USE OF ULTRA-WIDE-FIELD RETINAL IMAGING IN THE MANAGEMENT OF ACTIVE BEHÇET RETINAL VASCULITIS MARINA MESQUIDA, MD, VICTOR LLORENÇ, MD, JOSÉ RAMÓN FONTENLA, MD, PHD, MANUEL JAVIER NAVARRO, MD, ALFREDO ADÁN, MD, PHD Background: Retinal vasculitis (RV) is an important component of Behçet disease. It may be difficult to detect either clinically or with conventional retinal imaging. The role of ultra-wide-field (UWF) retinal imaging was assessed in the diagnosis and management of RV associated with Behçet disease. Methods: A total of 38 eyes of 20 patients with active RV associated to Behçet disease underwent UWF imaging with the Optos scanning laser ophthalmoscope, fundus autoflourescence, and/or fluorescein angiography. This study determined the UWF findings and percentage of patients in whom this imaging modality assisted in diagnosing the extent of vasculitis, planning treatment, and monitoring disease activity. Results: Optos UWF imaging assisted in diagnosing and quantifying the extent of RV in 16 patients (80%), planning medical treatment or laser photocoagulation in 13 of 20 patients (65%), and enhanced disease monitoring in 11 of 20 patients (55%). UWF fluorescein angiography revealed vasculitis not clinically evident in 28 of 33 eyes (84.8%). Predominant angiographic findings were diffuse vascular leakage (75.7%), peripheral retinal nonperfusion (66.7%), optic disk leakage (63.6%), macular leakage (30.3%), and macular edema (27.3%). Eighteen patients (34 eyes) underwent UWF fundus autoflourescence, showing multiple hyperfluorescent spots in retinal periphery in 28 eyes (82.3%). Conclusion: Ultra-wide-field imaging is a valuable tool in the management of patients with RV associated to Behçet disease and can be used for the diagnosis, treatment, and follow-up. Additional studies, including longitudinal evaluations, are needed to elucidate whether these findings or the subsequent management alterations may improve patients’ outcomes. RETINA 34:2121–2127, 2014
R
occlusive nature of RV in ocular BD.5,6 Leakage from posterior retinal vessels may be seen before there are obvious ophthalmoscopic signs of vasculitis. Moreover, in many RV, vessels anterior to the equator are involved and cause peripheral leakage, ischemia, and neovascularization, which are difficult to detect clinically. In consequence, visualization of the peripheral retina could be essential to the diagnosis, monitoring, and treatment of RV in BD. Ultra-wide-field (UWF) imaging with Optos system has been recently introduced and provides 200° of photographic, autofluorographic, and angiographic views of the ocular fundus that may be helpful in the clinical management and treatment of RV.7 The principal aim of this study was to present and describe the potential benefits of UWF imaging in the management of RV associated to BD.
etinal vasculitis (RV) associated to Behçet disease (BD) is a sight-threatening condition that may be challenging to diagnose and treat. The prognosis for vision in patients with BD and recurrent posterior segment disease may be dismal, chiefly because of inflammatory retinal vein occlusions, peripheral retinal ischemia, and macular edema.1–4 Management decision of this condition is often based on the clinical appearance and angiographic behavior of retinal lesions and vasculature. Fundus fluorescein angiography (FA) is the gold standard to detect and monitor both leaky and
From the Uveitis Unit, Department of Ophthalmology, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain. None of the authors have any financial/conflicting interests to disclose. Reprint requests: Alfredo Adán, MD, PhD, Sabino de Arana, 1. 08028 Barcelona, Spain; e-mail: [email protected]
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2122 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
Patients and Methods We present a retrospective review of 38 eyes of 20 consecutive patients with Behçet RV attending the Uveitis Clinic of the Hospital Clinic of Barcelona who underwent UWF imaging between January 2012 and September 2013. Inclusion criteria were patients diagnosed with BD fulfilling the diagnostic criteria of the International Study Group8 who presented with active RV. The diagnosis of active RV was based on the presence of peripheral vascular sheathing with or without retinal infiltrates, vitritis, or anterior chamber inflammation. Exclusion criteria were significant media opacities, trauma, or any other macular or retinal disorders. The Hospital Clinic of Barcelona Institutional Review Board approved this study according to local and national institutional review board guidelines. After informed consent, each patient underwent standard clinical examination, followed by UWF scanning laser ophthalmoscope retinal imaging. Fundus autofluorescence (FAF) and FA were also performed when possible. New and established patients with BD were recruited by 2 co-investigators (M.M. and A.A.). Ultra-wide-field pseudocolor, FA, and FAF images were obtained with Optomap Panoramic 200Tx (Optos PLC, Scotland, United Kingdom). Basic operation is a scanning laser ophthalmoscope with 2 laser wavelengths scanning at 532 nm (green laser separation) and 633 nm (red laser separation). Images can be viewed separately or superimposed by specific software (Vantage V2; Optos PLC) to yield semirealistic color imaging. Excitation and detection wavelengths for FAF imaging were 532 nm and 540 nm to 800 nm, respectively. Fluorescein angiography was performed using intravenous injection of 5 mL of 10% sodium fluorescein. All retinal images and fluorescein angiograms were obtained by the same physician (J.R.F.). All images were reviewed independently by two reading center–certified retina specialists (M.M. and V.L.).
