Pathophysiology of Infantile Spasms

  • Harry T. Chugani
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 497)


Recent observations have contributed significantly to our understanding of the pathophysiology of infantile spasms, and have allowed a number of hypotheses to be generated. Any consideration of the pathophysiology of infantile spasms must take into account the following features common to the population of subjects with infantile spasms:
  1. 1

    The spasms are generalized seizures which consist of brief muscle extension, flexion, or mixed flexion-extension jerks involving the neck, trunk, or extremities.47,49 Lateralizing or localizing clinical features may be present during the spasms.

  2. 2

    Infantile spasms can be associated with a wide variety of neurological conditions, including metabolic, dysplastic or dysgenetic abnormalities, and various prenatal, perinatal, and postnatal insults.51 In the symptomatic category, a specific neurological condition can be identified, whereas in the cryptogenic sub-group an underlying condition is suspected based on clinical features, EEG or other tests, but a specific diagnosis cannot be made.

  3. 3

    There is a small group (<5%) of infants with spasms, the idiopathic subgroup, which is believed not to be associated with any underlying condition. Neurodevelopment is normal at presentation, and there is a lack of focal features on clinical examination, seizure semiology or EEG. Reappearance of hypsar-rhythmia between consecutive spasms in a cluster is said to be an important feature in this subgroup.34 There is rapid response of the spasms to medical treatment and an ultimately benign course is expected. This rare situation may represent a case in which, during development, there is a chemical or physiological disturbance resulting in spasms, but which can be totally reversed with medical treatment.

  4. 4

    With rare exceptions,38 the spasms typically begin between age 3 and 8 months and disappear by age 2 to 3 years. In other words, there appears to be a developmental window during which various brain abnormalities may result in infantile spasms as one manifestation of the underlying disorder.

  5. 5

    Although the vast majority of brain lesions that have been identified in patients with infantile spasms involve the cerebral cortex, their locations are not specific to any cortical region.

  6. 6

    With some exceptions, the spasms do not appear to respond to conventional anticonvulsants, but rather, to therapeutic agents not typically used in epilepsy, such as corticosteroids. If the spasms respond to such treatment, the response is often abrupt and dramatic rather than graded, as is seen in other forms of epilepsy.



