1	Epilepsy: Seizure mechanisms Marc A. Dichter, M.D., Ph.D.
2	Epilepsy Common - 1-2% of population Chronic Effects all ages Expensive Partially treatable
3	Definitions Seizure = alteration in behavior associated with abnormal electrical activity of the brain Epilepsy = condition in which an individual has recurrent, spontaneous, unprovoked seizures
4	Why do people develop seizures? Many disturbances of brain physiology can produce seizures Trauma Ischemia Infection Electrolyte imbalances Chemical imbalances Toxins Drugs or drug withdrawal Many focal lesions may induce epilepsy Tumors Dysplasias Gliotic scars
5	Seizures are a natural consequence of intrinsic brain anatomy and physiology Any vertebrate brain can be induced to have a seizure with relatively little provocation People can have seizures for minimal reasons - e.g. fainting, sleep deprivation This is not epilepsy!
6	Three major questions: How do seizures develop and then propagate so readily through the brain? --“ICTOGENESIS” Why don’t we have seizures all the time? How is brain structure/function altered after injury to produce hyperexcitability? -- “EPILEPTOGENESIS”
7	The epilepsies are a family of conditions and seizures can occur in many different varieties Seizures need to be classified for diagnostic, prognostic and therapeutic reasons Many different classification schemes based on phenomena, EEG, anatomical localization, etc. Currrently accepted classification is based on seizure description and in some cases, EEG
8	Nomenclature The seizure is the “ictus” Time between seizures (when things seem to be “normal”) is the “interictal” period We can then talk about “ictal” events and “interictal” events
9	Seizure types Partial or focal seizures (assumes one or more focal areas of the cortex in which seizures originate) Simple Complex With secondary generalization
10	Seizure types Primary generalized seizures (assumes seizures start diffusely or in deep brain structures) Absence (“Petit mal”) Tonic clonic (“Grand mal”) Tonic Myoclonic Atonic
11	Status epilepticus Tonic clonic status Absence status Complex partial status Epilepsia partialis continua
12	EEG Records integrated synaptic currents from top 0.5 mm of cortex Shows regular patterns during different wake and sleep stages May be abnormal in individuals with epilepsy - abnormalities signify areas of hyperexcitability and hypersynchronous activation of cortex EEG patterns change with age; epileptiform waves may disappear
13	The Electroencephalogram (EEG) Recorded from scalp Based on synaptic currents in underlying 0.5 mm of cortex Coherent signals occur because of the columnar organization of the cortex
14	EEG patterns in epilepsy Focal spike or sharp wave discharges Focal slowing Spike and wave discharges - may be diffuse and synchronous at ~ 3 Hz Seizure discharges
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16	Causes of epilepsy Infection Trauma Status Genetic Idiopathic
17	Genetic epilepsies Seen in mice and rats, as well as other species Common in children (“idiopathic epilepsy”) Most forms in human are not single gene inheritance Many single gene mutations that cause epilepsy have now been identified and characterized Often polygenic
18	Many single gene mutations in both mice and humans produce epilepsy syndromes Many forms of absence epilepsy mostly abnormal Ca channels Na channels GABA_A receptors Some partial epilepsies Same phenotype can be produced by multiple gene abnormalities One gene may produce several phenotypes Some syndromes are age-related Other genes may affect expression of the epilepsy gene
19	Evaluation of individuals with seizures Look for acute illness (e.g. infection) Look for chemical imbalance, toxin exposure Look for anatomic lesion Family history
20	Critical issues in epilepsy research What is the origin of the hyperexcitability? How do seizures develop? How do seizures spread through the brain? How can the seizures be controlled? How can epilepsy be prevented?
