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Number 2 in a Series
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Pathophysiology of Epilepsy
Introduction
Epilepsy, a disease that has been in existence for ages, continues to affect approximately 50 million individuals worldwide, including about 2.7 million in the United States.1,2 The disease is often accompanied by neurobiologic, cognitive, psychological, and behavioral changes that may heighten susceptibility to seizures and affect quality of life. Anti-epileptic drugs (AEDs) are the primary option for the management of epilepsy. Although research over the years has led to significant advances in understanding the pathophysiology of epilepsy, the specific causes of several types of epilepsy are unknown,3 and there remains a great need for research on the neural mechanisms that potentially underlie drug resistance. This brochure aims to provide an overview of the pathophysiology of epilepsy.
Figure 1.
Neuronal axons have a resting membrane potential of about -70 mV inside vs outside. Action potentials occur due to net positive inward ion fluxes, resulting in local changes in the membrane potential.4,5 Membrane potentials vary with the activation of either ligand- or voltage-gated ion channels, which are affected by changes in either the membrane potential or intracellular ion concentrations (Figure 2).4
The ionic compositions of the intracellular fluid (cytosol) and of the surrounding extracellular fluid. A represents negatively charged proteins, which neutralize excess Na+ and K+ ions.4
Figure 2.
Reprinted with permission from Molecular Cell Biology, 4th ed., Lodish H, Berk A, Zipursky S, et al. 2000.
GABA, the principal inhibitory neurotransmitter in the brain, binds postsynaptically to the ionotropic receptor, GABAA (Figure 3), and presynaptically to the metabotropic receptor, GABAB.6
Figure 3. (Left) GABAA receptor: Synaptic (phasic) GABA receptor with a view of the extracellular face showing the two recognition sites for GABA and the benzodiazepine recognition site; (Right) A typical extrasynaptic (tonic) GABAA receptor with two GABA recognition sites (from Meldrum 2007).6
Reprinted with permission from Neurotherapeutics;4:18-61, Meldrum BS, Rogawski MA, Molecular targets for antiepileptic drug development. 2007.
ligand-binding site, while the remainder of the protein spans the membrane either four times (left) or three times (right). (B) Assembly of either four or five subunits into a complete receptor. (C) A diversity of subunits come together to form functional ionotropic neurotransmitter receptors.
Figure 4. (A) One of the subunits of a complete receptor. The long N-terminal region forms the
Reprinted with permission from Neuroscience, 2nd ed., Purves D, Augustine GJ, Fitzpatrick D, et al., editors. http://www.ncbi.nlm.nih.gov/books/NBK10834/figure/A492/?report=objectonly 2001
Glutamate, the principal excitatory neurotransmitter, binds to both ionotropic and metabotropic types of receptors. Glutamate acts on 3 classes of ionotropic receptorsn-methylD-aspartate (NMDA), -amino-3-hydroxy-5methyl-4-isoxazolepropionic acid (AMPA), and kainate (KA). AMPA receptors are the most abundant, followed by NMDA and KA receptors.7,8 These receptors contain subunits whose structure affects the biophysical properties of the receptor (Figure 4). AMPA receptors have lower glutamate affinity than NMDA receptors, but their faster kinetics account for the fast initial component of the excitatory postsynaptic potential (Figure 5).8
Figure 5.
Dual component excitatory postsynaptic potential showing the fast initial AMPA component and the slow NMDA component.
Redrawn with permission from Journal of Nutrition;130:1007S-15S, Meldrum BS, Glutamate as a neurotransmitter in the brain: review of physiology and pathology. 2000.