Positron Emission Tomography Partial Seizure Infantile Spasm Kynurenic Acid Lenticular Nucleus 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Airaksinen, E., Mustonen, K., and Tuomisto, L. ACTH therapy in infantile spasms: Effects on cerebrospinal amino acids, HVA, 5-hydroxyindoleacetic acid, and histamineCleve Clin. J. Med.56 (1989) S-269.Google Scholar
  2. 2.
    Baram, T.Z. Pathophysiology of massive infantile spasms: Perspective on the putative role of brain adrenal axisAnn. Neurol.33 (1993) 231–236.PubMedCrossRefGoogle Scholar
  3. 3.
    Baram, T.Z., Mitchell, WG., Snead, O.C., Horton, E. J., and Saito, M. Brain-adrenal axis hormones are altered in the CSF of infants with massive infantile spasmsNeurol.42 (1992) 1171–1175.CrossRefGoogle Scholar
  4. 4.
    Biegon, A., Rainbow, T.C., and McEwen, B.S. Corticosterone modulation of neurotransmitter receptors in rat hippocampus: A quantitative autoradiographic studyBrain Res.332 (1985) 309–314.PubMedCrossRefGoogle Scholar
  5. 5.
    Blennow, G. and Starck, L. High dose B6 treatment in infantile spasmsNeuropediatrics 17 (1986) 7–10.PubMedCrossRefGoogle Scholar
  6. 6.
    Branch, C.E. and Dyken, P.R. Choroid plexus papilloma and infantile spasmsAnn. Neurol.5 (1979) 302–304.PubMedCrossRefGoogle Scholar
  7. 7.
    Browning, R.A. Role of the brain-stem reticular formation in tonic-clonic seizures: lesion and pharmacological studiesFed. Proc.44 (1985) 2425–2431.PubMedGoogle Scholar
  8. 8.
    Carrazana, E.J., Lombroso, C.T., Mikati, M., Helmers, S., and Holmes, G.L. Facilitation of infantile spasms by partial seizuresEpilepsia34 (1993) 97–109.PubMedCrossRefGoogle Scholar
  9. 9.
    Chadwick, D., Harris, R., Jenner, P, Reynolds, E.H., and Marsden, C.D. Manipulation of brain serotonin in the treatment of myoclonusLancetii (1975) 434–443.CrossRefGoogle Scholar
  10. 10.
    Chiron, C., Dulac, O., Beaumont, D., Palacios, L., Pajot, N., and Mumford, J. Therapeutic trial of vigabatrin in refractory infantile spasms, JChild Neurol.6 (Suppl. 2) (1991) S52–S59.Google Scholar
  11. 11.
    Chiron, C., Dulac, O., Bulteau, C., Nuttin, C., Depas, G., Raynaud, C., and Syrota, A. Study of regional cerebral blood flow in West syndromeEpilepsia34 (1993) 707–715.PubMedCrossRefGoogle Scholar
  12. 12.
    Chugani, H.T., and Conti, J.R. Etiological classification of infantile spasms in 140 cases: Role of positron emission tomographyJ Child Neural.11(1) (1996) 44–48.CrossRefGoogle Scholar
  13. 13.
    Chugani, H.T., Mazziotta, J.C., Engel, J. Jr., and Phelps, M.E. Lennox-Gastaut syndrome: metabolic subtypes determined by 18FDG positron emission tomographyAnn. Neurol.21 (1987) 4–13.PubMedCrossRefGoogle Scholar
  14. 14.
    Chugani, H.T. and Phelps, M.E. Maturational changes in cerebral function in infants determined by 18FDG positron emission tomographyScience231 (1986) 840–843.PubMedCrossRefGoogle Scholar
  15. 15.
    Chugani, H.T., Phelps, M.E., and Mazziotta, J.C. Positron emission tomography study of human brain functional developmentAnn. Neural.22 (1987) 487–497.CrossRefGoogle Scholar
  16. 16.
    Chugani, H.T., Phelps, M.E., and Mazziotta, J.C. Positron emission tomography study of human brain functional developmentAnn. Neurol.22 (1987) 487–497.PubMedCrossRefGoogle Scholar
  17. 17.
    Chugani, H.T., Rintahaka, P.J., and Shewmon, D.A. Ictal patterns of cerebral glucose utilization in children with epilepsyEpilepsia35 (1994) 813–822.PubMedCrossRefGoogle Scholar
