Skip to main content Accessibility help
  • Print publication year: 2019
  • Online publication date: October 2019

Chapter 1 - Pathophysiology of Epilepsy


A seizure is a situational clinical event that may be instigated by any number of extrinsic or intrinsic precipitating factors and that results in an excessive, hypersynchronous discharge of a cortical neuronoglial population and manifests in the brain in either a localized or widespread manner. This abnormal activity takes over the normal functioning of one or more brain networks to result in seizures that characterize over 40 recognized epileptic syndromes.1

Related content

Powered by UNSILO
1.Berg, AT, Berkovic, SF, Brodie, MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia. 2010;51(4):676685.
2.McNamara, JO. Cellular and molecular basis of epilepsy. J Neurosci. 1994;14(6):34133425.
3.Tasker, JG, Hoffman, NW, Kim, YI, et al. Electrical properties of neocortical neurons in slices from children with intractable epilepsy. J Neurophysiol. 1996;75(2):931939.
4.Azevedo, FA, Carvalho, LR, Grinberg, LT, et al. Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled-up primate brain. J Comp Neurol. 2009;513(5):532541.
5.Hartzfeld, P, Elisevich, K, Pace, M, Smith, B, Gutierrez, JA. Characteristics and surgical outcomes for medial temporal post-traumatic epilepsy. Br J Neurosurg. 2008;22(2):224230.
6.Kotapka, MJ, Gennarelli, TA, Graham, DI, et al. Selective vulnerability of hippocampal neurons in acceleration-induced experimental head injury. J Neurotrauma. 1991;8(4):247258.
7.Nelson, KB, Ellenberg, JH. Prognosis in children with febrile seizures. Pediatrics. 1978;61(5):720727.
8.Lynch, NE, Stevenson, NJ, Livingstone, V, et al. The temporal evolution of electrographic seizure burden in neonatal hypoxic ischemic encephalopathy. Epilepsia. 2012;53(3):549557.
9.Markram, H, Toledo-Rodriguez, M, Wang, Y, et al. Interneurons of the neocortical inhibitory system. Nat Rev Neurosci. 2004;5(10):793807.
10.Kiernan, JA. Barr’s The Human Nervous System: An Anatomical Viewpoint. 9th edn. Baltimore: Lippincott Williams & Wilkins; 2009.
11.Wang, Y, Gupta, A, Toledo-Rodriguez, M, Wu, CZ, Markram, H. Anatomical, physiological, molecular and circuit properties of nest basket cells in the developing somatosensory cortex. Cereb Cortex. 2002;12(4):395410.
12.Chu, J, Anderson, SA. Development of cortical interneurons. Neuropsychopharmacology. 2015;40(1):1623.
13.Benarroch, EE. Neocortical interneurons: functional diversity and clinical correlations. Neurology. 2013;81(3):273280.
14.Rudy, B, Fishell, G, Lee, S, Hjerling-Leffler, J. Three groups of interneurons account for nearly 100% of neocortical GABAergic neurons. Dev Neurobiol. 2011;71(1):4561.
15.Jiang, X, Lachance, M, Rossignol, E. Involvement of cortical fast-spiking parvalbumin-positive basket cells in epilepsy. Prog Brain Res. 2016;226:81126.
16.Silberberg, G, Markram, H. Disynaptic inhibition between neocortical pyramidal cells mediated by Martinotti cells. Neuron. 2007;53(5):735746.
17.Hilscher, MM, Leao, RN, Edwards, SJ, Leao, KE, Kullander, K. Chrna2-Martinotti cells synchronize layer 5 type a pyramidal cells via rebound excitation. PLoS Biol. 2017;15(2):e2001392.
18.Tai, C, Abe, Y, Westenbroek, RE, Scheuer, T, Catterall, WA. Impaired excitability of somatostatin- and parvalbumin-expressing cortical interneurons in a mouse model of Dravet syndrome. Proc Natl Acad Sci USA. 2014;111(30):E3139E3148.
19.Rutecki, PA, Lebeda, FJ, Johnston, D. Epileptiform activity induced by changes in extracellular potassium in hippocampus. J Neurophysiol. 1985;54(5):13631374.
20.Prince, DA, Connors, BW, Benardo, LS. Mechanisms underlying interictal-ictal transitions. Adv Neurol. 1983;34:177187.
