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IV Immunoglobulin in MS Patients with Corticosteroid Refractory Optic Neuritis
Abstract & Commentary
By Erik J. Kobylarz, MD, PhD, Assistant Professor of Neurology and Neuroscience, Weill Cornell Medical College, Cornell University. Dr. Kobylarz reports no financial relationship relevant to this field of study.
Synopsis: The use of sustained pulsed dosing of intravenous immunoglobulin (IVIG) may be useful for treating multiple sclerosis (MS) patients with corticosteroid refractory optic neuritis.
Source: Tselis A, Perumal J, Caon C, et al. Treatment of corticosteroid refractory optic neuritis in multiple sclerosis patients with intravenous immunoglobulin. Eur J Neurol 2008;15:1163-1167. Epub 2008 Aug 21.
Patients with severe visual loss due to optic neuritis (ON) that does not respond to conventional intravenous methyprednisolone (IVMP) treatment have limited therapeutic options. Tselis and colleagues performed an open-label, non-randomized, controlled prospective IVIG treatment trial of MS patients with corticosteroid refractory ON. They compared the treatment group to control patients who received only corticosteroids.
Twenty-three patients who received IVIG treatment were compared with 24 matched patients not receiving this medication. All patients had visual acuity of 20/400 or worse in the affected eyes. IVMP was administered to both groups for five days without oral prednisone taper. IVIG was administered between 60 and 90 days after the onset of ON after the patients were deemed to be IVMP failures. IVIG was administered for five days followed by once-monthly infusions for five months. There was significant improvement in the IVIG group with 18/23 (78%) subjects achieving near normal vision (20/30 or better). Only 3/24 (12.5%) from the control group responded similarly. In addition, there was improvement of the P100 latency in five patients in the IVIG treated group in whom the visual evoked potential test was repeated at one year after onset. In contrast, there was no improvement in the P100 latency of six patients in the control group one year after onset. The afferent papillary defect resolved one year after onset of ON in 19 of 23 (82%) IVIG patients, but in only four of 24 (17%) control patients. The investigators concluded that the use of IVIG with pulsed dosing, following corticosteroids, may be useful for treating IVMP refractory ON patients.
IVIG is an established therapy for demyelinating diseases of the peripheral nervous system. IVIG has been shown to promote remyelination in a mouse model of inflammatory demyelinating disease.1 A meta-analysis of the four double-blind IVIG trials demonstrated that this treatment reduces the relapse rate and, possibly, disease progression in relapsing–remitting MS.2 Pöhlau et al concluded from their study that monthly IVIG infusion could delay progression of disease in patients with primary–progressive MS, and that there was a trend in favor of IVIG treatment in patients with secondary–progressive MS.3 Okada and colleagues found that intermittent IVIG successfully prevented relapses in their patients with neuromyelitis optica.4 However, Roed et al found no effect of IVIG on long-term visual function six months following the onset of acute ON.5 Fazekas et al demonstrated no significant benefit versus placebo in their multinational, randomized, double-blind, placebo-controlled, phase II trial of IVIG in patients with relapsing-remitting MS (RRMS).6 Therefore, the efficacy of IVIG in ON and RRMS remains uncertain at present.
The results of this small study by Tselis et al suggest that there may be a beneficial effect of IVIG in MS patients with ON. However, the authors correctly note several limitations of their study. The open-label, non-randomized design introduces unavoidable bias. In addition, the population is skewed, since the patients selected were those without any improvement of their visual acuity at three months after treatment with IVMP, which is atypical for most patients who experience ON. Lastly, visual acuity was used as a measure of afferent visual function, which is likely not the best outcome measure for studying therapeutic effects in ON. Contrast sensitivity, color vision, visual fields, and possibly optical coherence tomography would be better indicators of optic nerve recovery.
As the authors note, a large-scale, double-blind, placebo-controlled, prospective trial is indicated to confirm these results and to help determine which specific patients with severe ON may benefit from IVIG treatment. Such a study should be performed, since the previous studies yielded mixed results and treatment with IVIG is quite costly. Further experimental data in combination with clinical experience will assist in defining the specific mechanisms by which IVIG suppresses the central nervous system demyelination disease process and will clarify any future indications for IVIG treatment in ON and MS.
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2. Soelberg Sorensen P. Intravenous polyclonal human immunoglobulins in multiple sclerosis. Neurodegener Dis 2008;5:8-15. Review.
3. Pöhlau D, Przuntek H, Sailer M, et al. Intravenous immunoglobulin in primary and secondary chronic progressive multiple sclerosis: A randomized placebo controlled multicentre study. Mult Scler 2007;13:1107-1117.
4. Okada K, Tsuji S, Tanaka K. Intermittent intravenous immunoglobulin successfully prevents relapses of neuromyelitis optica. Intern Med 2007;46:1671-1672.
5. Roed HG, Langkilde A, Sellebjerg F, et al. A double-blind, randomized trial of IV immunoglobulin treatment in acute optic neuritis. Neurology 2005;64; 804-810.
6. Fazekas F, Lublin FD, Li D, Freedman MS, et al, for the PRIVIG Study Group and the UBC MS/MRI Research Group. Intravenous immunoglobulin in relapsing-remitting multiple sclerosis: A dose-finding trial. Neurology 2008;71:265-271.