Review article| Volume 23, ISSUE 7, P533-538, November 2001

Download started.


How do the many etiologies of West syndrome lead to excitability and seizures? The corticotropin releasing hormone excess hypothesis

  • Kristen L Brunson
    Department of Pediatrics, University of California at Irvine, Irvine, CA, 92697-4475, USA

    Department of Anatomy and Neurobiology, University of California at Irvine, Irvine, CA, 92697-4475, USA

    Department of Neurology, University of California at Irvine, Irvine, CA, 92697-4475, USA
    Search for articles by this author
  • Mariam Eghbal-Ahmadi
    Department of Pediatrics, University of California at Irvine, Irvine, CA, 92697-4475, USA

    Department of Anatomy and Neurobiology, University of California at Irvine, Irvine, CA, 92697-4475, USA

    Department of Neurology, University of California at Irvine, Irvine, CA, 92697-4475, USA
    Search for articles by this author
  • Tallie Z Baram
    Corresponding author. Tel.: +1-949-824-1063; fax: +1-949-824-1106
    Department of Pediatrics, University of California at Irvine, Irvine, CA, 92697-4475, USA

    Department of Anatomy and Neurobiology, University of California at Irvine, Irvine, CA, 92697-4475, USA

    Department of Neurology, University of California at Irvine, Irvine, CA, 92697-4475, USA
    Search for articles by this author


