Febrile Seizures and Mechanisms of Epileptogenesis: Insights from an Animal Model

  • Roland A. Bender
  • Celine Dubé
  • Tallie Z. Baram
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 548)


Temporal lobe epilepsy (TLE) is the most prevalent type of human epilepsy, yet the causes for its development, and the processes involved, are not known. Most individuals with TLE do not have a family history, suggesting that this limbic epilepsy is a consequence of acquired rather than genetic causes. Among suspected etiologies, febrile seizures have frequently been cited. This is due to the fact that retrospective analyses of adults with TLE have demonstrated a high prevalence (20->60%) of a history of prolonged febrile seizures during early childhood, suggesting an etiological role for these seizures in the development of TLE. Specifically, neuronal damage induced by febrile seizures has been suggested as a mechanism for the development of mesial temporal sclerosis, the pathological hallmark of TLE. However, the statistical correlation between febrile seizures and TLE does not necessarily indicate a causal relationship. For example, preexisting (genetic or acquired) ‘causes’ that result independently in febrile seizures and in TLE would also result in tight statistical correlation. For obvious reasons, complex febrile seizures cannot be induced in the human, and studies of their mechanisms and of their consequences on brain molecules and circuits are severely limited. Therefore, an animal model was designed to study these seizures. The model reproduces the fundamental key elements of the human condition: the age specificity, the physiological temperatures seen in fevers of children, the length of the seizures and their lack of immediate morbidity. Neuroanatomical, molecular and functional methods have been used in this model to determine the consequences of prolonged febrile seizures on the survival and integrity of neurons, and on hyperexcitability in the hippocampal-limbic network. Experimental prolonged febrile seizures did not lead to death of any of the seizure-vulnerable populations in hippocampus, and the rate of neurogenesis was also unchanged Neuronal function was altered sufficiently to promote synaptic reorganization of granule cells, and transient and long-term alterations in the expression of specific genes were observed. The contribution of these consequences of febrile seizures to the epileptogenic process is discussed.


Status Epilepticus Temporal Lobe Epilepsy Mossy Fiber Kainic Acid Febrile Seizure 
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  1. 1.
    Abou-Khalil B, Andermann E, Andermann F et al. Temporal lobe epilepsy after prolonged febrile convulsions: excellent outcome after surgical treatment. Epilepsia 1993; 34: 878 - 883.PubMedCrossRefGoogle Scholar
  2. 2.
    Alldredge BK, Lowenstein DL. Status epilepticus: new concepts. Curr Opin Neurol 1999; 12: 183 - 190.PubMedCrossRefGoogle Scholar
  3. 3.
    Altman J, Bayer SA. Migration and distribution of two populations of hippocampal granule cell precursors during the perinatal and postnatal periods. J Comp Neurol 1990; 301: 365 - 381.PubMedCrossRefGoogle Scholar
  4. 4.
    Amaral DG, Dent JA. Development of the mossy fibers of the dentate gyrus: I. A light and electron microscopic study of the mossy fibers and their expansions. J Comp Neurol 1981; 195: 51 - 86.PubMedCrossRefGoogle Scholar
  5. 5.
    Annegers JF, Hauser WA, Shirts SB et al. Factors prognostic of unprovoked seizures after febrile convulsions. N Engl J Med 1987; 316: 493 - 498.PubMedCrossRefGoogle Scholar
  6. 6.
    Armstrong DD. The neuropathology of temporal lobe epilepsy. J Neuropath Exp Neurol 1993; 52: 433 - 443.PubMedCrossRefGoogle Scholar
  7. 7.
    Avishai-Eliner S, Brunson KL, Sandman CA et al. Stressed out or in (utero)? Trends Neurosci 2002; 25: 518 - 524.PubMedCrossRefGoogle Scholar
  8. 8.
    Baram TZ. Mechanisms and outcome of febrile seizures: What have we learned from basic science approaches, and what needs studying? In: Baram TZ, Shinnar S, eds. Febrile seizures. San Diego, CA: Academic Press, 2002: 325 - 328.Google Scholar
  9. 9.
    Baram TZ, Hirsch E, Snead III OC et al. Corticotropin-releasing hormone-induced seizures in infant rats originate in the amygdala. Ann Neurol 1992; 31: 488 - 494.PubMedCrossRefGoogle Scholar
  10. 10.
