Skip to main content
Neurotherapeutics logoLink to Neurotherapeutics
. 2007 Oct;4(4):618–626. doi: 10.1016/j.nurt.2007.07.008

Corticosteroids for multiple sclerosis: I. Application for treating exacerbations

Elliot M Frohman 1,2,, Anjali Shah 1,2, Eric Eggenberger 3, Luanne Metz 4, Robert Zivadinov 5, Olaf Stüve 6
PMCID: PMC7479685  PMID: 17920542

Summary

Multiple sclerosis (MS) is an inflammatory demyelinating disorder characterized by a multiphasic course of neurological exacerbations, periods of clinical remission, and, in most patients, ultimately progressive deterioration of functional capabilities. The relapsing-remitting phase of the disease involves acute interruption in neurological functioning relating to areas of inflammation in discrete central-tract systems. The treatment of MS exacerbations with anti-inflammatory agents such as corticosteroids and adrenocorticotropic hormone has represented an established practice throughout the neurology community. Although there is scientific rationale supporting application of these agents for this purpose, the broad diversity of approaches to using these drugs in clinical practice is a derivative of expert opinion and anecdotal experience. Ultimately, the treatment of MS-related exacerbations is part science, but mostly art. This review discusses the pharmacology of these agents, to better understand how they may act to mitigate attacks and to provide some practical formulations for how to use them in the clinic for the benefit of patients.

