temporals a by a epilepsy

7/31/2019 Temporals a by a Epilepsy

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Temporal lobe epilepsy


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Overview

1. What is it? What does it look like? 2. Methods of experimentation

3. Neurobiology of TLE

A. Neurotransmitters/Receptors Glutamate/GABA/Kainate/Neuropeptide Y

B. Metabotropic Receptors

C. Protein Transporters

D. Pathologies and Volumetric deficits

4. Medication and Surgery

5. Concluding remarks


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What is TLE?

Temporal lobe epilepsyis recurrent seizureactivity originating inthe temporal lobe.

Focal (partial)

Simple partial

Complex Partial

Generalized Tonic

Clonic


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Symptoms of TLE

Seizures-usually complex partial

Usually duration is from 1-2 minutes

Auras

Motionless staring

Anxiety

Emergent past memories

Spiritual/Religious experience 1.5% of population worldwide

20% intractable


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Methods

Kindling-A reduction in the threshold for activityresulting in a seizure which is caused by repeatedseizure activity.

Status Epilepticus- Status Epilepticus is when thebrain is in a state of continuing seizure. Clinically, a

person will not regain consciousness in betweenseizures. (Status Epilepticus and Kindling are both induced experimentally

using either electrodes or drugs such as Kainic acid and pilocarpine)

EEG

PET

MRI and CT


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MRI scans of TLE

http://img.medscape.com/fullsize/migrated/editorial/journalcme/2008/18803/sellner.fig1.jpg


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EEG of TLE


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Neurotransmitters, their Receptors

and Relevance


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Glutamate Receptors and Subunits

AMPA-(GluR1, 2, 3, and 4)

Kainate-(GluR5, 6 and 7, and KA1 and 2)

NMDA-(NR1, NR2A, 2B, 2C and 2D)

Variations of specific subunits exist withinsubclasses of the receptors. The subunit signatureof a receptor is what ultimately determines its

biochemical and physical properties such as channelstructure, ion permeability, and gating kinetics.


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Glutamate Subunits and TLE

Kainate receptors containing the GluR6 unitcontribute to postsynaptic seizure occurrence.

This takes place in pyramidal neurons in the CA3

section of the Hippocampus Receptors containing the GluR7 unit are thought to

inhibit the onset of seizures.

Less seizure activity is found in lab mice that have an

increased expression of the NR2 subunit.


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The NMDA Receptor

Over activation of the NMDA receptor can lead toseizure activity particularly in the amygdala.

NMDA receptor antagonists increase threshold forexperimental seizure induction. Less effective inexisting seizures. (McNamara et al.,1988)

MK-801 is a good example of an antagonist

MK-801 structure


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NMDA Receptor


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MK-801

Binding Site

MK-801 and its Binding Site


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NMDA (cont)

MK-801 has been shown to inhibit the potentiation of circuitswhich could lead to long term seizure activity.

Potentiation of connections can be induced from kindling. This

is in part caused by the activation of the NMDA receptor.

In the supraoptic nucleus and adjacent limbic areas, there is anincrease in expression of the NR2B subunit and a decrease in

the NR2D subunit. For glutamate receptors, subunit

expression is more susceptible than actual modulation in

function to influence from seizure activity.


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AMPA Receptor

Seems to have stronginvolvement in seizure expressionin the Amygdala.

AMPA receptor antagonists canreduce this tendency.

Works only in the presence of the

drug. After withdrawal, goes backto normal.


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AMPA and NMDA in conjunction

It is commonly held that AMPA receptorsare critical for the induction of seizure

discharges, while NMDA receptors arecritical for inducing the trans-synapticalterations that underlie permanent kindledepileptogenesis. (Morimoto, 2004 17)


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Reorganization

The activation of NMDA receptors from a seizuremay drive potentiation that will result instrengthened seizure circuitry.

This may contribute to recurring epileptic activityafter the initial seizure.

Although potentiation is often present in seizurecircuits, epilepsy can also persist in the absence of

such potentiation.


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AMPA and NMDA Receptors


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Gamma-Amino Butyric Acid

(GABA) Receptors Subtypes

GABA-A: fast inhibition by bringing Chlorideions into the cell.

GABA-B: Presynaptic autoreceptors. Slowaction via K+ conduction

GABA-A is believed to be more involved.

