Epilepsy and Epileptic Syndrome

  • Tomonori Ono
  • Aristea S. GalanopoulouEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 724)


Epilepsy is one of the most common neurological disorders. In most patients with epilepsy, seizures respond to available medications. However, a significant number of patients, especially in the setting of medically-intractable epilepsies, may experience different degrees of memory or cognitive impairment, behavioral abnormalities or psychiatric symptoms, which may limit their daily functioning. As a result, in many patients, epilepsy may resemble a neurodegenerative disease. Epileptic seizures and their potential impact on brain development, the progressive nature of epileptogenesis that may functionally alter brain regions involved in cognitive processing, neurodegenerative processes that relate to the underlying etiology, comorbid conditions or epigenetic factors, such as stress, medications, social factors, may all contribute to the progressive nature of epilepsy. Clinical and experimental studies have addressed the pathogenetic mechanisms underlying epileptogenesis and neurodegeneration.

We will primarily focus on the findings derived from studies on one of the most common causes of focal onset epilepsy, the temporal lobe epilepsy, which indicate that both processes are progressive and utilize common or interacting pathways. In this chapter we will discuss some of these studies, the potential candidate targets for neuroprotective therapies as well as the attempts to identify early biomarkers of progression and epileptogenesis, so as to implement therapies with early-onset disease-modifying effects.


Status Epilepticus Temporal Lobe Epilepsy Lipoic Acid Hippocampal Sclerosis Temporal Lobe Epilepsy Patient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Hirtz D, Thurman DJ, Gwinn-Hardy K et al. How common are the “common” neurologic disorders? Neurology 2007; 68:326–337.PubMedGoogle Scholar
  2. 2.
    WHO. Epilepsy. Fact Sheet 2009. Scholar
  3. 3.
    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; 46:470–472.PubMedGoogle Scholar
  4. 4.
    Engel J Jr. A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE Task Force on Classification and Terminology. Epilepsia 2001; 42:796–803.PubMedGoogle Scholar
  5. 5.
    Engel J Jr. Do we belittle epilepsy by calling it a disorder rather than a disease? Epilepsia 2010; 51:2363–2364.PubMedGoogle Scholar
  6. 6.
    Pitkanen A. Therapeutic approaches to epileptogenesis—hope on the horizon. Epilepsia 2010; 51 Suppl 3:2–17.PubMedGoogle Scholar
  7. 7.
    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; 51:676–685.PubMedGoogle Scholar
  8. 8.
    Escayg A, Goldin AL. Sodium channel SCN1A and epilepsy: mutations and mechanisms. Epilepsia 2010; 51:1650–1658.PubMedGoogle Scholar
  9. 9.
    Galanopoulou AS. Dissociated gender-specific effects of recurrent seizures on GABA signaling in CA1 pyramidal neurons: role of GABA(A) receptors. J Neurosci 2008; 28:1557–1567.PubMedGoogle Scholar
  10. 10.
    Macdonald RL, Kang JQ, Gallagher MJ. Mutations in GABAA receptor subunits associated with genetic epilepsies. J Physiol 2010; 588:1861–1869.PubMedGoogle Scholar
  11. 11.
    Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989; 30:389–399.Google Scholar
  12. 12.
    Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000; 342:314–319.PubMedGoogle Scholar
  13. 13.
    Brodie MJ. Diagnosing and predicting refractory epilepsy. Acta Neurol Scand Suppl 2005; 181:36–39.PubMedGoogle Scholar
  14. 14.
    French JA, Williamson PD, Thadani VM et al. Characteristics of medial temporal lobe epilepsy: I. Results of history and physical examination. Ann Neurol 1993; 34:774–780.PubMedGoogle Scholar
  15. 15.
    Engel J Jr. Introduction to temporal lobe epilepsy. Epilepsy Res 1996; 26:141–150.PubMedGoogle Scholar
  16. 16.
    Engel J Jr. Mesial temporal lobe epilepsy: what have we learned? Neuroscientist 2001; 7:340–352.PubMedGoogle Scholar
  17. 17.
    Engel J. Natural history of mesial temporal lobe epilepsy with hippocampal sclerosis: how does kindling compare with other commonly used animal models? In: Corcoran ME, Moshé SL, eds. Kindling 6. New York: Springer, 2005:371–384.Google Scholar
  18. 18.
    Kwan P, Brodie MJ. Neuropsychological effects of epilepsy and antiepileptic drugs. Lancet 2001; 357:216–222.PubMedGoogle Scholar
  19. 19.
    Motamedi G, Meador K. Epilepsy and cognition. Epilepsy Behav 2003; 4 Suppl 2:S25–S38.PubMedGoogle Scholar
  20. 20.
    Andersson-Roswall L, Engman E, Samuelsson H et al. Cognitive outcome 10 years after temporal lobe epilepsy surgery: a prospective controlled study. Neurology 2010; 74:1977–1985.PubMedGoogle Scholar
  21. 21.