21	Mechanisms underlying seizures Focal seizures Generalized seizures
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23	The Depolarizing Shift and Hyperpolarization
24	Role of GABA in Epilepsy
25	GABA-mediated inhibition GABA (gamma-aminobutyric acid) is the main inhibitory neurotransmitter in forebrain GABA acts on GABA_A receptors to open Cl^- channels and hyperpolarize the cell Blocking GABA produces seizures Enhancing GABA’s effects blocks seizures GABA_B receptors exist on axon terminals (presynaptic inhibition) and on postsynaptic cells
26	GABA Synapse
27	Spread of seizure activity to normal areas of brain Utilize normal synaptic pathways Utilize normal synaptic mechanisms Frequency-dependent events likely to be important Local spread may involve non-synaptic mechanisms
28	How do seizures develop and spread
29	Epileptogenic zones Within the damaged and regenerating regions, small islands of principle neurons develop in which recurrent excitatory feedback overwhelms recurrent inhibitory feedback, and in which gap junctions between axons may be enhanced Within these small networks, groups of neurons fire repetitive highly synchronized bursts of action potentials These can be recorded with field (EEG) electrodes as fast ripples Under baseline conditions, these events remain confined to small regions and remain relatively infrequent
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31	Localization of FR
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33	Epileptogenic zones FR and intracellular correlates resemble activity seen in acute chemically induced epileptic regions – e.g synchronous bursts of neurons
34	Epileptogenic zones FR are generated by synchronous bursts of neurons
35	Ictogenesis Regions of synchronized bursting increase in size and intensity as lateral inhibition breaks down
36	Ictogenesis EEG shows increased energy, more frequent and larger very fast ripples, and other features, well before seizures begin (“the preictal cascade”).
37	Ictogenesis This process becomes regenerative Multiple excitatory synaptic events (utilizing AMPA, NMDA, and mGlu receptors) Endogenous voltage-dependent currents (e.g. Ca) Decreased feedback inhibition Enhanced coupling Increased neuronal excitability and synchrony A seizure finally develops in a localized area and then spreads to nearby and distant regions
38	Ictogenesis As overall excitability increases, the synchronized bursts increase in frequency With each synchronized burst, extracellular K increases, and as the bursts increase in frequency, the K_o remains partially elevated Increased K_o enhances axonal coupling and increases neuronal excitability Increased K_o decreases “inhibitory” effects of opening K channels
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40	Seizure development and spread Afterdischarges lengthen and become more complex Inhibition around the focus diminishes ADs spread to nearby and distant areas of cortex Areas of cortex with fast ripples may enlarge and coalesce
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45	Primary Generalized Epilepsy
46	Primary generalized epilepsy
47	Role of bursting neurons in seizures
48	Primary generalized seizures
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50	Activation of T currents by hyperpolarization
51	Post-inhibitory rebound spikes in thalamus
52	Genetic forms of epilepsy Mouse models Spontaneous epilepsy Transgenic mice with specific gene knockouts Human epilepsy syndromes Single gene mutations Susceptibility genes
53	Genetics of human epilepsies Primary generalized syndromes Benign familial neonatal convulsions – K channels (KCNQ2, KCNQ3) Progressive myoclonic epilepsy – Unverricht-Lundborg – Cystatin B Absence seizures – GABA(A) receptor subunits Partial epilepsy syndromes Autosomal dominant nocturnal frontal lobe epilepsy – Subunit of nicotinic acetylcholine receptor (CHRNA4 - alpha4 subunit) Febrile seizures plus (FEBS+) - Subunits of Na channel Several others recently identified
54	Genetics of human epilepsies Many syndromes known to be inherited Childhood absence Juvenile myoclonic epilepsy Benign rolandic epilepsy with centrotemporal spikes Some syndromes may be polygenic Susceptibility and modifying genes may play large roles
55	Epilepsy treatment Pharmacologic treatment Block voltage dependent Na currents Enhance GABA mediated inhibition Block T currents Other mechanisms (?) Surgical treatment Temporal lobectomy Lesionectomies Corpus callosotomy
56	Treatment must be matched to seizure type Drugs for focal seizures may not work against absence seizures Drugs for absence seizures may not work against focal seizures Some drugs may make some seizure types worse
57	Mechanisms of actions of antiepileptic drugs Block Na currents: voltage- and use-dependent Enhance GABA-mediated IPSPs Multiple specific mechanisms Receptor specific Receptor independent Block T type Ca currents Block kainate and enhance GABA Bind to specific proteins – downstream mechanisms not yet known Gabapentin – alpha 2 delta subunit of Ca channels Levetiracetam – SV2A (synaptic vesicular protein)
58	Use dependent and voltage-dependent block of Na channels
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60	Enhance GABA inhibition by other means First group of “designer” drugs for epilepsy Drugs block GABA uptake (Tiagabine) or block GABA metabolism (Vigabatrin - not available in US) Not receptor-specific - Increasing GABA at synapses allows activation of all GABA receptors Results are not always predictable Different seizure types may be affected in opposite ways
61	GABA Synapse
62	Block T type Ca currents
63	How are new antiepileptic drugs developed? Screen against seizure (not epilepsy) models in mice and rats Target-specific molecular mechanisms NMDA receptor antagonists AMPA receptor antagonists GABA agonists Adenosine agonists K channel activators Binding sites identified by other drugs