Epilepsy Flashcards
The scientific basis
Define epilepsy and seizures
The effects of seizures?
Epilepsy: a tendency to have recurrent seizures, only diagnosed after more than 1 seizure
Seizure: episodes of altered consciousness
- 99% terminates spontaneously
- can affect brain activity, cardiac function, respiratory centres
Epidemiology:
Highest in which areas?
Death rate?
Who does it affect?
- highest in deprived underdeveloped areas
- 3 people a day die - status epilepticus, trauma, sudden unexplained death in epilepsy (anyone with known epilepsy dead without witness and known cause)
- Bi-modal distribution (Kids and elderly)
How do patient’s with seizures present?
The symptoms reflect the locus of pathology and can manifest in different ways.
How do we diagnose patients with seizures?
Clinical hx:
- patients perspective, witness accounts
- Baseline EEG: to look for interictal activity
- Video-telemetry: EEG and video done while withdrawing medication
- Not efficient recording tool and not everyone with seizures have interictal activities on EEG
What is interictal activity?
Transient, abnormal focal neural discharges seen on EEG
Is the basis for most diagnoses (recordings during periods between seizures - which were long thought to be clinically silent
E.g. Yale pt drove in simulated cars while recording interictal discharges
When they had to do a challenging task, in this case, driving, if a interictal discharge occurs, the patient crashed the car without the patient realising why
- it’s deduced that the brain stopped being able to interpret signals
What are the co-morbidities of epilepsy?
- excess mortality
- Memory deficits - interictal events, drug side effects
- Schizophrenia - approx 7 fold increase in incidence
- Depression, stress, anxiety
- Downward social movement
What are the causes of epilepsy?
- Genetic
- Brain injury - trauma, stroke
- Brain infection - HPV, Measles (MMR release correlated to decrease in temporal lobe epilepsy)
- Brain disease - tumors
- Drugs (including alcohol)
What are the causes of seizures?
- Drugs (including alcohol)
- Electrical stimulation - Electrical convulsive therapy
- Sensory triggers: Flashing lights, audiogenic
- Metabolic imbalances = pH
- Hormonal state - association with menstrual cycle
- Brain state e.g. sleep to wake: transitions may be important, absence seizures don’t happen during sleep (correlation with spindles activity) whereas others only happen in sleep
- Temperature: febrile seizures
- Fatigue/stress
Explain the relationship of permutation of cells and epilepsy
In status epilepticus, by Liu et al 2012, the activation profile following this induced expression in 99.8% of neurons.
In memory protocol, information potential of status epilepticus activation pattern is very low where 100% activation = number of permutations (n choose n)=1
immediately post seizure, all neuronal activity is suppressed, leading to ta state as badly compromised for info as the preceding full ictal activity: n choose 0 = n choose n = 1 possible combination
What are the three key classes of interneurones that release GABA, what are their functions?
Which inhibits which?
- PV = Paravalbumin +ve: Ca2+ buffer, and subtly influences synaptic transmission - found on soma and initiates somatic inhibition (vetoing inhibition) causing a downward shift in firing rate even with increase excitatory drive
- Som = Somatostatin +ve: don’t know - found on dendrites and cause dendritic nhibition - causes a rightwards shift and can still achieve maximum firing rate but just takes more excitatory drive
Both PV and Som inhibits pyramidal cell. In reality, inhibition isn’t maintained continuously so vetoing inhibition happens at same time and stopped at same time so pyramidal cell can fire. However, in certain cases, vetoing inhibition can be maintained.
- VIP = Vasoactive intestinal peptide +ve: may have a role in regulating local vasculature in cortex
Inhibits Som and PV therefore causing overall disinhibition.
How can seizure activity be regulated by neuronal inhibition?
Miles et al 1983,
Had brain slice that blocked all inhibitory synaptic transmission (e.g. GABA). In a single neurone, he started stimulating that cell, after 3 stimuli, he entrained the entire network to the activity of this single neurone. This tells us that one neurone in the right situation can subsume to escalate the activity of the entire network
What is the role of neuronal synchronisation in memory formation?
The strength of neuronal activity is correlated with the activation of multiple neurons and the study of memory has been closely tied to the study of synchronous activity in the brain. Precise synchronization of neuronal activity is one of the underlying mechanisms by which information is stored in neural tissue.
Neuronal synchronization has also been linked to spike timing-dependent plasticity, a cellular mechanism thought to underlie learning and memory.
What is LTP and LTD, and what activates it?
LTP is induced by high-frequency stimulation (HFS) of the presynaptic afferents or by pairing low-frequency stimulation (LFS) with large postsynaptic depolarization
Under the STDP process, if an input spike to a neuron tends, on average, to occur immediately before that neuron’s output spike, then that particular input is made somewhat stronger (LTP). If an input spike tends, on average, to occur immediately after an output spike, then that particular input is made somewhat weaker (LTD) hence: “spike-timing-dependent plasticity”. Thus, inputs that might be the cause of the post-synaptic neuron’s excitation are made even more likely to contribute in the future, whereas inputs that are not the cause of the post-synaptic spike are made less likely to contribute in the future.
Because LTP and LTD can lead to long-lasting changes in neuronal properties, including receptor trafficking and spine motility, these studies provide a direct link between synchronous neuronal firing and the modifications that may underlie memory formation in the brain.
For many glutamatergic synapses, the inductions of LTP by HFS and LTD by LFS both require the activation of NMDA (N-methyl-daspartate) receptors and a rise in postsynaptic Ca2+ level.
What are the 2 qualities of inhibition?
A. Asymmetry of synaptic organisation:
Pyramidal cells are principal excitatory neurons in the cortex.
- receive excitatory inputs primarily from other pyramidal cells throughout the distal dendritic tree. Most proximal dendritic compartments, within about 50 μm from the soma, and the soma itself, receive no excitatory inputs.
- Inhibitory synapses on the other hand, are found on all dendritic compartments including the proximal dendrites, the soma, and the axonal initial segment
In interneurons, unlike pyramidal cells, they receive both excitatory and inhibitory synaptic drive across their entire somatodentritic axis.
- Thus the interneurons receive balanced inhibition and excitation whereas pyramidal cells may tend towards having their activity vetoed.
B. Asymmetry of functional connectivity
It is suggested that basket cells (fast-spiking interneurons) get a ‘readout’ from all local pyramidal cells whereas the pyramids get a readout only from a subset dominated by those other pyramidal cells with similar functional representations. Therefore, basket cells take a more complete sample of local activity, and furthermore may be particularly attuned to situations where there is activation across pyramidal populations that are not typically co-active
Describe the balance between inhibition and excitation
The asymmetry at the heart of the cortical microcircuit means that inhibition is dynamically modulated by excitation.
Therefore, as excitation increases, interneurone, kicks in.
Inhibition scales up more dramatically than excitation acting to suppress the initiation and spread of seizures.
