Epileptogenesis - Mechanisms and Clinical Implications
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The document discusses the process of epileptogenesis, including definitions of key terms and factors that contribute to the formation of epilepsy, such as genetic and acquired processes. It outlines mechanisms like excitotoxicity and synaptic reorganization, as well as potential biomarkers for predicting and monitoring epilepsy. Furthermore, it explores therapeutic interventions aimed at modifying epileptogenesis and the complex interplay between primary and secondary epileptogenic areas.
Epileptogenesis - Mechanisms and Clinical Implications
- 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.
- 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
- 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
Editor's Notes
- #20: is the essential factor in excitotoxicity (overactivation of enzymes and further cell damage and death) and further neurodegeneration