      West syndrome (WS) is associated with diverse etiological factors. This fact has suggested that there must be a ‘final common pathway’ for these etiologies, which operates on the immature brain to result in WS only at the maturational state present during infancy. Any theory for the pathogenesis of WS has to account for the unique features of this disorder. For example, how can a single entity have so many etiologies? Why does WS arise only in infancy, even when a known insult had occurred prenatally, and why does it disappear? Why is WS associated with lasting cognitive dysfunction? And, importantly, why do these seizures – unlike most others – respond to treatment by a hormone, ACTH? The established hormonal role of ACTH in human physiology is to function in the neuroendocrine cascade of the responses to all stressful stimuli, including insults to the brain. As part of this function, ACTH is known to suppress the production of corticotropin releasing hormone (CRH), a peptide that is produced in response to diverse insults and stressors.
      The many etiologies of WS all lead to activation of the stress response, including increased production and secretion of the stress-neurohormone CRH. CRH has been shown, in infant animal models, to cause severe seizures and death of neurons in areas involved with learning and memory. These effects of CRH are restricted to the infancy period because the receptors for CRH, which mediate its action on neurons, are most abundant during this developmental period. ACTH administration is known to inhibit production and release of CRH via a negative feedback mechanism. Therefore, the efficacy of ACTH for WS may depend on its ability to decrease the levels of the seizure-promoting stress-neurohormone CRH.
      This CRH-excess theory for the pathophysiology of WS is consistent not only with the profile of ACTH effects, but also with the many different ‘causes’ of WS, with the abnormal ACTH levels in the cerebrospinal fluid of affected infants and with the spontaneous disappearance of the seizures. Furthermore, if CRH is responsible for the seizures, and CRH-mediated neuronal injury contributes to the worsened cognitive outcome of individuals with WS, then drugs which block the actions of CRH on its receptors may provide a better therapy for this disorder.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Brain and Development
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Hrachovy R.A
        • Frost J.D
        Infantile spasms.
        Pediatr Clin North Am. 1989; 36: 311-329
        • Riikonen R
        Infantile spasms: some new theoretical aspects.
        Epilepsia. 1983; 24: 159-168
        • Vinters H.V
        • Fisher R.S
        • Cornford M.E
        Morphological substrates of infantile spasms: studies based on surgically resected cerebral tissue.
        Childs Nerv Syst. 1992; 8: 8-17
        • Dalla Bernadina B
        • Dulac O
        Introduction to etiology.
        in: Dulac O Chugani H Dalla Bernadina B Infantile spasms and West syndrome. W.B. Saunders, London1994: 166-171
        • Lyon G
        • Gastaut H
        Considerations on the significance attributed to unusual cerebral histological findings recently described in eight patients with primary generalized epilepsy.
        Epilepsia. 1985; 26: 365-367
        • Baram T.Z
        • Mitchell W.G
        • Tournay A
        • Snead III, O.C
        • Hanson R.A
        • Horton E.G
        High-dose corticotropin (ACTH) versus prednisone for infantile spasms: a prospective, randomized, blinded study.
        Pediatrics. 1996; 97: 375-379
        • Holmes G.L
        • Weber D.A
        Effects of ACTH on seizure susceptibility in the developing brain.
        Ann Neurol. 1986; 1: 82-88
        • Pentella K
        • Bachman D.S
        • Sandman C.A
        Trial of an ACTH 4–9 analogue in children with intractable seizures.
        Neuropediatrics. 1982; 13: 59-62
        • Willig R.P
        • Lagenstein I
        Use of ACTH fragments in children with infantile spasms.
        Neuropediatrics. 1982; 13: 55-58
        • Baram T.Z
        Pathophysiology of massive infantile spasms: perspective on the putative role of the brain adrenal axis.
        Ann Neurol. 1993; 33: 231-236
        • Baram T.Z
        • Mitchell W.G
        • Brunson K
        • Haden E
        Infantile spasms: hypothesis-driven therapy and pilot human infant experiments using corticotropin-releasing hormone receptor antagonists.
        Dev Neurosci. 1999; 21: 281-289
        • Baram T.Z
        • Hirsch E
        • Snead III, O.C
        • Schultz L
        Corticotropin-releasing hormone-induced seizures in infant rats originate in the amygdala.
        Ann Neurol. 1992; 31: 488-494
        • Baram T.Z
        • Ribak C.E
        Peptide-induced infant status epilepticus causes neuronal death and synaptic reorganization.
        NeuroReport. 1995; 6: 277-280
        • Avishai-Eliner S
        • Yi S.J
        • Baram T.Z
        Developmental profile of messenger RNA for the corticotropin-releasing hormone receptor in the rat limbic system.
        Dev Brain Res. 1996; 91: 159-163
        • Baram T.Z
        • Hatalski C.G
        Neuropeptide-mediated excitability: a key triggering mechanism for seizure generation in the developing brain.
        Trends Neurosci. 1998; 21: 471-476
        • Aldenhoff J.B
        • Gruol D.L
        • Rivier J
        • Vale W
        • Siggins G.R
        Corticotropin releasing factor decreases postburst hyperpolarizations and excites hippocampal neurons.
        Science. 1983; 221: 875-877
        • Hollrigel G.S
        • Chen K
        • Baram T.Z
        • Soltesz I
        The pro-convulsant actions of corticotropin-releasing hormone in the hippocampus of infant rats.
        Neuroscience. 1998; 84: 78-84
        • Hauger R.L
        • Irwin M.R
        • Lorang M
        • Aguilera G
        • Brown M.R
        High intracerebral levels of CRH result in CRH receptor downregulation in the amygdala and neuroimmune desensitization.
        Brain Res. 1993; 616: 283-292
        • Nalin A
        • Facchinetti F
        • Galli V
        • Petraglia F
        • Storchi R
        • Genazzani A.R
        Reduced ACTH content in cerebrospinal fluid of children affected by cryptogenic infantile spasms with hypsarrhythmia.
        Epilepsia. 1985; 26: 446-449
        • Baram T.Z
        • Mitchell W.G
        • Snead III, O.C
        • Horton E.J
        • Saito M
        Brain adrenal axis hormones are altered in the CSF of infants with massive infantile spasms.
        Neurology. 1992; 42: 1171-1175
        • Baram T.Z
        • Mitchell W.G
        • Snead III, O.C
        • Horton E.J
        Corticotropin and cortisol are increased in the cerebrospinal fluid of infants with massive infantile spasms.
        Pediatr Neurol. 1995; 13: 108-110
        • Heiskala H
        CSF ACTH and beta-endorphin in infants with West syndrome and ACTH therapy.
        Brain Dev. 1997; 5: 339-342
        • Yan X.X
        • Toth Z
        • Schultz L
        • Ribak C.E
        • Baram T.Z
        Corticotropin-releasing hormone (CRH)-containing neurons in the immature rat hippocampal formation: light and electron microscopic features and colocalization with glutamate decarboxylase and parvalbumin.
        Hippocampus. 1998; 8: 231-243
      1. Chen Y, Bender RA, Baram TZ. Novel and transient populations of corticotropin-releasing hormone-expressing neurons in developing hippocampus suggest unique functional roles: a quantitative spatiotemporal analysis. Submitted for publication.

