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Pathophysiology of Epilepsy Samah Reem Al-Qdah 20 / 4 / 2009 20 / 4 / 2009

 Dr. Samah Phsiology 5 done by: Reem Al-Qudah date: 20-4-2009

Pathophysiology of Epilepsy
In this lecture we are concerned about discussing the changes that occur to a normal neuron (with normal excitation, depolarization, repolarization and hyperpolarization) which transform it into a hyper-excitable neuron giving us the clinical manifestations of seizure () General information: Epilepsy is the commonest neurologic disorder with therapeutic indications (meaning you can treat seizures) Prevalence of epilepsy 0.5-1% Children are the most group of people who experience epilepsy There are a lot of the medications (called designed medication) which we try to design them according to the perceived pathophysiology of the seizure Understanding the pathophysiology of epilepsy is important in rational therapy So if u know the basic problem (hyper-excitation, excessive glutamate release or decrease in inhibitory net wok) you can target that to treat the seizure

Seizure and epilepsy

Seizure: is a clinical manifestation where you have a neuron which fires excessively, so there is hyper-excitability of a neuron coupled with hyper synchronization Hyper synchronization means that a hyper-excitable neuron will lead to excessive excitability of a large group of surrounding neurons and you end with millions of neurons in the brain firing excessively leading to the clinical manifestations of the seizure. The phenotype of the seizure depends on the site it occurs at If the seizure comes from the limbic system you will end up with temporal lobe or emotional disturbances

If it occurs in the rolandic area you will have motor seizure Wikipedia: rolandic area refers to the motor area If it starts in both sides of the brain you will end up with generalized seizure Seizure is a single event Epilepsy means recurrent seizures Seizure is a sudden time limited involuntary alteration of behavior with or without loss of consciousness accompanied by an abnormal electrical discharge Epilepsy is a disorder of the CNS whose symptoms are seizures Now you have: Reactive seizures: Occurring in normal nonepileptic tissue Expamles: someone with hypoglycemia has a normal brain but temporarily becoz of hypoglycemia he will have hyper-excitation of neurons and end with a seizure Normal brain with temporal disturbances leading to seizure Someone with encephalitis: here the temporal disturbance which might lead to seizure is infection Hyponatremia, severe dehydration, hypoxia. Epileptic seizures occurring in chronically epileptic tissue: Normal brain and at the same time may have chronic epileptogenic brain Exp: someone has hypoglycemia (has a normal brain), now if he experience prolonged hypoglycemia and recurrent seizures without treating the hypoglycemia, he will end up with a damaged brain and this is called a chronic epileptogenic brain Other examples on chronic disturbances: someone with a traumatic brain injury, brain tumor, congenital brain malformation and birth injury to the brain these are chronic epileptogenic brains with seizures (tendency for recurrent seizures)

Epileptogenesis: Sequence of events that converts normal neuronal networks into hyper-excitable networks There are various factors which may lead to epileptogenesis Could be genetic, acquired, infectious or medication induced

Seizures are of 2 types:

Partial Seizures: Simple Partial: Exp: a person with right hand clonic seizure, he is awake and fully aware this is simple seizure. Now if this patient experience a change in the level of consciousness with this seizure then it is called a complex partial seizure Info: Clonic seizures consist of rhythmic jerking movements of the arms and legs, sometimes on both sides of the body. Complex Partial Between these two there is alteration in the level of consciousness Generalized Seizures: are seizure that emanates (comes out) from both sides of the brain at the same Partial seizures may generalize; start from one site in the brain and spread to involve the whole brain. This is called secondary generalization These are types of generalized seizures mentioned in the slides (but not explained): Absence Atypical Absence Tonic Clonic Tonic-Clonic Atonic Myoclonic Mixed Forms

This is partial seizure, the seizure is focus then it spreads to involve the whole side and the contra-lateral side of the brain, so it is secondary generalization

This is also secondary generalization from another focus of seizure

This is primary generalized seizure: they usually start from the thalamocortical circuit Primary generalized: means they start from both sides of the brain at the same time without localization

