Epileptogenesis - Mechanisms and Clinical Implications

Förster et al. Nature Reviews Neuroscience advance online publication;published online 16 March 2006 | doi:10.1038/nrn1882

Definition of Terms

• Epileptogenesis refers to the transformation of the brain to a long-lasting state in which recurrent, spontaneous seizures occur

• Seizure expression is the process which is concerned with processes that trigger and generate seizures

• Epileptogenicity is the property of a tissue that is capable of generating spontaneous behavioral and/or electrographic seizures

– Clark, S. and Wilson, W. A., Adv. Neurol., 1999, 79, 607–630.

Epileptogenesis

PRIMARY SECONDARY

Epileptogenesis

GENETIC FACTORS

ACQUIRED PROCESSES

• Over 40 genes associated with human epilepsy have been identified

• at least 133 single gene mutations in mice have been linked to an epileptic phenotype

• it had been assumed that generalized rather than partial epilepsies, and idiopathic rather than symptomatic epilepsies had a genetic basis.

GENETIC FACTORS

ACQUIRED PROCESSES

• Acute or Chronic• increased AMPA and

NMDA synaptic transmission, acute decrease in GABAergic inhibitory synaptic transmission, and an increase in net excitatory effects, leading to increases in ectopic action potentials or depolarizing potentials.

GENETIC FACTORS

ACQUIRED PROCESSES

• Nonsynaptic mechanisms such as changes in coupling through gap junctions29, iron-mediated changes in Ca++ oscillations or glutamate release and generation of oxygen- free radicals

• acute neuronal loss alone is not necessary for the generation of acute epileptiform bursts in vitro

GENETIC FACTORS

ACQUIRED PROCESSES

• BNFC

• GEFS +

• ADNFLE

GENETIC FACTORS

• BNFC

• GEFS +

• ADNFLE

• Trauma

• Vascular

• TLE

GENETIC FACTORS

ACQUIRED PROCESSES

Minutes to hours

GABAA Receptor

Excitotoxicity-Role of Glu and GluRExcitotoxicity-Role of Glu and GluRExcitotoxicity is thought to be a major mechanism contributing to neuronal Excitotoxicity is thought to be a major mechanism contributing to neuronal degeneration in many acute CNS diseases, including ischemia, trauma and epilepsydegeneration in many acute CNS diseases, including ischemia, trauma and epilepsy

Presynaptic neuronPresynaptic neuron Opening of ion channel-Opening of ion channel-CaCa++++ influx and release of influx and release of CaCa++++ from ER

GlutamateGlutamate

Glu RcGlu Rc

Postsynaptic neuronPostsynaptic neuron

Activation of lipases, Activation of lipases, proteases, endonucleasesproteases, endonucleases

Glutamate Glutamate vesiclesvesicles

Direct cell damageDirect cell damage

Cell deathCell death

Formation of ROSFormation of ROS

Days

Weeks to Months to Years

Hippocampal Neurogenesis

(Li et al., 2000(Li et al., 2000)

At the electrical Level

• PDS

• LTP

• Fast Ripples

• Kindling!!!!

At the electrical Level

• PDS

• LTP

• Fast Ripples

• Kindling!!!!

Paroxysmal Depolarization Shifts

• Protracted bursts of action potentials typical of neurons in an epileptic neuronal aggregate

• Produces local synchonization

• How might these shifts be produced?

Long-term potentiation (LTP)

• Early and late

• Three phases each:– Induction

– Maintenance

– Expression

Early-LTP induction

• Excitatory stimulus of the cell causes excitatory post-synaptic potential (ESPS) (e.g. glutamate binding to AMPA receptor)

• Stimulus may be either a large single stimulus or many smaller rapid stimuli that summate (post-tetanic potentiation)

• Sufficient stimulus leads to unblocking of NMDA receptor and Ca influx into the cell

Early-LTP induction

• Ca influx leads to short-term activation of protein kinases

• Phosphorylation increases activity of AMPA receptor and mediates its insertion into the cell membrane

Calcium/calmodulin-dependent protein kinase II (CaMKII)

Maintenance/expression Early-LTP

• CaMKII and protein kinase C lose their Ca dependence

• Continued phosphorylation and upregulation of AMPA receptors

Late-LTP: Induction

• Persistent activation of protein kinases in early-LTP cause activation of extracellular signal regulated kinase (ERK)

Late-LTP: Maintenance

• ERK phosphorylates nuclear and cytoplasmic proteins that lead to changes in gene expression and protein synthesis