    Bender RA, Brewster A, Santoro B et al. Differential and age-dependent expression of hyperpolarization-activated, cyclic nucleotide-gated cation channel isoforms 1-4 suggests evolving roles in the developing rat hippocampus. Neuroscience 2001; 106: 689 - 698.PubMedCrossRefGoogle Scholar
  11. 11.
    Bender RA, Dubé C, Gonzalez-Vega R et al. Mossy fiber plasticity and enhanced hippocampal excitability, without hippocampal cell loss or altered neurogenesis, in an animal model of prolonged febrile seizures. Hippocampus 2002; 13: 399 - 412.CrossRefGoogle Scholar
  12. 12.
    Berg AT, Shinnar S Complex febrile seizures. Epilepsia 1996; 37: 126 - 133.PubMedCrossRefGoogle Scholar
  13. 13.
    Bower SP, Kilpatrick CJ, Vogrin SJ et al. Degree of hippocampal atrophy is not related to a history of febrile seizures in patients with proved hippocampal sclerosis. J Neurol Neurosurg Psychiatry 2000; 69: 733 - 8.PubMedCrossRefGoogle Scholar
  14. 14.
    Brewster A, Bender RA, Chen Y et al. Developmental febrile seizures modulate hippocampal gene expression of hyperpolarization-activated channels in an isoform and cell-specific manner. J Neurosci 2002; 22: 4591 - 4599.PubMedGoogle Scholar
  15. 15.
    Briellmann RS, Kamins RM, Berkovic SF et al. Hippocampal pathology in refractory temporal lobe epilepsy. T2-weighted signal change reflects dentate gliosis. Neurology 2002; 58: 265 - 271.PubMedCrossRefGoogle Scholar
  16. 16.
    Bruton CJ. The neuropathology of temporal lobe epilepsy (Maudsley Monographs, No 31 ). New York, NY: Oxford University Press, 1988.Google Scholar
  17. 17.
    Cendes F, Andermann F, Dubeau F et al. Early childhood prolonged febrile convulsions, atrophy and sclerosis of medial structures and temporal lobe epilepsy. An MRI volumetric study. Neurology 1993; 43: 1083 - 1087.PubMedCrossRefGoogle Scholar
  18. 18.
    Cendes F, Cook MJ, Watson C et al. Frequency and characteristics of dual pathology in patients with lesional epilepsy. Neurology 1995; 45: 2058 - 2064.PubMedCrossRefGoogle Scholar
  19. 19.
    Chen K, Baram TZ, Soltesz I et al. Febrile seizures in the developing brain result in persistent modification of neuronal excitability in limbic circuits. Nat Med 1999; 5: 888 - 894.PubMedCrossRefGoogle Scholar
  20. 20.
    Chen K, Aradi I, Thon N et al. Persistently modified h-channels after complex febrile seizures convert the seizure-induced enhancement of inhibition to hyperexcitability. Nat Med 2001; 7: 331 - 337.PubMedCrossRefGoogle Scholar
  21. 21.
    Cook MJ, Fish DR, Shorvon SD et al. Hippocampal volumetric and morphometric studies in frontal and temporal lobe epilepsy. Brain 1992; 115: 1001 - 1015.PubMedCrossRefGoogle Scholar
  22. 22.
    Cooper AJ, Egleston C. Accidental ingestion of Ecstasy by a toddler: unusual cause for convulsion in a febrile child. J Accid Emerg Med 1997; 14: 183 - 184.PubMedCrossRefGoogle Scholar
  23. 23.
    Coulter DA, DeLorenzo RJ. Basic mechanisms of status epilepticus. Adv Neurol 1999; 79: 725 - 733.PubMedGoogle Scholar
  24. 24.
    Dobbing J, Sands J. Quantitative growth and development of human brain. Arch Dis Child 1973; 48: 757 - 767.PubMedCrossRefGoogle Scholar
  25. 25.
    Engel Jr J, Williamson PD, Wieser HG. Mesial temporal lobe epilepsy. In: Engel Jr J, Pedley TA, eds. Epilepsy: A comprehensive textbook. Philadelphia, PA: Lippincott-Raven Publishers, 1997: 2417 - 2426.Google Scholar
  26. 26.
    DiFrancesco D. Pacemaker mechanisms in cardiac tissue. Annu Rev Physiol 1993; 55: 455 - 472.CrossRefGoogle Scholar
  27. 27.
    Dubé C, Chen K, Eghbal-Ahmadi M et al. Prolonged febrile seizures in the immature rat model enhance hippocampal excitability long term. Ann Neurol 2000; 47: 336 - 344.PubMedCrossRefGoogle Scholar
  28. 28.
