Abstract
Treatment of neurological disorders with intravenous immunoglobulin (IVIG) is an increasing feature of practice for an expanding range of indications. This article reviews the current literature regarding the role of IVIG treatment in multiple sclerosis (MS) and summarizes recommendations for the use of IVIG in different courses and clinical subsets of the disease.
Principally based on the results of four randomized, double-blind, placebo-controlled trials (RCTs) and a corresponding meta-analysis, the amount of evidence for the efficacy of IVIG treatment is currently most convincing for the relapsing-remitting course of MS (RRMS); nevertheless, it lags clearly behind that for beta interferon due to smaller study sizes, partial deficits in study design and not established optimal dosage. This prompted the basis for a consensus statement in some countries to recommend IVIG as second-line treatment in RRMS, when other licensed therapies (i. e., beta interferon, glatiramer acetate) are individually not tolerated due to side effects or concomitant disease. Recent evidence indicates that IVIG is also effective in clinically isolated syndrome (CIS) and should be considered as a therapeutic option, particularly when licensed immunotherapy can not be offered. During an acute relapse additional IVIG administration to established steroid treatment showed no benefit. Despite promising experimental data on promotion of remyelination, fixed chronic deficits were not reversed or improved by long-term IVIG treatment either. Currently there is no indication for IVIG treatment in the chronic progressive disease stages, since a large and well-designed RCT failed to show any beneficial effect in patients with secondary progressive MS (SPMS) and data derived from primary progressive MS (PPMS) are still pending. However, preliminary results of a so far unpublished RCT including patients with PPMS and SPMS suggest a strong trend towards a beneficial effect in PPMS. So far, IVIG is the only therapy investigated for reducing postpartum relapses, whereas immunomodulatory drugs are contraindicated during pregnancy and lactation period. Data evaluating the peripartal use of IVIG along with the positive results of the trials in RRMS justify postpartal IVIG treatment particularly for mothers, who choose to breastfeed, under consideration of the recommendations specified for the relapsing-remitting disease course. As recently shown IVIG administration right from the early weeks of pregnancy appears to be a promising strategy, but cannot be recommended from the viewpoint of evidence-based medicine.
Similar content being viewed by others
References
Achiron A, Pras E, Gilad R, Ziv I, Mandel M, Gordon CR, Noy S, Sarova-Pinhas I, Melamed E (1992) Open controlled therapeutic trial of intravenous immune globulin in relapsing-remitting Multiple Sclerosis. Arch Neurol 49:1233–1236
Achiron A, Gabbay U, Gilad R, Hassin-Baer S, Barak Y, Gornish M, Elizur A, Goldhammer Y, Sarova-Pinhas I (1998) Intravenous immunoglobulin treatment in multiple sclerosis. Effect on relapses. Neurology 50:398–402
Achiron A, Kishner I, Dolev M, Stern Y, Dulitzky M, Schiff E, Achiron R (2004) Effect of intravenous immunoglobulin treatment on pregnancy and postpartum-related relapses in multiple sclerosis. J Neurol 251:1133–1137
Achiron A, Kishner I, Sarova-Pinhas I, Raz H, Faibel M, Stern Y, Lavie M, Gurevich M, Dolev M, Magalashvili D, Barak Y (2004) Intravenous immunoglobulin treatment following the first demyelinating event suggestive of multiple sclerosis: a randomized, double-blind, placebo-controlled trial. Arch Neurol 61:1515–1520
Bieber A, Asakura K, Warrington A, Kaveri SV, Rodriguez M (2000) Antibody-mediated remyelination: relevance to multiple sclerosis. Mult Scler 6(Suppl 2):S1–S5
Bjartmar C, Wujek JR, Trapp BD (2003) Axonal loss in the pathology of MS: consequences for understanding the progressive phase of the disease. J Neurol Sci 206:165–171
Comi G, Filippi M, Barkhof F, Durelli L, Edan G, Fernandez O, Hartung H, Seeldrayers P, Sorensen PS, Rovaris M, Martinelli V, Hommes OR. Early Treatment of Multiple Sclerosis Study Group (2001) Effect on early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet 357:1576–1582
Comi G, Filippi M, Wolinsky JS (2001) European/Canadian multicenter, double-blind, randomized, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging-measured disease activity and burden in patients with relapsing multiple sclerosis. European/Canadian Glatiramer Acetate Study Group. Ann Neurol 49:290–297