Results Twenty patients (38 eyes) were included, with mean age of 37.15 years (24–66 years) and a male (75%) preponderance. Ocular involvement was typically bilateral (90%). Table 1 shows the patients’ demographics, baseline treatments, and influence of UWF findings in patient management. Twenty patients (38 eyes) underwent UWF pseudocolor retinal imaging. The common characteristic UWF fundus findings in this study were vein sheathing in 38 eyes (100%) (Figure 1), vitreous cells in 28 eyes (73.7%), retinal infiltrates in 20 eyes (52.6%)
2014 VOLUME 34 NUMBER 10
(Figure 2), retinal haemorrhages in 19 eyes (50%), retinal vein occlusion in 6 eyes (15.8%), arteriolitis in 1 eye (2.6%), and retinal tear in 1 eye (2.6%). Ultra-wide-field FAF was performed in 18 patients (34 eyes), showing peripheral changes outside the posterior pole in 28 eyes (82.3%), multifocal hyperfluorescent spots in 19 eyes (55.9%) (Figure 3), multifocal hypofluorescent spots in 17 eyes (50%), and hypofluorescent lesions along retinal vessels in 7 eyes (20.6%) (Figure 4). Seventeen patients (33 eyes) underwent UWF FA, disclosing the following findings: vasculitis not clinically evident in 28 eyes (84.8%), diffuse vascular leakage in 25 eyes (75.7%) (Figure 5), peripheral retinal nonperfusion in 22 eyes (66.7%), optic disk leakage in 21 eyes (63.6%), macular leakage in 10 eyes (30.3%), macular edema in 9 eyes (27.3%), and retinal neovascularization in 3 eyes (9.1%) (Figure 6). Overall, UWF retinal imaging revealed additional information that caused a change of treatment in 16 of 20 patients (80%), as shown in Table 1. For instance, laser photocoagulation was performed in 4 eyes (10.5%) for severe peripheral retinal ischemia and/or retinal neovascularization demonstrated with UWF FA. Immunomodulatory treatment was modified because of UWF findings in 13 of 20 patients (65%). Therapy was modified when active new inflammatory retinal lesions appeared in UWF imaging or extensive areas of peripheral nonperfusion were identified.
Discussion Retinal vasculitis represents an essential finding in BD and is a sign of sight-threatening disease. The treatment of Behçet RV usually requires immunosuppressive agents, which themselves may have lifethreatening side effects.9,10 Blockade of tumor necrosis factor a and treatment with interferon-a are effective in diminishing the severity of systemic BD, and reports on the effect on ocular disease are also encouraging.11,12 Hence, a thorough retinal assessment is essential in the decision-making process. In patients with active BDassociated RV, the presence and particularly the true extent of RV revealed by UWF imaging informed key decisions regarding the initiation and titration of immunosuppressive or biologic medications in our study. Overall, UWF retinal imaging revealed additional information that caused a change of management in 16 of 20 patients (80%) and enhanced disease monitoring in 11 of 20 patients (55%) in this study. Ultrawide-field imaging allowed clear documentation of peripheral retinal lesions and greatly simplified longitudinal comparisons for disease activity and progression.