        • Hatalski C.G
        • Guirguis C
        • Baram T.Z
        Corticotropin releasing factor mRNA expression in the hypothalamic paraventricular nucleus and the central nucleus of the amygdala is modulated by repeated acute stress in the immature rat.
        J Neuroendocrinol. 1998; 10: 663-669
        • Yi S.J
        • Baram T.Z
        Corticotropin-releasing hormone mediates the response to cold stress in the neonatal rat without compensatory enhancement of the peptide's gene expression.
        Endocrinology. 1994; 135: 2364-2368
        • Hatalski C.G
        • Brunson K.L
        • Tantayanubutr B
        • Chen Y
        • Baram T.Z
        Neuronal activity and stress differentially regulate hippocampal and hypothalamic corticotropin-releasing hormone expression in the immature rat.
        Neuroscience. 2000; 101: 571-580
        • Gottlieb A
        • Keydar Y
        • Epstein H.T
        Rodent brain growth stages: an analytical review.
        Biol Neonate. 1977; 32: 166-176
        • Baram T.Z
        • Schultz L
        Corticotropin-releasing hormone is a rapid and potent convulsant in the infant rat.
        Dev Brain Res. 1991; 61: 97-101
        • Gray T.S
        • Bingaman E.W
        The amygdala: corticotropin-releasing factor, steroids, and stress.
        Crit Rev Neurobiol. 1996; 10: 155-168
        • Swanson L.W
        • Sawchenko P.E
        • Rivier J
        • Vale W.W
        Organization of ovine corticotropin-releasing factor immunoreactive cells and fibers in the rat brain: an immunohistochemical study.
        Neuroendocrinology. 1983; 36: 165-186
        • Karst H
        • Wadman W.J
        • Joels M
        Corticosteroid receptor-dependent modulation of calcium currents in rat hippocampal CA1 neurons.
        Brain Res. 1994; 649: 234-242
        • Pavlides C
        • Kimura A
        • Magarinos A.M
        • McEwen B.S
        Hippocampal homosynaptic long-term depression/depotentiation induced by adrenal steroids.
        Neuroscience. 1995; 68: 379-385
        • Imaki T
        • Nahan J.L
        • Rivier C
        • Sawchenko P.E
        • Vale W
        Differential regulation of corticotropin-releasing factor mRNA in rat brain regions by glucocorticoids and stress.
        J Neurosci. 1991; 11: 585-599
        • Pilcher W.H
        • Joseph S.A
        Co-localization of CRF-ir perikarya and ACTH-ir fibers in rat brain.
        Brain Res. 1984; 299: 91-102
        • Pranzatelli M.R
        On the molecular mechanism of adrenocorticotrophic hormone in the CNS: neurotransmitters and receptors.
        Exp Neurol. 1994; 125: 142-161
        • de Wied D
        Behavioral effects of neuropeptides related to ACTH, MSH, and βLPH.
        Ann NY Acad Sci. 1977; 297: 263-275
        • Mountjoy K.G
        • Robbins L.S
        • Mortrud M.T
        • Cone R.D
        The cloning of a family of genes that encode the melanocortin receptors.
        Science. 1992; 257: 543-546
        • Adan R.A.H
        • Gispen W.H
        Brain melanocortin receptors: from cloning to function.
        Peptides. 1997; 8: 1279-1287
        • Wu H.C
        • Chen K.Y
        • Lee W.Y
        • Lee E.H.Y
        Antisense oligonucleotides to corticotropin-releasing factor impair memory retention and increase exploration in rats.
        Neuroscience. 1997; 78: 147-153
        • Joseph S.A
        • Pilcher W.H
        • Knigge K.M
        Anatomy of the corticotropin-releasing factor and opiomelanocortin systems of the brain.
        Fed Proc. 1985; 44: 100-107
        • Snead III, O.C
        • Benton J.W
        • Hosey L.C
        • Swann J.W
        • Spink D
        • Martin D
        • et al.
        Treatment of infantile spasms with high-dose ACTH: efficacy and plasma levels of ACTH and prednisone.
        Neurology. 1989; 39: 1027-1031
        • Nicholson W.E
        • Liddle R.A
        • Puett D
        • Liddle G.W
        Adrenocorticotropic hormone biotransformation, clearance, and catabolism.
        Endocrinology. 1978; 103: 1344-1351
        • Mezey E
        • Palkovitz M
        • de Kloet E.R
        • Verhoef J
        • de Wied D
        Evidence for pituitary-brain transport of a behaviorally potent ACTH analog.
        Life Sci. 1978; 22: 831-838
        • Brunson K.L
        • Khan N
        • Eghbal-Ahmadi M
        • Baram T.Z
        ACTH acts directly on amygdala neurons to down-regulate corticotropin releasing hormone gene expression.
        Ann Neurol. 2001; 29: 304-312
        • Hrachovy R.A
        • Frost J.D
        • Kellaway P
        • Zion T.E
        Double-blind study of ACTH vs. prednisone therapy in infantile spasms.
        J Pediatr. 1983; 103: 641-645
        • Gantz I
        • Miwa H
        • Konda Y
        • Shimoto Y
        • Tashiro T
        • Watson S.J
        • et al.
        Molecular cloning, expression, and gene localization of a fourth melanocortin receptor.
        J Biol Chem. 1993; 268: 15174-15179