  18. 18.
    Chugani, H.T., Shewmon, D.A., Khanna, S., and Phelps, M.E. Interictal and postictal focal hypermetabolism on positron emission tomographyPediatr Neural.9 (1993) 10–15.CrossRefGoogle Scholar
  19. 19.
    Chugani, H.T., Shewmon, D.A., Sankar, R., Chen, B.C., and Phelps, M.E. Infantile spasms: II. lenticular nuclei and brain stem activation on positron emission tomographyAnn. Neurol.31 (1992) 212–219.PubMedCrossRefGoogle Scholar
  20. 20.
    Chugani, H.T., Shewmon, D.A., Shields, W.D., Sankar, R., Comair, Y, Vinters, H.V., and Peacock, W.J. Surgery for intractable infantile spasms: neuroimaging perspectivesEpilepsia34 (1993) 764–771.PubMedCrossRefGoogle Scholar
  21. 21.
    Chugani, H.T., Shields, W.D., Shewmon, D.A., Olson, D.M., Phelps, M.E., and Peacock, W.J. Infantile spasms: I. PET identifies focal cortical dysgenesis in cryptogenic cases for surgical treatmentAnn. Neural.27 (1990) 406–413.CrossRefGoogle Scholar
  22. 22.
    Chugani, H.T., Shields, W.D., Shewmon, D.A., Olson, D.M., Phelps, M.E., and Peacock, W.J. Infantile spasms: I. PET identifies focal cortical dysgenesis in cryptogenic cases for surgical treatmentAnn. Neurol.27 (1990) 406–413.PubMedCrossRefGoogle Scholar
  23. 23.
    Coleman, M. Infantile spasms associated with 5-hydroxytryptophan administration in patients with Down’s syndromeNeurology21 (1971) 911–919.PubMedCrossRefGoogle Scholar
  24. 24.
    Cross, A.J. and Slater, P. High affinity serotonin binding sites in human brain: a comparison of cerebral cortex and basal ganglia, J.Neural Transm.76 (1989) 211–219.PubMedCrossRefGoogle Scholar
  25. 25.
    Cusmai, R., Dulac, O., and Diebler, C. Lesions focales dans les spasmes infantilesNeurophysiol. Clin.18 (1988) 235–241.PubMedCrossRefGoogle Scholar
  26. 26.
    Dalla Bernardina, B., Colamaria, V, and Capoville, G. Epileptic syndromes and cerebral malformations in infancy: multicentric studyBoll Lega Ital. Epil.45/46 (1984) 65–67.Google Scholar
  27. 27.
    Defiore, C.H. and Turner, B.B. [3H] Corticosterone binding in the caudate-putamenBrain Res.278 (1983) 93–101.PubMedCrossRefGoogle Scholar
  28. 28.
    De Kloet, E.R., Sybesma, H., and Reul, H.M. Selective control by corticosterone of serotoninl receptor capacity in raphe-hippocampal systemNeuroendocrinology42 (1986) 513–521.PubMedCrossRefGoogle Scholar
  29. 29.
    Donat, J.F. and Lo, W.D. Asymmetric hypsarrhythmia and infantile spasms in West syndrome, J.Child Neurol.9 (1994) 290–296.PubMedCrossRefGoogle Scholar
  30. 30.
    Donat, J.F. and Wright, F.S. Simultaneous infantile spasms and partial seizuresJ. Child Neurot6 (1991a) 246–250.CrossRefGoogle Scholar
  31. 31.
    Dreifuss, F.E. and Santilli, N.Valproic acid hepatic fatalities: Analysis of US casesNeurology, 36 (Suppl. 1) (1986) 175.Google Scholar
  32. 32.
    Dulac, O., Chiron, C., Jambaque, I., Plouin, P., and Raynaud, C. Infantile spasmsProgress in Clin. Neurosci.2 (1987) 97–109.Google Scholar
  33. 33.
    Dulac, O., Feingold, J., Plouin, P, Chiron, C., Pajot, N., and Ponsot, G. Genetic predisposition to West syndromeEpilepsia34 1993 732–737.PubMedCrossRefGoogle Scholar
  34. 34.
    Dulac, O. and Plouin, P. Cryptogenic/Idiopathic West Syndrome. In: O. Dulac, H.T. Chugani and B.D. Bernardina (Eds.)Infantile Spasms and West SyndromeWB Saunders, London (1994) pp. 232–243.Google Scholar