    Hermann B, Seidenberg M, Bell B et al. The neurodevelopmental impact of childhood-onset temporal lobe epilepsy on brain structure and function. Epilepsia 2002; 43:1062–1071.PubMedGoogle Scholar
  22. 22.
    O’Leary DS, Lovell MR, Sackellares JC et al. Effects of age of onset of partial and generalized seizures on neuropsychological performance in children. J Nerv Ment Dis 1983; 171:624–629.PubMedGoogle Scholar
  23. 23.
    T assinari CA, Michelucci R, Forti A et al. The electrical status epilepticus syndrome. Epilepsy Res Suppl 1992; 6:111–115.PubMedGoogle Scholar
  24. 24.
    Galanopoulou AS, Bojko A, Lado F et al. The spectrum of neuropsychiatric abnormalities associated with electrical status epilepticus in sleep. Brain Dev 2000; 22:279–295.PubMedGoogle Scholar
  25. 25.
    McVicar KA, Shinnar S. Landau-Kleffner syndrome, electrical status epilepticus in slow wave sleep and language regression in children. Ment Retard Dev Disabil Res Rev 2004; 10:144–149.PubMedGoogle Scholar
  26. 26.
    Tassinari CA, Rubboli G. Cognition and paroxysmal EEG activities: from a single spike to electrical status epilepticus during sleep. Epilepsia 2006; 47 Suppl 2:40–43.PubMedGoogle Scholar
  27. 27.
    Hrachovy RA, Frost JD Jr. Infantile epileptic encephalopathy with hypsarrhythmia (infantile spasms/West syndrome). J Clin Neurophysiol 2003; 20:408–425.PubMedGoogle Scholar
  28. 28.
    Lombroso CT. A prospective study of infantile spasms: clinical and therapeutic correlations. Epilepsia 1983; 24:135–158.PubMedGoogle Scholar
  29. 29.
    Berg AT, Cross JH. Towards a modern classification of the epilepsies? Lancet Neurol 2010:9.Google Scholar
  30. 30.
    Partikian A, Mitchell WG. Neurodevelopmental and epilepsy outcomes in a North American cohort of patients with infantile spasms. J Child Neurol 2010; 25:423–428.PubMedGoogle Scholar
  31. 31.
    Pellock JM, Hrachovy R, Shinnar S et al. Infantile spasms: a US consensus report. Epilepsia 2010; 51:2175–2189.PubMedGoogle Scholar
  32. 32.
    Koo B, Hwang PA, Logan WJ. Infantile spasms: outcome and prognostic factors of cryptogenic and symptomatic groups. Neurology 1993; 43:2322–2327.PubMedGoogle Scholar
  33. 33.
    Lux AL, Edwards SW, Hancock E et al. The United Kingdom Infantile Spasms Study (UKISS) comparing hormone treatment with vigabatrin on developmental and epilepsy outcomes to age 14 months: a multicentre randomised trial. Lancet Neurol 2005; 4:712–717.PubMedGoogle Scholar
  34. 34.
    Primec ZR, Stare J, Neubauer D. The risk of lower mental outcome in infantile spasms increases after three weeks of hypsarrhythmia duration. Epilepsia 2006; 47:2202–2205.PubMedGoogle Scholar
  35. 35.
    Kivity S, Lerman P, Ariel R et al. Long-term cognitive outcomes of a cohort of children with cryptogenic infantile spasms treated with high-dose adrenocorticotropic hormone. Epilepsia 2004; 45:255–262.PubMedGoogle Scholar
  36. 36.
    Darke K, Edwards SW, Hancock E et al. Developmental and epilepsy outcomes at age 4 years in the UKISS trial comparing hormonal treatments to vigabatrin for infantile spasms: a multi-centre randomised trial. Arch Dis Child 2010; 95:382–386.PubMedGoogle Scholar
  37. 37.
    Riikonen RS. Favourable prognostic factors with infantile spasms. Eur J Paediatr Neurol 2010; 14:13–18.PubMedGoogle Scholar
  38. 38.
    Giblin KA, Blumenfeld H. Is epilepsy a preventable disorder? New evidence from animal models. Neuroscientist 2010; 16:253–275.PubMedGoogle Scholar
  39. 39.
    Naegele JR. Neuroprotective strategies to avert seizure-induced neurodegeneration in epilepsy. Epilepsia 2007; 48 Suppl 2:107–117.PubMedGoogle Scholar
  40. 40.
    Albala BJ, Moshe SL, Okada R. Kainic-acid-induced seizures: a developmental study. Brain Res 1984; 315:139–148.PubMedGoogle Scholar
  41. 41.
    Stafstrom CE, Thompson JL, Holmes GL. Kainic acid seizures in the developing brain: status epilepticus and spontaneous recurrent seizures. Brain Res Dev Brain Res 1992; 65:227–236.PubMedGoogle Scholar
  42. 42.