Table 1. Demographics and Treatments Patient No.
Final Follow-up Treatment
Change in Management Because of UWF Findings
Sex
Laterality
1 2
66 34
M M
B B
PDN TCZ
PDN CZP
No Yes
3 4 5 6 7
24 45 30 32 30
M M F M F
U B U B B
ADA e2w ADA e4w PDN None PDN
ADA e2w ADA e2w PDN PDN CyA
No Yes No Yes Yes
8 9 10
40 38 46
M M F
B B B
IFX None PDN
11
29
F
B
CyA
12
43
M
B
ADA e4w
ADA e2w
Yes
13
29
M
B
GLM
Anti–IL-1b
Yes
14
37
M
B
None
PDN
Yes
15
35
F
B
PDN
Anti–IL-1b
Yes
16 17
34 35
M M
B B
PDN PDN
PDN + CyA PDN + CyA
Yes Yes
18
39
F
B
IFX
19
47
M
B
ADA e4w
20
30
M
B
None
IFX PDN + CyA PDN + laser photocoagulation IFX
IFX + laser photocoagulation ADA e2w PDN + CyA
No Yes Yes Yes
Yes Yes Yes
Reason for Change in Management Multiple retinal infiltrates in retinal periphery seen in UWF fundus photographs and multifocal hyperautofluorescent spots in UWF FAF Peripheral vascular leakage seen in UWF FA Peripheral RV seen in UWF FA Peripheral retinal infiltrates seen in UWF fundus photographs Peripheral RV seen in UWF FA Areas of capillary nonperfusion seen in FA Diffuse vascular leakage and vein sheathing seen in FA Multifocal hyperfluorescent spots observed in FAF Peripheral retinal infiltrates seen in UWF fundus photographs Peripheral retinal infiltrates seen in UWF fundus photographs Posterior and peripheral vascular leakage seen in FA Peripheral RV seen in UWF FA Multifocal hyper and hypoautofluorescent spots seen in FAF Areas of capillary nonperfusion seen in FA
ULTRA-WIDE-FIELD AND BEHÇET VASCULITIS MESQUIDA ET AL
Age
Baseline Treatment
Multifocal hyperautofluorescent spots observed in FAF Peripheral RV seen in UWF FA
B, bilateral; ADA, adalimumab; CyA, cyclosporine A; CZP, certolizumab pegol; e2w, every 2 weeks; e4w, every 4 weeks; F, female; IFX, infliximab; IL-1b, interleukin-1 beta; M, male; PDN, oral prednisone; TCZ, tocilizumab; U, unilateral; GLM, golimumab.
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2014 VOLUME 34 NUMBER 10
Fig. 1. Ultra-wide-field pseudocolor retinal images (A) showing retinal vein sheathing. Green laser light (red-free light) (532 nm) (B) highlights the anterior retinal structures and vasculature.
Peripheral vein sheathing and retinal infiltrates that denote disease activity were clearly detected with UWF pseudocolour imaging in this study. Green laser and red laser separation images also provided additional informative value in our patients. Green laser light (red-free light) (532 nm) highlights the anterior retinal structures and retinal vasculature and was especially useful in the visualization and quantification of lesions in the retina secondary to RV. Even in patients with significant vitritis, we were able to obtain high-definition images to inform our therapeutic decisions and enhanced disease monitoring. In following-up patients in our series, wide-angle images facilitated detection of peripheral lesions, their true extensions, and assessment of the response to treatment.
Fig. 2. Ultra-wide-field pseudocolor images in a 34-year-old male patient with BD with bilateral active retinal vasculitis and retinal infiltrates (A and B). Green laser light (red-free light) (532 nm) images (C and D) highlighted peripheral retinal infiltrates in both eyes.