Neuronal Excitability:
Basic mechanism of neuronal excitability is the action potential In the action potential there is net positive inward ion flux which causes depolarization We have a specific Na+, K+ grade maintained within the neuron by Na+/K+ ATPase pump Also we have safety mechanisms (to return the cell back to the normal status): Influx of K+ leads to hyper-polarization to prevent hyperexcitability the neuron should go through a refractory period This action potential is needed for neuronal transmission of impulses for neuronal activity Disturbance in this normal excitability is what leads to hyper-excitability

when there is a Hyper-excitable state, this means there is: Increased excitatory neurotransmission or Decreased inhibitory neurotransmission or Alteration in voltage gated ionic channels (ion channels are either voltage gated or ligand gated by neurotransmitters) or Intra/extracellular ionic alterations in favor of excitation This is how we end up with a hyper-excitable state Neuronal circuits: Axonal conduction: an action potential travels down the axon to the terminal buttons and then release neurotransmitters to the synaptic cleft Synaptic transmission Both of these processes (axonal conduction and synaptic transmission) employ ionic channels (we need ionic channels for these processes) Voltage gated channels Ligand gated channels Voltage Gated Channels: Of 2 types depending on the conduction: Depolarizing conductance It is excitatory Mediated by inward sodium and Ca currents Hyperpolarizing conductance It is inhibitory Primarily mediated by potassium channels also chloride channels play a role Ligand Gated Synaptic Transmission Also of 2 types (excitatory and inhibitory): Excitatory transmission Glutamate (NMDA) the principal excitatory neurotransmitter in the brain Inhibitory transmission GABA the principal inhibitory neurotransmitter in the brain

Glutamate: The brains major excitatory neurotransmitter There are two groups of glutamate receptors: Ionotropic (NMDA receptors): E.g. NMDA, AMPA, kinate. They modulate gated Ca+2 and Na+ channels and are responsible for fast synaptic transmission Metabotropic (non NMDA receptors): e.g. Inositol, cAMP. Modulate second messengers and are responsible for slow synaptic transmission. GABA The major inhibitory neurotransmitter in the CNS GABA A: presynaptic, mediated by Cl- channels GABA B: postsynaptic, mediated by K+ currents

Both Glutamate and GABA require active reuptake to be cleared from the synaptic left (to terminate their action); so when there is disturbance in the transport system this may have an influence on seizure propagation Factors that interfere with transporter function also activate or suppress epileptiform activity

Cellular Mechanisms of Seizure Generation: 1. Excitation: too much excitation favors seizures Caused by: a. Ionic: inward currents of Na, Ca from the slides b. Neurotransmitter: Glutamate, Aspartate 2. Inhibition: too little inhibition also favors the formation of seizures Caused by: a. Ionic: inward Cl, outward K from the slides b. Neurotransmitter: GABA Factors leading to hyper-excitability: 1. Intrinsic Factors (intrinsic to the neurons): Ion channels type, number and distribution (e.g. if there is scarring this will lead to redistribution of channels)

E.g. If there is a congenital brain malformation with islets of abnormal cortical tissue then these will have excessive NMDA receptors Biochemical modification of receptors: become more responsive Activation of second messenger systems Modulation of gene expression 2. Extrinsic factors (extrinsic to the neuron; outside the neuron): Changes in extracellular ionic concentrations Remodeling of synaptic location by fibrosis also we can have remodeling of synapses by sprouting (growth) of abnormal fibers (this happens in the hippocampal model described later) Modulation of transmitter metabolism or uptake

Mechanisms that lead to these changes: Basically inward flux of Na+ and Ca+2, and outward flux of K+ Endogenous factors: Genetic predisposition Environmental factors: Trauma or ischemia These convert non-bursting neurons to potentially epileptogenic populations Epileptogenesis The process by which normal healthy tissue is transformed into a relatively permanent epileptic state For epileptogenesis to occur there must be 2 things: 1. Hyperexcitability: The tendency of a neuron to discharge repetitively to a stimulus that normally causes a single action potential. Causes: trauma, ischemia, genetic predisposition, hypoxia, congenital brain malformation, infection these will lead to abnormal discharge which is coupled with abnormal synchronization 2. Abnormal synchronization: The property of a population of neurons to discharge together independently; meaning that the group of neurons around the abnormal neuron will fire synchronously If a hyper-excitable neuron is working alone nothing is going to happen

