- Email: [email protected]
Intravenous immunoglobulin in recurrent-relapsing inflammatory optic neuropathy
Intravenous immunoglobulin in recurrent-relapsing inflammatory optic neuropathy Hadas Stiebel-Kalish,*{ MD; Naama Hammel,*{ MD; Judith van Everdingen,{ MD; Ruth Huna-Baron{§; Andrew G. Lee," MD ABSTRACT N RE´SUME´ Objective: Recurrent-relapsing inflammatory optic neuropathy, including chronic relapsing inflammatory and autoimmune optic neuropathies, is rare, but can cause severe visual loss. Long-term steroids may preserve vision, yet side effects are frequent. We describe our experience with intravenous immunoglobulins (IVIg). Design: A semi-prospective case series from 4 medical centres. Participants: Patients with steroid responsive recurrent-relapsing optic neuropathy. Methods: Semiprospective case series of IVIg treatment in steroid-responsive recurrent-relapsing optic neuropathy at 4 medical centres. Outcome measures included visual outcome; time to, and duration of, remission; duration of corticosteroid use; and adverse events. Results: Vision stabilized in all 6 patients treated with IVIg without steroids for extended periods of time. None improved and none worsened. One adverse event occurred during an IVIg infusion after 3 uneventful years of IVIg maintenance. Average steroid use prior to IVIg was 12 months. After IVIg treatment, 5/6 patients no longer required corticosteroids. Two patients experienced late relapses on IVIg, one of whom was treated with cyclosporine, the other with steroids. Conclusions: IVIg can be considered an effective steroid-sparing agent in selected cases with steroid-dependent recurrent-relapsing autoimmune optic neuropathy. Objet : La neuropathie optique inflammatoire re´cidivante et re´currente, comprenant les neuropathies optiques re´cidivantes chroniques et auto-immunes, est rare, mais elle peut causer une se´ve`re perte visuelle. Le recours a` long terme de ste´roı¨des peut pre´server la vision, ne´anmoins les effets secondaires sont fre´quents. Nous de´crivons notre expe´rience de l’utilisation de l’immunoglobuline intraveineuse (IgIV). Nature : E´tude semi-re´trospective d’une se´rie de cas de 4 centres me´dicaux. Participants : Patients atteints d’une neuropathie optique re´cidivante et re´currente re´pondant aux ste´roı¨des Me´thodes : E´tude semi-prospective d’une se´rie de cas de neuropathie optique inflammatoire re´cidivante et re´currente sensible aux ste´roı¨des, traite´s a` l’IgIV dans 4 centres me´dicaux. La mesure des re´sultats comprenait le re´sultat visuel : le moment et la dure´e de la re´mission; la dure´e d’utilisation du corticoste´roı¨de; et les e´ve´nements inde´sirables. Re´sultats : La vision s’est stabilise´e chez les 6 patients traite´s a` l’IgIV sans ste´roı¨de pendant des pe´riodes de temps prolonge´ es. Il n’y a eu ni ame´ lioration ni aggravation. Un e´ ve´ nement inde´ sirable s’est produit pendant une infusion d’IgIV apre`s 3 anne´es de maintien de l’IgIV sans e´ve´nement. La dure´e d’utilisation de ste´roı¨de avant l’IgIV a e´te´ de 12 mois en moyenne. Apre`s le traitement a` l’IgIV, 5 patients sur 6 n’ont plus eu besoin de corticoste´roı¨des. Il y a eu re´cidive tardive chez 2 patients sous IgIV; un a e´te´ traite´ avec de la cyclosporine, l’autre, avec des ste´roı¨des. Conclusions : L’IgIV peut eˆtre conside´re´e comme un agent efficace pour e´pargner les ste´roı¨des dans des cas se´lectifs de neuropathie optique auto-immune re´currente et re´cidivante de´pendant de la ste´roı¨de.
R
ecurrent-relapsing inflammatory optic neuropathy includes autoimmune optic neuropathy (AON) and chronic-relapsing inflammatory optic neuropathy (CRION), and is a rare, often bilateral, typically steroidresponsive optic neuropathy. The typical course of AON was first described in the 1980’s by Kupersmith1 and Dutton et al.2 Although patients with AON have positive
serum autoantibodies such as antinuclear antibodies, rheumatoid factor, anticardiolipin antibodies, and (or) a positive skin biopsy of nonlesional skin, the full criteria for rheumatologic disorders (systemic lupus erythematosis [SLE], Wegener’s vasculitis, rheumatoid arthritis) are not met. AON is a diagnosis of exclusion, distinguished from demyelinating, granulomatous, infectious, and other
From *the Neuro-Ophthalmology Unit, Department of Ophthalmology, Rabin Medical Center, Petah Tikva, Israel; {Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; {Rotterdam Eye Hospital, Rotterdam, The Netherlands; §Neuro-Ophthalmology Service, Goldschleger Eye Institute, Sheba Medical Center, Tel Hashomer, Israel; and "Neuro-Ophthalmology Unit, Departments of Ophthalmology, Neurology, and Neurosurgery, and the H. Stanley Thompson Neuro-ophthalmology Clinic at The University of Iowa Hospitals and Clinics, Iowa City, Iowa
Correspondence to Hadas Stiebel-Kalish, MD, Chief, NeuroOphthalmology Unit, Department of Ophthalmology, Rabin Medical Center, Petah Tikva 49100, Israel; [email protected] This article has been peer-reviewed. Cet article a e´te´ e´value´ par les pairs. Can J Ophthalmol 2010;45:71–5 doi:10.3129/i09-238
Originally received Mar. 21, 2009. Revised July 31, 2009 Accepted for publication Aug. 10, 2009 Published online Jan. 13, 2010 CAN J OPHTHALMOL—VOL. 45, NO. 1, 2010