21.Dudek, FE, Obenaus, A, Tasker, JG. Osmolality-induced changes in extracellular volume alter epileptiform bursts independent of chemical synapses in the rat: importance of non-synaptic mechanisms in hippocampal epileptogenesis. Neurosci Lett. 1990;120(2):267270.
22.Traub, RD, Dudek, FE, Taylor, CP, Knowles, WD. Simulation of hippocampal afterdischarges synchronized by electrical interactions. Neuroscience. 1985;14(4):10331038.
23.Jefferys, JG, Haas, HL. Synchronized bursting of CA1 hippocampal pyramidal cells in the absence of synaptic transmission. Nature. 1982;300(5891):448450.
24.Vizi, ES, Fekete, A, Karoly, R, Mike, A. Non-synaptic receptors and transporters involved in brain functions and targets of drug treatment. Br J Pharmacol. 2010;160(4):785809.
25.Lendvai, B, Vizi, ES. Nonsynaptic chemical transmission through nicotinic acetylcholine receptors. Physiol Rev. 2008;88(2):333349.
26.Jin, MM, Chen, Z. Role of gap junctions in epilepsy. Neurosci Bull. 2011;27(6):389406.
27.Elisevich, K, Rempel, SA, Smith, BJ, Edvardsen, K. Hippocampal connexin 43 expression in human complex partial seizure disorder. Exp Neurol. 1997;145(1):154164.
28.Nadarajah, B, Thomaidou, D, Evans, WH, Parnavelas, JG. Gap junctions in the adult cerebral cortex: regional differences in their distribution and cellular expression of connexins. J Comp Neurol. 1996;376(2):326342.
29.Venance, L, Piomelli, D, Glowinski, J, Giaume, C. Inhibition by anandamide of gap junctions and intercellular calcium signalling in striatal astrocytes. Nature. 1995;376(6541):590594.
30.Trachtenberg, MC, Pollen, DA. Neuroglia: biophysical properties and physiologic function. Science. 1970;167(3922):12481252.
31.Deans, MR, Gibson, JR, Sellitto, C, Connors, BW, Paul, DL. Synchronous activity of inhibitory networks in neocortex requires electrical synapses containing connexin36. Neuron. 2001;31(3):477485.
32.Baude, A, Bleasdale, C, Dalezios, Y, Somogyi, P, Klausberger, T. Immunoreactivity for the GABAA receptor alpha1 subunit, somatostatin and Connexin36 distinguishes axoaxonic, basket, and bistratified interneurons of the rat hippocampus. Cereb Cortex. 2007;17(9):20942107.
33.Steyn-Ross, ML, Steyn-Ross, DA, Sleigh, JW. Modelling general anaesthesia as a first-order phase transition in the cortex. Prog Biophys Mol Biol. 2004;85(2–3):369385.
34.Voss, LJ, Sleigh, JW. Gap junctions regulate seizure activity – but in unexpected ways. In: Dere, E, ed. Gap Junctions in the Brain: Physiological and Pathological Roles. Waltham, MA: Academic Press; 2013:217229.
35.Grenier, F, Timofeev, I, Steriade, M. Focal synchronization of ripples (80-200 Hz) in neocortex and their neuronal correlates. J Neurophysiol. 2001;86(4):18841898.
36.Schmitz, D, Schuchmann, S, Fisahn, A, et al. Axo-axonal coupling. a novel mechanism for ultrafast neuronal communication. Neuron. 2001;31(5):831840.
37.Traub, RD, Whittington, MA, Buhl, EH, et al. A possible role for gap junctions in generation of very fast EEG oscillations preceding the onset of, and perhaps initiating, seizures. Epilepsia. 2001;42(2):153170.
38.Van Rijn, C, Meinardi, H. Neurochemistry and epileptology. Epilepsia. 2009;50(Suppl 3):1729.
39.Meldrum, BS. Glutamate as a neurotransmitter in the brain: review of physiology and pathology. J Nutr. 2000;130(4S Suppl):1007s1015s.
40.Anwyl, R. Metabotropic glutamate receptor-dependent long-term potentiation. Neuropharmacology. 2009;56(4):735740.
41.Danbolt, NC. Glutamate uptake. Prog Neurobiol. 2001;65(1):1105.
42.Jones, EA, Yurdaydin, C, Basile, AS. The GABA hypothesis: state of the art. Adv Exp Med Biol. 1994;368:89101.