Key Words: Corticosteroids, ACTH, pulse steroids

References

  • 1.Uhthoff W. Untersuchungen über die bei der multiplen Herdsklerose vorkommenden Augenstorungen [In German] Arch Psychiatr Nervenkrankh. 1889;20:55–55. [Google Scholar]
  • 2.Hansen BS, Hussain RZ, Lovett-Racke AE, Thomas JA, Racke MK. Multiple toll-like receptor agonists act as potent adjuvants in the induction of autoimmunity. J Neuroimmunol. 2006;172:94–103. doi: 10.1016/j.jneuroim.2005.11.006. [DOI] [PubMed] [Google Scholar]
  • 3.Goodin D, Frohman EM, Garmany GP, et al. Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology. 2002;58:169–178. doi: 10.1212/wnl.58.2.169. [DOI] [PubMed] [Google Scholar]
  • 4.Dalakas MC. Current treatment of the inflammatory myopathies. Curr Opin Rheumatol. 1994;6:595–601. doi: 10.1097/00002281-199411000-00008. [DOI] [PubMed] [Google Scholar]
  • 5.Kirwan JR, The Arthritis and Rheumatism Council Low-Dose Glucocorticoid Study Group The effect of glucocorticoids on joint destruction in rheumatoid arthritis. N Engl J Med. 1995;333:142–146. doi: 10.1056/NEJM199507203330302. [DOI] [PubMed] [Google Scholar]
  • 6.Hall S, Conn DL. Immunosuppressive therapy for vasculitis. Curr Opin Rheumatol. 1995;7:25–29. [PubMed] [Google Scholar]
  • 7.Guillevin L, Lhote F. Distinguishing polyarteritis nodosa from microscopic polyangiitis and implications for treatment. Curr Opin Rheumatol. 1995;7:20–24. [PubMed] [Google Scholar]
  • 8.Youssef PP, Haynes DR, Triantafillou S, et al. Effects of pulse methylprednisolone on inflammatory mediators in peripheral blood, synovial fluid, and synovial membrane in rheumatoid arthritis. Arthritis Rheum. 1997;40:1400–1408. doi: 10.1002/art.1780400807. [DOI] [PubMed] [Google Scholar]
  • 9.Droogan AG, Crockard AD, McMillan SA, Hawkins SA. Effects of intravenous methylprednisolone therapy on leukocyte and soluble adhesion molecule expression in MS. Neurology. 1998;50:224–229. doi: 10.1212/wnl.50.1.224. [DOI] [PubMed] [Google Scholar]
  • 10.Filipovic SR, Drulovic J, Stojsavljevic N, Levic Z. The effects of high-dose intravenous methylprednisolone on event-related potentials in patients with multiple sclerosis. J Neurol Sci. 1997;152:147–153. doi: 10.1016/S0022-510X(97)00159-7. [DOI] [PubMed] [Google Scholar]
  • 11.Patzold T, Schwengelbeck M, Ossege LM, Malin JP, Sindem E. Changes of the MS Functional Composite and EDSS during and after treatment of relapses with methylprednisolone in patients with multiple sclerosis. Acta Neurol Scand. 2002;105:164–168. doi: 10.1034/j.1600-0404.2002.1o135.x. [DOI] [PubMed] [Google Scholar]
  • 12.Humm AM, Z’Graggen WJ, Buhler R, Magistris MR, Rosier KM. Quantification of central motor conduction deficits in multiple sclerosis patients before and after treatment of acute exacerbation by methylprednisolone. J Neurol Neurosurg Psychiatry. 2006;77:345–350. doi: 10.1136/jnnp.2005.065284. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Buttgereit F, Wehling M, Burmester GR. A new hypothesis of modular glucocorticoid actions: steroid treatment of rheumatic diseases revisited. Arthritis Rheum. 1998;41:761–767. doi: 10.1002/1529-0131(199805)41:5<761::AID-ART2>3.0.CO;2-M. [DOI] [PubMed] [Google Scholar]
  • 14.Gold R, Buttgereit F, Toyka KV. Mechanism of action of glucocorticosteroid hormones: possible implications for therapy of neuroimmunological disorders. J Neuroimmunol. 2001;117:1–8. doi: 10.1016/S0165-5728(01)00330-7. [DOI] [PubMed] [Google Scholar]
  • 15.Wehling M. Specific, nongenomic actions of steroid hormones. Annu Rev Physiol. 1997;59:365–393. doi: 10.1146/annurev.physiol.59.1.365. [DOI] [PubMed] [Google Scholar]
  • 16.Boumpas DT, Chrousos GP, Wilder RL, Cupps TR, Balow JE. Glucocorticoid therapy for immune-mediated diseases: basic and clinical correlates. Ann Intern Med. 1993;119:1198–1208. doi: 10.7326/0003-4819-119-12-199312150-00007. [DOI] [PubMed] [Google Scholar]
  • 17.Adcock IM, Caramori G, Ito K. New insights into the molecular mechanisms of corticosteroids actions. Curr Drug Targets. 2006;7:649–660. doi: 10.2174/138945006777435344. [DOI] [PubMed] [Google Scholar]
  • 18.Falkenstein E, Norman AW, Wehling M. Mannheim classification of nongenomically initiated (rapid) steroid action(s) J Clin Endocrinol Metab. 2000;85:2072–2075. doi: 10.1210/jc.85.5.2072. [DOI] [PubMed] [Google Scholar]
