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):

True or false

Epilepsy is the most common serious chronic neurological condition worldwide



What is the impact of epilepsy?

Physical morbidity - injury, cognitive, medical

Psychiatric morbidity

Social morbidity

Medication side effects



what is the mortality ratio of epilepsy?


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


What is SUDEP?

Sudden unexpected death in epilepsy

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


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

24-40x higher


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



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


1. What does drug resistant epilepsy cause?

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


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


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


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


What is the holy grail of epilepsy therapy development?

Disease modifying treatments


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


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


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


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


True or false

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



What is Tau?

Exists in two primary states
- dephosphorylated on the microtubule

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


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


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


True or false

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


increase in Hyperphos-tau reversed


What does selenate treatment do to spontanous seizures?

reduces them - less seizures per day


Does selenate treatment reduce neurodegeneration?



What does the water maze test show about selenate treatment?

Selenate reduces cognitive memory decline`


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

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


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


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

persistent decrease of seizure expression


Z944, a novel _____ calcium blocker suppresses seizures in GAERS

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

an anti-epiletogenic


True or false

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


it decreased - had a good co-morbidity effect


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


True or false

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


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

we need to lift the pre-clinical evidence bar


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