    Galanopoulou AS, Vidaurre J, Moshe SL. Under what circumstances can seizures produce hippocampal injury: evidence for age-specific effects. Dev Neurosci 2002; 24:355–363.PubMedGoogle Scholar
  43. 43.
    Galanopoulou AS, Alm EM, Veliskova J. Estradiol reduces seizure-induced hippocampal injury in ovariectomized female but not in male rats. Neurosci Lett 2003; 342:201–205.PubMedGoogle Scholar
  44. 44.
    Raol YS, Budreck EC, Brooks-Kayal AR. Epilepsy after early-life seizures can be independent of hippocampal injury. Ann Neurol 2003; 53:503–511.PubMedGoogle Scholar
  45. 45.
    Shapiro LA, Wang L, Ribak CE. Rapid astrocyte and microglial activation following pilocarpine-induced seizures in rats. Epilepsia 2008; 49 Suppl 2:33–41.PubMedGoogle Scholar
  46. 46.
    Pitkanen A, Sutula TP. Is epilepsy a progressive disorder? Prospects for new therapeutic approaches in temporal-lobe epilepsy. Lancet Neurol 2002; 1:173–181.PubMedGoogle Scholar
  47. 47.
    Vezzani A, Ravizza T, Balosso S et al. Glia as a source of cytokines: implications for neuronal excitability and survival. Epilepsia 2008; 49 Suppl 2:24–32.PubMedGoogle Scholar
  48. 48.
    de Lanerolle NC, Lee TS, Spencer DD. Astrocytes and epilepsy. Neurotherapeutics 2010; 7:424–438.PubMedGoogle Scholar
  49. 49.
    Yang T, Zhou D, Stefan H. Why mesial temporal lobe epilepsy with hippocampal sclerosis is progressive: uncontrolled inflammation drives disease progression? J Neurol Sci 2010; 296:1–6.PubMedGoogle Scholar
  50. 50.
    Wang YY, Smith P, Murphy M et al. Global expression profiling in epileptogenesis: does it add to the confusion? Brain Pathol 2010; 20:1–16.PubMedGoogle Scholar
  51. 51.
    Cavazos JE, Cross DJ. The role of synaptic reorganization in mesial temporal lobe epilepsy. Epilepsy Behav 2006; 8:483–493.PubMedGoogle Scholar
  52. 52.
    Boyett JM, Buckmaster PS. Somatostatin-immunoreactive interneurons contribute to lateral inhibitory circuits in the dentate gyrus of control and epileptic rats. Hippocampus 2001; 11:418–422.PubMedGoogle Scholar
  53. 53.
    Buckmaster PS, Dudek FE. In vivo intracellular analysis of granule cell axon reorganization in epileptic rats. J Neurophysiol 1999; 81:712–721.PubMedGoogle Scholar
  54. 54.
    Sutula T. Seizure-induced axonal sprouting: assessing connections between injury, local circuits and epileptogenesis. Epilepsy Curr 2002; 2:86–91.PubMedGoogle Scholar
  55. 55.
    Lopantsev V, Both M, Draguhn A. Rapid plasticity at inhibitory and excitatory synapses in the hippocampus induced by ictal epileptiform discharges. Eur J Neurosci 2009; 29:1153–1164.PubMedGoogle Scholar
  56. 56.
    Badawy RA, Harvey AS, Macdonell RA. Cortical hyperexcitability and epileptogenesis: understanding the mechanisms of epilepsy—part 2. J Clin Neurosci 2009; 16:485–500.PubMedGoogle Scholar
  57. 57.
    André VM, Cepeda C, Vinters HV et al. Interneurons, GABAA currents and subunit composition of the GABAA receptor in type I and type II cortical dysplasia. Epilepsia 2010; 51(Suppl 3):166–170.PubMedGoogle Scholar
  58. 58.
    Cepeda C, André VM, Yamazaki I et al. Comparative study of cellular and synaptic abnormalities in brain tissue samples from pediatric tuberous sclerosis complex and cortical dysplasia type II. Epilepsia 2010; 51(Suppl 3):160–165.PubMedGoogle Scholar
  59. 59.
    Rivera C, Voipio J, Thomas-Crusells J et al. Mechanism of activity-dependent downregulation of the neuron-specific K-Cl cotransporter KCC2. J Neurosci 2004; 24:4683–4691.PubMedGoogle Scholar
  60. 60.
    Brooks-Kayal AR, Raol YH, Russek SJ. Alteration of epileptogenesis genes. Neurotherapeutics 2009; 6:312–318.PubMedGoogle Scholar
  61. 61.
    Ben-Ari Y. Excitatory actions of gaba during development: the nature of the nurture. Nat Rev Neurosci 2002; 3:728–739.PubMedGoogle Scholar
  62. 62.
    Galanopoulou AS. GABA(A) receptors in normal development and seizures: friends or foes? Curr Neuropharmacol 2008; 6:1–20.PubMedGoogle Scholar
  63. 63.