  • 19.Buttgereit F, Brand MD, Burmester GR. Equivalent doses and relative drug potencies for non-genomic glucocorticoid effects: a novel glucocorticoid hierarchy. Biochem Pharmacol. 1999;58:363–368. doi: 10.1016/S0006-2952(99)00090-8. [DOI] [PubMed] [Google Scholar]
  • 20.Yong VW, Power C, Forsyth P, Edwards DR. Metalloproteinases in biology and pathology of the nervous system. Nat Rev Neurosci. 2001;2:502–511. doi: 10.1038/35081571. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Rosenberg GA, Dencoff JE, Correa N, Reiners M, Ford CC. Effect of steroids on CSF matrix metalloproteinases in multiple sclerosis: relation to blood-brain barrier injury. Neurology. 1996;46:1626–1632. doi: 10.1212/wnl.46.6.1626. [DOI] [PubMed] [Google Scholar]
  • 22.Orchinik M, Murray TF, Moore FL. A corticosteroid receptor in neuronal membranes. Science. 1991;252:1848–1851. doi: 10.1126/science.2063198. [DOI] [PubMed] [Google Scholar]
  • 23.Gametchu B. Glucocorticoid receptor-like antigen in lymphoma cell membranes: con-elation to cell lysis. Science. 1987;236:456–461. doi: 10.1126/science.3563523. [DOI] [PubMed] [Google Scholar]
  • 24.Gametchu B, Watson CS, Wu S. Use of receptor antibodies to demonstrate membrane glucocorticoid receptor in cells from human leukemic patients. FASEB J. 1993;7:1283–1292. doi: 10.1096/fasebj.7.13.8405814. [DOI] [PubMed] [Google Scholar]
  • 25.Diba F, Watson CS, Gametchu B. 5′UTR sequences of the glucocorticoid receptor 1A transcript encode a peptide associated with translational regulation of the glucocorticoid receptor. J Cell Biochem. 2001;81:149–161. doi: 10.1002/1097-4644(20010401)81:1<149::AID-JCB1031>3.0.CO;2-W. [DOI] [PubMed] [Google Scholar]
  • 26.Chaudhari BR, Murphy RF, Agrawal DK. Following the TRAIL to apoptosis. Immunol Res. 2006;35:249–262. doi: 10.1385/IR:35:3:249. [DOI] [PubMed] [Google Scholar]
  • 27.Navratil JS, Liu CC, Aheam JM. Apoptosis and autoimmunity. Immunol Res. 2006;36:3–12. doi: 10.1385/IR:36:1:3. [DOI] [PubMed] [Google Scholar]
  • 28.Buttgereit F, Krauss S, Brand MD. Methylprednisolone inhibits uptake of Ca2+ and Na+ ions into concanavalin A-stimulated thymocytes. Biochem J. 1997;326:329–332. doi: 10.1042/bj3260329. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Schmidt J, Gold R, Schonrock L, Zettl UK, Hartung HP, Toyka KV. T-cell apoptosis in situ in experimental autoimmune enceph-alomyelitis following methylprednisolone pulse therapy. Brain. 2000;123:1431–1441. doi: 10.1093/brain/123.7.1431. [DOI] [PubMed] [Google Scholar]
  • 30.Zamvil SS, Steinman L. The T lymphocyte in experimental allergic encephalomyelitis. Annu Rev Immunol. 1990;8:579–621. doi: 10.1146/annurev.iy.08.040190.003051. [DOI] [PubMed] [Google Scholar]
  • 31.Levine S, Wenk EJ, Muldoon TN, Cohen SG. Enhancement of experimental allergic encephalomyelitis by adrenalectomy. Proc Soc Exp Biol Med. 1962;111:383–385. doi: 10.3181/00379727-111-27799. [DOI] [PubMed] [Google Scholar]
  • 32.McCombe PA, Nickson I, Tabi Z, Pender MP. Corticosteroid treatment of experimental autoimmune encephalomyelitis in the Lewis rat results in loss of V beta 8.2+ and myelin basic protein-reactive cells from the spinal cord, with increased total T-cell apoptosis but reduced apoptosis of V beta 8.2+ cells. J Neuroimmunol. 1996;70:93–101. doi: 10.1016/S0165-5728(96)00043-4. [DOI] [PubMed] [Google Scholar]
  • 33.Pender MP, Nguyen KB, McCombe PA, Kerr JF. Apoptosis in the nervous system in experimental allergic encephalomyelitis. J Neurol Sci. 1991;104:81–87. doi: 10.1016/0022-510X(91)90219-W. [DOI] [PubMed] [Google Scholar]
  • 34.Durelli L, Cocito D, Riccio A, et al. High-dose intravenous methylprednisolone in the treatment of multiple sclerosis: clinical-immunologic correlations. Neurology. 1986;36:238–243. doi: 10.1212/wnl.36.2.238. [DOI] [PubMed] [Google Scholar]
  • 35.Beck RW, Cleary PA, Anderson MM, et al. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. N Engl J Med. 1992;326:581–588. doi: 10.1056/NEJM199202273260901. [DOI] [PubMed] [Google Scholar]
  • 36.Sellebjerg F, Frederiksen JL, Nielsen PM, Olesen J. Double-blind, randomized, placebo-controlled study of oral, high-dose methylprednisolone in attacks of MS. Neurology. 1998;51:529–534. doi: 10.1212/wnl.51.2.529. [DOI] [PubMed] [Google Scholar]
