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Treatment of Infantile Spasms: The Ideal and the Mundane

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UC IrvineUC Irvine Previously Published WorksTitleTreatment of Infantile Spasms: The Ideal and the MundanePermalinkhttps://escholarship.org/uc/item/2924d90wJournalEpilepsia, 44(8)ISSN0013-9580AuthorBaram, Tallie ZPublication Date2003-08-01DOI10.1046/j.1528-1157.2003.44086.xCopyright InformationThis work is made available under the terms of a Creative Commons Attribution License, availalbe at https://creativecommons.org/licenses/by/4.0/ Peer reviewedeScholarship.org Powered by the California Digital LibraryUniversity of CaliforniaTreatment of Infantile Spasms: The Ideal and the MundaneTallie Z. BaramDepartments of Pediatrics, Anatomy/Neurobiology and Neurology, University of California atIrvine. Irvine, California U.S.AOver 150 years after the description of infantile spasms (IS, 1), fifty years after thedelineation of hypsarrhythmia (2), and forty years after the coining of the term “westsyndrome” (3), there is little progress in understanding and effectively treating this disorder.This may not be surprising, because there is little consensus about most features of thisenigmatic syndrome: is it a generalized seizure disorder, as classified by the ILAE (4), orfocal seizures arising from “hidden” limbic (5) or brainstem (6) regions? Are the spasmstruly seizures, or does the pervasive hypsarrhythmia signify a state of virtual statusepilepticus? Some of the least defined aspects of infantile spasms remain in the treatmentarena. Indeed, even the need for treatment has been debated (7), particularly in view of thefact that IS seems to remit spontaneously in most affected infants (8, but see 9). However, abroad consensus does exist on the merits of therapy for IS. This is particularly true becauseof often clear regression of an affected infant—whether or not his/her development had beennormal prior to the onset of spasms (10,11). Further, successful treatment may lead todramatic improvements in cognition and function. Therefore, a quest for effective, welltolerated therapies for IS has been the Golden Fleece of the clinical Argonauts in the field.The relative ineffectiveness of conventional anticonvulsants for IS had been established bythe mid 20th century (reviewed in 10,11). The pioneering work of Sorel (12) suggested thatthe neuropeptide corticotropin (ACTH), acting directly within the brain (13–15) mightsuppress IS. Early anecdotal clinical success with ACTH (12,16) was confirmed by blindedcontrolled studies, although the rate of ACTH efficacy varied from ~40 to 88% (17,18).Whereas the rapid and robust effects of ACTH in eradicating IS and the hypsarrhythmiareported in these studies were impressive, the underlying mechanisms remained unclear.Actions directly within the brain were suggested by concurrent work in animals (13,19), butthe lack of efficacy of analogs that do not release endogenous steroids (14,15) led to theconclusion that ACTH acted on IS by releasing endogenous glucocorticoids, a viewsupported by the (more limited) efficacy of the latter hormones (19,20). The notion thatACTH and glucocorticoids share a hormonal action that alters immune (20), stress (21),inflammatory or other derangements in IS became prevalent, to the point that both classes ofcompounds are commonly referred to as “steroids” (20). In addition, the rationale for the useof one is often based on efficacy and side effects of the other.More recently, unique mechanisms of action of ACTH, entering the CNS and acting onmelanocortin receptors (MCRs) to reduce an excitatory neuropeptide in limbic structures hasbeen put forth (22). These data suggest that analogs of ACTH that bind MCRs but do notrelease steroids might constitute the longed-for Golden Fleece—the successful, hypothesis-driven therapy that is free of severe systemic side effects of ACTH and high dose steroids(21,22).Whereas this ethereal goal might be realized in the future, much effort has been directedover the past 50 years to evaluate the role of available anticonvulsants for IS, and each newpromising drug has been tested on these seizures (e.g., 23,24). The discovery of vigabatrin inparticular raised tremendous hope: The drug controlled the spasms and improved orNIH Public AccessAuthor ManuscriptEpilepsia. Author manuscript; available in PMC 2011 May 24.Published in final edited form as:Epilepsia. 