L7 - Epilepsy: Addressing Current Treatment Gaps Flashcards Preview

Seminars in Translational Medicine > L7 - Epilepsy: Addressing Current Treatment Gaps > Flashcards

Flashcards in L7 - Epilepsy: Addressing Current Treatment Gaps Deck (32):
1

True or false

Epilepsy is the most common serious chronic neurological condition worldwide

True

2

What is the impact of epilepsy?

Physical morbidity - injury, cognitive, medical

Psychiatric morbidity

Social morbidity

Medication side effects

Mortality

3

what is the mortality ratio of epilepsy?

3.0

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

4

What is SUDEP?

Sudden unexpected death in epilepsy

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

5

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

24-40x higher

6

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

50-100

7

What are the current epilepsy ''treatment gaps''

1. Drug resistant epilepsy

2.medication tolerability

3. No anti-epileptogenic or disease modifying treatments

4. No treatments for co-mordbidities

8

1. What does drug resistant epilepsy cause?

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

9

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

up to 90%

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

10

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

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

11

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

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

No treatment proven to reduce psychiatric or neurocognitive co-morbidities

12

What is the holy grail of epilepsy therapy development?

Disease modifying treatments

13

What are the benefits of an effective Disease modifying treatment?

Prevention/cure of epilepsy

Less drug resistance

Lesser AED dose and number required = less side effects

less psychiatric and neurocognitive comorbidities

14

True or false

There are no current successful disease modifying therapies for epilepsy?

False - Epilepsy surgery

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

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

15

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

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

16

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

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

17

True or false

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

true

18

What is Tau?

Exists in two primary states
- dephosphorylated on the microtubule

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

19

What does Sodium Selenate do?

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

20

What is the epileptic mouse model?

post-Kanic Acid status epilepticus model of MTLE

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

21

True or false

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

true

increase in Hyperphos-tau reversed

22

What does selenate treatment do to spontanous seizures?

reduces them - less seizures per day

23

Does selenate treatment reduce neurodegeneration?

Yes

24

What does the water maze test show about selenate treatment?

Selenate reduces cognitive memory decline`

25

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

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

26

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

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

27

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

persistent decrease of seizure expression

28

Z944, a novel _____ calcium blocker suppresses seizures in GAERS

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

an anti-epiletogenic

29

True or false

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

False

it decreased - had a good co-morbidity effect

30

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

Is anti-epileptogenic

Has epilepsy comorbidity modifying effects: reduced depressive behavious

promising disease modifying approach

31

True or false

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

false

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

we need to lift the pre-clinical evidence bar

32

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

targetting p-tau

and blocking t-type calcium channels