Mechanisms of Ictogenesis
Hyperexcitation is the key factor underlying ictogenesis (Figure 6). Excessive excitation may originate from individual neurons, the neuronal environment, or neuronal networks.3 Excitability from individual neurons may arise from structural or functional changes in the postsynaptic membrane; alterations in the type, number, and distribution of voltage- and ligand-gated ion channels; or biochemical modification of receptors that increase permeability to Ca2+, favoring development of the prolonged depolarization that precedes seizures10 Excitability arising from the neuronal environment may result from both physiologic and structural changes. Physiologic changes include alterations in concentrations of ions, metabolic alterations, and in neurotransmitter levels. Structural changes affect both neurons and glia. Seizure- associated astrocytes reportedly are complex, arborized, highly branched processes with a stellate appearance and with a ratio of Na+ to K+ conductance that is 3-4 fold higher than that observed in normal astrocytes. Consequently, glial K+ buffering may be affected and may lead to epileptic activity. 3,11 Extracellular Ca 2+ concentration decreases by over 85% during a seizure, preceding the changes in K+ concentration by milliseconds. However, Ca2+ levels return to normal faster than K+ levels Alterations in the neuronal network may facilitate excitability through sprouting of the axons of the granule cells of the dentate gyrus or mossy fibers; loss of inhibitory neurons; loss of excitatory neurons needed to activate inhibitory neurons; or changes in neuronal firing properties due to channelopathies
Nonsynaptic Mechanisms
Changes in ionic concentrations observed during hyperexcitationincreased extracellular K+ or decreased extracellular Ca2+, for examplemay be caused by decreases in extracellular size or volume. Failure of Na+-K+ pumps due to hypoxia or ischemia is known to promote epileptogenesis in animal models, and interference with Cl--K+ transport, which controls intracellular Cl and regulates GABA-activated inhibitory Cl currents, may lead to enhanced excitation. Excitability of synaptic terminals depends on the extent of depolarization and the amount of neurotransmitter released. Synchronization following abnormal bursts of spikes in the axonal branching of thalamocortical relay cells plays a key role in epileptogenesis. Ephaptic interactions that occur between neighboring neurons separated by small extracellular spaces also contribute to increased synchronization.
Figure 6.
Synaptic Mechanisms
Synaptic pathophysiology of epilepsy and epileptic disorders primarily involves reduced GABAergic inhibition or enhanced glutamatergic excitation. GABA GABA levels have been shown to be reduced in the cerebrospinal fluid (CSF) of patients with certain kinds of epilepsy, such as infantile spasms and untreated generalized tonic-clonic seizures, and in excised epileptic tissue from patients with drug-resistant epilepsy, suggesting that these patients have decreased inhibition.12 Dogs with epilepsy have been shown to have low CSF levels of GABA, and mice genetically susceptible to audiogenic seizures have a lower number of GABA receptors than non-seizure prone animals. Reduced [3H]-GABA binding to GABA receptors has been reported in human brain tissue, and low glutamic acid decarboxylase levels have been shown in kindled rats and in excised human epileptic tissue, suggestive of decreased GABAergic inhibition.3 Glutamate Hippocampal recordings from conscious human brains have shown sustained increases in the levels of extracellular glutamate levels during and preceding seizures. GABA levels remain low in the epileptogenic hippocampus, but during seizures, GABA concentrations increase, although mostly in the non-epileptogenic hippocampus. This leads to a toxic increase in extracellular glutamate due to reduced inhibition in the epileptogenic areas.13 In human hippocampal epilepsy, densities of glutamate AMPA receptor subunits correlated with the locations of the densest aberrant mossy fibers. Increases in AMPA receptors in a KA model of epileptic rats preceded mossy fiber ingrowth, and demonstrated a greater increase than the increase in presynaptic mossy fiber Figure 7. Panel A, B showing simplified thalamocortical inputs14; KA receptors have also been shown to be network and spike wave complex. involved in ongoing glutamatergic transmission in granule cells of chronic epileptic animals.15 Thus, while the role of NMDA receptors in epilepsy has been known for some time, there is now growing evidence of the role of AMPA and KA receptors in epilepsy.
Figure 8.
Reprinted by permission from Macmillan Publishers Ltd: Nature Medicine, Rogawski MA. Astrocytes get in the act in epilepsy. Nat Med 2005;11:919-20, 2005.