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IVIg in recurrent-relapsing optic neuropathy—Stiebel-Kalish et al. inflammatory or infiltrative optic neuropathies. Frequent relapses necessitate long-term immunosuppression.3–5 CRION was described by Kidd et al.3 as a form of inflammatory optic neuropathy that is frequently bilateral, often painful, and characterized by relapses and remissions, which responds well to steroids. Corticosteroids are the accepted first-line treatment for AON. Long-term steroid side effects commonly lead to addition or substitution of steroid-sparing agents (i.e., methotrexate, cyclophosphamide, azathioprine, chlorambucil, and mycophenylate are commonly added, often limited by side effects.)6,7 Intravenous immunoglobulin (IVIg) has been used successfully in the peripheral neuropathies associated with various vasculitides, including Sjogren’s syndrome, SLE, vaccination-induced vasculitis, ChurgStrauss vasculitis, mixed cryoglobulinemia, polyarteritis nodosa, sarcoidosis, and scleroderma.8 IVIg has also been beneficial in single case series of AON.9–11 We describe 6 patients with recurrent-relapsing steroid-responsive optic neuropathies successfully treated with IVIg. METHODS
A semiprospective observational cohort study was performed at 4 academic institutions (The Rabin Medical Center, Israel; the University of Iowa, Iowa; Rotterdam Eye Hospital, The Netherlands; and Sheba Medical Center, Israel) between 2000 and 2008. We included adults with recurrent-relapsing optic neuropathy treated with IVIg with adequate follow-up. AON was defined as an optic neuropathy with evidence of serologic autoimmunity (i.e., positive antinuclear antibodies, anticardiolipin antibodies, and beta-2 glycoprotein antibodies) in which demyelinating, granulomatous, infectious, and distinct rheumatologic etiologies were excluded. A non–sunexposed skin biopsy was not routinely available at all centres. CRION was defined, as published by Kidd et al.,3 as a form of inflammatory optic neuropathy that is frequently bilateral, is characterized by relapses and remissions, and responds well to steroids. None of the patients had signs, symptoms, clinical course, or magnetic resonance findings suggestive of neuromyelitis optica, although aquaporin or neuromyelitis optica antibodies were unavailable at the time of treatment. Patient characteristics are described in Table 1. The primary outcome measure was visual function (improvement, stabilization, or progression). Visual function and visual field definitions used in this study are listed in Table 2. Secondary outcome measures included treatment side effects; ability to achieve clinical remission; ability to discontinue corticosteroids; duration to remission; and duration of corticosteroid use before and after IVIg. Institutional review board approval was obtained, and the cases were reviewed in accordance with the Declaration of Helsinki.
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RESULTS
Of 10 patients with recurrent-relapsing inflammatory (steroid-responsive) optic neuropathy, 2 patients developed defined rheumatologic disorders within 1 year (SLE in one patient, Wegener’s disease in another) and were not treated with IVIg, and 2 patients stabilized with low-dose steroids and methotrexate. Table 3 summarizes the clinical features of the 6 patients included in this case series. One patient treated with IVIg included in this series initially had no evidence of SLE at presentation, but developed signs and symptoms leading to the diagnosis of SLE 5 years later. Regarding the primary outcome measures, of the 12 eyes (6 patients with bilateral AON) treated with IVIg, visual acuity improved in 2, stabilized in 10, and worsened in none. Visual field defects improved in 3 eyes, similar to the improvement achieved with steroids, stabilized in 7/10 eyes, and worsened in none. Secondary outcome measures are listed in Table 4. Table 1—The work-up for patients with recurrent-relapsing steroid-responsive optic neuropathy A recurrent-relapsing steroid-responsive visual loss due to an optic neuropathy in which demyelinating, granulomatous, infectious, and distinct rheumatologic etiologies were excluded by: 1. Normal or noncontributory findings on magnetic resonance imaging scan of the brain and orbit with fat suppression with and without gadolinium (findings not typical for demyelinative, granulomatous, or vasculitic disease) Normal chest x-rays Normal serum angiotensin converting enzyme Normal Mantoux skin test 2. Variable laboratory testing performed: serum antinuclear antibody, rheumatoid factor, complete blood count, blood chemistry, sedimentation rate, core antineutrophilic cytoplasmic antibody and perinuclear antineutrophilic cytoplasmic antibody, immune electrophoresis, serology for syphilis, Bartonella, Lyme disease 3. An examination by a rheumatologist and revision of laboratory tests not meeting criteria for systemic autoimmune disease (systemic lupus erythematosis, Wegener’s disease, rheumatoid arthritis, etc.), despite presence of autoimmune antibodies
Table 2—Visual outcome criteria (for this study) Visual function Improvement
An increase of at least one Snellen line of best-corrected distance visual testing accompanied by another visual measure (e.g., improvement in relative afferent pupillary defect along with improved colour vision testing and [or] visual field testing) on 2 consecutive visits separated by 3 mo
Stabilization
No change in visual acuity on 2 consecutive visits separated by 3 mo
Progression
Worsening of visual acuity associated with at least one other visual function measure
Automated visual field interpretation Stable
Pattern of visual field defect unchanged from the prior test, or MD and CPSD within ¡0.8 dB on at least 2 separate consecutive tests
Improved
A decrease in MD and CPSD of at least 0.8 dB on at least 2 consecutive tests
Progressed
2 consecutive visual field tests revealing a +0.8 dB higher MD or CPSD
Note: mo., months; MD, mean deviation; CPSD, corrected standard pattern deviation; dB, decibel.
