Physiology 5 - Epilepsy

8/3/2019 Physiology 5 - Epilepsy

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Pathophysiology of Epilepsy

Samah

Reem Al-Qdah

20 / 4 / 2009

20 / 4 / 2009


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Dr. Samah done by: Reem Al-Qudah

Phsiology 5 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 epilepsySeizure: is a clinical manifestation where you have a neuron which fires

excessively, so there is hyper-excitability of a neuron coupled with hyper

synchronizationHyper synchronization means that a hyper-excitable neuron will lead toexcessive excitability of a large group of surrounding neurons and youend with millions of neurons in the brain firing excessively leading to theclinical 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


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If it occurs in the rolandic area you will have motorseizureWikipedia: 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 behaviorwith or without loss of consciousness accompanied by an abnormal

electrical discharge

Epilepsy is a disorder of the CNS whose symptoms are seizuresNow you have:

Reactive seizures:Occurring in normal nonepileptic tissue

Expamles:

someone with hypoglycemia has a normal brain but temporarilybecoz 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 brainOther 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)


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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 PartialBetween these two there is alteration in the level of consciousness

Generalized Seizures: are seizure that emanates (comes out) fromboth 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 calledsecondary

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


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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

This is also secondary generalization from

another focus of seizure

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

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 hyper-

excitability

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


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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 areeither voltage gated or ligand gated by neurotransmitters) or

Intra/extracellular ionic alterations in favor of excitationThis 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 channelsLigand gated channels

Voltage Gated Channels:

Of 2 types depending on the conduction:

Depolarizing conductanceIt is excitatoryMediated by inward sodium and Ca currents

Hyperpolarizing conductanceIt 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


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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 responsiblefor 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

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, Aspartate2. Inhibition: too little inhibition also favors the formation of seizures

Caused by:

a. Ionic: inward Cl, outward K from the slidesb. Neurotransmitter: GABA

Factors leading to hyper-excitability:1.Intrinsic Factors (intrinsic to the neurons):

Ion channels type, numberand distribution (e.g. if there is scarringthis will lead to redistribution of channels)

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


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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 ischemiaThese convert non-bursting neurons to potentially epileptogenic populations

Epileptogenesis

The process by which normal healthy tissue is transformed into arelatively permanent epileptic stateFor epileptogenesis to occur there must be 2 things:

1. Hyperexcitability: The tendency of a neuron to dischargerepetitively to a stimulus that normally causes a single action

potential.

Causes: trauma, ischemia, genetic predisposition, hypoxia,

congenital brain malformation, infection these will lead toabnormal discharge which is coupled with abnormal

synchronization

2. Abnormal synchronization: The property of a population ofneurons to discharge together independently; meaning that the

group of neurons around the abnormal neuron will fire

synchronouslyIf a hyper-excitable neuron is working alone nothing is going to happen


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Conclusion: onesingle neurons hyper-excitability along with hypersynchronization with the surrounding neurons leads to epileptogenesis

Why does Synchronization occur?

Recurrent excitatory synapses; recurrent excitation, positive feedbackloops 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 concentrationsAll 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

Prevents K+-induced depolarizationRestores ionic balanceNa+-K+ pump

Synchronization of neuronal firingUltra-fast excitatory transmissionElectricalsynapses

Limits excitationProlonged IPSPGABAB

receptor

Limits excitationIPSPGABAA

receptor

Maintains PDS; Ca2+ activatespathophysiological intracellular processes

Prolonged, slow EPSPNMDA receptor

Initiates PDSFast EPSPNon-NMDAreceptor (ie,AMPA)

Excess transmitter release; activatespathophysiological intracellular processes

Transmitter release; carries depolarizingcharge from dendrites to soma

Voltage-gatedCa2+ channel

Limits repetitive firingAHP following action potential; setsrefractory period

Ca2+-dependentK+ channel

Abnormal action potential repolarizationAction potential down-strokeVoltage-gated K+

channel

Repetitive action potential firingSub-threshold EPSP; action potential up-stroke

Voltage-gatedNa+ channel

Possible role in epilepsyRole in normal neuronal functionChannel or

receptor

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


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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

Potassium channel mutations: Impairedrepolarization

Benign familial neonatal convulsionsIon channelschannelopathies

Many possible mechanisms, including thedepolarizing action of GABA early indevelopment

Neonatal seizuresSynapsedevelopment

Excess glycine leads to activation of NMDAreceptors

Non-ketotic hyperglycinemiaNeurotransmitterreceptors:Excitatory

Abnormal GABA receptor subunit(s)

Angelman syndrome, juvenile myoclonic

epilepsy

Neurotransmitter

receptors:Inhibitory

Decreased GABA synthesis: B6, a co-factor for

GADPyridoxine (vitamin B

6) dependency

Neurotransmittersynthesis

Abnormal structure of dendrites and dendriticspines: Altered current flow in neuron

Down syndrome and possibly othersyndromes with mental retardation andseizures

Neuron structure

Altered neuronal circuits: Formation ofaberrant excitatory connections ("sprouting")

Cerebral dysgenesis, post-traumatic scar,mesial temporal sclerosis (in TLE)

Neuronal network

Pathophysiologic mechanismConditionLevel of brainfunction

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

epilepsySomeone 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 inhibitionA 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.