Conclusion: one single neurons hyper-excitability along with hyper synchronization with the surrounding neurons leads to epileptogenesis
Why does Synchronization occur? Recurrent excitatory synapses; recurrent excitation, positive feedback loops Electronic coupling by gap junction, this is seen especially in neonates because they have very active gap junctions and they have more gap junctions than the mature brain this is why they easily develop seizures Electrical field and ephaptic effects: a whole electrical field of ions Changes in extracellular ion concentrations All of these will lead to abnormal synchronization Different kinds of seizures are probably related to different combinations of the above This slide represents examples on channels and receptors in normal and epileptogenic brains:
Roles of channels and receptors in normal and epileptic firing

Channel or receptor Voltage-gated Na+ channel Voltage-gated K channel Ca -dependent K+ channel

2+ +

Role in normal neuronal function Sub-threshold EPSP; action potential upstroke Action potential down-stroke AHP following action potential; sets refractory period Transmitter release; carries depolarizing charge from dendrites to soma Fast EPSP Prolonged, slow EPSP IPSP Prolonged IPSP Ultra-fast excitatory transmission Restores ionic balance

Possible role in epilepsy Repetitive action potential firing Abnormal action potential repolarization Limits repetitive firing Excess transmitter release; activates pathophysiological intracellular processes Initiates PDS Maintains PDS; Ca2+ activates pathophysiological intracellular processes Limits excitation Limits excitation Synchronization of neuronal firing Prevents K+-induced depolarization

Voltage-gated Ca2+ channel Non-NMDA receptor (ie, AMPA) NMDA receptor GABAA receptor GABAB receptor Electrical synapses Na -K pump
+ +

From the above slide: e.g. voltage gated Na+ channels: they are important for the action potential up-stroke, in pathological conditions they lead to repetitive action potential firing not just one up-stroke

Ca+2- dependent K+- channel: involved in hyper-polarization, but in epilepsy they limit repetitive firing leading to an epileptogenic state This slide gives examples on pathophysiological defects:

Examples of specific pathophysiological defects leading to epilepsy

Level of brain function Neuronal network Neuron structure Neurotransmitter synthesis Neurotransmitter receptors: Inhibitory Neurotransmitter receptors: Excitatory Synapse development Ion channels channelopathies

Condition Cerebral dysgenesis, post-traumatic scar, mesial temporal sclerosis (in TLE) Down syndrome and possibly other syndromes with mental retardation and seizures Pyridoxine (vitamin B6) dependency Angelman syndrome, juvenile myoclonic epilepsy Non-ketotic hyperglycinemia

Pathophysiologic mechanism Altered neuronal circuits: Formation of aberrant excitatory connections ("sprouting") Abnormal structure of dendrites and dendritic spines: Altered current flow in neuron Decreased GABA synthesis: B6, a co-factor for GAD Abnormal GABA receptor subunit(s) Excess glycine leads to activation of NMDA receptors Many possible mechanisms, including the depolarizing action of GABA early in development Potassium channel mutations: Impaired repolarization

Neonatal seizures Benign familial neonatal convulsions

E.g. from above: In cerebral dysgenesis or post-traumatic scar there will be altered neuronal circuits and formation of abnormal connections or sprouting leading to epilepsy Someone with Down syndrome has abnormal neuronal structures which lead to abnormal dendrites and altered current flow in the neuron These are theories trying to explain why these situations lead to epilepsy All of these will ultimately lead to excessive excitation or decreased inhibition A patient with pyridoxine deficiency has decrease in neurotransmitters synthesis so he has a decrease in GABA synthesis (an inhibitor) which will lead to excessive seizures Pathophysiology of Epilepsy: Basically involve: Neurons transition from normal firing pattern to interictal bursts to an ictal stage (ictus means seizure). So first you have interictal burst with hyper synchronization and if there is enough neurons involved this will lead to seizure Mesial temporal lobe epilepsy is the most prevalent focal epilepsy.