OS 12/12
After 3 y of uneventful IVIg treatment: chills, dyspnea, headaches
4y
2/27/2009, 20/40 OU bilateral moderate optic atrophy
IVIg adverse events
Y without steroids following IVIg
Date and final visual outcome
7/19/2009 OD 2/200 (since 2003) OS 20/40 bilateral optic atrophy
5
3y 9/30/2009 20/20 OU Trace RAPD OD 12/12 OU bilateral mild optic atrophy
4/30/2009 OD 20/25 partial optic atrophy OU
None
2.5 y
Methotrexate with prednisone: Kaposi’s sarcoma
Cushingoid features, acne
2006
6 mo
OS 12/12
OD 10/12
7y 02/24/2009 20/50 OD (amblyopia) OS 20/20 bilateral optic atrophy
1/20/2009 20/30 OD 20/50 OS bilateral mild atrophy
None
Twice during a few wk
Azathioprine and prednisone: failed
Insomnia, mood swings
1997, 2002
1 mo before IVIg, followed by on and off 5 y
—
No pupillary reactions
OS No LP
OD No LP
1y
None
1y
Methotrexate: hair loss
Cushingoid features
2006
15 mo
—
Trace RAPD OS
OS 20/50
+2 RAPD OD
OD 20/50
OS 20/25
No autoantibodies; headache; pain on eye movement; hyposensibility of right cheek; slight proteineuria
Weak ANA + 1:32
6
F
44
4/4/1996
F
48
5/30/2006
OD 20/50
1y
None
None
4 y (D/C due to relapse in 2007)
1 y, cyclosporine started recently
cellcept: failed (LFT elevations, tinnitus, hearing loss), cyclosporine
azathioprine: failed
Methotrexate: failed
Mood swings, insomnia
2004, 2007, 2008
3y
4y
IVIg was the first steroidsparing agent of choice
Cushingoid features, osteoporosis
1997, 2000, 2001, 2003
4 relapses in 7 y
—
Amaurotic OS
OS bare LP, 6-y-old optic atrophy
OD 20/25
Raynaud’s phenomenon No autoimmune antibodies; post ITP mild chronic hydrocephalus; CSF and ICP normal
4
No autoimmune antibodies
F
53
5/12/2006
Patient number
M
39
3/15/2004
3
F
2
*Ishihara: colour vision was tested using 12 Ishihara plates. Note: y, year; F, female; M, male; RF, rheumatoid factor; RA, rheumatoid arthritis; TSH, thyroid stimulating hormone; CSF, cerebrospinal fluid; ICP, intracranial pressure; ITP, immune thrombocytopenic pressure; ANA, antinuclear anti-body; LP, lumbar puncture; RAPD, relative afferent pupillary defect; mo, month; IVIg, intravenous immunoglobulins; LFT, liver function tests; wk, week; D/C, discontinued.
3y
Duration of IVIg
Steroid-sparing agents Methotrexate: optic used and reason for failure neuropathy relapse
Cushingoid features, hypertension, insomnia
OD 0/12
Ishihara*
2001, 2002
OS 12/12
+2 RAPD OD
RAPD
Steroid side effects
OD 8/12
OS 20/30
Y of relapse
+2 RAPD OD
OD 20/60
Presenting visual acuity
12 mo
OS 20/30
RF+ on 2/6 tests; did not meet RA criteria; mildly low TSH; no anti-TSH antibodies
Presence of antibodies
Duration of steroids
OD 20/70
F
Gender
44
43
Age at presentation (y)
19/7/1996
2/5/2001
Date of presentation
1
Table 3—Course of recurrent-relapsing autoimmune optic neuropathy in 6 patients before and after intravenous immunoglobulin treatment
IVIg in recurrent-relapsing optic neuropathy—Stiebel-Kalish et al.
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IVIg in recurrent-relapsing optic neuropathy—Stiebel-Kalish et al. CONCLUSIONS
To our knowledge, this study is the largest Englishlanguage series of IVIg treatment in patients with recurrent-relapsing inflammatory optic neuropathy. All 6 patients, who were originally steroid responsive, were able to discontinue steroids for extended periods of time while maintaining remission, similar to the rates described with other immunosuppressive regimens. We recognize the limitations of our study. First, inflammatory recurrent optic neuropathies such as AON and CRION are rare; therefore, our sample size was small. Second, the semiprospective design (all patients were recorded in a prospective fashion; missing data were reexamined retrospectively) and the selection bias inherent in this design are limiting factors. The scarce nature of AON/ CRION makes a prospective study unlikely. The efficacy of steroid therapy, along with the devastating possible result of withholding steroid treatment, makes a comparative drug trial unethical. Each batch of IVIg is made from a human pool of 3000– 30 000 donors12 and contains 95% immunoglobulin (Ig) G, ,2.5% IgA, and negligible IgM. After infusion of 2 g/ kg IVIg, serum IgG levels increase 5-fold, returning to normal by 21 to 32 days. IgG enters the cerebrospinal fluid, where the concentration increases 2-fold, returning to normal within 1 week. A direct action on remeyelination12 may explain the lengthy beneficial effect in our patients. The mechanism of action of IVIg is complex, involving interference with activation of complement and the cytokine network, modulation of idiotype network, expression of Fc receptors, and activation, differentiation, and effector functions of T and B cells and of antigenpresenting cells such as dendritic cells. The therapeutic
Table 4—Secondary outcome measures Drug side effects before IVIg
Steroid side effects occurred in 5 patients (cushingoid features, new hypertension, insomnia, and acne) Hair loss from methotrexate occurred in 2/5 patients One patient with pre-existing immune-suppression after splenectomy developed Kaposi’s sarcoma of her leg while taking 12.5 mg methotrexate and prednisone
Ability to achieve remission without IVIg
Relapse occurred in one patient treated with methotrexate and prednisone and in one patient treated with azathioprine and prednisone
Ability to discontinue corticosteroids following IVIg
Occurred in 5/6 patients while on IVIg (patient 2 for 4 y)
Ability to achieve remission following IVIg
Remission was achieved in all 6 patients while on IVIg for extended periods of time
Duration of corticosteroid use before IVIg
1–15 mo
Corticosteroid use after IVIg
Following IVIg treatment, 5/6 patients no longer required corticosteroids. One patient experienced a relapse after 4 y of IVIg
Note: IVIg, intravenous immunoglobulin; y, year; mo, month.