    Rakhade SN, Jensen FE. Epileptogenesis in the immature brain: emerging mechanisms. Nat Rev Neurol 2009; 5:380–391.PubMedGoogle Scholar
  64. 64.
    Knudsen EI. Sensitive periods in the development of the brain and behavior. J Cogn Neurosci 2004; 16:1412–1425.PubMedGoogle Scholar
  65. 65.
    Ben-Ari Y, Holmes GL. Effects of seizures on developmental processes in the immature brain. Lancet Neurol 2006; 5:1055–1063.PubMedGoogle Scholar
  66. 66.
    Sanchez RM, Koh S, Rio C et al. Decreased glutamate receptor 2 expression and enhanced epileptogenesis in immature rat hippocampus after perinatal hypoxia-induced seizures. J Neurosci 2001; 21:8154–8163.PubMedGoogle Scholar
  67. 67.
    Zhang G, Raol YH, Hsu FC et al. Effects of status epilepticus on hippocampal GABAA receptors are age-dependent. Neuroscience 2004; 125:299–303.PubMedGoogle Scholar
  68. 68.
    Isaeva E, Isaev D, Khazipov R et al. Selective impairment of GABAergic synaptic transmission in the flurothyl model of neonatal seizures. Eur J Neurosci 2006; 23:1559–1566.PubMedGoogle Scholar
  69. 69.
    Swann JW, Le JT, Lee CL. Recurrent seizures and the molecular maturation of hippocampal and neocortical glutamatergic synapses. Dev Neurosci 2007; 29:168–178.PubMedGoogle Scholar
  70. 70.
    O’Reilly RC. Biologically based computational models of high-level cognition. Science 2006; 314:91–94.PubMedGoogle Scholar
  71. 71.
    Veliskova J, Moshe SL. Sexual dimorphism and developmental regulation of substantia nigra function. Ann Neurol 2001; 50:596–601.PubMedGoogle Scholar
  72. 72.
    Galanopoulou AS, Moshe SL. The epileptic hypothesis: developmentally related arguments based on animal models. Epilepsia 2009; 50 Suppl 7:37–42.PubMedGoogle Scholar
  73. 73.
    Cancedda L, Fiumelli H, Chen K et al. Excitatory GABA action is essential for morphological maturation of cortical neurons in vivo. J Neurosci 2007; 27:5224–5235.PubMedGoogle Scholar
  74. 74.
    Wang DD, Kriegstein AR. GABA regulates excitatory synapse formation in the neocortex via NMDA receptor activation. J Neurosci 2008; 28:5547–5558.PubMedGoogle Scholar
  75. 75.
    Mathern GW, Babb TL, Armstrong TM. Hippocampal sclerosis. Philadelphia: Lippincott-Raven, 1997:133–155.Google Scholar
  76. 76.
    Thom M, Sisodiya SM, Beckett A et al. Cytoarchitectural abnormalities in hippocampal sclerosis. J Neuropathol Exp Neurol 2002; 61:510–519.PubMedGoogle Scholar
  77. 77.
    Blumcke I, Zuschratter W, Schewe JC et al. Cellular pathology of hilar neurons in ammon’s horn sclerosis. J Comp Neurol 1999; 414:437–453.PubMedGoogle Scholar
  78. 78.
    Kalviainen R, Salmenpera T, Partanen K et al. Recurrent seizures may cause hippocampal damage in temporal lobe epilepsy. Neurology 1998; 50:1377–1382.PubMedGoogle Scholar
  79. 79.
    Theodore WH, Bhatia S, Hatta J et al. Hippocampal atrophy, epilepsy duration and febrile seizures in patients with partial seizures. Neurology 1999; 52:132–136.PubMedGoogle Scholar
  80. 80.
    Tasch E, Cendes F, Li LM et al. Neuroimaging evidence of progressive neuronal loss and dysfunction in temporal lobe epilepsy. Ann Neurol 1999; 45:568–576.PubMedGoogle Scholar
  81. 81.
    Salmenpera T, Kalviainen R, Partanen K et al. Hippocampal and amygdaloid damage in partial epilepsy: a cross-sectional MRI study of 241 patients. Epilepsy Res 2001; 46:69–82.PubMedGoogle Scholar
  82. 82.
    Cendes F, Andermann F, Gloor P et al. Atrophy of mesial structures in patients with temporal lobe epilepsy: cause or consequence of repeated seizures? Ann Neurol 1993; 34:795–801.PubMedGoogle Scholar
  83. 83.
    Spanaki MV, Kopylev L, Liow K et al. Relationship of seizure frequency to hippocampus volume and metabolism in temporal lobe epilepsy. Epilepsia 2000; 41:1227–1229.PubMedGoogle Scholar
  84. 84.
    Mathern GW, Adelson PD, Cahan LD et al. Hippocampal neuron damage in human epilepsy: Meyer’s hypothesis revisited. Prog Brain Res 2002; 135:237–251.PubMedGoogle Scholar
  85. 85.