43.Mathern, GW, Mendoza, D, Lozada, A, et al. Hippocampal GABA and glutamate transporter immunoreactivity in patients with temporal lobe epilepsy. Neurology. 1999;52(3):453472.
44.Bradford, HF. Glutamate, GABA and epilepsy. Prog Neurobiol. 1995;47(6):477511.
45.Blumenfeld, H. Cellular and network mechanisms of spike-wave seizures. Epilepsia. 2005;46(Suppl 9):2133.
46.Haut, SR, Albin, RL. Dopamine and epilepsy: hints of complex subcortical roles. Neurology. 2008;71(11):784785.
47.Starr, MS. The role of dopamine in epilepsy. Synapse. 1996;22(2):159194.
48.Giorgi, FS, Pizzanelli, C, Biagioni, F, Murri, L, Fornai, F. The role of norepinephrine in epilepsy: from the bench to the bedside. Neurosci Biobehav Rev. 2004;28(5):507524.
49.McNamara, JO, Byrne, MC, Dasheiff, RM, Fitz, JG. The kindling model of epilepsy: a review. Prog Neurobiol. 1980;15(2):139159.
50.Avanzini, G. Do seizures promote epileptogenesis and cause cognitive decline? Eur Neurol Rev. 2015;9(2).
51.Hildebrand, MS, Dahl, HH, Damiano, JA, et al. Recent advances in the molecular genetics of epilepsy. J Med Genet. 2013;50(5):271279.
52.Myers, CT, Mefford, HC. Advancing epilepsy genetics in the genomic era. Genome Med. 2015;7(1):91.
53.Wither, RG, Borlot, F, MacDonald, A, et al. 22q11.2 deletion syndrome lowers seizure threshold in adult patients without epilepsy. Epilepsia. 2017;58(6):10951101. Kovel, CG, Trucks, H, Helbig, I, et al. Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies. Brain. 2010;133(Pt 1):2332.
55.Helbig, I, Mefford, HC, Sharp, AJ, et al. 15q13.3 microdeletions increase risk of idiopathic generalized epilepsy. Nat Genet. 2009;41(2):160162.
56.Helbig, I, Hodge, SE, Ottman, R. Familial cosegregation of rare genetic variants with disease in complex disorders. Eur J Hum Genet. 2013;21(4):444450. Ligt, J, Willemsen, MH, van Bon, BW, et al. Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med. 2012;367(20):19211929.
58.Abbas, W, Kumar, A, Herbein, G. The eEF1A proteins: at the crossroads of oncogenesis, apoptosis, and viral infections. Front Oncol. 2015;5:75.
59.Heinzen, EL, Radtke, RA, Urban, TJ, et al. Rare deletions at 16p13.11 predispose to a diverse spectrum of sporadic epilepsy syndromes. Am J Hum Genet. 2010;86(5):707718.
60.Crompton, DE, Scheffer, IE, Taylor, I, et al. Familial mesial temporal lobe epilepsy: a benign epilepsy syndrome showing complex inheritance. Brain. 2010;133(11):32213231.
61.Hedera, P, Blair, MA, Andermann, E, et al. Familial mesial temporal lobe epilepsy maps to chromosome 4q13.2-q21.3. Neurology. 2007;68(24):21072112.
62.Ottman, R, Risch, N, Hauser, WA, et al. Localization of a gene for partial epilepsy to chromosome 10q. Nat Genet. 1995;10(1):5660.
63.Kalachikov, S, Evgrafov, O, Ross, B, et al. Mutations in LGI1 cause autosomal-dominant partial epilepsy with auditory features. Nat Genet. 2002;30(3):335341.
64.Steinlein, OK, Mulley, JC, Propping, P, et al. A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet. 1995;11(2):201203.
65.Liu, JY, Kasperaviciute, D, Martinian, L, Thom, M, Sisodiya, SM. Neuropathology of 16p13.11 deletion in epilepsy. PLoS One. 2012;7(4):e34813.
66.Ishida, S, Picard, F, Rudolf, G, et al. Mutations of DEPDC5 cause autosomal dominant focal epilepsies. Nat Genet. 2013;45(5):552555.
67.Dibbens, LM, de Vries, B, Donatello, S, et al. Mutations in DEPDC5 cause familial focal epilepsy with variable foci. Nat Genet. 2013;45(5):546551.