Hippocampal pyramidal cells are the most studied cells in the CNS

The Hippocampal Model:

Back to anatomy (lec 7): the neocortex is composed of 6 layers and the allocortex is composed of 3 layers. Now the hippocampus (subiculum, hippocampus proper and the dentate gyrus) is located on the medial aspect of the temporal lobe The hippocampus and dentate gyrus represent the 3 cell layers allocortex (the hippocampus and the dentate gyrus are part of the allocotex), the subiculum is the transitional zone between the 3 cell layers (allocortex) and the 6 cell layers of the neocortex This is a simple model of epileptogenesis thats why it is well studied, and it is the most common form of focal epilepsy The most epileptogenic area of the brain is the hippocampus The major source of input to the hippocampus is the entorhinal cortex by ways of perforant path to the granule cell in the dentate gyrus So the entorhinal cortex sends input to the granule cell of gyrus The granule cell is a projection cell (principle cell) meaning it modulates the activity of distal neurons even outside the hippocampus. At the same time it also sends collaterals (mossy fibers) to the CA3 areas (inhibitory fibers), CA3 areas connect to the CA1 cells and these will send feedback inhibition to the granule cell
Entorrhina cortex: is located at the caudal end of the temporal lobe and is an important memory center in the brain

the dentate

So we have feed forward inhibition and feedback inhibition Dentate gyrus by way of mossy fibers (collateral) connects to CA3 CA3 connects to CA1 through Schaffer collateral pathway entorhinal cortex granule cell CA3 CA1

So when there is loss in cells from the CA1 area the result will be excessive sprouting of the granule cell

This excessive sprouting will lead to:

Excessive excitation and loss of excitatory cells that activate inhibitory cells (CA1 cells activate the inhibitory CA3 calls)which will lead to loss of inhibition These are some of the mechanisms that are believed to underlay temporal lobe epilepsy or hippocampal model of epileptogenesis In sections from epileptic areas, neurons from specific regions (CA1) are lost or damaged Why does this happen? Variety of brain insults can lead to the phenomena of mossy fiber sprouting: Trauma, hypoxia, infections, stroke, This leads to Synaptic reorganization (mossy fiber sprouting) which causes recurrent hyperexcitability axonal over sprouting loss of inhibitory inter-neurons loss of excitatory interneurons driving inhibitory neurons All of this is theory but still it is the most understood model of epileptogenesis Electroencephalography-EEG EEG is graphical depiction of cortical electrical activity recorded from the scalp For exp: in hyper-excitability, the graphical picture of this hyperexcitability is the EEG (visualized manifestation of this hyperexcitability) EEG gives high temporal resolution: meaning what you see in EEG is what is happening now in the brain EEG has poor spatial resolution because it picks up the excitability of millions of neurons at the same time to be able to record EEG The most important electrophysiological test for the evaluation of epilepsy

Physiological Basis of the EEG

In the picture there is a neuron, excitation of the neuron will cause release of neurotransmitters, formation of an action potential and this action potential will move down the neuron First, there will be influx of positive ions (in the postsynaptic membrane) leading to what is called a negative sink (that part of neuron will be surrounded by negative charges) The action potential will move down the dendrite. Eventually, these positive ions that have entered will have to leave at the other side of the neuron(distal part) so in the distal side there will be source of positivity Proximal (near the synapse) negative Distal positive This will create a dipole which is picked up by the EEG as a deflection You cant pick up a single excitatory post synaptic potential by EEG, because there is scalp, skin, subcutaneous tissue, bone, meninges, CSF then comes the cell so you need millions of cells Why are we able to pick up postsynaptic potential by EEG? 1. Pyramidal cells all have the same polarity and orientation (perpendicular to the surface and all of them will give one wave form) 2. Many cells are synchronously activated at the same time So EEG picks up millions of postsynaptic potentials in order to give one wave form EEG Applications Seizures/epilepsy: study them and see if a person has a tendency fof epilepsy or not Altered consciousness: slowing in the wave forms Sleep Focal and diffuse alteration in brain function