    Cavazos JE, Sutula TP. Progressive neuronal loss induced by kindling: a possible mechanism for mossy fiber synaptic reorganization and hippocampal sclerosis. Brain Res 1990; 527:1–6.PubMedGoogle Scholar
  86. 86.
    Cavazos JE, Das I, Sutula TP. Neuronal loss induced in limbic pathways by kindling: evidence for induction of hippocampal sclerosis by repeated brief seizures. J Neurosci 1994; 14:3106–3121.PubMedGoogle Scholar
  87. 87.
    Bengzon J, Kokaia Z, Elmer E et al. Apoptosis and proliferation of dentate gyrus neurons after single and intermittent limbic seizures. Proc Natl Acad Sci USA 1997; 94:10432–10437.PubMedGoogle Scholar
  88. 88.
    Pretel S, Applegate CD, Piekut D. Apoptotic and necrotic cell death following kindling induced seizures. Acta Histochem 1997; 99:71–79.PubMedGoogle Scholar
  89. 89.
    Kotloski R, Lynch M, Lauersdorf S et al. Repeated brief seizures induce progressive hippocampal neuron loss and memory deficits. Prog Brain Res 2002; 135:95–110.PubMedGoogle Scholar
  90. 90.
    Lowenstein DH. Epilepsy after head injury: an overview. Epilepsia 2009; 50 Suppl 2:4–9.PubMedGoogle Scholar
  91. 91.
    Agrawal A, Timothy J, Pandit L et al. Post-traumatic epilepsy: an overview. Clin Neurol Neurosurg 2006; 108:433–439.PubMedGoogle Scholar
  92. 92.
    Willmore LJ, Ueda Y. Posttraumatic epilepsy: hemorrhage, free radicals and the molecular regulation of glutamate. Neurochem Res 2009; 34:688–697.PubMedGoogle Scholar
  93. 93.
    Willmore LJ, Sypert GW, Munson JB. Recurrent seizures induced by cortical iron injection: a model of posttraumatic epilepsy. Ann Neurol 1978; 4:329–336.PubMedGoogle Scholar
  94. 94.
    Sharma V, Babu PP, Singh A et al. Iron-induced experimental cortical seizures: electroencephalographic mapping of seizure spread in the subcortical brain areas. Seizure 2007; 16:680–690.PubMedGoogle Scholar
  95. 95.
    Reilly PL. Brain injury: the pathophysiology of the first hours. ‘Talk and die revisited’. J Clin Neurosci 2001; 8:398–403.PubMedGoogle Scholar
  96. 96.
    Thompson HJ, Lifshitz J, Marklund N et al. Lateral fluid percussion brain injury: a 15-year review and evaluation. J Neurotrauma 2005; 22:42–75.PubMedGoogle Scholar
  97. 97.
    Pitkanen A, McIntosh TK. Animal models of posttraumatic epilepsy. J Neurotrauma 2006; 23:241–261.PubMedGoogle Scholar
  98. 98.
    Pitkanen A, Immonen RJ, Grohn OH et al. From traumatic brain injury to posttraumatic epilepsy: what animal models tell us about the process and treatment options. Epilepsia 2009; 50 Suppl 2:21–29.PubMedGoogle Scholar
  99. 99.
    Coulter DA, Rafiq A, Shumate M et al. Brain injury-induced enhanced limbic epileptogenesis: anatomical and physiological parallels to an animal model of temporal lobe epilepsy. Epilepsy Res 1996; 26:81–91.PubMedGoogle Scholar
  100. 100.
    Reeves TM, Lyeth BG, Phillips LL et al. The effects of traumatic brain injury on inhibition in the hippocampus and dentate gyrus. Brain Res 1997; 757:119–132.PubMedGoogle Scholar
  101. 101.
    Mendez M, Lim G. Seizures in elderly patients with dementia: epidemiology and management. Drugs Aging 2003; 20:791–803.PubMedGoogle Scholar
  102. 102.
    Larner AJ. Epileptic seizures in AD patients. Neuromolecular Med 2010; 2010:71–77.Google Scholar
  103. 103.
    Minkeviciene R, Rheims S, Dobszay MB et al. Amyloid beta-induced neuronal hyperexcitability triggers progressive epilepsy. J Neurosci 2009; 29:3453–3462.PubMedGoogle Scholar
  104. 104.
    Palop JJ, Chin J, Roberson ED et al. Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer’s disease. Neuron 2007; 55:697–711.PubMedGoogle Scholar
  105. 105.
    Roch C, Leroy C, Nehlig A et al. Magnetic resonance imaging in the study of the lithium-pilocarpine model of temporal lobe epilepsy in adult rats. Epilepsia 2002; 43:325–335.PubMedGoogle Scholar
  106. 106.