68.Lal, D, Reinthaler, EM, Schubert, J, et al. DEPDC5 mutations in genetic focal epilepsies of childhood. Ann Neurol. 2014;75(5):788792.
69.Picard, F, Makrythanasis, P, Navarro, V, et al. DEPDC5 mutations in families presenting as autosomal dominant nocturnal frontal lobe epilepsy. Neurology. 2014;82(23):21012106.
70.D’Gama, AM, Geng, Y, Couto, JA, et al. Mammalian target of rapamycin pathway mutations cause hemimegalencephaly and focal cortical dysplasia. Ann Neurol. 2015;77(4):720725.
71.Lim, JS, Kim, WI, Kang, HC, et al. Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy. Nat Med. 2015;21(4):395400.
72.Singh, NA, Charlier, C, Stauffer, D, et al. A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nat Genet. 1998;18(1):25-29.
73.Heron, SE, Crossland, KM, Andermann, E, et al. Sodium-channel defects in benign familial neonatal-infantile seizures. Lancet. 2002;360(9336):851852.
74.Claes, L, Del-Favero, J, Ceulemans, B, et al. De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am J Hum Genet. 2001;68(6):13271332.
75.Mefford, HC. CNVs in epilepsy. Curr Genet Med Rep. 2014;2(3):162167.
76.Nava, C, Dalle, C, Rastetter, A, et al. De novo mutations in HCN1 cause early infantile epileptic encephalopathy. Nat Genet. 2014;46(6):640645.
77.Carvill, GL, Weckhuysen, S, McMahon, JM, et al. GABRA1 and STXBP1: novel genetic causes of Dravet syndrome. Neurology. 2014;82(14):12451253.
78.Moller, RS, Wuttke, TV, Helbig, I, et al. Mutations in GABRB3: from febrile seizures to epileptic encephalopathies. Neurology. 2017;88(5):483492.
79.Torkamani, A, Bersell, K, Jorge, BS, et al. De novo KCNB1 mutations in epileptic encephalopathy. Ann Neurol. 2014;76(4):529540.
80.Carvill, GL, Heavin, SB, Yendle, SC, et al. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat Genet. 2013;45(7):825830.
81.Suls, A, Jaehn, JA, Kecskes, A, et al. De novo loss-of-function mutations in CHD2 cause a fever-sensitive myoclonic epileptic encephalopathy sharing features with Dravet syndrome. Am J Hum Genet. 2013;93(5):967975.
82.Galizia, EC, Myers, CT, Leu, C, et al. CHD2 variants are a risk factor for photosensitivity in epilepsy. Brain. 2015;138(Pt 5):11981207.
83.Liu, JS. Molecular genetics of neuronal migration disorders. Curr Neurol Neurosci Rep. 2011;11(2):171178.
84.Fox, JW, Lamperti, ED, Eksioglu, YZ, et al. Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia. Neuron. 1998;21(6):13151325.
85.Sheen, VL, Dixon, PH, Fox, JW, et al. Mutations in the X-linked filamin 1 gene cause periventricular nodular heterotopia in males as well as in females. Hum Mol Genet. 2001;10(17):17751783.
86.Srikandarajah, N, Martinian, L, Sisodiya, SM, et al. Doublecortin expression in focal cortical dysplasia in epilepsy. Epilepsia. 2009;50(12):26192628.
87.Chevassus-au-Louis, N, Baraban, SC, Gaiarsa, JL, Ben-Ari, Y. Cortical malformations and epilepsy: new insights from animal models. Epilepsia. 1999;40(7):811821.
88.Jacobs, KM, Kharazia, VN, Prince, DA. Mechanisms underlying epileptogenesis in cortical malformations. Epilepsy Res. 1999;36(2–3):165188.
89.Hauser, WA. Seizure disorders: the changes with age. Epilepsia. 1992;33(Suppl 4):S6S14.
90.Gaiarsa, JL, Tseeb, V, Ben-Ari, Y. Postnatal development of pre- and postsynaptic GABAB-mediated inhibitions in the CA3 hippocampal region of the rat. J Neurophysiol. 1995;73(1):246255.
91.Leinekugel, X, Medina, I, Khalilov, I, Ben-Ari, Y, Khazipov, R. Ca2+ oscillations mediated by the synergistic excitatory actions of GABA(A) and NMDA receptors in the neonatal hippocampus. Neuron. 1997;18(2):243255.
