Epilepsy

Introduction

Affects roughly 1 in 100 people at some point in their lives

Two main categories of epilepsy
o Idiopathic (primary) epilepsy
No apparent cause can be found, possible family history
and caused by genetics
Current research is looking into the genes that may
contribute however there are currently no links
o Symptomatic (secondary) epilepsy
Where there is a known cause such as:
Cerebrovascular disease (stroke)
Brain tumour
Severe head injury
And others such as drug and alcohol abuse
Is more common in the elderly, particularly in those over
60
Triggers of a seizure can include
o Stress
o Lack of sleep
o Drugs and alcohol
o Flashing lights is only in 5% of epilepsy cases
Not all seizures are convulsive
o 60% convulsive
o 40% non-convulsive such as absent seizures where the patient
has a decreased level of consciousness for around 10 seconds

Cause

Epileptic seizures are the result of abnormally high activity of the

neurons in the cortex of the brain
(http://onlinelibrary.wiley.com/doi/10.1111/j.00139580.2005.66104.x/abstract)
Exact cause remains unknown
In symptomatic epilepsy an injury or failure of the blood brain
barrier can cause up regulation of excitatory
Normal brain activity is non-synchronous (Pathophysiology of disease : an
introduction to clinical medicine (6th ed.). New York: McGraw-Hill Medical)
During a seizure neuronal firing is synchronised and excessive
Abnormal neuronal firing starts at a single point then propagates across the brain
Evidence to say that seizures are not random
Epilepsy causes the threshold of stimulus required to cause a seizure to be lowered
Seizures can be partial when they begin in only one hemisphere of the brain

Cellular cause

Unlike the overall electrical patterns seen in the brain the firing at
the single neuron level seems highly heterogeneous as found by
microelectrodes
o Suggests complex interactions between different neuronal
groups
Cessation of firing is however highly homogenous
Neurons outside the initial start site seem to show activity in the
minutes before the seizure
Mutations in genes coding for proteins essential for neuron function
such as channel proteins have been implemented
Unregulated excitatory channel opening has been implemented
however there is little evidence to show exactly which channels are
affected

Current treatment options

Currently seizures are controllable in 70% of cases

Sodium valproate is most commonly used
o Also used to treat bi-polar disorder and migraines
o Reduces flow through Na+ and Ca2+ channels
o Alters GABA turnover in synapses by making it stay in the
synapse for longer
o Is an older drug but has polypharmacology properties
meaning it can have these multiple effects, although why is
unknown
Lack of link between method of action and efficacy
o Poorly understood

Research question

Completely block Na, Ca or GABA and see what happen to the

seizures and brainwaves

Cellular system

Could use neuron cell cultures, some with more GABA neurons than
others and then stimulate seizures
o More controlled
o easier to observe activity
o BUT as they are outside of natural environment they may not
function as they may in real life

o Also are harvested at stem cell stage so development is

interrupted
Use lis-1 (a gene that regulates dynein) nematode worms first as
these are often used in epilepsy research
o Use GABA antagonist to trigger seizures In lis-1 nematodes
o Could have fatal gene inserted into cells with a cre lox P
system then have cre linked to a GABAergic neuron specific
promoter
Then use fruit flies
Then Mice?

Plausibility
References
http://www.nhs.uk/conditions/Epilepsy/Pages/Introduction.aspx