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effects of IVIg most likely reflect the functions of natural antibodies in maintaining immune homeostasis in healthy individuals.13 IVIg is reported to be safe and well tolerated by most adults and children.12,14 All proprietary preparations of IVIg are reported to have comparable safety, efficacy, and cost. Mild adverse reactions (headache, flushing, low backache, nausea) respond to slowing of infusion rate and nonsteroidal anti-inflammatory drugs. Patients with cardiovascular disease or congestive heart failure should have a slower rate of infusion to avoid fluid overload.12,14 An anaphylactic reaction may occur in patients with severe IgA deficiency, a common (1:1000) but usually asymptomatic condition. About 29% of individuals have IgA antibodies, with risk for anaphylaxis to trace IgA.14 One patient in our series, after 3 years of uneventful IVIg treatment, suffered chills, dyspnea, and headaches. Work-up did not reveal pulmonary embolus or an acute coronary event. Because she had received IVIg without side effects for 3 years, it is unlikely that IgA anaphylaxis caused the event. Levels of IgA are reported in the drug insert of each IVIg preparation. Rare severe side effects include thromboembolic events,15 aseptic meningitis, acute renal failure in dehydrated patients with pre-existing renal failure,16,17 and anaphylaxis. Thromboembolic complications occur because of hyperviscosity, especially in patients having risk factors including advanced age, previous thromboembolic events, immobilization, diabetes mellitus, hypertension, or dyslipidemia, or those receiving high-dose IVIg in a rapid infusion rate or an excessive dose. Slow infusion rate and good hydration may prevent renal failure, thromboembolic events, and aseptic meningitis. Katz et al.18 describe their experience with more than 200 patients receiving IVIg for different autoimmune diseases and near 10 000 infusions for relapsing-remitting multiple sclerosis patients, the occurrence of adverse effects was 24%–36% after highdose IVIg: most were headaches and all were mild adverse events. They conclude that IVIg is a safe therapy when given in a slow infusion rate to well-hydrated patients, while avoiding patients with known risk factors.18 IVIg for the treatment of autoimmune disorders should be administered as a 5-day course of 2 g/kg of body weight. Each daily dose of 400 mg/kg should be given in not less than 8 hours.18,19 In summary, we believe that IVIg can be an effective steroid-sparing agent in selected cases with recurrentrelapsing inflammatory optic neuropathy. Physicians treating recurrent-relapsing optic neuropathy can familiarize themselves through this report with the pharmacokinetics and known adverse events of IVIg. IVIg can be considered in patients who cannot tolerate, fail, or cannot taper off corticosteroids, especially if other steroid-sparing regimens are contraindicated or have failed. The authors have no proprietary or commercial interest in any materials discussed in this article.
IVIg in recurrent-relapsing optic neuropathy—Stiebel-Kalish et al. REFERENCES 1. Kupersmith MJ, Burde RM, Warren FA, Klingele TG, Frohman LP, Mitnick H. Autoimmune optic neuropathy: evaluation and treatment. J Neurol Neurosurg Psychiatry 1988;51: 1381–6. 2. Dutton JJ, Burde RM, Klingele TG. Autoimmune retrobulbar optic neuritis. Am J Ophthalmol 1982;94:11–7. 3. Kidd D, Burton B, Plant GT, Graham EM. Chronic relapsing inflammatory optic neuropathy (CRION). Brain 2003;126: 276–84. 4. Kupersmith MJ, Burde RM, Warren FA, Klingele TG, Frohman LP, Mitnick H. Autoimmune optic neuropathy: evaluation and treatment. J Neurol Neurosurg Psychiatry 1988;51:1381–6. 5. Pe´rez-Diaz H, Casado JL, Ucle´s-Sa´nchez A, Saiz A. Chronic relapsing inflammatory optic neuropathy (CRION) without detection of IgG-NMO antibodies [in Spanish]. Neurologia 2007;22:553–5. 6. Myers TD, Smith JR, Wertheim MS, Egan RA, Shults WT, Rosenbaum JT. Use of corticosteroid sparing systemic immunosuppression for treatment of corticosteroid dependent optic neuritis not associated with demyelinating disease. Br J Ophthalmol 2004;88:673–80. 7. Smith JR, Rosenbaum JT. A role for methotrexate in the management of non-infectious orbital inflammatory disease. Br J Ophthalmol 2001;85:1220–4. 8. Levy Y, Uziel Y, Zandman G, et al. Response of vasculitic peripheral neuropathy to intravenous immunoglobulin. Ann N Y Acad Sci 2005;1051:779–86. 9. Frohman L, Turbin R, Bielory L, Wolansky L, Lambert WC, Cook S. Autoimmune optic neuropathy with anticardiolipin antibody mimicking multiple sclerosis in a child. Am J Ophthalmol 2003;136:358–60.