Confavreux C, Vukusic S, Adeleine P (2003) Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process. Brain 126:770–782
Cook SD, Troiano R, Rohowsky-Kochan C, Jotkowitz A, Bielory L, Mehta PD, Oleske J, Bansil S, Dowling PC (1992) Intravenous gamma globulin in progressive MS. Acta Neurol Scand 86:171–175
Dyck PJ, Litchy WJ, Kratz KM, Suarez GA, Low PA, Pineda AA, Windebank AJ, Karnes JL, O’Brien PC (1994) A plasma exchange versus immune globuline infusion trial in chronic inflammatory demyelinating polyradiculoneuropathy. Ann Neurol 36:838–845
Fazekas F, Deisenhammer F, Strasser-Fuchs S, Nahler G, Mamoli B (1997) Randomised placebo-controlled trial of monthly intravenous immunoglobulin therapy in relapsing-remitting multiple sclerosis.Austrian Immunoglobulin in Multiple Sclerosis Study Group. Lancet 349:589–593
Haas J, Maas-Enriquez M, Hartung HP (2005) Intravenous immunoglobulins in the treatment of relapsing remitting multiple sclerosis—results of a retrospective multicenter observational study over five years. Mult Scler 11:562–567
Hommes OR, Sorensen PS, Fazekas F, Enriquez MM, Koelmel HW, Fernandez O, Pozilli C, O’Connor P (2004) Intravenous immunoglobulin in secondary progressive multiple sclerosis: randomised placebo-controlled trial. Lancet 364:1149–1156
Jacobs LD, Beck RW, Simon JH, Kinkel RP, Brownscheidle CM, Murray TJ, Simonian NA, Slasor PJ, Sandrock AW (2000) Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis: CHAMPS Study Group. N Engl J Med 343:898–904
Jacobs LD, Cookfair DL, Rudick RA, Herndon RM, Richert JR, Salazar AM, Fischer JS, Goodkin DE, Granger CV, Simon JH, Alam JJ, Bartoszak DM, Bourdette DN, Braiman J, Brownscheidle CM, Coats ME, Cohan SL, Dougherty DS, Kinkel RP, Mass MK, Munschauer FE 3rd, Priore RL, Pullicino PM, Scherokman BJ, Whitham RH et al. (1996) Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol 39:285–294
Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, Lisak RP, Myers LW, Panitch HS, Rose JW, Schiffer RB (1995) Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology 45:1268–1276
Kappos L, Polman C, Freedman MS, Edan GC, Hartung HP, Miller DH, Montalban X, Barkhof F, Bauer L, Jakobs P, Sandbrink R on behalf of the BENEFIT Study Group (2005) Betaferon in Newly Emerging Multiple Sclerosis for Initial Treatment (BENEFIT): clinical results. Mult Scler (Suppl 1):10
Kieseier BC, Kiefer R, Gold R, Hemmer B, Willison HJ, Hartung HP (2004) Advances in understanding and treatment of immune-mediated disorders of the peripheral nervous system. Muscle Nerve 30:131–156
Koçer B, Yildirim-Gurel S, Tali ET, Irkec C, Isik S (2004) The role of qualitative and quantitative MRI assessment of multiple sclerosis lesions according to their in evaluating the efficacy of intravenous immunoglobulin G. Neuroradiology 46:287–290
Lewanska M, Siger-Zajdel M, Selmaj K (2002) No difference in efficacy of two different doses of intravenous immunoglobulins in MS: clinical and MRI assessment. Eur J Neurol 9:565–572
MS-Therapie Konsensus Gruppe (1999) Immunomodulatorische Stufentherapie der multiplen Sklerose. Nervenarzt 70:371–386
MS-Therapie Konsensus Gruppe (2000) Immunomodulatorische Stufentherapie der multiplen Sklerose. I. Ergänzung.Nervenarzt 72:150–157
MS-Therapie Konsensus Gruppe (2002) Immunmodulatorische Stupentherapie der multiplen Sklerose. Neue Aspekte und praktische Umsetzung. Nervenarzt 73:556–563
Multiple Sclerosis Therapy Consensus Group (2004) Escalating immunotherapy of multiple sclerosis. J Neurol 251:1329–1339
Murray PD, McGavern DB, Sathornsumetee S, Rodriguez M (2001) Spontaneous remyelination following extensive demyelination is associated with improved neurological function in a viral model of multiple sclerosis. Brain 124:1403–1416
Noseworthy JH, O’Brien PC, Petterson TM, Weis J, Stevens L, Peterson WK, Sneve D, Cross SA, Leavitt JA, Auger RG, Weinshenker BG, Dodick DW, Wingerchuk DM, Rodriguez M (2001) A randomized trial of intravenous immunoglobulin in inflammatory demyelinating optic neuritis. Neurology 56:1514–1522
Noseworthy JH, O’Brien PC, Weinshenker BG, Weis JA, Petterson TM, Erickson BJ, Windebank AJ, Whisnant JP, Stolp-Smith KA, Harper CM Jr, Low PA, Romme LJ, Johnson M, An KN, Rodriguez M (2000) IV immunoglobulin does not reverse established weakness in MS. Neurology 55:1135–1143
