4: Epilepsie Flashcards
Diagnose
Seizure = temporary disruptions of normal brain function; abnormal, excessive neuronal activity
Epilepsie = chronic condition of repeated epileptic seizures
• after 2 unprovoked seizures
• Genetic epilepsy syndrom
Classification of seizures
Focal seizure:
- Onset in part of the brain
- simple-focal: consciousness normal, no temporal evolution (stays focal)
- complex-focal: consciousness impaired, secondary generalization
- originate from enhanced excitability in small group of neurons (epileptic focus)
- Pathological (hyper)synchronization is caused by breakdown of surrounding inhibition btw neurons
Generalized seizure:
- onset in whole brain
- Consciousness always impaired
- primary/secondary generalization
• Focal and secondary generalized seizures: local seizure focus with possible spreading to the whole brain
• Primary generalized seizures: pathological cortical hyperexcitability and thalamocortical afferents
ILAE: Classification of seizures and epilepsies:
• seizure types (focal/generalized/unknown) -> epilepsy types (focal/generalized/combined/unknown) -> syndromes
Different states of epileptic focus:
interictal(btw seizures)
ictal (seizure)
status epilepticus (ongoing seizure)
The ‚epileptogenic‘ zone:
part of the brain that must be removed to render the patient seizure free
Clinical implications of ictal dynamics:
• ictal wavefront moves at ca. 1 mm/s as neurones are slowly recruited into firing (up to 300 mm/s)
= propagation of excitation/inhibition into neighbouring brain areas
• area seen to be recruited into ictal activity on EEG is not necessarily firing
• -> seizure semiology (firing) can be generated by activation of brain areas (slowly) and by disruption of brain networks(more rapidly)
Treatment of Epilepsie
• Pharmacotherapy:
Anticonvulsive drugs: act on cellular level in whole brain (e.g. Na channel blocker, GABA agonists)
• Surgical treatment:
Focal resection: selective removal of the cortical epileptogenic zone
Vagal nerve stimulation: increase inhibitory signaling
Deep brain stimulation: modulate the epileptogenic network
• Disease specific treatment:
Immuno-suppressive therapy in encephalitis (disease modifying)
• Ketongenic diet:
Inducing an anticonvulsive ketogenic state (systemic metabolic)
-> trend towards more personalized therapies
Scales
• Macro-scale:
Malformation in development, prior seizures, infection, stroke, trauma, tumor
• Meso-scale:
Cell birth, Cell death, Sprouting, Rewiring
• Micro-scale:
Synaptic Molecules, Ca2+ channels, K+ channels, Na+ channels
EEG
Scalp EEG:
• field potential resulting from combined activity of thousands of neurons
• Na+-spikes of single neurons are not visible in regular EEG
• Cortical areas of at least 6 cm2 must be involved in synchronous or near synchronous activity before the scalp EEG is observed
Intracranial EEG:
• neurosurgical monitoring to localize the focus of epileptic seizure -> implanted depth-electrodes
• macro-depth electrodes & micro-electrodes
• Microelectrodes have small surface and high impedance -> allows to differentiate signals from local single neurons
Thesis: Excitatory-inhibitory balance regulation:
• Excitatory (Glutamat) and inhibitory (GABA) neurotransmitter balance
• Epilepsie/seizures -> shift in balance
• Loss of GABAergic neurons, Reduction of GABAergic channels, Re-distribution of GABA-receptor subunits
• Changes in neuron-glia cell interaction (reduction of glutamate uptake)
• Rewiring: increase in excitatory connectivity
• Inhibitory neurons die
-> but not so simple
• Most of the neuronal loss in TLE is from glutamatergic pyramidal cells
• GABAergic neurons only comprise 5-15% of the neurons in the temporal lobe and the loss of neurons is paralleled in the two populations
• No relationship between amount of GABAergic interneuron loss and likelihood of epilepsy
• No correlation of interneuron loss and ictal onset site
• but inhibitory neurons initialize a seizure
• Excitatory neurons are inactive during seizure
-> More inhibition than excitation at seizure onset:
When many interneurons are active simultaneously
Voltage gated ion channels
• Neurons create various excitatory spikes along dendritic tree
• output of neuron is different (bigger) if dendritic and somatic inputs excite neuron simultaneously
• Dendritic spikes are able to combine inputs from different cortical layers
• Paroxysmal depolarization shifts in surface EEG, intracranial EEG and intracellular recording
• Paroxysmal depolarization shifts carried by dendritic plateau potentials
• Recordings with Ca2+ chelator BAPTA leads to larger depolarizations during PDS
• Ca2+ channel blocker QX-314 attenuates depolarization during PDS
Reversal potential of one ion and membrane potential:
• rate of net current flow for particular ion is proportional to difference between the membrane potential and equilibrium potential for that ion
• To estimate membrane potential the concentration of the major ions Sodium, Potassium and Chloride has to be taken into account
-> accumulation of potassium in extracellular space
Epilepsy research is divided into studies focusing on seizure initiation, propagation, or termination
• Interneuronal dynamics are important during seizure initiation
• sudden transition of interneurons into synchrony
• Accumulation of potassium in the extracellular space
• Shift of membrane potential of surrounding neurons to more depolarized states
During epileptogenesis neuronal networks undergo extensive rewiring leading to:
− changing interneuron connectivity
− Synaptic reorganization of neural microcircuits
− Modifying network synchronicity
− Altering brain oscillations
− Changes in expressions of voltage gated Na+, Ca2+ and/or K+ channels
-> Promotion of synchronous interneuron activity
-> changes in neural activity lead to rewiring of the neural network
-> combination of this leads to imbalance of excitation & inhibition