10. Frohman LP, Cook SD, Bielory L. Dysgammaglobulinemia in steroid-dependent optic neuritis: response to gammaglobulin treatment. J Clin Neuroophthalmol 1991;11:241–5. 11. Kurz D, Egan RA, Rosenbaum JT. Treatment of corticosteroid dependent optic neuropathy with intravenous immunoglobulin. Am J Ophthalmol 2005;140:1132–3. 12. Dalakas MC. Mechanism of action of intravenous immunoglobulin and therapeutic considerations in the treatment of autoimmune neurologic diseases. Neurology 1998;51:S2–S8. 13. Vani J, Elluru S, Negi VS, et al. Role of natural antibodies in immune homeostasis: IVIg perspective. Autoimmun Rev 2008;7:440–4. 14. Carbone J. Adverse reactions and pathogen safety of intravenous immunoglobulin. Curr Drug Saf 2007;2:9–18. 15. Katz U, Shoenfeld Y. Review: intravenous immunoglobulin therapy and thromboembolic complications. Lupus 2005;14: 802–8. 16. Orbach H, Tishler M, Shoenfeld Y. Intravenous immunoglobulin and the kidney—a two-edged sword. Semin Arthritis Rheum 2004;34:593–601. 17. Orbach H, Katz U, Sherer Y, Shoenfeld Y. Intravenous immunoglobulin: adverse effects and safe administration. Clin Rev Allergy Immunol 2005;29:173–84. 18. Katz U, Achiron A, Sherer Y, Shoenfeld Y. Safety of intravenous immunoglobulin (IVIG) therapy. Autoimmun Rev 2007;6: 257–9. 19. Katz U, Shoenfeld Y. Review: intravenous immunoglobulin therapy and thromboembolic complications. Lupus 2005;14: 802–8. Keywords: optic neuritis, immune system disease, immunology, neuro-ophthalmology
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R
ecurrent-relapsing inflammatory optic neuropathy includes autoimmune optic neuropathy (AON) and chronic-relapsing inflammatory optic neuropathy (CRION), and is a rare, often bilateral, typically steroidresponsive optic neuropathy. The typical course of AON was first described in the 1980’s by Kupersmith1 and Dutton et al.2 Although patients with AON have positive
serum autoantibodies such as antinuclear antibodies, rheumatoid factor, anticardiolipin antibodies, and (or) a positive skin biopsy of nonlesional skin, the full criteria for rheumatologic disorders (systemic lupus erythematosis [SLE], Wegener’s vasculitis, rheumatoid arthritis) are not met. AON is a diagnosis of exclusion, distinguished from demyelinating, granulomatous, infectious, and other
From *the Neuro-Ophthalmology Unit, Department of Ophthalmology, Rabin Medical Center, Petah Tikva, Israel; {Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; {Rotterdam Eye Hospital, Rotterdam, The Netherlands; §Neuro-Ophthalmology Service, Goldschleger Eye Institute, Sheba Medical Center, Tel Hashomer, Israel; and "Neuro-Ophthalmology Unit, Departments of Ophthalmology, Neurology, and Neurosurgery, and the H. Stanley Thompson Neuro-ophthalmology Clinic at The University of Iowa Hospitals and Clinics, Iowa City, Iowa
Correspondence to Hadas Stiebel-Kalish, MD, Chief, NeuroOphthalmology Unit, Department of Ophthalmology, Rabin Medical Center, Petah Tikva 49100, Israel; [email protected] This article has been peer-reviewed. Cet article a e´te´ e´value´ par les pairs. Can J Ophthalmol 2010;45:71–5 doi:10.3129/i09-238
Originally received Mar. 21, 2009. Revised July 31, 2009 Accepted for publication Aug. 10, 2009 Published online Jan. 13, 2010 CAN J OPHTHALMOL—VOL. 45, NO. 1, 2010
71
IVIg in recurrent-relapsing optic neuropathy—Stiebel-Kalish et al. inflammatory or infiltrative optic neuropathies. Frequent relapses necessitate long-term immunosuppression.3–5 CRION was described by Kidd et al.3 as a form of inflammatory optic neuropathy that is frequently bilateral, often painful, and characterized by relapses and remissions, which responds well to steroids. Corticosteroids are the accepted first-line treatment for AON. Long-term steroid side effects commonly lead to addition or substitution of steroid-sparing agents (i.e., methotrexate, cyclophosphamide, azathioprine, chlorambucil, and mycophenylate are commonly added, often limited by side effects.)6,7 Intravenous immunoglobulin (IVIg) has been used successfully in the peripheral neuropathies associated with various vasculitides, including Sjogren’s syndrome, SLE, vaccination-induced vasculitis, ChurgStrauss vasculitis, mixed cryoglobulinemia, polyarteritis nodosa, sarcoidosis, and scleroderma.8 IVIg has also been beneficial in single case series of AON.9–11 We describe 6 patients with recurrent-relapsing steroid-responsive optic neuropathies successfully treated with IVIg. METHODS
A semiprospective observational cohort study was performed at 4 academic institutions (The Rabin Medical Center, Israel; the University of Iowa, Iowa; Rotterdam Eye Hospital, The Netherlands; and Sheba Medical Center, Israel) between 2000 and 2008. We included adults with recurrent-relapsing optic neuropathy treated with IVIg with adequate follow-up. AON was defined as an optic neuropathy with evidence of serologic autoimmunity (i.e., positive antinuclear antibodies, anticardiolipin antibodies, and beta-2 glycoprotein antibodies) in which demyelinating, granulomatous, infectious, and distinct rheumatologic etiologies were excluded. A non–sunexposed skin biopsy was not routinely available at all centres. CRION was defined, as published by Kidd et al.,3 as a form of inflammatory optic neuropathy that is frequently bilateral, is characterized by relapses and remissions, and responds well to steroids. None of the patients had signs, symptoms, clinical course, or magnetic resonance findings suggestive of neuromyelitis optica, although aquaporin or neuromyelitis optica antibodies were unavailable at the time of treatment. Patient characteristics are described in Table 1. The primary outcome measure was visual function (improvement, stabilization, or progression). Visual function and visual field definitions used in this study are listed in Table 2. Secondary outcome measures included treatment side effects; ability to achieve clinical remission; ability to discontinue corticosteroids; duration to remission; and duration of corticosteroid use before and after IVIg. Institutional review board approval was obtained, and the cases were reviewed in accordance with the Declaration of Helsinki.