Pöhlau D, Federlein J, Postert T, Sailer M, Bethke F, Kappos L, Haas J, Przuntek H (1997) Intravenous immunoglobulin (IVIG) treatment for patients with primary or secondary progressive multiple sclerosis—outline of a double-blind randomized, placebo-controlled trial. Mult Scler 3:149–152
Pöhlau D, Przuntek H, Späth P, Andresen I and the IVIG Study Group (2005) Intravenous immunoglobulin treatment for patients with primary or secondary progressive multiple sclerosis. Mult Scler (Suppl 1):163
PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group (1998) Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. Lancet 352:1498–1504
Prineas JW, Kwon EE, Cho E, Sharer LR, Barnett MH, Oleszak EL, Hoffman B, Morgan BP (2001) Immunopathology of secondary-progressive multiple sclerosis. Ann Neurol 50:646–657
Rodriguez M, Lennon VA (1990) Immunoglobulins promote remyelination in the central nervous system. Ann Neurol 27:12–17
Rodriguez M, Miller DJ, Lennon VA (1996) Immunoglobulins reactive with myelin basic protein promote CNS remyelination. Neurology 46:538–545
Roed HG, Langkilde A, Sellebjerg FT, Lauritzen M, Bang P, Morup A, Frederiksen JL (2005) A double-blind, randomized trial of IV immunoglobulin treatment in acute optic neuritis. Neurology 64:804–810
Rothfelder U, Neu I, Pelka R (1982) Therapy of multiple sclerosis with immunoglobulin G MMW Munch Med Wochenschr 124:74–78
Schuller E, Govaerts A (1983) First results of immunotherapy with immunoglobulin G in multiple sclerosis patients. Eur Neurol 22:205–212
Simone IL, Carrara D, Tortorella C, Ceccarelli A, Livrea P (2000) Early onset multiple sclerosis. Neurol Sci 21(4 Suppl 2):S861–S863
Sorensen PS, Wanscher B, Jensen CV, Schreiber K, Blinkenberg M, Ravnborg M, Kirsmeier H, Larsen V, Lee ML (1998) Intravenous immunoglobulin G reduces MRI activity in relapsing multiple sclerosis. Neurology 50:1273–1281
Sorensen PS, Fazekas F, Lee M (2002) Intravenous immunoglobulin G for the treatment of relapsing-remitting multiple sclerosis: a meta-analysis. Eur J Neurol 9:557–563
Sorensen PS, Haas J, Sellebjerg F, Olsson T, Ravnborg M; TARIMS Study Group (2004) IV immunoglobulins as add-on treatment to methylprednisolone for acute relapses in MS. Neurology 63:2028–2033
Stangel M, Boegner F, Klatt CH, Hofmeister C, Seyfert S (2000) Placebo controlled pilot trial to study the remyelinating potential of intravenous immunoglobulins in multiple sclerosis. J Neurol Neurosurg Psychiatry 68:89–92
Stangel M, Gold R (2004) Use of IV immunoglobulins in neurology. Evidence-based consensus. Nervenarzt 75:801–815
Stangel M, Hartung HP (2002) Despair of repair. J Neurol Neurosurg Psychiatry 72:1–4
Teksam M, Tali T, Kocer B, Isik S (2000) Qualitative and quantitative volumetric evaluation of the efficacy of intravenous immunoglobulin in multiple sclerosis: preliminary report. Neuroradiology 42:885–889
The IFNB Multiple Sclerosis Study Group (1993) Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 43:655–661
Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L (1998) Axonal transection in the lesions of multiple sclerosis. N Engl J Med 338:278–285
van der Meche FG, Schmitz PI (1992) A randomized trial comparing intravenous immune globulin and plasma exchange in Guillain-Barre syndrome. Dutch Guillain-Barre Study Group. N Engl J Med 326:1123–1129
van Doorn PA, Vermeulen M, Brand A, Mulder PG, Busch HF (1991) Intravenous immunoglobulin treatment in patients with chronic inflammatory demyelinating polyneuropathy. Clinical and laboratory characteristics associated with improvement. Arch Neur 48:217–220
Vermeulen M, Van Doorn PA, Brand A, Strengers PF, Jennekens FG, Busch HF (1993) Intravenous immunoglobulin treatment in patients with chronic inflammatory demyelinating polyneuropathy: a double blind, placebo controlled study. J Neurol Neurosurg Psychiatry 56:36–39
Visser LH, Beekman R, Tijssen CC, Uitdehaag BM, Lee ML, Movig KL, Lenderink AW (2004) A randomized, double-blind, placebo-controlled pilot study of i. v. immune globulins in combination i.v methylprednisolone in the treatment of relapses in patients with MS. Mult Scler 10:89–91
Author information
Authors and Affiliations
Corresponding author
Additional information
An erratum to this article is available at http://dx.doi.org/10.1007/s00415-008-0881-z.
Rights and permissions
About this article
Cite this article
Dudesek, A., Zettl, U.K. Intravenous immunoglobulins as therapeutic option in the treatment of multiple sclerosis. J Neurol 253 (Suppl 5), v50–v58 (2006). https://doi.org/10.1007/s00415-006-5007-x
Issue Date:
DOI: https://doi.org/10.1007/s00415-006-5007-x