  35. 35.
    Fukuyama, Y, Shionaga, A., and Iida, Y. Polygraphic study during whole night sleep in infantile spasmsEur. Neurot.18 (1979) 302–311.CrossRefGoogle Scholar
  36. 36.
    Fusco, L. and Vigevano, F. Ictal clinical electroencephalographic findings of spasms in West syndromeEpilepsia34 (1993) 671–678.PubMedCrossRefGoogle Scholar
  37. 37.
    Gale, K. Mechanisms of seizure control mediated by gamma-aminobutyric acid: role of the substantia nigraFed Proc.44 (1985) 2414–2424.PubMedGoogle Scholar
  38. 38.
    Gobbi, G., Bruno, L., Pini, A., Rossi, P.G., and Tassinari, C.A. Periodic Spasms: An unclassified type of epileptic seizure in childhoodDevelop Med. and Child Neurot29 (1987) 766–775.CrossRefGoogle Scholar
  39. 39.
    Herrick-Davis, K., Maisonneuve, I.M., and Titeler, M. Postsynaptic localization and up-regulation of serotonin 5-HT1D receptors in rat brainBrain Res.483 (1989) 155–157.PubMedCrossRefGoogle Scholar
  40. 40.
    Hrachovy, R.A. and Frost, J.D. Jr. Infantile spasms: A disorder of the developing nervous system. In: P. Kellaway and J.L. Noebels (Eds.)Problems and Concepts in Developmental NeurophysiologyJohns Hopkins University Press, Baltimore (1989) pp. 131–147.Google Scholar
  41. 41.
    Hrachovy, R.A., Frost, J.D., Glase, D.G., and Rose, D. Treatment of infantile spasms with methysergide and alpha-methylparatyrosineEpilepsia30 (1989) 607–610.PubMedCrossRefGoogle Scholar
  42. 42.
    Hrachovy, R.A., Frost, J.D. Jr., and Glaze, D.G. Treatment of infantile spasms with tetrabenazineEpilepsia29 (1988) 561–563.PubMedCrossRefGoogle Scholar
  43. 43.
    Hrachovy, R.A., Frost, J.D. Jr., and Kellaway, P. Sleep characteristics in infantile spasmsNeurology31 (1981) 688–694.PubMedCrossRefGoogle Scholar
  44. 44.
    Jinuma, K., Yanai, K., Yanagisa, T., Fueki, N., Tada, K., Ito, M., Matsuzawa, T., and Ido, T. Cerebral glucose metabolism in five patients with Lennox-Gastaut syndromePediatr. Neurol.3 (1987) 12–18.CrossRefGoogle Scholar
  45. 45.
    Ito, M., Mikawa, H., and Taniguchi, T. Cerebrospinal fluid GABA levels in children with infantile spasmsNeurology34 (1984) 235–238.PubMedCrossRefGoogle Scholar
  46. 46.
    Izumi, T., Ogawa, T., Koizumi, H., and Fukuyama, Y. Low levels of CSF gangliotetraose-series gangliosides in West syndrome: implications of brain maturation disturbancePediatr. Neurol.9 (1993) 293–296.PubMedCrossRefGoogle Scholar
  47. 47.
    Jeavons, P.M. and Bower, B.D.Infantile spasms: A review of the literature and a study of 112 cases Clinics in Develop. Med. No.15Spastic Society and Heinemann, London (1964).Google Scholar
  48. 48.
    Jellinger, K. Neuropathological aspects of infantile spasmsBrain Dew.9 (1987) 349–357.CrossRefGoogle Scholar
  49. 49.
    Kellaway, P., Hrachovy, R.A., Frost, J.D., and Zion, T. Precise characterization and quantification of infantile spasmsAnn. Neurot.6 (1979) 214–218.CrossRefGoogle Scholar
  50. 50.
    Klawans, H., Goetz, C., and Weiner, W.J. 5-hydroxytryptophan induced myoclonus in guinea pigs and the possible role of serotonin in infantile spasmsNeurology23 (1973) 1234–1240.PubMedCrossRefGoogle Scholar
  51. 51.
    Lacy, J.R. and Penry, J.K. Infantile Spasms, Raven Press, New York (1976).Google Scholar
  52. 52.