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CAN J OPHTHALMOL—VOL. 45, NO. 1, 2010
RESULTS
Of 10 patients with recurrent-relapsing inflammatory (steroid-responsive) optic neuropathy, 2 patients developed defined rheumatologic disorders within 1 year (SLE in one patient, Wegener’s disease in another) and were not treated with IVIg, and 2 patients stabilized with low-dose steroids and methotrexate. Table 3 summarizes the clinical features of the 6 patients included in this case series. One patient treated with IVIg included in this series initially had no evidence of SLE at presentation, but developed signs and symptoms leading to the diagnosis of SLE 5 years later. Regarding the primary outcome measures, of the 12 eyes (6 patients with bilateral AON) treated with IVIg, visual acuity improved in 2, stabilized in 10, and worsened in none. Visual field defects improved in 3 eyes, similar to the improvement achieved with steroids, stabilized in 7/10 eyes, and worsened in none. Secondary outcome measures are listed in Table 4. Table 1—The work-up for patients with recurrent-relapsing steroid-responsive optic neuropathy A recurrent-relapsing steroid-responsive visual loss due to an optic neuropathy in which demyelinating, granulomatous, infectious, and distinct rheumatologic etiologies were excluded by: 1. Normal or noncontributory findings on magnetic resonance imaging scan of the brain and orbit with fat suppression with and without gadolinium (findings not typical for demyelinative, granulomatous, or vasculitic disease) Normal chest x-rays Normal serum angiotensin converting enzyme Normal Mantoux skin test 2. Variable laboratory testing performed: serum antinuclear antibody, rheumatoid factor, complete blood count, blood chemistry, sedimentation rate, core antineutrophilic cytoplasmic antibody and perinuclear antineutrophilic cytoplasmic antibody, immune electrophoresis, serology for syphilis, Bartonella, Lyme disease 3. An examination by a rheumatologist and revision of laboratory tests not meeting criteria for systemic autoimmune disease (systemic lupus erythematosis, Wegener’s disease, rheumatoid arthritis, etc.), despite presence of autoimmune antibodies
Table 2—Visual outcome criteria (for this study) Visual function Improvement
An increase of at least one Snellen line of best-corrected distance visual testing accompanied by another visual measure (e.g., improvement in relative afferent pupillary defect along with improved colour vision testing and [or] visual field testing) on 2 consecutive visits separated by 3 mo
Stabilization
No change in visual acuity on 2 consecutive visits separated by 3 mo
Progression
Worsening of visual acuity associated with at least one other visual function measure
Automated visual field interpretation Stable
Pattern of visual field defect unchanged from the prior test, or MD and CPSD within ¡0.8 dB on at least 2 separate consecutive tests
Improved
A decrease in MD and CPSD of at least 0.8 dB on at least 2 consecutive tests
Progressed
2 consecutive visual field tests revealing a +0.8 dB higher MD or CPSD
Note: mo., months; MD, mean deviation; CPSD, corrected standard pattern deviation; dB, decibel.
OS 12/12
After 3 y of uneventful IVIg treatment: chills, dyspnea, headaches
4y
2/27/2009, 20/40 OU bilateral moderate optic atrophy
IVIg adverse events
Y without steroids following IVIg
Date and final visual outcome
7/19/2009 OD 2/200 (since 2003) OS 20/40 bilateral optic atrophy
5
3y 9/30/2009 20/20 OU Trace RAPD OD 12/12 OU bilateral mild optic atrophy
4/30/2009 OD 20/25 partial optic atrophy OU
None
2.5 y
Methotrexate with prednisone: Kaposi’s sarcoma
Cushingoid features, acne
2006
6 mo
OS 12/12
OD 10/12
7y 02/24/2009 20/50 OD (amblyopia) OS 20/20 bilateral optic atrophy
1/20/2009 20/30 OD 20/50 OS bilateral mild atrophy
None
Twice during a few wk
Azathioprine and prednisone: failed
Insomnia, mood swings
1997, 2002
1 mo before IVIg, followed by on and off 5 y
—
No pupillary reactions
OS No LP
OD No LP
1y
None
1y
Methotrexate: hair loss
Cushingoid features
2006
15 mo
—
Trace RAPD OS
OS 20/50
+2 RAPD OD
OD 20/50
OS 20/25
No autoantibodies; headache; pain on eye movement; hyposensibility of right cheek; slight proteineuria
Weak ANA + 1:32
6
F
44
4/4/1996
F
48
5/30/2006
OD 20/50
1y
None
None
4 y (D/C due to relapse in 2007)
1 y, cyclosporine started recently
cellcept: failed (LFT elevations, tinnitus, hearing loss), cyclosporine
azathioprine: failed
Methotrexate: failed
Mood swings, insomnia
2004, 2007, 2008
3y
4y
IVIg was the first steroidsparing agent of choice
Cushingoid features, osteoporosis
1997, 2000, 2001, 2003
4 relapses in 7 y
—
Amaurotic OS
OS bare LP, 6-y-old optic atrophy
OD 20/25
Raynaud’s phenomenon No autoimmune antibodies; post ITP mild chronic hydrocephalus; CSF and ICP normal
4
No autoimmune antibodies
F
53
5/12/2006
Patient number
M
39
3/15/2004
3
F
2
*Ishihara: colour vision was tested using 12 Ishihara plates. Note: y, year; F, female; M, male; RF, rheumatoid factor; RA, rheumatoid arthritis; TSH, thyroid stimulating hormone; CSF, cerebrospinal fluid; ICP, intracranial pressure; ITP, immune thrombocytopenic pressure; ANA, antinuclear anti-body; LP, lumbar puncture; RAPD, relative afferent pupillary defect; mo, month; IVIg, intravenous immunoglobulins; LFT, liver function tests; wk, week; D/C, discontinued.