92.Holmes, GL, Ben-Ari, Y. Seizures in the developing brain: perhaps not so benign after all. Neuron. 1998;21(6):12311234.
93.Edebol-Tysk, K. Epidemiology of spastic tetraplegic cerebral palsy in Sweden. I. Impairments and disabilities. Neuropediatrics. 1989;20(1):4145.
94.Yu, JY, Pearl, PL. Metabolic causes of epileptic encephalopathy. Epilepsy Res Treat. 2013;2013:124934.
95.Vezzani, A, Granata, T. Brain inflammation in epilepsy: experimental and clinical evidence. Epilepsia. 2005;46(11):17241743.
96.Li, G, Bauer, S, Nowak, M, et al. Cytokines and epilepsy. Seizure. 2011;20(3):249256.
97.Nowak, M, Bauer, S, Haag, A, et al. Interictal alterations of cytokines and leukocytes in patients with active epilepsy. Brain Behav Immun. 2011;25(3):423428.
98.Hirschberg, DL, Moalem, G, He, J, et al. Accumulation of passively transferred primed T cells independently of their antigen specificity following central nervous system trauma. J Neuroimmunol. 1998;89(1–2):8896.
99.Holmin, S, Soderlund, J, Biberfeld, P, Mathiesen, T. Intracerebral inflammation after human brain contusion. Neurosurgery. 1998;42(2):291298; discussion 298–299.
100.Lenzlinger, PM, Hans, VH, Joller-Jemelka, HI, et al. Markers for cell-mediated immune response are elevated in cerebrospinal fluid and serum after severe traumatic brain injury in humans. J Neurotrauma. 2001;18(5):479489.
101.Ravizza, T, Gagliardi, B, Noe, F, et al. Innate and adaptive immunity during epileptogenesis and spontaneous seizures: evidence from experimental models and human temporal lobe epilepsy. Neurobiol Dis. 2008;29(1):142160.
102.Mukherjee, S, Bricker, PC, Shapiro, LA. Alteration of hippocampal cytokines and astrocyte morphology observed in rats 24 hour after fluid percussion injury. J Neurol Disord Stroke. 2014;2(4):1078.
103.Vezzani, A, Ravizza, T, Balosso, S, Aronica, E. Glia as a source of cytokines: implications for neuronal excitability and survival. Epilepsia. 2008;49(Suppl 2):2432.
104.Alapirtti, T, Rinta, S, Hulkkonen, J, et al. Interleukin-6, interleukin-1 receptor antagonist and interleukin-1beta production in patients with focal epilepsy: a video-EEG study. J Neurol Sci. 2009;280(1–2):9497.
105.Quirico-Santos, T, Meira, ID, Gomes, AC, et al. Resection of the epileptogenic lesion abolishes seizures and reduces inflammatory cytokines of patients with temporal lobe epilepsy. J Neuroimmunol. 2013;254(1–2):125130.
106.Strauss, KI, Elisevich, KV. Brain region and epilepsy-associated differences in inflammatory mediator levels in medically refractory mesial temporal lobe epilepsy. J Neuroinflammation. 2016;13(1):270.
107.Sinha, S, Patil, SA, Jayalekshmy, V, Satishchandra, P. Do cytokines have any role in epilepsy? Epilepsy Res. 2008;82(2–3):171176.
108.Erickson, MA, Morofuji, Y, Owen, JB, Banks, WA. Rapid transport of CCL11 across the blood-brain barrier: regional variation and importance of blood cells. J Pharmacol Exp Ther. 2014;349(3):497507.
109.Sutton, C, Brereton, C, Keogh, B, Mills, KH, Lavelle, EC. A crucial role for interleukin (IL)-1 in the induction of IL-17-producing T cells that mediate autoimmune encephalomyelitis. J Exp Med. 2006;203(7):16851691.
110.Pollard, JR, Eidelman, O, Mueller, GP, et al. The TARC/sICAM5 ratio in patient plasma is a candidate biomarker for drug resistant epilepsy. Front Neurol. 2012;3:181.
111.Lyck, R, Enzmann, G. The physiological roles of ICAM-1 and ICAM-2 in neutrophil migration into tissues. Curr Opin Hematol. 2015;22(1):5359.