    Livingston, J.H., Beaumont, D., Arzimanoglou, A., and Aicardi, J. Vigabatrin in the treatment of epilepsy in childrenBr. J Clin. Pharmacol.27 (1989) S109–5112.CrossRefGoogle Scholar
  53. 53.
    Loscher, W., and Siemes, H. Cerebrospinal fluid g-aminobutyric acid levels in children with different types of epilepsy: Effect of anticonvulsant treatmentEpilepsia26 (1985) 314–319.PubMedCrossRefGoogle Scholar
  54. 54.
    Maeda, N., Watanabe, K., Negoro, T., Aso, K., Haga, Y, Kito, M., Ohki, T., Ito, K., and Kato, T. Transient focal cortical hypometabolism in idiopathic West syndromePediatr. Neurol.9 (1993) 430–434.PubMedCrossRefGoogle Scholar
  55. 55.
    Maeda, N., Watanabe, K., Negoro, T., Aso, K., Ohki, T., Ito, K., and Kato, T. Evolutional changes of cortical hypometabolism in West’s syndromeLancet343 (1994) 1620–1623.PubMedCrossRefGoogle Scholar
  56. 56.
    Meencke, H.J. and Gerhard, C. Morphological aspects of aetiology and the course of infantile spasms (West-Syndrome)Neuropediatr.16 (1985) 59–66.CrossRefGoogle Scholar
  57. 57.
    Menkes, J.Textbook of Child Neurology4th Ed. Lea & Febiger, Philadelphia. London (1990) pp. 31–35.Google Scholar
  58. 58.
    Mimaki, T., Ono, J., and Yabuuchi, H. Temporal lobe astrocytoma with infantile spasmsAnn. Neurol.14 (1983) 695–696.PubMedCrossRefGoogle Scholar
  59. 59.
    Miyazaki, M., Hashimoto, T., Fujii, E., Tayama, M., and Kuroda, Y. Infantile spasms: localized cerebral lesions on SPECTEpilepsia35 (1994) 988–992.PubMedCrossRefGoogle Scholar
  60. 60.
    Miyazaki, M., Hashimoto, T., Tayama, M., and Kuroda, Y. Brainstem involvement in infantile spasms: a study employing brainstem evoked potentials and magnetic resonance imagingNeuropediatrics24 (1993) 126–130.Google Scholar
  61. 61.
    Morimatsu, Y, Murofushi, R., Handa, T., Shinoara, T., and Shiraki, H. Pathological studies of several physically and mentally handicapped-with special reference to four cases of infantile spasmsAdv. Neurot Sei.16 (1972) 465–470.Google Scholar
  62. 62.
    Nalin, A., Facchinetti, F., Galli, V., Petraglia, F., Storchi, R., and Genazzani, A.R. Reduced ACTH content in cerebrospinal fluid of children affected by crytogenic infantile spasms with hypsarrhythmiaEpilepsia26 (1985) 446–449.PubMedCrossRefGoogle Scholar
  63. 63.
    Nausieda, P.A., Carvey, PM., and Braun, A. Long-term suppression of central serotonergic activity by corticosteroids: A possible model of steroid-responsive myoclonic disordersNeurology32 (1982) 772–775.PubMedCrossRefGoogle Scholar
  64. 64.
    Nieuwenhuys, R.Chemoarchitecture of the brainSpringer-Verlag, New York (1985).CrossRefGoogle Scholar
  65. 65.
    Ogata, H., Mitsudome, A., Yokota, K., and Pachibana, H. Three cases of infantile spasms with brain cystic lesionsBrain & Dev.7 (1985) 184.Google Scholar
  66. 66.
    Palm, D.G., Brandt, M., and Korinthenberg, R. West syndrome and Lennox-Gastaut syndrome in children with porencephalic cysts: long-term follow-up after neurosurgical treatment. In: E. Niedermeyer and R. Degen (Eds.)The Lennox-Gastaut syndromeAlan R. Liss, New York (1988) pp. 419–426.Google Scholar
  67. 67.
    Pietz, J., Benninger, C., Schäfer, H., Sontheimer, D., Mittermaier, G., and Rating, D. Treatment of infantile spasms with high-dosage vitamin B6Epilepsia34 (1993) 757–763.PubMedCrossRefGoogle Scholar
  68. 68.
    Pinard, J.M., Delalande, O., Plouin, P., and Dulac, O. Callosotomy in West syndrome suggests a cortical origin of hypsarrhythmiaEpilepsia.34 (1993) 780–787.PubMedCrossRefGoogle Scholar