All of these can be studied by looking at the EEG of a patient EEG: Recording the electrical activity of the brain, mostly from the scalp Frequency of waveforms Delta frequency:0 to 4 Hz per second these are slow waves Theta 4 to 8 Hz during drowsiness or in children is normal Alpha 8 to 12 Hz during wakefulness Beta More than 12 Hz Very fast activity usually medication induced Particularly helpful in the analysis of seizures and epilepsy A) Fast activity B) Mixed activity C) Mixed activity D) Alpha activity (8 to 13 Hz) E) Theta activity (4 to under 8 Hz) F) Mixed delta and theta activity G) Predominant delta activity (<4 Hz) Not shown: Beta activity (>13 Hz)
Note: A and F are the only ones the doc mentioned

EEG: Interictal Spike (what we see in EEG in case of epilepsy) We see a spike and a wave The cellular correlate of EEG spike is the paroxysmal depolarization shift (PDS): meaning what we see in EEG is a reflection of the PDSs formed in the neurons A PDS is an event occurring in a single neuron (hyper-excitability of a single neuron) PDS is caused by initial depolarization initiated by AMPA receptors, then maintenance of the PDS is done by NMDA receptors Summation of millions of PDSs gives us a spike on EEG

So in the pic. You see depolarization is maintained and plateau and then there is hyperpolarization through GABA inhibition and chloride conductance. (lower diagram) Combination of many of these is what gives us in EEG a spike and this hyperpolarization followed by a slow wave So on EEG, we say we saw an epileptiform spike and wave discharge So as we said before, a neuron for a specific reason (infection, hypoxia, genetic, metabolic, trauma, congenital malformation) will be hyper-excitable and for that same reason the network around this neuron will be alterwd leading to abnormal synchronization (increase excitation, decrease inhibition).. This leads to millions of cells having PDS which is picked up on EEG by a spike and wave discharge
This is focal epileptic discharge EEG We have normal alpha and theta rhythm and an abnormal appearing spike (epileptiform) and wave discharge So you will know that underneath the right electrode (particularly in the vertex area) there are millions of PDSs It is focal becoz it comes out from one part of the brain Here there is a spike and wave discharge

Focal epilepsy is much more understood than generalized epilepsy In focal epilepsy as we said there is the hippocampal model In generalized epilepsy there are a lot of theories, but what is known is that it is basically a change and alteration in the rhythm between the thalamus and the cortex (problem in the thalamocortical circuit so the neurons become loft between excitation and inhibition)

Absence Seizures Is a primary generalized seizure Here the person may appear to be staring into space with or without jerking or twitching movements of the eye muscles.() Involve the GABAergic neurons of the nucleus reticularis thalami as pacemakersthe thalamocortical loop Activation of transient Ca channels (T channels) and GABA B mediated hyperpolarization3-4 Hz oscillations Ethosuximide suppresses the T-current of the transient Ca channels (so ethosuximide is used for treatment of absence seizures) Actually a lot of the information that we know about absence seizures came from the observation that ethosuximide can treat or end absence seizures Here you can see that the whole brain is involved in spike and wave discharges If we look at it every second we can tell that this is a 3-Hz spike and wave discharge; meaning every second there is 3 spike and wave discharges Called generalized 3-Hz spike and wave discharge leading to absence seizures (imp) Termination of seizures Mechanisms unclear, but may include voltage-, calcium-, or neurotransmitter-dependent potassium or chloride channels Chronic Models of Epileptogenesis We already talked about one model which is the hippocampal model another model is kindling model Kindling: repeated administration of electrical stimulus or convulsant drugs (this is experimentally) Experimentally: when you administer a convulsant drug repeatedly, with each administration the excitation potential increases.

Eventually, you will end up with a seizure also afterwards you will have spontaneous seizures without the need to apply the stimulus This is one of the theories behind chronic epileptogenesis E.g. A person with a brain injury after 5 years may develop seizures, this is because there is repetitive abnormal stimulation and with each time the response increases in size till it eventually becomes a seizure

The end finally

Done by: Reem al-Qudah S.A.R.H
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