    Roch C, Leroy C, Nehlig A et al. Predictive value of cortical injury for the development of temporal lobe epilepsy in 21-day-old rats: an MRI approach using the lithium-pilocarpine model. Epilepsia 2002; 43:1129–1136.PubMedGoogle Scholar
  107. 107.
    Wieshmann UC, Woermann FG, Lemieux L et al. Development of hippocampal atrophy: a serial magnetic resonance imaging study in a patient who developed epilepsy after generalized status epilepticus. Epilepsia 1997; 38:1238–1241.PubMedGoogle Scholar
  108. 108.
    Van Landingham KE, Heinz ER, Cavazos JE et al. Magnetic resonance imaging evidence of hippocampal injury after prolonged focal febrile convulsions. Ann Neurol 1998; 43:413–426.Google Scholar
  109. 109.
    Kuster GW, Braga-Neto P, Santos-Neto D et al. Hippocampal sclerosis and status epilepticus: cause or consequence? A MRI study. Arq Neuropsiquiatr 2007; 65:1101–1104.PubMedGoogle Scholar
  110. 110.
    Tokumitsu T, Mancuso A, Weinstein PR et al. Metabolic and pathological effects of temporal lobe epilepsy in rat brain detected by proton spectroscopy and imaging. Brain Res 1997; 744:57–67.PubMedGoogle Scholar
  111. 111.
    Connelly A, Van Paesschen W, Porter DA et al. Proton magnetic resonance spectroscopy in MRI-negative temporal lobe epilepsy. Neurology 1998; 51:61–66.PubMedGoogle Scholar
  112. 112.
    Woermann FG, McLean MA, Bartlett PA et al. Short echo time single-voxel 1H magnetic resonance spectroscopy in magnetic resonance imaging-negative temporal lobe epilepsy: different biochemical profile compared with hippocampal sclerosis. Ann Neurol 1999; 45:369–376.PubMedGoogle Scholar
  113. 113.
    Shih JJ, Weisend MP, Lewine J et al. Areas of interictal spiking are associated with metabolic dysfunction in MRI-negative temporal lobe epilepsy. Epilepsia 2004; 45:223–229.PubMedGoogle Scholar
  114. 114.
    Gomes WA, Lado FA, de Lanerolle NC et al. Spectroscopic imaging of the pilocarpine model of human epilepsy suggests that early NAA reduction predicts epilepsy. Magn Reson Med 2007; 58:230–235.PubMedGoogle Scholar
  115. 115.
    Shen J, Zhang L, Tian X et al. Use of short echo time two-dimensional 1H-magnetic resonance spectroscopy in temporal lobe epilepsy with negative magnetic resonance imaging findings. J Int Med Res 2009; 37:1211–1219.PubMedGoogle Scholar
  116. 116.
    Rugg-Gunn FJ, Eriksson SH, Symms MR et al. Diffusion tensor imaging of cryptogenic and acquired partial epilepsies. Brain 2001; 124:627–636.PubMedGoogle Scholar
  117. 117.
    Dube C, Yu H, Nalcioglu O et al. Serial MRI after experimental febrile seizures: altered T2 signal without neuronal death. Ann Neurol 2004; 56:709–714.PubMedGoogle Scholar
  118. 118.
    Nairismagi J, Grohn OH, Kettunen MI et al. Progression of brain damage after status epilepticus and its association with epileptogenesis: a quantitative MRI study in a rat model of temporal lobe epilepsy. Epilepsia 2004; 45:1024–1034.PubMedGoogle Scholar
  119. 119.
    Kim CH, Koo BB, Chung CK et al. Thalamic changes in temporal lobe epilepsy with and without hippocampal sclerosis: a diffusion tensor imaging study. Epilepsy Res 2010; 90:21–27.PubMedGoogle Scholar
  120. 120.
    Liacu D, de Marco G, Ducreux D et al. Diffusion tensor changes in epileptogenic hippocampus of TLE patients. Neurophysiol Clin 2010; 40:151–157.PubMedGoogle Scholar
  121. 121.
    Shon YM, Kim YI, Koo BB et al. Group-specific regional white matter abnormality revealed in diffusion tensor imaging of medial temporal lobe epilepsy without hippocampal sclerosis. Epilepsia 2010; 51:529–535.PubMedGoogle Scholar
  122. 122.
    Mirrione MM, Schiffer WK, Siddiq M et al. PET imaging of glucose metabolism in a mouse model of temporal lobe epilepsy. Synapse 2006; 59:119–121.PubMedGoogle Scholar
  123. 123.
    Jupp B, O’Brien TJ. Application of coregistration for imaging of animal models of epilepsy. Epilepsia 2007; 48 Suppl 4:82–89.PubMedGoogle Scholar
  124. 124.
    Goffin K, Van Paesschen W, Dupont P et al. Longitudinal microPET imaging of brain glucose metabolism in rat lithium-pilocarpine model of epilepsy. Exp Neurol 2009; 217:205–209.PubMedGoogle Scholar
  125. 125.