  69. 69.
    Plouin, P., Dulac, O., Jalin, C., and Chiron, C. Twenty-four-hour ambulatory EEG monitoring in infantile spasmsEpilepsia34 (1993) 686–691.PubMedCrossRefGoogle Scholar
  70. 70.
    Pranzatelli, M.R. Putative neurotransmitter abnormalities in infantile spasms: Cerebrospinal fluid neurochemistry and drug effects, JChild Neurol.9 (1994) 119–129.PubMedCrossRefGoogle Scholar
  71. 71.
    Sarrieau, A., Dussaillant, M., Sapolsky, R.M., Aitken, D.H., Olivier, A., Lal, S., Rostene, W.H., Quirion, R., and Meaney, M.J. Glucocorticoid binding sites in human temporal cortexBrain Res.442 (1988) 157–160.PubMedCrossRefGoogle Scholar
  72. 72.
    Schwartzberg, D.G. and Nakane, P.K. ACTH-related peptide containing neurons within the medulla oblongata of the ratBrain Res.276 (1983) 351–356.PubMedCrossRefGoogle Scholar
  73. 73.
    Shewmon, D.A., Shields, WD., Chugani, H.T., and Peacock, W.J. Contrasts between pediatric and adult epilepsy surgery: Rationale and strategy for focal resectionJ. Epilepsy3 (suppl. 1) (1991) 141–155.Google Scholar
  74. 74.
    Shewmon, D.A., Shields, W.D., Olson, D.M., Peacock, WJ., and Chugani, H.T. Multifocal independent epileptogenicity in children treated by focal cortical resectionEpilepsia30 (1989) 660.Google Scholar
  75. 75.
    Shields, W.D., Shewmon, D.A., Chugani, H.T., and Peacock, W.J. The role of surgery in the treatment of infantile spasmsJ Epilepsy3 (Suppl.) (1990) 321–324.Google Scholar
  76. 76.
    Silverstein, F. and Johnston, M.V. Cerebrospinal fluid monoamine metabolites in patients with infantile spasmsNeurology34 (1984) 102–105.PubMedCrossRefGoogle Scholar
  77. 77.
    Van Bogaert, E, Chiron, C., Adamsbaum, C., Robain, O., Diebler, C., and Dulac, O. Value of magnetic resonance imaging in West syndrome of unknown etiologyEpilepsia34 (1993) 701–706.PubMedCrossRefGoogle Scholar
  78. 78.
    Vinters, H.V., De Rosa, M.J., and Farrell, M.A. Neuropathologie study of resected cerebral tissue from patients with infantile spasmsEpilepsia34 (1993b) 772–779.PubMedCrossRefGoogle Scholar
  79. 79.
    Waeber, C., Dietl, M.M., Hoyer, D., Probst, A., and Palacios, J.M. Visualization of a novel serotonergic recognition site (5-HT1D) in the human brain by autoradiographyNeurosci. Lett.88 (1988) 11–16.PubMedCrossRefGoogle Scholar
  80. 80.
    Waeber, C., Hoyer, D., and Palacois, J.M. GR 43175: A preferential 5-HT1D agent in monkey and human brains as shown by autoradiographySynapse4 (1989) 168–170.PubMedCrossRefGoogle Scholar
  81. 81.
    Watanabe, K., Negoro, T., Aso, K., and Matsumoto, A. Reappraisal of interictal electroencephalograms in infantile spasmsEpilepsia34 (1993) 679–685.PubMedCrossRefGoogle Scholar
  82. 82.
    Yamamoto, H., Shindo, I., Egawa, B., and Horiguchi, K. Kynurenic acid is decreased in cerebrospinal fluid of patients with infantile spasmsPediatr. Neurot10 (1994) 9–12.CrossRefGoogle Scholar
  83. 83.
    Yamamoto, N., Watanabe, K., Negoro, T., Furune, S., Takahashi, I., Nomura, K., and Matsumoto, A. Partial seizures evolving to infantile spasmsEpilepsia29 (1988) 34–40.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • Harry T. Chugani
    • 1
  1. 1.Division of Pediatric Neurology and the PET Center Children’s Hospital of MichiganWayne State UniversityDetroit

Personalised recommendations