    Dubé C. Do prolonged febrile seizures in an immature rat model cause epilepsy? In: Baram TZ, Shinnar S, eds. Febrile seizures. San Diego, CA: Academic Press, 2002: 215 - 229.CrossRefGoogle Scholar
  29. 29.
    Eghbal-Ahmadi M, Yin H, Stafstrom CE et al. Altered expression of specific AMPA type glutamate receptor subunits after prolonged experimental febrile seizures in CA3 of immature rat hippocampus. Soc Neurosci Abstr 2001; 31: 684. 6.Google Scholar
  30. 30.
    Falconer MA, Serafetinides EA, Corsellis JAN. Etiology and pathogenesis of temporal lobe epilepsy. Arch Neurol 1964; 10: 233 - 248.PubMedCrossRefGoogle Scholar
  31. 31.
    Fernandez G, Effenberger O, Vinz B et al. Hippocampal malformation as a cause of familial febrile convulsions and subsequent hippocampal sclerosis. Neurology 1998; 50: 909 - 917.PubMedCrossRefGoogle Scholar
  32. 32.
    Fewell JE, Wong VH. Interleukin-lbeta-induced fever does not alter the ability of 5- to 6-day-old rat pups to autoresuscitate from hypoxia-induced apnoea. Exp Physiol 2002; 87: 17 - 24.PubMedCrossRefGoogle Scholar
  33. 33.
    Fish DR, Spencer SS. Clinical correlations: MRI and EEG. Magn Reson Imaging 1995; 13: 1113 - 1117.CrossRefGoogle Scholar
  34. 34.
    Franz O, Liss B, Neu A et al. Single-cell mRNA expression of HCN1 correlates with a fast gating phenotype of hyperpolarization-activated cyclic nucleotide-gated ion channels (Ih) in central neurons. Eur J Neurosci 2000; 12: 2685 - 2693.PubMedCrossRefGoogle Scholar
  35. 35.
    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.PubMedCrossRefGoogle Scholar
  36. 36.
    Gallyas F, Guldner FH, Zoltay G et al. Golgi-like demonstration of “dark” neurons with an argyrophil III method for experimental neuropathology. Acta Neuropathol (Berlin) 1990; 79: 620 - 628.CrossRefGoogle Scholar
  37. 37.
    Gallyas F, Zoltay G, Horvath Z et al. Light microscopic response of neuronal somata, dendrites, axons to postmortem concussive head injury. Acta Neuropathol (Berlin) 1992; 83: 499 - 503.CrossRefGoogle Scholar
  38. 38.
    Germano IM, Zhang YF, Sperber EF et al. Neuronal migration disorders increase seizure susceptibility to febrile seizures. Epilepsia 1996; 37: 902 - 910.PubMedCrossRefGoogle Scholar
  39. 39.
    Gottlieb A, Keydar I, Epstein HT. Rodent brain growth stages: an analytical review. Biol Neonate 1977; 32: 166 - 176.PubMedCrossRefGoogle Scholar
  40. 40.
    Hamati-Haddad A, Abou-Khalil B Epilepsy: diagnosis and localization in patients with antecedent childhood febrile convulsions. Neurology 1998; 50: 917 - 922.PubMedCrossRefGoogle Scholar
  41. 41.
    Harvey AS, Grattan-Smith JD, Desmond PM et al. Febrile seizures and hippocampal sclerosis: frequent and related findings in intractable temporal lobe epilepsy of childhood. Pediatr Neurol 1995; 12: 201 - 206.PubMedCrossRefGoogle Scholar
  42. 42.
    Hauser WA. The prevalence and incidence of convulsive disorders in children. Epilepsia 1994; 35 (Suppl 2) S1 - S6.PubMedCrossRefGoogle Scholar
  43. 43.
    Herschkowitz N, Kagan J, Zilles K. Neurobiological bases of behavioral development in the first year. Neuropediatrics 1997; 28: 296 - 306.PubMedCrossRefGoogle Scholar
  44. 44.
    Hjeresen DL, Diaz J. Ontogeny of susceptibility to experimental febrile seizures in rats. Dev Psychobiol 1988; 21: 261 - 275.PubMedCrossRefGoogle Scholar
  45. 45.
    Houser CR. Neuronal loss and synaptic reorganization in temporal lobe epilepsy. Adv Neurol 1999; 79: 743 - 761.PubMedGoogle Scholar
  46. 46.