    Guo Y, Gao F, Wang S et al. In vivo mapping of temporospatial changes in glucose utilization in rat brain during epileptogenesis: an 18F-fluorodeoxyglucose-small animal positron emission tomography study. Neuroscience 2009; 162:972–979.PubMedGoogle Scholar
  126. 126.
    Shinnar S, Kang H, Berg AT et al. EEG abnormalities in children with a first unprovoked seizure. Epilepsia 1994; 35:471–476.PubMedGoogle Scholar
  127. 127.
    Shinnar S, Berg AT, Moshe SL et al. The risk of seizure recurrence after a first unprovoked afebrile seizure in childhood: an extended follow-up. Pediatrics 1996; 98:216–225.PubMedGoogle Scholar
  128. 128.
    Berg AT, Shinnar S, Levy SR et al. Early development of intractable epilepsy in children: a prospective study. Neurology 2001; 56:1445–1452.PubMedGoogle Scholar
  129. 129.
    Spooner CG, Berkovic SF, Mitchell LA et al. New-onset temporal lobe epilepsy in children: lesion on MRI predicts poor seizure outcome. Neurology 2006; 67:2147–2153.PubMedGoogle Scholar
  130. 131.
    Shinnar S, Hesdorffer DC, Nordli DR Jr et al. Phenomenology of prolonged febrile seizures: results of the FEBSTAT study. Neurology 2008; 71:170–176.PubMedGoogle Scholar
  131. 132.
    Beume LA, Steinhoff BJ. Long-term outcome of difficult-to-treat epilepsy in childhood. Neuropediatrics 2010; 41:135–139.PubMedGoogle Scholar
  132. 133.
    Sutula TP, Hagen J, Pitkanen A. Do epileptic seizures damage the brain? Curr Opin Neurol 2003; 16:189–195.PubMedGoogle Scholar
  133. 134.
    Gleissner U, Sassen R, Schramm J et al. Greater functional recovery after temporal lobe epilepsy surgery in children. Brain 2005; 128:2822–2829.PubMedGoogle Scholar
  134. 135.
    Jambaque I, Dellatolas G, Dulac O et al. Verbal and visual memory impairment in children with epilepsy. Neuropsychologia 1993; 31:1321–1337.PubMedGoogle Scholar
  135. 136.
    Elsharkawy AE, May T, Thorbecke R et al. Long-term outcome and determinants of quality of life after temporal lobe epilepsy surgery in adults. Epilepsy Res 2009; 86:191–199.PubMedGoogle Scholar
  136. 137.
    Jonas R, Nguyen S, Hu B et al. Cerebral hemispherectomy: hospital course, seizure, developmental, language and motor outcomes. Neurology 2004; 62:1712–1721.PubMedGoogle Scholar
  137. 138.
    Tubbs RS, Nimjee SM, Oakes WJ. Long-term follow-up in children with functional hemispherectomy for Rasmussen’s encephalitis. Childs Nerv Syst 2005; 21:461–465.PubMedGoogle Scholar
  138. 139.
    Bittigau P, Sifringer M, Ikonomidou C. Antiepileptic drugs and apoptosis in the developing brain. Ann N Y Acad Sci 2003; 993:103–114.PubMedGoogle Scholar
  139. 140.
    Dhanushkodi A, Shetty AK. Is exposure to enriched environment beneficial for functional post-lesional recovery in temporal lobe epilepsy? Neurosci Biobehav Rev 2008; 32:657–674.PubMedGoogle Scholar
  140. 141.
    Hamed SA. The multimodal prospects for neuroprotection and disease modification in epilepsy: relationship to its challenging neurobiology. Restor Neurol Neurosci 2010; 28:323–348.PubMedGoogle Scholar
  141. 142.
    Sutula T, Cavazos J, Golarai G. Alteration of long-lasting structural and functional effects of kainic acid in the hippocampus by brief treatment with phenobarbital. J Neurosci 1992; 12:4173–4187.PubMedGoogle Scholar
  142. 143.
    Pitkanen A, Kubova H. Antiepileptic drugs in neuroprotection. Expert Opin Pharmacother 2004; 5:777–798.PubMedGoogle Scholar
  143. 144.
    Yan HD, Ji-qun C, Ishihara K et al. Separation of antiepileptogenic and antiseizure effects of levetiracetam in the spontaneously epileptic rat (SER). Epilepsia 2005; 46:1170–1177.PubMedGoogle Scholar
  144. 145.
    Blumenfeld H, Klein JP, Schridde U et al. Early treatment suppresses the development of spike-wave epilepsy in a rat model. Epilepsia 2008; 49:400–409.PubMedGoogle Scholar
  145. 146.
    Muller-Schwarze AB, Tandon P, Liu Z et al. Ketogenic diet reduces spontaneous seizures and mossy fiber sprouting in the kainic acid model. Neuroreport 1999; 10:1517–1522.PubMedGoogle Scholar
  146. 147.