  • 37.Brusaferri F, Candelise L. Steroids for multiple sclerosis and optic neuritis: a meta-analysis of randomized controlled clinical trials. J Neurol. 2000;247:435–442. doi: 10.1007/s004150070172. [DOI] [PubMed] [Google Scholar]
  • 38.Rose AS, Kuzma JW, Kurtzke JF, Namerow NS, Sibley WA, Tourtellotte WW. Cooperative study in the evaluation of therapy in multiple sclerosis: ACTH vs. placebo—final report. Neurology. 1970;20:1–59. doi: 10.1212/wnl.20.5_part_2.1. [DOI] [PubMed] [Google Scholar]
  • 39.Humm AM, Z’Graggen WJ, Buhler R, Magistris MR, Rosier KM. Quantification of central motor conduction deficits in multiple sclerosis patients before and after treatment of acute exacerbation by methylprednisolone. J Neurol Neurosurg Psychiatry. 2006;77:345–50. doi: 10.1136/jnnp.2005.065284. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Filippini G, Brusaferri F, Sibley WA, Citterio A, Ciucci G, Midgard R, Candelise L. Corticosteroids or ACTH for acute exacerbations in multiple sclerosis. [DOI] [PMC free article] [PubMed]
  • 41.Ciucci G, Midgard R, Candelise L. Corticosteroids or ACTH for acute exacerbations in multiple sclerosis. Cochrane Database Syst Rev 2000;(4):CD001331. [DOI] [PMC free article] [PubMed]
  • 42.Hoogervorst EL, Polman CH, Barkhof F. Cerebral volume changes in multiple sclerosis patients treated with high-dose intravenous methylprednisolone. Mult Scler. 2002;8:415–419. doi: 10.1191/1352458502ms838oa. [DOI] [PubMed] [Google Scholar]
  • 43.Herishanu YO, Badama S, Sarov B, Abarbanel JM, Segal S, Bearman JE. A possible harmful late effect of methylprednisolone therapy on a time cluster of optic neuritis. Acta Neurol Scand. 1989;80:569–574. doi: 10.1111/j.1600-0404.1989.tb03928.x. [DOI] [PubMed] [Google Scholar]
  • 44.Stüve O, Marra CM, Jerome K, et al. Immune surveillance in multiple sclerosis patients treated with natalizumab. Ann Neurol. 2006;59:743–747. doi: 10.1002/ana.20858. [DOI] [PubMed] [Google Scholar]
  • 45.Stiive O, Marra CM, Jerome K, et al. Altered CD4:CD8 T cells ratios in cerebrospinal fluid of natalizumab-treated multiple sclerosis patients. Arch Neurol. 2006;63:1383–1387. doi: 10.1001/archneur.63.10.1383. [DOI] [PubMed] [Google Scholar]
  • 46.Stüve O, Marra CM, Petra CD, et al. The potential risk of progressive multifocal leukoencephalopathy with natalizumab therapy: possible interventions. Arch Neurol. 2007;64:169–176. doi: 10.1001/archneur.64.2.169. [DOI] [PubMed] [Google Scholar]
  • 47.Sellebjerg F, Schaldemose Nielsen H, Fredericksen JL, Olesen J. A randomized, controlled trial of oral high-dose methylprednisolone in acute optic neuritis. Neurology. 1999;52:1479–1484. doi: 10.1212/wnl.52.7.1479. [DOI] [PubMed] [Google Scholar]
  • 48.Alam SM, Kyriakides T, Lawden M, Newman PK. Methylprednisolone in multiple sclerosis: a comparison of oral with intravenous therapy at equivalent high dose. J Neurol Neurosurg Psychiatry. 1993;56:1219–1220. doi: 10.1136/jnnp.56.11.1219. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Barnes D, Hughes RAC, Morris RW, et al. Randomised trial of oral and intravenous methylprednisolone in acute relapses of multiple sclerosis. Lancet. 1997;349:902–906. doi: 10.1016/S0140-6736(96)06453-7. [DOI] [PubMed] [Google Scholar]
  • 50.Metz LM, Sabuda D, Hilsden RJ, Enns R, Meddings JB. Gastric tolerance of high-dose pulse oral prednisone in multiple sclerosis. Neurology. 1999;53:2093–2096. doi: 10.1212/wnl.53.9.2093. [DOI] [PubMed] [Google Scholar]
  • 51.Morrow SA, Stoian CA, Dmitrovic J, Chan SC, Metz LM. The bioavailability of IV methylprednisolone and oral prednisone in multiple sclerosis. Neurology. 2004;63:1079–1080. doi: 10.1212/01.wnl.0000138572.82125.f5. [DOI] [PubMed] [Google Scholar]
  • 52.Lackner TE. Interaction of dexamethasone with phenytoin. Pharmacotherapy. 1991;11:344–347. [PubMed] [Google Scholar]
  • 53.Pradat P, Robert-Gnansia E, Di Tanna GL, Rosano A, Lisi A, Mastroiacovo P, Contributors to the MADRE database First trimester exposure to corticosteroids and oral clefts. Birth Defects Res A Clin Mol Terato. 2003;67:968–970. doi: 10.1002/bdra.10134. [DOI] [PubMed] [Google Scholar]

Articles from Neurotherapeutics are provided here courtesy of Elsevier

RESOURCES