    Ikonomidou-Turski C, Cavalheiro EA, Turski WA et al. Convulsant action of morphine, [D-AIa2, D-Leu5] -enkephalin and naloxone in the rat amygdala: electroencephalographic, morphological and behavioral sequelae. Neuroscience 1987; 20: 671 - 686.PubMedCrossRefGoogle Scholar
  47. 47.
    Ioos C, Fohlen M, Villeneuve N et al. Hot water epilepsy: A benign and unrecognized form. J Child Neurol 2000; 15: 125 - 128.PubMedCrossRefGoogle Scholar
  48. 48.
    Jackson GD, McIntosh AM, Briellmann RS et al. Hippocampal sclerosis studied in identical twins. Neurology 1998; 51: 78 - 84.PubMedCrossRefGoogle Scholar
  49. 49.
    Kälviäinen R, Salmonperä T, Partanen K et al. Recurrent seizures may cause hippocampal damage in temporal lobe epilepsy. Neurology 1998; 50: 1377 - 1382.PubMedCrossRefGoogle Scholar
  50. 50.
    Knudsen FU. Febrile seizures-treatment and outcome. Brain Dev 1996; 18: 438 - 449.PubMedCrossRefGoogle Scholar
  51. 51.
    Iagerspetz KY, Vaatainen T. Bacterial endotoxin and infection cause behavioural hypothermia in infant mice. Comp Biochem Physiol A 1987; 88: 519 - 521.CrossRefGoogle Scholar
  52. 52.
    Lewis DV. Febrile convulsions and mesial temporal lobe sclerosis. Curr Opin Neurol 1999; 12: 197 - 201.PubMedCrossRefGoogle Scholar
  53. 53.
    Liu Z, Gatt A, Mikati M et al. Effect of temperature on kainic acid-induced seizures. Brain Res 1993; 631: 51 - 58.PubMedCrossRefGoogle Scholar
  54. 54.
    Mani KS, Mani AJ, Ramesh CK et al. Hot-water epilepsy-a peculiar type of reflex epilepsy: clinical and EEG features in 108 cases. Trans Am Neurol Assoc 1974; 99: 224 - 226.PubMedGoogle Scholar
  55. 55.
    Mathern GW, Babb TL, Vickrey BG et al. The clinical-pathogenic mechanisms of hippocampal neuron loss and surgical outcomes in temporal lobe epilepsy. Brain 1995; 118: 105 - 118.PubMedCrossRefGoogle Scholar
  56. 56.
    Mathern GW, Babb TL, Armstrong DL. Hippocampal sclerosis. In: Engel Jr J, Pedley TA, eds. Epilepsy: A comprehensive textbook. Philadelphia, PA: Lippincott-Raven Publishers, 1997: 133 - 155.Google Scholar
  57. 57.
    Mathern GW, Pretorius JK, Leite JP et al. Hippocampal neuropathology in children with severe epilepsy. In: Neblig A, Motte J, Moshé SL, Plouin P, eds. Childhood epilepsies and brain development. London, England. John Libbey and Co., 1999: 171 - 185.Google Scholar
  58. 58.
    McCabe BK, Silveira DC, Cilio MR et al. Reduced neurogenesis after neonatal seizures. J Neurosci 2001; 21: 2094 - 2103.PubMedGoogle Scholar
  59. 59.
    Morimoto T, Nagao H, Sano N et al. Electroencephalographic study of rat hyperthermic seizures. Epilepsy 1991; 32: 289 - 293.CrossRefGoogle Scholar
  60. 60.
    National Insitutes of Health Febrile seizures: Consensus development conference summary Bethesda, MD: National Institutes of Health,1980:3(2).Google Scholar
  61. 61.
    O’Brien TJ, So EL, Meyer FB et al. Progressive hippocampal atrophy in chronic intractable temporal lobe epilepsy. Ann Neurol 1999; 45: 526 - 529.PubMedCrossRefGoogle Scholar
  62. 62.
    Pape HC. Queer current and pacemaker: the hyperpolarization-activated cation current in neurons. Annu Rev Physiol 1996; 58: 299 - 327.PubMedCrossRefGoogle Scholar
  63. 63.
    Parent JM, Yu TW, Leibowitz RT et al. Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus. J Neurosci 1997; 17: 3727 - 3738.PubMedGoogle Scholar
  64. 64.
    Ribak CE, Seress L, Amaral DG. The development, ultrastructure and synaptic connections of the mossy cells of the dentate gyrus. J Neurocytol 1985; 14: 835 - 857.PubMedCrossRefGoogle Scholar
  65. 65.