2003 August ; 44(8): 993–994.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscripteliminated hypsarrhythmia initially in uncontrolled (25), then in larger controlled trials(26,27), and particularly in IS associated with tuberous sclerosis (28). Whereas the preciseefficacy of vigabatrin has not been fully defined (27,29), the medication has rapidly gainedprominence as a key step forward in the Argonauts’ quest for optimal IS therapy.The use of vigabatrin for IS has more recently been significantly curtailed by the emergenceof apparently irreversible retinal changes and altered peripheral vision upon its use. Whilethese side effects have diminished the likelihood of the drug’s approval in the U.S.,vigabatrin remains an important mainstay in the treatment of IS in Europe, together withearlier anticonvulsants with some established efficacy, such as nitrazepam (30). In addition,among the emerging crop of new anticonvulsant medications, none has shown exceptionalefficacy for the disorder. Based on all of this, how should a clinician treat an infant with IS?Whereas the optimal therapy for this disorder remains elusive, the paper by Capovilla andcolleagues in this issue describes some of the approaches that are being utilized in Europe.The paper discusses the use of nitrazepam and vigabatrin, and addresses specifically theissue of treatment duration: when is it safe to discontinue the medication? Using acollaborative multicenter approach, the authors demonstrate that at least in some infants,treatment may be stopped, without seizure recurrence, after several months. Thisinformation should be significantly helpful to clinicians who are facing these issues.Other related questions continue unanswered: How many infants with IS were seen? Howmany were treated with these drugs and did not respond, or were excluded for a variety ofreasons?—in other words, what is the likelihood that a clinician treating an infant withnitrazepam or vigabatrin will be successful in controlling the spasms and in discontinuingtherapy. These answers are still shrouded in mists, as are those for the cardinal questions ofwhich drugs to use and how to evaluate their efficacy. Still, while the optimal therapy for IS,based on the understanding of its pathophysiology, remains our Golden Fleece, the paper byCapovilla et al., provides useful hints for practical management of the disorder.References1. West WJ. On a peculiar form of infantile convulsions. Lancet. 1841; 1:724–5.2. Gibbs, FA.; Gibbs, EL. Epilepsy. Vol. 2. Cambridge, MA: Addison-Wesley; 1952. Atlas ofelectroencephalography.3. Eling P, Renier WO, Pomper J, Baram TZ. The mystery of the doctor’s son, or the riddle of WestSyndrome. Neurology. 2002; 58:953–5. [PubMed: 11914414]4. Commision on classification and terminology of the International League against Epilpsy. Epilepsia.1989; 30:389–99. [PubMed: 2502382]5. Acharya JN, Wyllie E, Luders HO, Kotagal P, Lancman M, Coelho M. Seizure symptomatology ininfants with localization-related epilepsy. Neurology. 1997; 48:189–96. [PubMed: 9008517]6. Hrachovy RA, Frost JD. Infantile spasms. Pediatr Clin North Am. 1989; 36:311–29. [PubMed:2538796]7. Lerman P, Kivity S. The efficacy of corticotropin in primary infantile spasms. J Pediatr. 1982;101:294–6. [PubMed: 6284904]8. Hrachovy RA, Glaze DG, Frost JD Jr. A retrospective study of spontaneous remission and long-term outcome in patients with infantile spasms. Epilepsia. 