3y
Duration of IVIg
Steroid-sparing agents Methotrexate: optic used and reason for failure neuropathy relapse
Cushingoid features, hypertension, insomnia
OD 0/12
Ishihara*
2001, 2002
OS 12/12
+2 RAPD OD
RAPD
Steroid side effects
OD 8/12
OS 20/30
Y of relapse
+2 RAPD OD
OD 20/60
Presenting visual acuity
12 mo
OS 20/30
RF+ on 2/6 tests; did not meet RA criteria; mildly low TSH; no anti-TSH antibodies
Presence of antibodies
Duration of steroids
OD 20/70
F
Gender
44
43
Age at presentation (y)
19/7/1996
2/5/2001
Date of presentation
1
Table 3—Course of recurrent-relapsing autoimmune optic neuropathy in 6 patients before and after intravenous immunoglobulin treatment
IVIg in recurrent-relapsing optic neuropathy—Stiebel-Kalish et al.
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IVIg in recurrent-relapsing optic neuropathy—Stiebel-Kalish et al. CONCLUSIONS
To our knowledge, this study is the largest Englishlanguage series of IVIg treatment in patients with recurrent-relapsing inflammatory optic neuropathy. All 6 patients, who were originally steroid responsive, were able to discontinue steroids for extended periods of time while maintaining remission, similar to the rates described with other immunosuppressive regimens. We recognize the limitations of our study. First, inflammatory recurrent optic neuropathies such as AON and CRION are rare; therefore, our sample size was small. Second, the semiprospective design (all patients were recorded in a prospective fashion; missing data were reexamined retrospectively) and the selection bias inherent in this design are limiting factors. The scarce nature of AON/ CRION makes a prospective study unlikely. The efficacy of steroid therapy, along with the devastating possible result of withholding steroid treatment, makes a comparative drug trial unethical. Each batch of IVIg is made from a human pool of 3000– 30 000 donors12 and contains 95% immunoglobulin (Ig) G, ,2.5% IgA, and negligible IgM. After infusion of 2 g/ kg IVIg, serum IgG levels increase 5-fold, returning to normal by 21 to 32 days. IgG enters the cerebrospinal fluid, where the concentration increases 2-fold, returning to normal within 1 week. A direct action on remeyelination12 may explain the lengthy beneficial effect in our patients. The mechanism of action of IVIg is complex, involving interference with activation of complement and the cytokine network, modulation of idiotype network, expression of Fc receptors, and activation, differentiation, and effector functions of T and B cells and of antigenpresenting cells such as dendritic cells. The therapeutic
Table 4—Secondary outcome measures Drug side effects before IVIg
Steroid side effects occurred in 5 patients (cushingoid features, new hypertension, insomnia, and acne) Hair loss from methotrexate occurred in 2/5 patients One patient with pre-existing immune-suppression after splenectomy developed Kaposi’s sarcoma of her leg while taking 12.5 mg methotrexate and prednisone
Ability to achieve remission without IVIg
Relapse occurred in one patient treated with methotrexate and prednisone and in one patient treated with azathioprine and prednisone
Ability to discontinue corticosteroids following IVIg
Occurred in 5/6 patients while on IVIg (patient 2 for 4 y)
Ability to achieve remission following IVIg
Remission was achieved in all 6 patients while on IVIg for extended periods of time
Duration of corticosteroid use before IVIg
1–15 mo
Corticosteroid use after IVIg
Following IVIg treatment, 5/6 patients no longer required corticosteroids. One patient experienced a relapse after 4 y of IVIg
Note: IVIg, intravenous immunoglobulin; y, year; mo, month.