    Rocca WA, Sharbrough FW, Hauser WA et al. Risk factors for complex partial seizures: a population-based case-control study. Ann Neurol 1987; 21: 22 - 31.PubMedCrossRefGoogle Scholar
  66. 66.
    Sankar R, Shin D, Liu H et al. Granule cell neurogenesis after status epilepticus in the immature rat brain. Epilepsia Suppl 2001; 7: 53 - 56.Google Scholar
  67. 67.
    Santoro B, Tibbs GR. The HCN gene family: molecular basis of the hyperpolarization-activated pacemaker channels. Ann NY Acad Sci 1999; 868: 741 - 764.PubMedCrossRefGoogle Scholar
  68. 68.
    Santoro B, Chen S, Lüthi A et al. Molecular and functional heterogeneity of hyperpolarization-activated pacemaker channels in the mouse CNS. J Neurosci 2000; 20: 5264 - 5275.PubMedGoogle Scholar
  69. 69.
    Schickerova R, Mares P, Trojan S. Correlation between electrocorticographic and motor phenomena induced by pentamethylenetetrazol during ontogenesis in rats. Exp Neurol 1984; 84: 153 - 164.PubMedCrossRefGoogle Scholar
  70. 70.
    Schlessinger AR, Cowan WM, Gottlieb ID. An autoradiographic study of the time of origin and the pattern of granule cell migration in the dentate gyrus of the rat. J Comp Neurol 1975; 159: 149 - 176.PubMedCrossRefGoogle Scholar
  71. 71.
    Seress L, Mrzljak L. Postnatal development of mossy cells in the human dentate gyrus: a light microscopic Golgi study. Hippocampus 1992; 2: 127 - 142.PubMedCrossRefGoogle Scholar
  72. 72.
    Shinnar S. Prolonged febrile seizures and mesial temporal lobe sclerosis. Ann Neurol 1998; 43: 411 - 412.PubMedCrossRefGoogle Scholar
  73. 73.
    Shinnar S. Human Data: What do we know about febrile seizures and what further information is needed? In: Baram TZ, Shinnar S, eds. Febrile seizures. San Diego, CA: Academic Press, 2002: 317 - 324.CrossRefGoogle Scholar
  74. 74.
    Stafstrom CE. The incidence and prevalence of febrile seizures. In: Baram TZ, Shinnar S, eds. Febrile seizures. San Diego, CA: Academic Press, 2002; 1 - 25.CrossRefGoogle Scholar
  75. 75.
    Sundgren-Andersson AK, Ostlund P, Bartfai T. Simultaneous measurement of brain and core temperature in the rat during fever, hyperthermia, hypothermia and sleep. Neuroimmunomodulation 1998; 5: 241 - 247.PubMedCrossRefGoogle Scholar
  76. 76.
    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.PubMedCrossRefGoogle Scholar
  77. 77.
    Thon N, Chen K, Aradi I et al. Physiology of limbic hyperexcitability after experimental complex febrile seizures: interactions of seizure-induced alterations at multiple levels of neuronal organization. In: Baram TZ, Shinnar S, eds. Febrile seizures. San Diego, CA: Academic Press, 2002: 203 - 213.CrossRefGoogle Scholar
  78. 78.
    Toth Z, Yan XX, Haftoglou S et al. Seizure-induced neuronal injury: vulnerability to febrile seizures in an immature rat model. J Neurosci 1998; 18: 4285 - 4294.PubMedGoogle Scholar
  79. 79.
    VanLandingham ICE, Heinz ER, Cavazos JE et al. Magnetic resonance imaging evidence of hippocampal injury after prolonged focal febrile convulsions. Ann Neurol 1998; 43: 413 - 426.CrossRefGoogle Scholar
  80. 80.
    Van Paesschen W, Duncan JS, Stevens JM et al. Longitudinal quantitative hippocampal magnetic resonance imaging study of adults with newly diagnosed partial seizures• one-year follow-up results. Epilepsia 1998; 39: 633 - 639.PubMedCrossRefGoogle Scholar
  81. 81.
    Zimmerman HM. The histopathology of convulsive disorders in children. J Pediatr 1940; 13: 359 - 390.Google Scholar

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© Springer Science+Business Media New York 2004

Authors and Affiliations

  • Roland A. Bender
  • Celine Dubé
  • Tallie Z. Baram

There are no affiliations available

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