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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 la ers of the neocortex

Entorrhina cortex: islocated at the caudal

end of the temporal

lobe and is an

important memory

center in the brain

Hippocampal pyramidal cells are the most studied cells in the CNS

The Hippocampal Model:

This is a simple model of epileptogenesis thats why it is

well studied, and it is the most common form of focalepilepsy

The most epileptogenic area of the brain is the

hippocampus

The major source of input to the hippocampus is theentorhinal 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 the dentate

gyrus

The granule cell is a projectioncell (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

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


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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 ofinhibitionThese are some of the mechanisms that are believed to underlay temporal lobe epilepsy orhippocampal 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 neuronsAll of this is theory but still it is the most understood model of

epileptogenesis

Electroencephalography-EEG

EEG is graphical depiction of cortical electrical activity recordedfrom the scalpFor exp: in hyper-excitability, the graphical picture of this hyper-

excitability is the EEG (visualized manifestation of this hyper-

excitability)

EEG gives high temporal resolution: meaning what you see in EEG iswhat is happening now in the brain

EEG has poor spatial resolution because it picks up the excitability ofmillions of neurons at the same time to be able to record EEG

The most important electrophysiological test for the evaluation ofepilepsy


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Physiological Basis of the EEGIn the picture there is a neuron, excitation of

the neuron will cause release of

neurotransmitters, formation of an actionpotential 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 distalside there will be source of positivity

Proximal (near the synapse) negative

Distal positiveThis 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 potentialby EEG?

1.Pyramidal cells all have the same polarity andorientation (perpendicular to the surface and all

of them will give one wave form)

2.Many cells are synchronously activated at thesame 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 fofepilepsy or not

Altered consciousness: slowing in the wave forms Sleep Focal and diffuse alteration in brain function


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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 scalpFrequency ofwaveforms

Deltafrequency:0 to 4 Hzper second these are slow waves

Theta4 to 8 Hz during drowsiness or in children is normal Alpha8 to 12 Hz during wakefulness BetaMore than 12 Hz Very fast activity usually

medication induced

Particularly helpful in the analysis of seizures and epilepsyA) 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 activityG) Predominant delta 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 asingle neuron)

PDS is caused by initial depolarization initiated by AMPAreceptors, then maintenance of the PDS is done by NMDA

receptors

Summation of millions of PDSs gives us a spike on EEG


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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 samereason 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

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)

This is focal epileptic discharge EEG

We have normal alpha and theta rhythm and anabnormal appearing spike (epileptiform) and

wave discharge

So you will know that underneath the rightelectrode (particularly in the vertex area) there

are millions of PDSs

It is focal becoz it comes out from one part ofthe brain

Here there is a spike and wave

discharge


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Absence SeizuresIs 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 aspacemakersthe thalamocortical loop

Activation of transient Ca channels (T channels) and GABA Bmediated 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 wholebrain 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 spikeand 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 EpileptogenesisWe already talked about one model which is the hippocampal model

another model is kindling model

Kindling: repeated administration of electrical stimulus or convulsantdrugs (this is experimentally)

Experimentally: when you administer a convulsant drug repeatedly,

with each administration the excitation potential increases.
http://en.wikipedia.org/wiki/Muscle_contractionhttp://en.wikipedia.org/wiki/Eye_muscleshttp://en.wikipedia.org/wiki/Eye_muscleshttp://en.wikipedia.org/wiki/Muscle_contraction


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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 finallyDone by: Reem al-QudahS.A.R.HTa7yeih lal da2ra o a3da2ha wal8a2meen 3alaiha2hda2 mn jamee3 a3da2 el da2ra o el8a2meen 3alaiha la a7la banat 6eb 2006:Narmeen : a39abk (u r really a truefriend), bal8ees : shokran 3al taw9eeleh,narjs : bdoonk ma kont fhmt el brain bllab, lo6fyeih: sahar bt7kelk mo7adaratk btjanen, 9ofia: mata nawyeih tdawme, 5olod: shway shway3al kotob, Miramar: kollek zo2Asfeen 2za nseena 7adaAh 9a7 tamam: bra2a bt7keelk 2nha ma aklat cake (3ad kan zakeeeeeeeee)

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Physiology 5 - Epilepsy