IDIOPATHIC RETINAL VASCULITIS, ANEURYSMS, AND NEURORETINITIS (IRVAN) SYNDROME ASSOCIATED WITH POSITIVE PERINUCLEAR ANTINEUTROPHIL CYTOPLASMIC ANTIBODY (P-ANCA) Masoud Soheilian, MD,*† Ramin Nourinia, MD,* Ali Tavallali, MD,* Gholam A. Peyman, MD‡
Purpose: To describe an unusual case of idiopathic retinal vasculitis, aneurysms, and neuroretinitis syndrome associated with a positive perinuclear antineutrophil cytoplasmic antibody test. Methods: This is an interventional case report. A 22-year-old man with decreased vision underwent ophthalmoscopic, angiographic, and laboratory evaluation. The left eye underwent laser therapy due to circinate retinopathy and more severe involvement. Results: Extensive systemic workup was negative. The only positive laboratory test was a positive perinuclear antineutrophil cytoplasmic antibody (1/40 dilution) detected by indirect immunofluorescence and enzyme-linked immunosorbent assay (positive for antimyeloperoxidase antibody). The patient was observed for 2 years. The disorder remained limited to the eyes, and further systemic workup was unrevealing; perinuclear antineutrophil cytoplasmic antibody titer remained positive. Vision remained stable in the treated eye and was slightly reduced in the untreated eye. Conclusion: Idiopathic retinal vasculitis, aneurysms, and neuroretinitis syndrome may be suggestive of a retinal form of perinuclear antineutrophil cytoplasmic antibody–associated vasculitis. RETINAL CASES & BRIEF REPORTS X:1–1, 2009
I
From the *Ophthalmology Department and Ophthalmic Research Center, Labbafinejad Medical Center, Shaheed Beheshti University of Medical Sciences, Tehran, Iran; †Negah Eye Center, Tehran, Iran; and the ‡Department of Ophthalmology, Tulane University Health Sciences Center, New Orleans, Louisiana.
diopathic retinal vasculitis, aneurysms, and neuroretinitis (IRVAN) syndrome is a rare clinical entity characterized by bilateral retinal arteritis, numerous aneurysmal dilatations of the retinal and optic nerve head arterioles, neuroretinitis, and uveitis. Iritis and vitritis are inconsistent findings. This syndrome typically affects young, healthy individuals; is predominant in women; and is not associated with any systemic abnormalities. Visual loss is caused by exudative maculopathy and neovascular sequelae of retinal ischemia.1,2 The etiology behind this syndrome has not yet been established. However, an inflammatory process involving alternate segments along the vascular tree may play a role. With this definition, IRVAN syndrome
The authors declare no proprietary interest. Reprint requests: Masoud Soheilian, MD, Ophthalmology Department, Labbafinejad Medical Center, Pasdaran Avenue, Boostan 9 Street, Tehran, Iran; e-mail: masoud_soheilian@ yahoo.com
1
RETINAL CASES & BRIEF REPORTSℜ
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Fig. 1. Fundus photograph of the right eye shows diffuse exudative retinopathy.
may be considered as a localized form of vasculitis limited to the retina. However, antineutrophil cytoplasmic antibody (ANCA) has been described in patients with systemic vasculitis and glomerulonephritis. The presence of this antibody has emerged as a new diagnostic tool and a marker of disease activity for vasculitis.3 Two ANCA patterns may be seen with indirect immunofluorescence: cytoplasmic ANCA (C-ANCA) and perinuclear ANCA (P-ANCA). The major antigen for C-ANCA is proteinase 3, which is found within the azurophilic granules of the neutrophil. The major antigen for P-ANCA is myeloperoxidase, a lysosomal enzyme within neutrophil. Some clinical overlap has been seen, but these patterns have different disease associations. The C-ANCA pattern has predominantly been associated with Wegener granulomatosis (WG), and P-ANCA has been associated with microscopic polyarteritis nodosa (PAN) and other systemic vasculitis.4 To the best of our knowledge, no association between IRVAN syndrome and a positive ANCA test has been reported. In this study, we report a young man with IRVAN syndrome and a positive P-ANCA titer detected by both indirect immunofluorescence and enzyme-linked immunosorbent assay.
