Lecture 10: Epilepsy Pathophysiology and Pharmacology Flashcards
What are examples of etiologies that can lead to seizures?
- Acute
-infection, drugs, alcohol, stroke, AVM - Chronic
-tumor, mesial temporal sclerosis, mutations in channels
Pretty much everything lol - Multiple structural lesions
-tumor, stroke, hemorrhage, dysplasia - Alter normal circuitry
-miswired by developmental lesions - Numerous functional alterations of neurons (channelopathies, drugs, synaptic alterations)
What are seizures?
A symptom of something wrong in the brain
What do people seize?
There is an interplay among etiology, physiology and susceptibility
What are the unifying mechanisms behind acute and chronic etiologies?
The DECREASE in inhibitory signal -GABA receptor change -loss of interneurons -change of interneuron activity The INCREASE in excitatory signals -mossy fiber sprouting (hippocampus) -changes in EAA (excitatory amino acid) receptors -presynaptic changes (glutamate)
What is concept of epileptogenesis?
The general processes occurring in the brain before patient develops spontaneous seizures after an insult
Brain insult + genetics + age leads to acute damage
-leads to progressive damage
-hyperexcitability
-seizures
-causes more progressive damage
Which of the following are mechanisms involved in focal seizure generation?
Paroxysmal Depolarizing Shift
What does a simple cortical network look like? Significance?
Pyramidal cells are interconnected by collaterals
- send feedback to interneurons
- interneurons then send either feedforward or feedback mechanisms
What is the mechanism focal seizure generation?
- PDS
2. Sustained repetitive firing
What is the functional unit of a seizure?
Paroxysmal Depolarization Shift (PDS)
What is the paroxysmal depolarization shift?
The neurophysiological hallmark of partial onset seizures
-cellular correlate of the focal interictal epileptiform spike/sharp wave
What is MOA of paroxysmal depolarization?
Caused by a prolonged CALCIUM-dependent depolarization
Leads to sodium mediated action potentials
(prominent hyperpolarization due to opening of calcium dependent potassium channels)
In general
-EPSPs sum with repetitive neuronal firing (paired pulse facilitation)
-IPSPs decline with repetitive activation (paired pulse inhibition)
-feed forward excitation and inhibition
-in combination, there is loss of inhibitory control and runaway excitation
What is sustained repetitive firing?
Mechanism of seizure generation
Similar to PDS but can occur WITHOUT Ca inward current
Mediated by voltage gated Na channels
What happens if you introduce TTX (tetrodotoxin) to cells that show sustained repetitive firing?
No sustained repetitive firing (because current follows TTX and goes wayyy up)
Why are you susceptible to seizures in early development?
- GABA is excitatory during development
- NMDA receptors develop before AMPA receptors
- young children are in an excitatory state
What is the significance of GABA being excitatory during development?
High intracellular [Cl-] during development (gradient established by NKCC1/KCC2…sodium, potassium and chloride cotransporters)
-that means when GABA binds its receptors, Cl- runs OUT of cell
-depolarization
Change to high KCC2 occurs post-natally
-once KCC2 is established, you get low intracellular Cl- so when GABA binds to receptor, Cl- flows into the cell
-hyperpolarization
Significance: Since GABA is excitatory, there is no inhibitory feedback!!
What is the significance of NMDA receptors developing first?
Mg block easily removed during development due to depolarizing nature of GABA!
Makes it so that neuron is in an even more excitatory state
AMPA expressed also doesn’t included the GluR2 unit; therefore, AMPA becomes permeable to Ca, leading to Ca depolarizing the cell as well
What are Giant Depolarizing Potentials (GDPs)? Significance?
Giant Depolarizing Potentials synchronize large cortical areas and synchronize cortical development
Makes you more susceptible to seizure
Occurs in early age
Caused by the hyperexcitability of young bloods
What are complex partial seizures?
Focal Seizures
What are general characteristics of generalized seizures?
Focal (complex partial seizures) and generalized seizures can have similar presentation
- different mechanisms than partial mechanism
i. thalamo-cortical involvement
ii. Possible molecular of a mechanisms - different medications
- can be both genetic and acquired
What is the ANATOMY of a generalized seizure?
- Start from intralaminar nuclei of the thalamus
- intralaminar nuclei have diffuse cortical connections
- Thalamic nuclei receive burst firing from cortex
- Intralaminiar nuclei also capable of synchronizing widespread cortical activity
What is the MOA of a generalized seizure?
Thalamocortical involvement
T-type Calcium channels in both intralaminar nuclei and cortex
The excitatory thalamic-cortical interplay is regulated by reticular nuclei
When reticular nuclei is dysregulated and no more inhibitory signals are left, then it is thought that t-type calcium channels does its thing and leads to seizures
What is the significance of T-type calcium channels?
Found in intralaminar nuclei of thalamus and cortex
Lead to generalized burts
-hyperpolarization leads to activation (or de-inactivation)
-allows for PROLONGED depolarization
-rapid voltage Na channel firing/neuronal spiking
What are the epilepsy therapeutic principles?
A drug which decreases frequency and severity of seizures
Treats symptom of seizures, not underlying epileptic condition
Does not prevent the development of epilepsy in individuals who have acquired a risk for seizure
Goal is to maximize quality of life by minimizing seizures and adverse drug effects
What are types of Anti epileptic drugs (AEDs)?
Bromides Phenobarbital Phenytoin Ethosuximide Carbamazepine Clonazepam Valproate
What are Mechanisms of actions for AED?
- blockers of repetitive activation of sodium channel
- GABA enhancers
- Decrease glutamate
- T-type Calcium channel blockers
- Synaptic transmission modulators
Act to restore excitation/inhibition imbalance
What are types of sodium channel blockers?
Blocks voltage-dependent Na channels at high firing frequency
-inhibits SUSTAINED REPETITIVE FIRING
-used for focal epilepsies
Examples: Phenytoin, carbamazepine, Oxcarbazepine, Lamotrigine
What is mechanism to decrease glutamate?
- Prolong GABA mediated chloride channel openings
Ex. Barbiturates - Increase frequency of GABA-mediated chloride channel openings
Ex. benzodiazepines
What are the mechanisms of Excitation amino acid antagonists?
- Antagonizes glutamate at AMPA/kainite receptor
Ex. Topiramate - Blocks T-type calcium channels and sodium
Ex. Zonisamide - Modulate NMDA via strychnine-insensitve glycine receptor
Ex. Felbamate
What are types of synaptic mechanisms?
- GABA reuptake inhibitors
- Increases GABA formation
- Decreasing excitatory neurotransmitter release
What type of medications are used for absence seizures?
Ca channel blockers
-generalized seizures
What are surgical techniques for epilepsy?
Resection of epileptic zone Corpus callostomy Vagus Nerve Stimulator Brain stimulation -anterior nucleus of the thalamus Ketogenic Diet Low glycemic Index diet Vietnam therapy (Vit B6)
Which of the following is a mechanism by which at least one anti-epileptic drug works?
Blocking T-type calcium channels