1991; 32:212–4. [PubMed: 1848513]9. de Menezes MA, Rho JM. Clinical and electrographic features of epileptic spasms persisting beyondthe second year of life. Epilepsia. 2002; 43:623–30. [PubMed: 12060022]10. Schwartzkroin, PA.; Rho, JM., editors. Epilepsy, infantile spasms and developmentalencephalopathy. Academic Press; 2002.11. Fukuyama, Y., editor. West syndrome and other infantile epileptic encephalopathies. Elsevier;2001.Baram Page 2Epilepsia. Author manuscript; available in PMC 2011 May 24.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscript12. Sorel L, Dusaucy-Bauloye A. A propos de 21 cas d’hypsarythmia de Gibbs. Son traitementspectaculaire par l’ACTH. Acta Neurol Psychiatr Belg. 1958; 58:130–41. [PubMed: 13532578]13. de Wied D. Behavioral effects of neuropeptides related to ACTH, MSH, and LPH. Ann NY AcadSci. 1977; 297:263–75. [PubMed: 211902]14. Pentella K, Bachman DS, Sandman CA. Trial of an ACTH 4–9 analogue in children withintractable seizures. Neuropediatrics. 1982; 13:59–62. [PubMed: 6290927]15. Willig RP, Lagenstein I. Use of ACTH fragments in children with infantile spasms.Neuropediatrics. 1982; 13:55–8. [PubMed: 6290926]16. Snead OC III, Benton JW, Hosey LC, et al. Treatment of infantile spasms with high-dose ACTH:Efficacy and plasma levels of ACTH and prednisone. Neurol. 1989; 39:1027–31.17. Hrachovy RA, Frost JD, Glaze DG. High-dose long-duration versus low-dose short durationcorticotropin therapy for infantile spasms. J Pediatr. 1994; 124:803–806. [PubMed: 8176573]18. Baram TZ, Mitchell WG, Tournay A, et al. High-dose corticotropin (ACTH) versus prednisone forinfantile spasms: a prospective, randomized, blinded study. Pediatrics. 1996; 97:375–9. [PubMed:8604274]19. Hrachovy RA, Frost JD, Kellaway P, Zion TE. Double-blind study of ACTH vs prednisone therapyin infantile spasms. J Pediatrics. 1983; 103:641–5.20. Riikonen RS. Steroids or vigabatrin in the treatment of infantile spasms? Pediatr Neurol. 2000;23:403–8. [PubMed: 11118795]21. Baram TZ. Pathophysiology of massive infantile spasms: perspective on the putative role of thebrain adrenal axis. Ann Neurol. 1993; 33:231–6. [PubMed: 8388675]22. Brunson KL, Khan N, Eghbal-Ahmadi M, Baram TZ. ACTH acts directly on amygdala neurons todown-regulate corticotropin releasing hormone gene expression. Ann Neurol. 2001; 49:304–12.[PubMed: 11261504]23. Schlumberger E, Chavez F, Palacios L, Rey E, Pajot N, Dulac O. Lamotrigine in treatment of 120children with epilepsy. Epilepsia. 1994; 35:359–67. [PubMed: 8156958]24. Glauser TA, Clark PO, Strawsburg R. A pilot study of topiramate in the treatment of infantilespasms. Epilepsia. 1998; 39:1324–8. [PubMed: 9860068]25. Chiron C, Dulac O, Luna D, Palacios L, Mondragon S, Beaumont D, Mumford JP. Vigabatrin ininfantile spasms. Lancet. 1990; 335:363–4. [PubMed: 1967808]26. Vigevano F, Cilio MR. Vigabatrin versus ACTH as first-line treatment for infantile spasms: arandomized, prospective study. Epilepsia. 1997; 38:1270–4. [PubMed: 9578521]27. Elterman RD, Shields WD, Mansfield KA, Nakagawa J. US Infantile Spasms Vigabatrin StudyGroup. Randomized trial of vigabatrin in patients with infantile spasms. Neurology. 2001;57:1416–21. [PubMed: 11673582]28. Chiron C, Dumas C, Jambaque I, Mumford J, Dulac O. Randomized trial comparing vigabatrin andhydrocortisone in infantile spasms due to tuberous sclerosis. Epilepsy Res. 1997; 26:389–95.[PubMed: 9095401]29. Lux AL, Edwards SW, Osborne JP, Hancock E, Johnson AL, Verity CM, Kennedy CR,O’Callaghan FJ, Newton RW. Randomized trial of vigabatrin in patients with infantile spasms.Neurology. 2002; 59:648. [PubMed: 12196676]30. Millichap JG, Ortiz WR. Nitrazepam in myoclonic epilepsies. Am J Dis Child. 1966; 112:242–8.[PubMed: 5945538]Baram Page 3Epilepsia. Author manuscript; available in PMC 2011 May 24.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscript

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Treatment of infantile spasms: the ideal and the mundane.

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