Fluorescein angiography is an essential tool in the management of patients with BD because it allows the documentation of important clinical findings, such as dye leakage from the papillary and retinal capillaries, vascular wall staining, retinal vein occlusion, cystoid macular edema, vascular remodeling as a result of capillary nonperfusion, areas of retinal ischemia as a result of occlusive vasculitis, and retinal and/or optic disk neovascularization. The degree of background retinal and optic disk vascular leakage as assessed by FA at times of clinical activity or quiescence is critical to make therapeutic decisions in BD. Moreover, signs of RV may be difficult to detect clinically as demonstrated in several of our cases where vasculitis was only discovered with the aid of UWF FA. Our study has shown that UWF FA may disclose peripheral and
ULTRA-WIDE-FIELD AND BEHÇET VASCULITIS MESQUIDA ET AL
2125
Fig. 3. Ultra-wide-field retinal images (A and B) showing retinal infiltrates, vitreous haze, and retinal vasculitis in a 37-year-old male patient with active BD. Ultrawide-field FAF images revealed multiple hyperfluorescent spots in retinal periphery (C and D). These abnormalities were more visible with FAF rather than UWF pseudocolor imaging.
posterior changes such as fluorescein leakage from retinal capillaries in 84.8% patients, even with no visual loss or abnormal fundus findings. In consequence, UWF FA seems to evaluate precisely the early and
subclinical retinal involvement. Peripheral retinal nonperfusion was demonstrated in 66.7% of the eyes. Our results suggest that the absence of macroscopic changes in the retina does not preclude ischemic peripheral
Fig. 4. Ultra-wide-field retinal imaging (A), FA (B), and FAF (C) of a 48-year-old patient with BD and suspected pigmented paravenous retinochoroidal atrophy, showing multiple chorioretinal atrophic hypofluoresent lesions adjacent to retinal vessels and surrounding the optic disk.
2126 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
2014 VOLUME 34 NUMBER 10
Fig. 5. Fundus images of a 30-year-old male patient with BD with retinal infiltrates visible in UWF pseudocolor imaging (A) unnoted in conventional 30° fundus photographs (B). UWF FA disclosed diffuse vascular leakage in posterior pole and peripheral retinal vessels, optic disk leakage, and macular edema (C) that led to treatment switch. Vascular leakage was visualized only partially in conventional FA (D).
abnormalities in Behçet RV. In consequence, UWF FA is a very helpful tool for determining whether the vasculitis has an occlusive nature and for quantifying the true extent of the capillary nonperfusion. Areas of
Fig. 6. Ultra-wide-field fundus imaging (A) showing retinal vasculitis and vitritis in a 39-year-old woman with active BD. Ultra-wide-field FA (B) disclosed severe and extensive peripheral capillary nonperfusion, vascular leakage, and optic disk leakage. The true extent of the peripheral retinal ischemia was difficult to detect with conventional 30° FA (C). Ultra-wide-field FA disclosing peripheral retinal nonperfusion and neovascularization in a 46-year-old female patient with BD (D). The ischemia region had been previously treated with laser photocoagulation. However, an area of capillary nonperfusion that had not been treated was then photocoagulated because of UWF FA findings.
retinal ischemia and neovascularization were easily identified in the present series, aiding targeted laser photocoagulation. Indeed, laser photocoagulation was performed in 4 eyes (10.5%) for severe peripheral
ULTRA-WIDE-FIELD AND BEHÇET VASCULITIS MESQUIDA ET AL
retinal ischemia or neovascularization demonstrated with UWF FA. In our experience, UWF FA disclosed the true extent, nature, and severity of RV and informed key decisions regarding the initiation of biologic medications or shortening their dose regimen. Our findings are similar to those reported by Leder et al13 and suggest that UW FA can provide relevant information in the management of RV. Although recently Reznicek et al14 reported the diagnostic value of wide-field FAF in patients with noninfectious posterior uveitis, to date, there are no reports on the use of FAF imaging in Behçet uveitis. Eighteen patients (34 eyes) of our series underwent UWF FAF. In this case series, UWF FAF images revealed significantly more specific information regarding number and extension of retinal abnormalities than color imaging. Different degrees of alteration