Pathophysiology of seizures and epilepsy
- Carl E Stafstrom, MD, PhD
Carl E Stafstrom, MD, PhD
- Professor of Neurology and Pediatrics
- Johns Hopkins University
- Jong M Rho, MD
Jong M Rho, MD
- Professor of Paediatrics, Clinical Neurosciences, Physiology, and Pharmacology
- Dr. Robert Haslam Chair in Child Neurology
- University of Calgary
An epileptic seizure is an episode of neurologic dysfunction in which abnormal neuronal firing is manifest clinically by changes in motor control, sensory perception, behavior, or autonomic function. Epilepsy is the condition of recurrent spontaneous seizures arising from aberrant electrical activity within the brain. While anyone can experience a seizure under the appropriate pathophysiological conditions, epilepsy suggests an enduring alteration of brain function that facilitates seizure recurrence. Epileptogenesis is the process by which the normal brain becomes prone to epilepsy .
The aberrant electrical activity that underlies epilepsy is the result of biochemical processes at the cellular level promoting neuronal hyperexcitability and neuronal hypersynchrony. However, a single neuron, discharging abnormally, is insufficient to produce a clinical seizure, which occurs only in the context of large neuronal networks. Several key cortical and subcortical structures are involved in generating a seizure.
This topic reviews the cellular basis for focal and generalized seizure activity, with specific attention to ion channels, the essential currency of neuronal excitability, and the hippocampus, one of the most seizure-prone areas of the brain. The pharmacology of anti-seizure drugs and issues related to the assessment and management of patients with epilepsy are discussed separately.(See "Antiepileptic drugs: Mechanism of action, pharmacology, and adverse effects" and "Overview of the management of epilepsy in adults".)
CLASSIFICATION OF SEIZURES
Epilepsy is not a singular disease, but is heterogeneous in terms of clinical expression, underlying etiologies, and pathophysiology (table 1). As such, specific mechanisms and pathways underlying specific seizure types may vary. Epileptic seizures are broadly classified according to their site of origin and pattern of spread (figure 1).
●Focal seizures arise from a localized region of the brain and have clinical manifestations that reflect that area of brain. Focal discharges can remain localized or they can spread to nearby cortical areas, to subcortical structures and/or transmit through commissural pathways to involve the whole cortex. The latter sequence describes the secondary generalization of focal seizures. As an example, a seizure arising from the left motor cortex may cause jerking movements of the right upper extremity. If epileptiform discharges spread to adjacent areas and then the entire brain, it is called a secondarily generalized tonic-clonic seizure.
- Pitkänen A, Lukasiuk K. Molecular and cellular basis of epileptogenesis in symptomatic epilepsy. Epilepsy Behav 2009; 14 Suppl 1:16.
- McCormick DA, Contreras D. On the cellular and network bases of epileptic seizures. Annu Rev Physiol 2001; 63:815.
- Chang BS, Lowenstein DH. Epilepsy. N Engl J Med 2003; 349:1257.
- Gatto CL, Broadie K. Genetic controls balancing excitatory and inhibitory synaptogenesis in neurodevelopmental disorder models. Front Synaptic Neurosci 2010; 2:4.
- Stafstrom CE. Recognizing seizures and epilepsy: insights from pathophysiology. In: Epilepsy, Miller JW, Goodkin HP. (Eds), Wiley Blackwell, Hoboken 2014. p.3-9.
- Child ND, Benarroch EE. Differential distribution of voltage-gated ion channels in cortical neurons: implications for epilepsy. Neurology 2014; 82:989.
- Rho JM, Stafstrom CE. Neurophysiology of epilepsy. In: Pediatric Neurology: Principles and Practice, 5th, Swamain KF, Ashwal S, Ferreiro DM, Schor NF. (Eds), Mosby Elsevier, Philadelphia 2012. p.711.
- Stafstrom CE. Persistent sodium current and its role in epilepsy. Epilepsy Curr 2007; 7:15.
- Catterall WA, Swanson TM. Structural Basis for Pharmacology of Voltage-Gated Sodium and Calcium Channels. Mol Pharmacol 2015; 88:141.
- Lossin C. A catalog of SCN1A variants. Brain Dev 2009; 31:114.
- Rogawski MA, Löscher W. The neurobiology of antiepileptic drugs. Nat Rev Neurosci 2004; 5:553.
- Gambardella A, Labate A. The role of calcium channel mutations in human epilepsy. Prog Brain Res 2014; 213:87.
- Brown DA. Muscarinic acetylcholine receptors (mAChRs) in the nervous system: some functions and mechanisms. J Mol Neurosci 2010; 41:340.
- Stephen LJ, Brodie MJ. Pharmacotherapy of epilepsy: newly approved and developmental agents. CNS Drugs 2011; 25:89.
