L7 - Epilepsy: Addressing Current Treatment Gaps Flashcards
True or false
Epilepsy is the most common serious chronic neurological condition worldwide
True
What is the impact of epilepsy?
Physical morbidity - injury, cognitive, medical
Psychiatric morbidity
Social morbidity
Medication side effects
Mortality
what is the mortality ratio of epilepsy?
3.0
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
50-100
What are the current epilepsy ‘‘treatment gaps’’
- Drug resistant epilepsy
- medication tolerability
- No anti-epileptogenic or disease modifying treatments
- No treatments for co-mordbidities
- What does drug resistant epilepsy cause?
increased incidence of injury, death, psychiatric co-morbidities, socio-economic disadvantage, reduced QOL
- 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
- 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
- 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
true
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
true
increase in Hyperphos-tau reversed
What does selenate treatment do to spontanous seizures?
reduces them - less seizures per day
Does selenate treatment reduce neurodegeneration?
Yes
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?
False
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
false
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