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effects of IVIg most likely reflect the functions of natural antibodies in maintaining immune homeostasis in healthy individuals.13 IVIg is reported to be safe and well tolerated by most adults and children.12,14 All proprietary preparations of IVIg are reported to have comparable safety, efficacy, and cost. Mild adverse reactions (headache, flushing, low backache, nausea) respond to slowing of infusion rate and nonsteroidal anti-inflammatory drugs. Patients with cardiovascular disease or congestive heart failure should have a slower rate of infusion to avoid fluid overload.12,14 An anaphylactic reaction may occur in patients with severe IgA deficiency, a common (1:1000) but usually asymptomatic condition. About 29% of individuals have IgA antibodies, with risk for anaphylaxis to trace IgA.14 One patient in our series, after 3 years of uneventful IVIg treatment, suffered chills, dyspnea, and headaches. Work-up did not reveal pulmonary embolus or an acute coronary event. Because she had received IVIg without side effects for 3 years, it is unlikely that IgA anaphylaxis caused the event. Levels of IgA are reported in the drug insert of each IVIg preparation. Rare severe side effects include thromboembolic events,15 aseptic meningitis, acute renal failure in dehydrated patients with pre-existing renal failure,16,17 and anaphylaxis. Thromboembolic complications occur because of hyperviscosity, especially in patients having risk factors including advanced age, previous thromboembolic events, immobilization, diabetes mellitus, hypertension, or dyslipidemia, or those receiving high-dose IVIg in a rapid infusion rate or an excessive dose. Slow infusion rate and good hydration may prevent renal failure, thromboembolic events, and aseptic meningitis. Katz et al.18 describe their experience with more than 200 patients receiving IVIg for different autoimmune diseases and near 10 000 infusions for relapsing-remitting multiple sclerosis patients, the occurrence of adverse effects was 24%–36% after highdose IVIg: most were headaches and all were mild adverse events. They conclude that IVIg is a safe therapy when given in a slow infusion rate to well-hydrated patients, while avoiding patients with known risk factors.18 IVIg for the treatment of autoimmune disorders should be administered as a 5-day course of 2 g/kg of body weight. Each daily dose of 400 mg/kg should be given in not less than 8 hours.18,19 In summary, we believe that IVIg can be an effective steroid-sparing agent in selected cases with recurrentrelapsing inflammatory optic neuropathy. Physicians treating recurrent-relapsing optic neuropathy can familiarize themselves through this report with the pharmacokinetics and known adverse events of IVIg. IVIg can be considered in patients who cannot tolerate, fail, or cannot taper off corticosteroids, especially if other steroid-sparing regimens are contraindicated or have failed. The authors have no proprietary or commercial interest in any materials discussed in this article.
IVIg in recurrent-relapsing optic neuropathy—Stiebel-Kalish et al. REFERENCES 1. Kupersmith MJ, Burde RM, Warren FA, Klingele TG, Frohman LP, Mitnick H. Autoimmune optic neuropathy: evaluation and treatment. J Neurol Neurosurg Psychiatry 1988;51: 1381–6. 2. Dutton JJ, Burde RM, Klingele TG. Autoimmune retrobulbar optic neuritis. Am J Ophthalmol 1982;94:11–7. 3. Kidd D, Burton B, Plant GT, Graham EM. Chronic relapsing inflammatory optic neuropathy (CRION). Brain 2003;126: 276–84. 4. Kupersmith MJ, Burde RM, Warren FA, Klingele TG, Frohman LP, Mitnick H. Autoimmune optic neuropathy: evaluation and treatment. J Neurol Neurosurg Psychiatry 1988;51:1381–6. 5. Pe´rez-Diaz H, Casado JL, Ucle´s-Sa´nchez A, Saiz A. Chronic relapsing inflammatory optic neuropathy (CRION) without detection of IgG-NMO antibodies [in Spanish]. Neurologia 2007;22:553–5. 6. Myers TD, Smith JR, Wertheim MS, Egan RA, Shults WT, Rosenbaum JT. Use of corticosteroid sparing systemic immunosuppression for treatment of corticosteroid dependent optic neuritis not associated with demyelinating disease. Br J Ophthalmol 2004;88:673–80. 7. Smith JR, Rosenbaum JT. A role for methotrexate in the management of non-infectious orbital inflammatory disease. Br J Ophthalmol 2001;85:1220–4. 8. Levy Y, Uziel Y, Zandman G, et al. Response of vasculitic peripheral neuropathy to intravenous immunoglobulin. Ann N Y Acad Sci 2005;1051:779–86. 9. Frohman L, Turbin R, Bielory L, Wolansky L, Lambert WC, Cook S. Autoimmune optic neuropathy with anticardiolipin antibody mimicking multiple sclerosis in a child. Am J Ophthalmol 2003;136:358–60.
10. Frohman LP, Cook SD, Bielory L. Dysgammaglobulinemia in steroid-dependent optic neuritis: response to gammaglobulin treatment. J Clin Neuroophthalmol 1991;11:241–5. 11. Kurz D, Egan RA, Rosenbaum JT. Treatment of corticosteroid dependent optic neuropathy with intravenous immunoglobulin. Am J Ophthalmol 2005;140:1132–3. 12. Dalakas MC. Mechanism of action of intravenous immunoglobulin and therapeutic considerations in the treatment of autoimmune neurologic diseases. Neurology 1998;51:S2–S8. 13. Vani J, Elluru S, Negi VS, et al. Role of natural antibodies in immune homeostasis: IVIg perspective. Autoimmun Rev 2008;7:440–4. 14. Carbone J. Adverse reactions and pathogen safety of intravenous immunoglobulin. Curr Drug Saf 2007;2:9–18. 15. Katz U, Shoenfeld Y. Review: intravenous immunoglobulin therapy and thromboembolic complications. Lupus 2005;14: 802–8. 16. Orbach H, Tishler M, Shoenfeld Y. Intravenous immunoglobulin and the kidney—a two-edged sword. Semin Arthritis Rheum 2004;34:593–601. 17. Orbach H, Katz U, Sherer Y, Shoenfeld Y. Intravenous immunoglobulin: adverse effects and safe administration. Clin Rev Allergy Immunol 2005;29:173–84. 18. Katz U, Achiron A, Sherer Y, Shoenfeld Y. Safety of intravenous immunoglobulin (IVIG) therapy. Autoimmun Rev 2007;6: 257–9. 19. Katz U, Shoenfeld Y. Review: intravenous immunoglobulin therapy and thromboembolic complications. Lupus 2005;14: 802–8. Keywords: optic neuritis, immune system disease, immunology, neuro-ophthalmology
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