- 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; 18:25.
- Rogawski MA. KCNQ2/KCNQ3 K+ channels and the molecular pathogenesis of epilepsy: implications for therapy. Trends Neurosci 2000; 23:393.
- Neubauer BA, Waldegger S, Heinzinger J, et al. KCNQ2 and KCNQ3 mutations contribute to different idiopathic epilepsy syndromes. Neurology 2008; 71:177.
- Simeone TA, Sanchez RM, Rho JM. Molecular biology and ontogeny of glutamate receptors in the mammalian central nervous system. J Child Neurol 2004; 19:343.
- Kalia LV, Kalia SK, Salter MW. NMDA receptors in clinical neurology: excitatory times ahead. Lancet Neurol 2008; 7:742.
- Vyklicky V, Korinek M, Smejkalova T, et al. Structure, function, and pharmacology of NMDA receptor channels. Physiol Res 2014; 63 Suppl 1:S191.
- Avanzini G, Franceschetti S. Cellular biology of epileptogenesis. Lancet Neurol 2003; 2:33.
- Kumar J, Mayer ML. Functional insights from glutamate receptor ion channel structures. Annu Rev Physiol 2013; 75:313.
- Rogawski MA. AMPA receptors as a molecular target in epilepsy therapy. Acta Neurol Scand Suppl 2013; :9.
- Conn PJ. Physiological roles and therapeutic potential of metabotropic glutamate receptors. Ann N Y Acad Sci 2003; 1003:12.
- Ure J, Baudry M, Perassolo M. Metabotropic glutamate receptors and epilepsy. J Neurol Sci 2006; 247:1.
- Rakhade SN, Loeb JA. Focal reduction of neuronal glutamate transporters in human neocortical epilepsy. Epilepsia 2008; 49:226.
- Lancaster E, Martinez-Hernandez E, Dalmau J. Encephalitis and antibodies to synaptic and neuronal cell surface proteins. Neurology 2011; 77:179.
- Nabbout R. Autoimmune and inflammatory epilepsies. Epilepsia 2012; 53 Suppl 4:58.
- Leypoldt F, Armangue T, Dalmau J. Autoimmune encephalopathies. Ann N Y Acad Sci 2015; 1338:94.
- van der Hel WS, Verlinde SA, Meijer DH, et al. Hippocampal distribution of vesicular glutamate transporter 1 in patients with temporal lobe epilepsy. Epilepsia 2009; 50:1717.
- Sigel E, Steinmann ME. Structure, function, and modulation of GABA(A) receptors. J Biol Chem 2012; 287:40224.
- Staley KJ. Wrong-way chloride transport: is it a treatable cause of some intractable seizures? Epilepsy Curr 2006; 6:124.
- Ben-Ari Y, Khalilov I, Kahle KT, Cherubini E. The GABA excitatory/inhibitory shift in brain maturation and neurological disorders. Neuroscientist 2012; 18:467.
- Kaila K, Price TJ, Payne JA, et al. Cation-chloride cotransporters in neuronal development, plasticity and disease. Nat Rev Neurosci 2014; 15:637.
- Simeone TA, Donevan SD, Rho JM. Molecular biology and ontogeny of gamma-aminobutyric acid (GABA) receptors in the mammalian central nervous system. J Child Neurol 2003; 18:39.
- Plecko B. Pyridoxine and pyridoxalphosphate-dependent epilepsies. Handb Clin Neurol 2013; 113:1811.
- D'Ambrosio R. The role of glial membrane ion channels in seizures and epileptogenesis. Pharmacol Ther 2004; 103:95.
- Barker-Haliski M, White HS. Glutamatergic Mechanisms Associated with Seizures and Epilepsy. Cold Spring Harb Perspect Med 2015; 5:a022863.
- de Lanerolle NC, Lee TS, Spencer DD. Astrocytes and epilepsy. Neurotherapeutics 2010; 7:424.
- Tian GF, Azmi H, Takano T, et al. An astrocytic basis of epilepsy. Nat Med 2005; 11:973.
- Aronica E, Ravizza T, Zurolo E, Vezzani A. Astrocyte immune responses in epilepsy. Glia 2012; 60:1258.
- Nadler JV. The recurrent mossy fiber pathway of the epileptic brain. Neurochem Res 2003; 28:1649.
- Buzsáki G, Draguhn A. Neuronal oscillations in cortical networks. Science 2004; 304:1926.
- Rektor I, Kuba R, Brázdil M, Chrastina J. Do the basal ganglia inhibit seizure activity in temporal lobe epilepsy? Epilepsy Behav 2012; 25:56.
- Staba RJ, Bragin A. High-frequency oscillations and other electrophysiological biomarkers of epilepsy: underlying mechanisms. Biomark Med 2011; 5:545.