    Meyerhoff JL, Lee JK, Rittase BW et al. Lipoic acid pretreatment attenuates ferric chloride-induced seizures in the rat. Brain Res 2004; 1016:139–144.PubMedGoogle Scholar
  147. 148.
    Yokoi I, Toma J, Liu J et al. Adenosines scavenged hydroxyl radicals and prevented posttraumatic epilepsy. Free Radic Biol Med 1995; 19:473–479.PubMedGoogle Scholar
  148. 149.
    Kabuto H, Yokoi I, Ogawa N. Melatonin inhibits iron-induced epileptic discharges in rats by suppressing peroxidation. Epilepsia 1998; 39:237–243.PubMedGoogle Scholar
  149. 150.
    Miyamoto R, Shimakawa S, Suzuki S et al. Edaravone prevents kainic acid-induced neuronal death. Brain Res 2008; 1209:85–91.PubMedGoogle Scholar
  150. 151.
    Kamida T, Fujiki M, Ooba H et al. Neuroprotective effects of edaravone, a free radical scavenger, on the rat hippocampus after pilocarpine-induced status epilepticus. Seizure 2009; 18:71–75.PubMedGoogle Scholar
  151. 152.
    Komatsu M, Hiramatsu M, Willmore LJ. Zonisamide reduces the increase in 8-hydroxy-2′-deoxyguanosine levels formed during iron-induced epileptogenesis in the brains of rats. Epilepsia 2000; 41:1091–1094.PubMedGoogle Scholar
  152. 153.
    Mori A, Yokoi I, Noda Y et al. Natural antioxidants may prevent posttraumatic epilepsy: a proposal based on experimental animal studies. Acta Med Okayama 2004; 58:111–118.PubMedGoogle Scholar
  153. 154.
    Guo X, Dawson VL, Dawson TM. Neuroimmunophilin ligands exert neuroregeneration and neuroprotection in midbrain dopaminergic neurons. Eur J Neurosci 2001; 13:1683–1693.PubMedGoogle Scholar
  154. 155.
    Chen CM, Lin JK, Liu SH et al. Novel regimen through combination of memantine and tea polyphenol for neuroprotection against brain excitotoxicity. J Neurosci Res 2008; 86:2696–2704.PubMedGoogle Scholar
  155. 156.
    Paradiso B, Marconi P, Zucchini S et al. Localized delivery of fibroblast growth factor-2 and brain-derived neurotrophic factor reduces spontaneous seizures in an epilepsy model. Proc Natl Acad Sci USA 2009; 106:7191–7196.PubMedGoogle Scholar
  156. 157.
    Noe F, Nissinen J, Pitkanen A et al. Gene therapy in epilepsy: the focus on NPY. Peptides 2007; 28:377–383.PubMedGoogle Scholar
  157. 158.
    Moldrich RX, Chapman AG, De Sarro G et al. Glutamate metabotropic receptors as targets for drug therapy in epilepsy. Eur J Pharmacol 2003; 476:3–16.PubMedGoogle Scholar
  158. 159.
    Elliott-Hunt CR, Kazlauskaite J, Wilde GJ et al. Potential signalling pathways underlying corticotrophin-releasing hormone-mediated neuroprotection from excitotoxicity in rat hippocampus. J Neurochem 2002; 80:416–425.PubMedGoogle Scholar
  159. 160.
    Napolioni V, Moavero R, Curatolo P. Recent advances in neurobiology of Tuberous Sclerosis Complex. Brain Dev 2009; 31:104–113.PubMedGoogle Scholar
  160. 161.
    Holmes GL, Stafstrom CE. Tuberous sclerosis complex and epilepsy: recent developments and future challenges. Epilepsia 2007; 48:617–630.PubMedGoogle Scholar
  161. 162.
    Wong M. Mechanisms of epileptogenesis in tuberous sclerosis complex and related malformations of cortical development with abnormal glioneuronal proliferation. Epilepsia 2008; 49:8–21.PubMedGoogle Scholar
  162. 163.
    Zeng LH, Rensing NR, Wong M. The mammalian target of rapamycin signaling pathway mediates epileptogenesis in a model of temporal lobe epilepsy. J Neurosci 2009; 29:6964–6972.PubMedGoogle Scholar
  163. 164.
    Ljungberg MC, Sunnen CN, Lugo JN et al. Rapamycin suppresses seizures and neuronal hypertrophy in a mouse model of cortical dysplasia. Dis Model Mech 2009; 2:389–398.PubMedGoogle Scholar
  164. 165.
    Naegele JR, Maisano X, Yang J et al. Recent advancements in stem cell and gene therapies for neurological disorders and intractable epilepsy. Neuropharmacology 2010; 58:855–864.PubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2012

Authors and Affiliations

  1. 1.Saul R. Korey Department of NeurologyAlbert Einstein College of MedicineBronxUSA
  2. 2.Dominick P. Purpura Department of NeuroscienceAlbert Einstein College of MedicineBronxUSA

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