45 - Cellular Basis of Epilepsy Flashcards
Lifetime prevalence of epileptic seizure globally
9%
Groups in which epilepsy is more common
Under-developed countries, lower socioeconomic groups
Standardised mortality rate of epileptics versus general population
~3x (risk is higher in those with more poorly-controlled epilepsy)
What is an epileptic seizure?
A transient occurrence of clinical signs and/or symptoms due to excessive and hyper-synchronous activity of populations of neurons in the brain.
Broad type of neuronal firing in epilepsy
Discrete group of neurons begin firing synchronously, innervate another group of neurons which then also begin firing synchronously. These innervate first set of neurons, and this forms a loop of oscillatory firing.
Secondary seizure
Where synchronised firing from the initial epileptic focus spreads to other regions.
What is epilepsy?
A group of neurological diseases with enduring alterations in the brain resulting in abnormally increased predisposition to seizures.
Having a single seizure does not equal epilepsy.
Proportion of epileptics who have a genetic basis
~30% (also called idiopathic or primary)
Things that can cause structural/metabolic epilepsy
Brain tumour, encephalitis (symptomatic or secondary epilepsy)
Name for epilepsy of unknown aetiology
Cryptogenic (EG meso-temporal sclerosis - a type of hippocampal sclerosis)
What is a seizure to epilepsy?
A symptom
ILAE classifications of seizures
1
2
3
1) Focal/partial
2) Generalised
3) Unclassifiable
Focal/partial seizures
Arise in a limited number of cortical neuron within one hemisphere.
Can spread to involve the whole brain.
Generalised seizures
Appear to arise simultaneously in both hemispheres
much more likely to be a genetic basis
ILAE classifications of epilepsies
1
2
3
1) Genetic (idiopathic)
2) Structural/metabolic (symptomatic)
3) Unknown
Genetic (idiopathic) epilepsy 1 2 3 4
Underlying brain is structurally and functionally normal.
–Usually onset during childhood/teenage and may remit.
–Usually respond well to medication.
–Likely have a genetic basis - ion channels
Structural/metabolic epilepsy
1
2
3
Seizures result from some identifiable structural/functional brain abnormality.
–Uncommonly remit, and often incompletely controlled with medication.
- Can sometimes be treated with surgery
Complex partial seizures
Arise in temporal limbic areas.
Lead to altered conscious state.
Current broad concept of what leads to epilepsy
1
2
3
• Disturbance in the balance between inhibition and excitation of cortical neurones and neuronal networks.
– either increases or decreases in neuronal inhibition or excitation.
• Result in neuronal networks that fire in an uncontrolled, hypersynchronous, self sustained manner.
• May result from a wide variety of causes:
– Genetic, congenital/developmental, traumatic, infectious,
metabolic, drugs etc.
Brain mechanics that can be altered, leading to epilepsy 1 2 3 4
•Alterations in neuronal network components
– Loss of inhibitory neurons
– Gain of excitatory neurons
(neurogenesis)
– Aberrant sprouting (after a brain injury, axons can get disconnected, and this can go wrong)
- Alterations in intrinsic neuronal cellular excitability
- Alterations synaptic transmission
- Alterations in the extra-neuronal environment (EG astrocytes not taking up glutamate properly)
Location of the hippocampus
Medial temporal lobe
Most-sensitive structure to inducing seizure activity
Hippocampus
Epileptic remodelling in the hippocampus
1
2
3
Fewer neurons in the dentate gyrus.
Hypertrophy of glial cells.
Increased connections to other hippocampal areas
4 main subregions of hippocampus
CA1, CA2, CA3, dentate gyrus
Effect of a seizure on probability of subsequent seizures
A seizure (from drugs, fever, etc) makes a subsequent seizure more likely
Peaks for onset of epilepsy (age)
Smaller peak in childhood (drops after 20)
Largest peak is after 60 - 80 years old
Aetiology of early-childhood-onset epilepsy
Congenital or perinatal CNS insults (EG infection)
Aetiology of late childhood, early adulthood-onset epilepsy
Idiopathic or genetic
Aetiology of adult-onset epilepsy
Mostly symptomatic (i.e. trauma, ischaemia, tumours, haemorrhage, degenerative diseases).
Proportion of genetic epilepsies that are of a Mendelian monogenetic inheritance pattern
5-10%
affecting most important genes for proteins in the brain can lead to altered neuronal function, therefore epilepsy
Most-common type of inheritance of genetic epilepsies
Complex genetic inheritance.
Combination of genetic influences and environmental factors.
Most useful imaging modality for epilepsy
High resolution MRI
Five major groups of structural pathologies that can lead to epilepsy
–Medial temporal sclerosis 198 (49.1%)
–Malformations of cortical development 82 (20.3%)
–Low grade tumours 58 (14.4%)
–Vascular Malformations 39 (9.7%)
–Encephalomalacia (post-traumatic) 20 (5.0%)
Medial temporal sclerosis
1
2
3
Most common pathology in adults with partial epilepsy.
Resistant to drugs.
MRI features:
– Hippocampal atrophy, increased T2 signal, decreased T1
signal, loss of internal architecture
Focal cortical dysplasia
Focal regions of disturbed cortical development adn architecture,
Uncertain aetiology
MRI features of focal cortical dysplasia 1 2 3 4
–Focal thickening of the cerebral cortex.
–Blurring of the grey/white interface.
–gyral abnormalities e.g. polymicrogyria, macrogyria.
–May be associated with a region of increased T2 signal
Periventricular nodular heterotopia
A generalised malformation due to abnormal neuronal migration.
–Nodular masses of grey matter diffusely lining the ventricular walls.
•Bilateral or focal
–Cortex and neurological function usually normal.
–Can be inherited (bilateral)
•X-linked dominant form (FLNA gene).
•Autosomal recessive form (ARFGEF2)
Most common low grade tumour contributing to epilepsy
Gliomas
Cavernoma
A tangled mass of tightly arranged abnormal vessels made of common hypocellular walls.