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Fig. 2. Fundus photograph of the left eye shows retinal edema, lipid exudates, and marked irregularity of retinal artery caliber.
and 4). An extensive systemic workup was performed and was negative. All laboratory tests, including C-reactive protein, antinuclear antibody (ANA), anti– double-stranded DNA, hepatitis B surface antigen, hepatitis C virus antibody, and human immunodeficiency virus tests, were negative. The only positive test was P-ANCA (1/40 titer). Detection of P-ANCA was performed with indirect immunofluorescence. The antigen-specific enzyme-linked immunosorbent assay method was used to test the sera for the presence of either myeloperoxidase or anti-proteinase 3 antibodies and showed a positive reaction for myeloperoxidase. Scattered confluent laser treatment of involved areas and modified grid macular photocoagulation were performed in the most severely affected eye. The patient was observed for 2 years. The disorder remained limited to the eyes, and further systemic workup was unrevealing; P-ANCA titer remained positive at the most recent follow-up (1/40 titer). Vision remained stable in the treated eye and was slightly reduced in the untreated eye.
Discussion Kincaid and Schatz5 were the first to describe the clinical association of macroaneurysms with retinal
Case Report A 22-year-old male farmer with an 8-month history of blurred vision in the right eye and decreased visual acuity in the left eye was referred in June 2002. Visual acuity was 20/20 in the right eye and 20/200 in the left. External and slit-lamp biomicroscopic examinations were unremarkable. On funduscopy, circinate exudative maculopathy and retinopathy were noted (Figures 1 and 2). Fluorescein angiography disclosed saccular aneurysm formation at bifurcation sites of arterioles and vessel wall staining (Figures 3
Fig. 3. Fluorescein angiogram of the right eye reveals saccular aneurysms, dilated and tortuous arteries, and diffuse staining.
IRVAN
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Fig. 4. Fluorescein angiogram of the left eye illustrates focal areas of delayed choroidal filling, saccular aneurysms at bifurcation site of arterioles, arterial wall staining, and leakage.
vasculitis and neuroretinitis. Samuel et al2 described the largest series of this condition and were the first to coin the acronym IRVAN. This condition usually affects young, healthy women, and its major features are multiple tied knot-like aneurysmal dilations of the retinal arteries, exudative retinopathy, diffuse staining of the optic disk, and nonperfusion of peripheral capillaries.5 IRVAN syndrome affects the retinal and optic disk vasculature and also choroidal circulation in some cases. Vascular dilation may be a result of the inflammatory process in the retinal artery walls. Because both the retinal and choroidal vessels can be damaged in this disorder, the differential diagnosis includes a range of inflammatory and infectious vascular diseases. Behcet disease, sarcoidosis, multiple sclerosis, and collagen-related vascular disorders such as PAN, WG, and systemic lupus erythematosus may also cause neuroretinitis and macroaneurysms.6 Because the male patient reported in this study was systemically normal, most of the aforementioned differential diagnoses were easily excluded. In our patient, P-ANCA was positive on three occasions during follow-up. The prevalence of ANCA in the healthy general population has been reported to be ⬍1%.7 Neutrophilmediated injury of human endothelial cells is considered an important mechanism in the pathogenesis of ANCA-related vasculitides.3 The C-ANCA pattern has predominantly been associated with WG (sensitivities ranging from 34% to 92% and specificities
between 88% and 100%). However, P-ANCA is found in ⬃10% of WG cases. Perinuclear antineutrophil cytoplasmic antibody has been associated mostly with microscopic PAN.8 It is found in 50% to 80% of affected patients, whereas 40% have the C-ANCA autoantibody pattern. The average diagnostic sensitivity of P-ANCA for macroscopic PAN is 15% and for C-ANCA is 5%.8 It is important to point out the possibility of a false-positive result. To avoid this problem with the indirect immunofluorescence test, antigen-specific enzymelinked immunosorbent assays are usually used to test specifically for myeloperoxidase and proteinase 3. These antigens are associated with ANCA-associated vasculitis.9 In our patient, ANA titer was negative, and indirect immunofluorescence showed a perinuclear fluorescence with a titer of 1:40 on three occasions. Furthermore, antigen-specific enzyme-linked immunosorbent assay was positive for antimyeloperoxidase antibody. Because our patient was systemically normal, PAN and WG were excluded. Based on the findings of exudative retinopathy, multiple aneurysms, and no systemic pathology, we diagnosed IRVAN syndrome in this healthy middle-aged man with a positive P-ANCA. To the best of our knowledge, no case report has described IRVAN syndrome with a positive P-ANCA. This case of IRVAN syndrome may be suggestive of a retinal form of P-ANCA-associated vasculitis. We believe that IRVAN syndrome should be added to the
RETINAL CASES & BRIEF REPORTSℜ
4
list of disorders that may cause P-ANCA-associated vasculitis. Key words: idiopathic retinal vasculitis, aneurysms, and neuroretinitis (IRVAN), perinuclear antineutrophil cytoplasmic antibody (P-ANCA).