Agonists- alleviate seizures

Antagonists-exacerbate seizures


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GABA Receptors (cont)

Beta subunits determine channel properties and GABAaffinity.

Modulations Upregulation of GABA-A receptors in Dentate Gyrus in

response to seizure activity. An increase in binding sites is evident in the

hippocampus and amygdala.

Decrease in actual binding occurring

Receptor density increase of 34-40%-(Nusser et al.

1998) This was found through tracking the Beta 2 and3 subunits in dentate granule cells.

Enlarged synaptic terminals


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GABA-A Receptor

GABA-B Receptor

Integral Membrane

Protein (Hydrophobic ends

exposed)

Peripheral

Membrane

Protein

(Hydrophilic ends

exposed)


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Neuropeptide Y

NPY is a 36 amino acid peptide found in GABA containinginterneurons.

Brain Derived Neurotropic Factor (BDNF) regulates NPY expression

Activation of Y2 receptors by NPY has inhibitory effect ontransmission of glutamate.

mRNA transcription for NPY is increased in hippocampus cells as aresponse to experimental kindling.

Seizure activity modulates Y receptors making them more sensitive tobinding.

In rats, an increase in expression of the gene for the synthesis of NPYcaused a decrease of 65% in the ability to lower threshold

experimentally. Is the brain compensating?


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Metabotropic Receptors and

Protein Transporters


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mGluR

mGluR is the class of Glutamate metabotropicreceptors.

Groups II and III of mGluR are presynapticautoreceptors and are believed to be involved in

irregular release of glutamate. Little is known about the effects of kindling; however,

agonist drugs of these receptors have an inhibitingeffect on seizure activity.

A decrease in sensitivity of these agonists my indicatea loss of mGluR-mediated hyperpolarization.-(Holmes, et al. 1996)


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Protein Transporters

A glutamate transporter protein uses reuptakemechanisms in order to modify the amount of excessglutamate in the synapse.

EAAT=Excitatory Amino Acid Transporter

Subtypes (EATT1-5) unique in composition and action

Experimental inhibition causes concentrations to be toodense resulting in neurodegeneration from excitotoxicity.

Implications: Malfunction of these mechanisms result innot only cell death but also chronic epilepsy.

GABA has its own protein transporter EAAC1 whose

inhibition would cause similar hyperactivity. GABAsynthesis is decreased.


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Pathologies and Volume Deficits


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Pathologies: Ammons Horn

Sclerosis (AHS) Present in 2/3 of TLE patients

Characterized by heavy cell loss in theCA1, CA3, and CA4 sections of thehippocampus.

The CA2 area and granule cells of thedentate gyrus is not as affected asother areas.

Astroglyosis- astrocyte increase due tocell loss


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Dentate Gyrus


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Dentate Gyrus

Experimental kindling may actually inhibit granulecell firing in the DG in the short term.

Despite excitatory potentials, the threshold forfiring is actually increased temporarily.

May be why granule cells are on average lessdamaged than pyramidal cells in thehippocampus.

Hippocampus-lowest seizure threshold


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Pyramidal

Cells

Axonal

Sprouting


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Volume Abnormalities

There are deficits in corticalvolume within the temporallobe for a person sufferingfrom TLE.

There may be volumedeficits in the lobe contralateral to the side thatexperiences the seizures.

Cortical Lobe volumedeficits correlate with theamount of cell death in

each area of thehippocampus.

Atrophied

Hippocampus


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Medication and

Pharmacoresistance

Examples of Antiepileptic drugs: Phenobarbital

Dilantin

Tegretol Neurotin

Many antiepileptic medications act as GABA agonists

Pharmacoresistance occurs in advanced stages ofTemporal Lobe epilepsy. Medication ceases to be

effective. Surgery is often the next step.


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Temporal Lobe Surgery

Only considered when medications have failed to alleviatesymptoms or have lost their potency.

Seizure Locus-removal is a very common procedure.

Temporal lobe resection

Successful in reducing or eliminating seizures about 70-90%of the time.

Multiple subpial transection-when focus is not operable oris out of reach.

Study in 2000-seizure disappearance-surgery 64%,

medication alone 8% Surgery is not always successful-Intractable


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Resection


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Fin

temporals a by a epilepsy

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