Mutated Gene
SCN1B SCN1A SCN2A GABRG2
Gene Product
Sodium-channel subunit Sodium-channel subunit Sodium-channel subunit GABAA receptor subunit Potassium channel Potassium channel Neuronal nicotinic acetylcholine-receptor subunit Neuronal nicotinic acetylcholine-receptor subunit GABAA receptor subunit Leucine-rich transmembrane protein
KCNQ2 KCNQ3
Autosomal dominant nocturnal frontal-lobe epilepsy Childhood absence epilepsy and febrile seizures Autosomal dominant partial epilepsy with auditory features
Epilepsy-associated neuronal migration Several developmental disorders of neuronal migration, with underlying genetic or intrauterine causes, are associated with epilepsy. Agyria or lack of gyri and sulci, and pachygyria (thick convolutions) are commonly associated with abnormalities in neuronal migration. Such cortical malformations, including microgyric cortices, have been associated with increases in postsynaptic glutamate receptors and decreases in GABA receptors, a condition that can promote epileptogenesis.3 Tuberous sclerosis, X-linked lissencephaly, and double cortex syndrome are other examples of developmental disorders associated with epilepsy and disordered neuronal migration.3 Autoimmune pathogenesis Rasmussens encephalitis is a progressive degenerative disease affecting children. Patients have seizures that are typically resistant to AEDs. Progressive hemiparesis with dementia is a characteristic of this rare disease.17 Recent discovery of anti-GluR3 antibodies suggests that this disease may be the result of autoimmune pathogenesis.3
Modulation of voltage-gated ion channels Ion channelsNa +, Ca 2+, and K +shape the sub-threshold electrical activity of the neuron, regulate response to synaptic activity, and thus contribute to the PDS involved in seizure generation. Voltage-gated Na+ channels are responsible for the rising phase of the action potential, with fast current generating the action potential and persistent current contributing to burst discharges by enhancing after-depolarization potentials.6 Ca2+ channels can allow Ca2+ entry into the cell, thus causing depolarization and activating other ion channels. This process is especially important in the thalamus where neuronal T-type Ca2+ channels lead to burst firing and oscillatory activity, as in the sleep and wake cycle.21 Ca2+ channels come under 2 major groupshigh-voltage activated (HVA) and low-voltage activated (LVA). HVA Ca2+ channels are responsible for Ca2+ entry and presynaptic release of neurotransmitters, while LVA channels trigger low-threshold spikes that in turn trigger burst firing mediated by Na+ channels. Burst ring is associated with the synchronicity observed in the thalamus, as in absence epilepsy. Thus, AEDs that block voltage-gated Ca2+ channels are an important target for AEDs. 6,22 Some AEDs that inhibit Na + channels also block T-type Ca 2+ channels.21 Modulation of ligand-gated ion channels Conductance of ligand-gated channels is modulated by binding to neurotransmitters that regulate inhibition and excitation. AEDs can suppress epileptic activity by enhancing GABA-mediated inhibition or by suppressing glutamatergic excitation. Enhancement of synaptic inhibition: Many of the existing AEDs aim to enhance GABAergic inhibition by interacting with fast ionotropic GABAA receptors or by modifying the activity of enzymes and transporters involved in GABA synthesis or reuptake.6 Suppression of synaptic excitation: Glutamatergic excitation may be influenced through action on NMDA, AMPA, or KA receptors. However, AMPA receptors are the most abundant ionotropic glutamate receptors that mediate synaptic signaling.7
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the flow of their substrates against their concentration gradients, resulting in lowered plasma levels of the drug despite adequate administration.24 In epileptogenic brain specimens of patients with uncontrolled epilepsy, high levels of P-gp and MRP have been illustrated in both vascular endothelial cells and brain parenchymal cells.24 However, due to the lack of control specimens, it is unclear if this overexpression of transporters exists before the onset of epilepsy, or if it is a consequence of the seizures or the treatment.24 Thus, although there is some evidence in support of the transporter hypothesis, it remains an area of active research.
Conclusions
Mechanisms underlying epilepsy, ictogenesis, and epileptogenesis are complex and manifold depending on the specific type of epilepsy. The hallmark mechanisms common to most epilepsies are hyperexcitability and excessive synchronicity. Treatment paradigms are complicated by the complexity of the nervous system. For example, GABA, which is inhibitory in the mature brain, can be excitatory in the immature brain. There is a need for greater research into the mechanisms underlying drug resistance itself.