5. 6.
References 1.
2.
3.
4.
Chang TS, Aylward GW, Davis JUL, et al. Idiopathic retinal vasculitis, aneurysms, and neuroretinitis. Ophthalmology 1995;102: 1089–1097. Samuel MA, Equi RA, Chang TS, et al. Idiopathic retinitis, vasculitis, aneurysms, and neuroretinitis (IRVAN): new observations and a proposed staging system. Ophthalmology 2007; 114:1526 –1529. Mayet WJ, Helmreich-Becker I, Meyer Zum KH. The pathophysiology of anti-neutrophil cytoplasmic antibodies (ANCA) and their clinical relevance. Crit Rev Oncol Hematol 1996;23: 151–156. Rao J, Weinberger M, Oddone E, Allen NB, Landsman P,
7.
8.
9.
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Feussner JR. The role of antineutrophil cytoplasmic antibody (c-ANCA) testing in the diagnosis of Wegener granulomatosis: a literature review and meta-analysis. Ann Intern Med 1995;123:925–932. Kincaid J, Schatz H. Bilateral retinal arteritis with multiple aneurysmal dilatations. Retina 1983;3:171–178. Sashihara H, Hayashi H, Oshima K. Regression of retinal arterial aneurysms in a case of idiopathic retinal vasculitis, aneurysms, and neuroretinitis (IRVAN). Retina 1999;19: 250 –251. Xiao H, Heeringa P, Hu P, et al. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. J Clin Invest 2002;110: 955–963. Soheilian M. Polyarteritis Nodosa. In: Foster CS, Vitale AT, eds. Diagnosis and Treatment of Uveitis. 1st ed. Philadelphia, PA: W.B. Saunders Co.; 2002:653– 660. Mandl L, Solomon D, Smith E, Lew RA, Katz JN, Shmerling RH. Using antineutrophil cytoplasmic antibody testing to diagnose vasculitis: can test-ordering guidelines improve diagnostic accuracy? Arch Intern Med 2002;162:1509 –1514.
Purpose: To describe an unusual case of idiopathic retinal vasculitis, aneurysms, and neuroretinitis syndrome associated with a positive perinuclear antineutrophil cytoplasmic antibody test. Methods: This is an interventional case report. A 22-year-old man with decreased vision underwent ophthalmoscopic, angiographic, and laboratory evaluation. The left eye underwent laser therapy due to circinate retinopathy and more severe involvement. Results: Extensive systemic workup was negative. The only positive laboratory test was a positive perinuclear antineutrophil cytoplasmic antibody (1/40 dilution) detected by indirect immunofluorescence and enzyme-linked immunosorbent assay (positive for antimyeloperoxidase antibody). The patient was observed for 2 years. The disorder remained limited to the eyes, and further systemic workup was unrevealing; perinuclear antineutrophil cytoplasmic antibody titer remained positive. Vision remained stable in the treated eye and was slightly reduced in the untreated eye. Conclusion: Idiopathic retinal vasculitis, aneurysms, and neuroretinitis syndrome may be suggestive of a retinal form of perinuclear antineutrophil cytoplasmic antibody–associated vasculitis. RETINAL CASES & BRIEF REPORTS X:1–1, 2009
I
From the *Ophthalmology Department and Ophthalmic Research Center, Labbafinejad Medical Center, Shaheed Beheshti University of Medical Sciences, Tehran, Iran; †Negah Eye Center, Tehran, Iran; and the ‡Department of Ophthalmology, Tulane University Health Sciences Center, New Orleans, Louisiana.