Late-LTP: Expression

• Protein products are thought to lead to increase in:– Number and surface area of dendritic spines

– Postsynaptic sensitivity to neurotransmitter perhaps by enhanced synthesis of AMPA receptors

Propagation in temporal lobe epilepsy: kindling

• Mesial temporal circuit can sustain epileptic activity

• Repeated electrical stimulation of the amygdala gradually leads to spontaneous seizures due to reorganization of synaptic connections in the dentate gyrus

Epileptogenesis

PRIMARY SECONDARY

• Gowers in 1912 - ‘seizures beget seizures’

• Secondary epileptogenesis

• Mirror focus

• Kindling

• A primary epileptogenic area has a macroscopic abnormality and can generate seizures independent of the presence of surrounding or remote epileptogenic areas

• A secondary epileptogenic area becomes epileptogenic because of the influence of epileptogenic activity in a primary epileptogenic area, which is separated from it by at least one synapse

• Morrell, F., Epilepsia, 1960, 1, 538–560

• A mirror focus is a type of secondary epileptogenesis in which the secondary epileptogenic zone is located in a contralateral homotopic area with regard to the primary epileptogenic zone

• Morrell, F., in Basic Mechanisms of Epilepsies (eds Jasper, H. H., Ward, Jr A. A. and Pope, A.), Little Brown, Boston, 1969, pp. 357–370

• Secondary epileptogenesis likely to be due to kindling• Goddard, G. V., Nature, 1967, 214, 1020–1021

Phases of Secondary Epileptogenesis

• dependent phase

• intermediate phase

• independent phase– Depend on the interrelationship of primary and

secondary zones

– Morrell, F. and Tsuru, N., Biol. Bull., 1974, 147, 492, Morrell, F. and Tsuru, N., electroencephalogr. Clin. Neurophysiol., 1976, 60, 1–11

Epilepsy Biomarkers/ Surrogate Markers

• Markers of epileptogenesis

• Markers of epileptogenicity

Definition of Terms

• Epileptogenesis refers to the transformation of the brain to a long-lasting state in which recurrent, spontaneous seizures occur

• Seizure expression is the process which is concerned with processes that trigger and generate seizures

• Epileptogenicity is the property of a tissue that is capable of generating spontaneous behavioral and/or electrographic seizures

– Clark, S. and Wilson, W. A., Adv. Neurol., 1999, 79, 607–630.

Epilepsy Biomarkers/ Surrogate Markers

• Markers of epileptogenesis• Development of an epileptic condition

• Monitoring of the condition once epilepsy is established

• Markers of epileptogenicity• Localization of the epileptogenic lesion

• Measurement of severity

Use of biomarkers

• Predict who are likely to develop chronic seizures

• Predict pharmacoresistance

• Delineate brain areas for resection

• Determine the efficacy of therapy

• Develop anti epileptogenic drugs…

Target Mechanisms

• Cell Loss ( eg. Hippocampal atrophy)• Axonal sprouting• Synaptic reorganization• Altered neuronal function• Neurogenesis• Altered glial function and gliosis• Inflammation• Angiogenesis• Altered excitability and synchrony

Potential Biomarkers

• Hippocampal changes on MRI

• Interictal Spikes, fMRI

• Fast Ripples

• Excitability

• AMT imaging

• Gene expression profiles

Potential Biomarkers

• Hippocampal changes on MRI

• Interictal Spikes, fMRI

• Fast Ripples

• Excitability

• AMT imaging

• Gene expression profiles

Hippocampal T2 signal changes after prolonged febrile seizures

High-Resolution Hippocampal Imaging

HHR Structural (voxel size = .4 x .4 x 3mm)HHR Functional EPI (voxel size = 1.6 x 1.6 x 3 mm)

High-resolution MRI of the MTL

(Zeineh, Engel, Thompson, Bookheimer Neuroimage, 2001)

(Ekstrom, Bazih, Suthana, (Ekstrom, Bazih, Suthana, Al-Hakim, Ogura, Zeineh, Burggren, Bookheimer. Neuroimag, 2009)

Can we modify epileptogenesis ?

• Topiramate

• Vigabatrin

• Zonisamide

• Celecoxib

• Verapamil !!!

Summary …

Genetic Factors

Acquired Factors

Biochemical Factors

Microstructural reorganizationAltered gene

expression

Gain/Loss of Function

Secondary epileptogenesis

EPILEPTOGENIC PHENOTYPE

IN VIVO ASSESSMENT

THERAPEUTICS

REVERSAL !!!