti-epiletogenic

Question 29

True or false

Z944 increased the depressiove-like behaviour in post-SE animals?

Answer 29

False

it decreased - had a good co-morbidity effect

Question 30

So in conclusion, blocking T-type calcium channels with z944…

Answer 30

Is anti-epileptogenic

Has epilepsy comorbidity modifying effects: reduced depressive behavious

promising disease modifying approach

Question 31

True or false

Clincal trials of anti-epileptogenesis/disease modification are less difficult than anti-seizure trials

Answer 31

false

other way around - pre-clinical trials are longer, more labour intensive and more expensive

we need to lift the pre-clinical evidence bar

Question 32

Evidence from studies in chronic epile[psy models suggest that translational epilepsy research is possible with…

Answer 32

targetting p-tau

and blocking t-type calcium channels