References
1. Glauser TA, Sankar R. Core elements of epilepsy diagnosis and management: expert consensus from the Leadership in Epilepsy, Advocacy, and Development (LEAD) faculty. Curr Med Res Opin 2008;24: 3463-77. 2. Epilepsy. In: Fact sheet N999. http://www.who.int/mediacentre/factsheets/fs999/en/index.html#: World Health Organization; 2009. 3. Engelborghs S, DHooge R, De Deyn PP. Pathophysiology of epilepsy. Acta Neurol Belg 2000;100: 201-13. 4. Lodish H, Berk A, Zipursky S, Matsudaira P, Baltimore D, Darnell J. Molecular Cell Biology. 4 ed. New York: W. H. Freeman and Company; 2000. 5. Basic Neurochemistry. 6th ed. Philadelphia: Lippincott-Raven; 1999. 6. Meldrum BS, Rogawski MA. Molecular targets for antiepileptic drug development. Neurotherapeutics 2007;4:18-61. 7. Rogawski MA. Revisiting AMPA receptors as an antiepileptic drug target. Epilepsy Curr 2011;11:56-63. 8. Meldrum BS. Glutamate as a neurotransmitter in the brain: review of physiology and pathology. J Nutr 2000;130:1007S-15S. 9. Fisher RS, van Emde Boas W, Blume W, et al. Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia 2005;46:470-2. 10. Pathophysiology of Epilepsy. In. http://www.aesnet.org/go/professional-development/educationalopportunities/epilepsy-education-program: American Epilepsy Society; 2010. 11. Bordey A, Sontheimer H. Properties of human glial cells associated with epileptic seizure foci. Epilepsy Res 1998;32:286-303. 12. Loscher W, Siemes H. Cerebrospinal fluid gamma-aminobutyric acid levels in children with different types of epilepsy: effect of anticonvulsant treatment. Epilepsia 1985;26:314-9.
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References
13. During MJ, Spencer DD. Extracellular hippocampal glutamate and spontaneous seizure in the conscious human brain. Lancet 1993;341:1607-10. 14. Babb TL, Mathern GW, Leite JP, Pretorius JK, Yeoman KM, Kuhlman PA. Glutamate AMPA receptors in the fascia dentata of human and kainate rat hippocampal epilepsy. Epilepsy Res 1996;26:193-205. 15. Epsztein J, Represa A, Jorquera I, Ben-Ari Y, Crepel V. Recurrent mossy fibers establish aberrant kainate receptor-operated synapses on granule cells from epileptic rats. J Neurosci 2005;25:8229-39. 16. Blumenfeld H. From molecules to networks: cortical/subcortical interactions in the pathophysiology of idiopathic generalized epilepsy. Epilepsia 2003;44 Suppl 2:7-15. 17. Acharya JN. Recent advances in epileptogenesis. Curr Sci 2002;82:10. 18. Rogawski MA. Astrocytes get in the act in epilepsy. Nat Med 2005;11:919-20. 19. Bialer M, White HS. Key factors in the discovery and development of new antiepileptic drugs. Nat Rev Drug Discov 2010;9:68-82. 20. Chang BS, Lowenstein DH. Epilepsy. N Engl J Med 2003;349:1257-66. 21. Rogawski MA, Loscher W. The neurobiology of antiepileptic drugs. Nat Rev Neurosci 2004;5: 553-64. 22. Perez-Reyes E. Molecular physiology of low-voltage-activated t-type calcium channels. Physiol Rev 2003;83:117-61. 23. Kwan P, Brodie MJ. Refractory epilepsy: mechanisms and solutions. Expert Rev Neurother 2006;6:397-406. 24. Lazarowski A, Czornyj L, Lubienieki F, Girardi E, Vazquez S, DGiano C. ABC transporters during epilepsy and mechanisms underlying multidrug resistance in refractory epilepsy. Epilepsia 2007;48 Suppl 5:140-9.
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