diopathic retinal vasculitis, aneurysms, and neuroretinitis (IRVAN) syndrome is a rare clinical entity characterized by bilateral retinal arteritis, numerous aneurysmal dilatations of the retinal and optic nerve head arterioles, neuroretinitis, and uveitis. Iritis and vitritis are inconsistent findings. This syndrome typically affects young, healthy individuals; is predominant in women; and is not associated with any systemic abnormalities. Visual loss is caused by exudative maculopathy and neovascular sequelae of retinal ischemia.1,2 The etiology behind this syndrome has not yet been established. However, an inflammatory process involving alternate segments along the vascular tree may play a role. With this definition, IRVAN syndrome
The authors declare no proprietary interest. Reprint requests: Masoud Soheilian, MD, Ophthalmology Department, Labbafinejad Medical Center, Pasdaran Avenue, Boostan 9 Street, Tehran, Iran; e-mail: masoud_soheilian@ yahoo.com
1
RETINAL CASES & BRIEF REPORTSℜ
2
Fig. 1. Fundus photograph of the right eye shows diffuse exudative retinopathy.
may be considered as a localized form of vasculitis limited to the retina. However, antineutrophil cytoplasmic antibody (ANCA) has been described in patients with systemic vasculitis and glomerulonephritis. The presence of this antibody has emerged as a new diagnostic tool and a marker of disease activity for vasculitis.3 Two ANCA patterns may be seen with indirect immunofluorescence: cytoplasmic ANCA (C-ANCA) and perinuclear ANCA (P-ANCA). The major antigen for C-ANCA is proteinase 3, which is found within the azurophilic granules of the neutrophil. The major antigen for P-ANCA is myeloperoxidase, a lysosomal enzyme within neutrophil. Some clinical overlap has been seen, but these patterns have different disease associations. The C-ANCA pattern has predominantly been associated with Wegener granulomatosis (WG), and P-ANCA has been associated with microscopic polyarteritis nodosa (PAN) and other systemic vasculitis.4 To the best of our knowledge, no association between IRVAN syndrome and a positive ANCA test has been reported. In this study, we report a young man with IRVAN syndrome and a positive P-ANCA titer detected by both indirect immunofluorescence and enzyme-linked immunosorbent assay.
●
2009
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VOLUME X
●
NUMBER X
Fig. 2. Fundus photograph of the left eye shows retinal edema, lipid exudates, and marked irregularity of retinal artery caliber.
and 4). An extensive systemic workup was performed and was negative. All laboratory tests, including C-reactive protein, antinuclear antibody (ANA), anti– double-stranded DNA, hepatitis B surface antigen, hepatitis C virus antibody, and human immunodeficiency virus tests, were negative. The only positive test was P-ANCA (1/40 titer). Detection of P-ANCA was performed with indirect immunofluorescence. The antigen-specific enzyme-linked immunosorbent assay method was used to test the sera for the presence of either myeloperoxidase or anti-proteinase 3 antibodies and showed a positive reaction for myeloperoxidase. Scattered confluent laser treatment of involved areas and modified grid macular photocoagulation were performed in the most severely affected eye. The patient was observed for 2 years. The disorder remained limited to the eyes, and further systemic workup was unrevealing; P-ANCA titer remained positive at the most recent follow-up (1/40 titer). Vision remained stable in the treated eye and was slightly reduced in the untreated eye.
Discussion Kincaid and Schatz5 were the first to describe the clinical association of macroaneurysms with retinal
Case Report A 22-year-old male farmer with an 8-month history of blurred vision in the right eye and decreased visual acuity in the left eye was referred in June 2002. Visual acuity was 20/20 in the right eye and 20/200 in the left. External and slit-lamp biomicroscopic examinations were unremarkable. On funduscopy, circinate exudative maculopathy and retinopathy were noted (Figures 1 and 2). Fluorescein angiography disclosed saccular aneurysm formation at bifurcation sites of arterioles and vessel wall staining (Figures 3
Fig. 3. Fluorescein angiogram of the right eye reveals saccular aneurysms, dilated and tortuous arteries, and diffuse staining.
IRVAN
3
Fig. 4. Fluorescein angiogram of the left eye illustrates focal areas of delayed choroidal filling, saccular aneurysms at bifurcation site of arterioles, arterial wall staining, and leakage.
