Mechanisms of epileptogenesis, epileptogenicity, anatomical substrate, role of GABA, hippocampal circuitry, applications in clinical practice.

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

2. 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.

3. Epileptogenesis
PRIMARY
SECONDARY

4. Epileptogenesis
GENETIC
FACTORS
ACQUIRED
PROCESSE
S

6. GENETIC
FACTORS
• 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.
ACQUIRED
PROCESSES

7. 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.

8. 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

9. GENETIC
FACTORS
• BNFC
• GEFS +
• ADNFLE

11. GENETIC
FACTORS
• BNFC
• GEFS +
• ADNFLE
ACQUIRED
PROCESSES
• Trauma
• Vascular
• TLE

17. Minutes to hours

18. GABAA Receptor

19. Excitotoxicity-Role of Glu and GluR
Excitotoxicity is thought to be a major mechanism contributing to neuronal
degeneration in many acute CNS diseases, including ischemia, trauma and epilepsy
Postsynaptic neuron
Presynaptic neuron
Glu Rc
Glutamate
vesicles
Glutamate
Opening of ion channelCa++ influx and release of
Ca++ from ER
Activation of lipases,
proteases, endonucleases
Direct cell damage Formation of ROS
Cell death

23. Days

29. Weeks to Months to Years

44. Hippocampal Neurogenesis
(Li et al., 2000)
2000

65. At the electrical Level
• PDS
• LTP
• Fast Ripples
• Kindling!!!!

66. At the electrical Level
• PDS
• LTP
• Fast Ripples
• Kindling!!!!

67. 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?

69. Long-term potentiation (LTP)
• Early and late
• Three phases each:
– Induction
– Maintenance
– Expression

70. 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

71. 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)

72. Maintenance/expression EarlyLTP
• CaMKII and protein kinase C lose their Ca
dependence
• Continued phosphorylation and upregulation
of AMPA receptors

73. Late-LTP: Induction
• Persistent
activation of
protein kinases in
early-LTP cause
activation of
extracellular signal
regulated kinase
(ERK)

74. Late-LTP: Maintenance
• ERK
phosphorylates
nuclear and
cytoplasmic
proteins that lead
to changes in gene
expression and
protein synthesis

75. 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

76. 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

77. Epileptogenesis
PRIMARY
SECONDARY

78. • Gowers in 1912 - ‘seizures beget seizures’
• Secondary epileptogenesis
• Mirror focus
• Kindling

79. • 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

80. • 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

81. 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

82. Epilepsy Biomarkers/
Surrogate Markers
• Markers of epileptogenesis
• Markers of epileptogenicity

83. 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.

84. 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

85. 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…

86. 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

87. Potential Biomarkers
•
•
•
•
•
•
Hippocampal changes on MRI
Interictal Spikes, fMRI
Fast Ripples
Excitability
AMT imaging
Gene expression profiles

88. Potential Biomarkers
•
•
•
•
•
•
Hippocampal changes on MRI
Interictal Spikes, fMRI
Fast Ripples
Excitability
AMT imaging
Gene expression profiles

89. Hippocampal T2 signal changes
after prolonged febrile seizures

91. 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)

92. High-resolution MRI of the MTL
(Zeineh, Engel, Thompson, Bookheimer Neuroimage, 2001)
(Ekstrom, Bazih, Suthana, Al-Hakim, Ogura, Zeineh, Burggren, Bookheimer. Neuroimag, 2009)

109. Can we modify epileptogenesis ?
• Topiramate
• Vigabatrin
• Zonisamide
• Celecoxib
• Verapamil !!!

110. Summary …
Gain/Loss of
Function
Genetic Factors
Acquired Factors
Biochemical
Factors
Altered gene
expression
Microstructural
reorganization
Secondary
epileptogenesis

111. THERAPEUTICS
IN VIVO
ASSESSMENT
EPILEPTOGENIC
PHENOTYPE
REVERSAL !!!