- Jin MM, Chen Z. Role of gap junctions in epilepsy. Neurosci Bull 2011; 27:389.
- Hochman DW. The extracellular space and epileptic activity in the adult brain: explaining the antiepileptic effects of furosemide and bumetanide. Epilepsia 2012; 53 Suppl 1:18.
- Gnatkovsky V, Librizzi L, Trombin F, de Curtis M. Fast activity at seizure onset is mediated by inhibitory circuits in the entorhinal cortex in vitro. Ann Neurol 2008; 64:674.
- Sutula, T, Pitkänen, A. Do Seizures Damage the Brain? Elsevier, Amsterdam 2002.
- Velísek L, Moshé SL. Effects of brief seizures during development. Prog Brain Res 2002; 135:355.
- Bertram E. The relevance of kindling for human epilepsy. Epilepsia 2007; 48 Suppl 2:65.
- Pitkänen A, Sutula TP. Is epilepsy a progressive disorder? Prospects for new therapeutic approaches in temporal-lobe epilepsy. Lancet Neurol 2002; 1:173.
- Austin JK, Caplan R. Behavioral and psychiatric comorbidities in pediatric epilepsy: toward an integrative model. Epilepsia 2007; 48:1639.
- Anderson J, Hamandi K. Understanding juvenile myoclonic epilepsy: contributions from neuroimaging. Epilepsy Res 2011; 94:127.
- Perez-Reyes E. Molecular physiology of low-voltage-activated t-type calcium channels. Physiol Rev 2003; 83:117.
- Heron SE, Khosravani H, Varela D, et al. Extended spectrum of idiopathic generalized epilepsies associated with CACNA1H functional variants. Ann Neurol 2007; 62:560.
- Chen Y, Lu J, Pan H, et al. Association between genetic variation of CACNA1H and childhood absence epilepsy. Ann Neurol 2003; 54:239.
- Coulter DA, Huguenard JR, Prince DA. Specific petit mal anticonvulsants reduce calcium currents in thalamic neurons. Neurosci Lett 1989; 98:74.
- Robinson RB, Siegelbaum SA. Hyperpolarization-activated cation currents: from molecules to physiological function. Annu Rev Physiol 2003; 65:453.
- Poolos NP, Warner LN, Humphreys SZ, Williams S. Comparative efficacy of combination drug therapy in refractory epilepsy. Neurology 2012; 78:62.
- Benarroch EE. HCN channels: function and clinical implications. Neurology 2013; 80:304.
- Han HA, Cortez MA, Snead OC. GABA-B receptor and absence epilepsy. In: Jasper's Basic Mechanisms of the Epilepsies, Noebels JL, et al. (Eds), Oxford Univeristy Press, New York 2012. p.242.
- Hauser, W, Hersdorffer, D. Epilepsy: Frequency, Causes and Consequences. Demos, New York 1990.
- Wong M. Advances in the pathophysiology of developmental epilepsies. Semin Pediatr Neurol 2005; 12:72.
- Rakhade SN, Jensen FE. Epileptogenesis in the immature brain: emerging mechanisms. Nat Rev Neurol 2009; 5:380.
- Bozzi Y, Casarosa S, Caleo M. Epilepsy as a neurodevelopmental disorder. Front Psychiatry 2012; 3:19.
- Raol YH, Lund IV, Bandyopadhyay S, et al. Enhancing GABA(A) receptor alpha 1 subunit levels in hippocampal dentate gyrus inhibits epilepsy development in an animal model of temporal lobe epilepsy. J Neurosci 2006; 26:11342.
- Margineanu DG. Epileptic hypersynchrony revisited. Neuroreport 2010; 21:963.
- Mylvaganam S, Ramani M, Krawczyk M, Carlen PL. Roles of gap junctions, connexins, and pannexins in epilepsy. Front Physiol 2014; 5:172.
- Swann JW, Le JT, Lam TT, et al. The impact of chronic network hyperexcitability on developing glutamatergic synapses. Eur J Neurosci 2007; 26:975.
- Benarroch EE. Na+, K+-ATPase: functions in the nervous system and involvement in neurologic disease. Neurology 2011; 76:287.
- CLASSIFICATION OF SEIZURES
- CELLULAR PHYSIOLOGY
- Ion channels
- Voltage-dependent conductances
- - Depolarizing conductances
- - Hyperpolarizing conductances
- Synaptic transmission
- - Excitatory transmission
- - Inhibitory transmission
- Role of glia
- PATHOPHYSIOLOGY OF EPILEPSY
- Focal epilepsy: Mesial temporal lobe epilepsy
- - Paroxysmal depolarization shift
- - Synchronizing mechanisms
- - Consequences of repeated seizures
- Primary generalized epilepsy: Absence epilepsy
- Susceptibility of the immature brain