vasculitis and neuroretinitis. Samuel et al2 described the largest series of this condition and were the first to coin the acronym IRVAN. This condition usually affects young, healthy women, and its major features are multiple tied knot-like aneurysmal dilations of the retinal arteries, exudative retinopathy, diffuse staining of the optic disk, and nonperfusion of peripheral capillaries.5 IRVAN syndrome affects the retinal and optic disk vasculature and also choroidal circulation in some cases. Vascular dilation may be a result of the inflammatory process in the retinal artery walls. Because both the retinal and choroidal vessels can be damaged in this disorder, the differential diagnosis includes a range of inflammatory and infectious vascular diseases. Behcet disease, sarcoidosis, multiple sclerosis, and collagen-related vascular disorders such as PAN, WG, and systemic lupus erythematosus may also cause neuroretinitis and macroaneurysms.6 Because the male patient reported in this study was systemically normal, most of the aforementioned differential diagnoses were easily excluded. In our patient, P-ANCA was positive on three occasions during follow-up. The prevalence of ANCA in the healthy general population has been reported to be ⬍1%.7 Neutrophilmediated injury of human endothelial cells is considered an important mechanism in the pathogenesis of ANCA-related vasculitides.3 The C-ANCA pattern has predominantly been associated with WG (sensitivities ranging from 34% to 92% and specificities
between 88% and 100%). However, P-ANCA is found in ⬃10% of WG cases. Perinuclear antineutrophil cytoplasmic antibody has been associated mostly with microscopic PAN.8 It is found in 50% to 80% of affected patients, whereas 40% have the C-ANCA autoantibody pattern. The average diagnostic sensitivity of P-ANCA for macroscopic PAN is 15% and for C-ANCA is 5%.8 It is important to point out the possibility of a false-positive result. To avoid this problem with the indirect immunofluorescence test, antigen-specific enzymelinked immunosorbent assays are usually used to test specifically for myeloperoxidase and proteinase 3. These antigens are associated with ANCA-associated vasculitis.9 In our patient, ANA titer was negative, and indirect immunofluorescence showed a perinuclear fluorescence with a titer of 1:40 on three occasions. Furthermore, antigen-specific enzyme-linked immunosorbent assay was positive for antimyeloperoxidase antibody. Because our patient was systemically normal, PAN and WG were excluded. Based on the findings of exudative retinopathy, multiple aneurysms, and no systemic pathology, we diagnosed IRVAN syndrome in this healthy middle-aged man with a positive P-ANCA. To the best of our knowledge, no case report has described IRVAN syndrome with a positive P-ANCA. This case of IRVAN syndrome may be suggestive of a retinal form of P-ANCA-associated vasculitis. We believe that IRVAN syndrome should be added to the
RETINAL CASES & BRIEF REPORTSℜ
4
list of disorders that may cause P-ANCA-associated vasculitis. Key words: idiopathic retinal vasculitis, aneurysms, and neuroretinitis (IRVAN), perinuclear antineutrophil cytoplasmic antibody (P-ANCA).
5. 6.
References 1.
2.
3.
4.
Chang TS, Aylward GW, Davis JUL, et al. Idiopathic retinal vasculitis, aneurysms, and neuroretinitis. Ophthalmology 1995;102: 1089–1097. Samuel MA, Equi RA, Chang TS, et al. Idiopathic retinitis, vasculitis, aneurysms, and neuroretinitis (IRVAN): new observations and a proposed staging system. Ophthalmology 2007; 114:1526 –1529. Mayet WJ, Helmreich-Becker I, Meyer Zum KH. The pathophysiology of anti-neutrophil cytoplasmic antibodies (ANCA) and their clinical relevance. Crit Rev Oncol Hematol 1996;23: 151–156. Rao J, Weinberger M, Oddone E, Allen NB, Landsman P,
7.
8.
9.
●
2009
●
VOLUME X
●
NUMBER X
Feussner JR. The role of antineutrophil cytoplasmic antibody (c-ANCA) testing in the diagnosis of Wegener granulomatosis: a literature review and meta-analysis. Ann Intern Med 1995;123:925–932. Kincaid J, Schatz H. Bilateral retinal arteritis with multiple aneurysmal dilatations. Retina 1983;3:171–178. Sashihara H, Hayashi H, Oshima K. Regression of retinal arterial aneurysms in a case of idiopathic retinal vasculitis, aneurysms, and neuroretinitis (IRVAN). Retina 1999;19: 250 –251. Xiao H, Heeringa P, Hu P, et al. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. J Clin Invest 2002;110: 955–963. Soheilian M. Polyarteritis Nodosa. In: Foster CS, Vitale AT, eds. Diagnosis and Treatment of Uveitis. 1st ed. Philadelphia, PA: W.B. Saunders Co.; 2002:653– 660. Mandl L, Solomon D, Smith E, Lew RA, Katz JN, Shmerling RH. Using antineutrophil cytoplasmic antibody testing to diagnose vasculitis: can test-ordering guidelines improve diagnostic accuracy? Arch Intern Med 2002;162:1509 –1514.