on the level of the retinal pigment epithelium, with consecutive changes in lipofuscin distribution may not be visible on color fundus images but are more reliable being detected with FAF. The most frequent FAF finding in our series was the presence of multiple hyperfluorescent spots in the retinal periphery in 28 eyes (82.3%). These abnormalities were more visible with FAF rather than with UWF pseudocolor imaging. Our findings suggest that active RV also induces retinal epithelium alterations in the retinal periphery. In consequence, FAF abnormalities could be frequent in Behçet uveitis and are readily revealed by UWF FAF imaging, manifesting with distinct patterns. For evaluating and monitoring those, FAF imaging adds to the clinical fundus examination in our patients. Multiple chorioretinal atrophic hypofluoresent lesions adjacent to retinal veins were seen in two eyes of one of our patients. Perivascular retinal pigmentary changes have not been previously described in BD. Our case presented with similar findings to those described in pigmented paravenous retinochoroidal atrophy.15 This is a rare disorder of unknown origin characterized by bone corpuscle pigmentation accumulation along the distribution of the retinal veins. It seems likely that there are cases of paravascular inflammation or vasculitis associated with well-known conditions (e.g., BD). Our patient at the time of diagnosis presented with active RV. In summary, our results suggest that the UWF technology may be important to detect inflammation early and to follow treatment in patients with BD RV. This technology may lead investigators to change their assessment of the severity or stability of the disease activity and therefore alter management of the patients. Additional studies, including longitudinal evaluations, are needed to determine whether these findings, or the
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subsequent management alterations, may be able to improve patients’ outcomes. Key words: Behçet uveitis, retinal vasculitis, ultrawide-field imaging, fluorescein angiography, fundus autofluorescence. Acknowledgment The authors are very grateful to Professor Andrew Dick for his critical reading of the present article. References 1. Takeuchi M, Hokama H, Tsukahara R, et al. Risk and prognostic factors of poor visual outcome in Behcet’s disease with ocular involvement. Graefes Arch Clin Exp Ophthalmol 2005; 243:1147–1152. 2. Tugal-Tutkun I, Onal S, Altan-Yaycioglu R, et al. Uveitis in Behçet disease: an analysis of 880 patients. Am J Ophthalmol 2004;138:373–380. 3. Evereklioglu C. Current concepts in the etiology and treatment of Behçet disease. Surv Ophthalmol 2005;50:297–350. 4. Deuter CM, Kötter I, Wallace GR, et al. Behçet’s disease: ocular effects and treatment. Prog Retin Eye Res 2008;27: 111–136. 5. Yu HG, Kim MJ, Oh FS. Fluorescein angiography and visual acuity in active uveitis with Behçet disease. Ocul Immunol Inflamm 2009;17:41–46. 6. Atmaca LS, Sonmez PA. Fluorescein and indocyanine green angiography findings in Behçet’s disease. Br J Ophthalmol 2003;87:1466–1468. 7. Campbell JP, Leder HA, Sepah YJ, et al. Wide-field retinal imaging in the management of noninfectious posterior uveitis. Am J Ophthalmol 2012;154:908–911. 8. The International Study Group for Behçet’s Disease. Evaluation of diagnostic (“classification”) criteria in Behçet’s disease —towards internationally agreed criteria. Br J Rheumatol 1992;31:299–308. 9. Toker E, Kazoko glu H, Acar N. High dose intravenous steroid therapy for severe posterior segment uveitis in Behçet’s disease. Br J Ophthalmol 2002;86:521–523. 10. Taylor SR, Singh J, Menezo V, et al. Behçet disease: visual prognosis and factors influencing the development of visual loss. Am J Ophthalmol 2011;152:1059–1066. 11. Okada AA, Goto H, Ohno S, Mochizuki M; Ocular Behçet’s Disease Research Group of Japan. Multicenter study of infliximab for refractory uveoretinitis in Behçet disease. Arch Ophthalmol 2012;130:592–598. 12. Perra D, Alba MA, Callejas JL, et al. Adalimumab for the treatment of Behçet’s disease: experience in 19 patients. Rheumatology (Oxford) 2012;51:1825–1831. 13. Leder HA, Campbell JP, Sepah YJ, et al. Ultra-wide-field retinal imaging in the management of non-infectious retinal vasculitis. J Ophthalmic Inflamm Infect 2013;3:30. 14. Reznicek L, Kernt M, Seidensticker F, et al. Autofluorescence in posterior uveitis. Ophthalmology 2012;119:1712–1713. 15. Murray AT, Kirkby GR. Pigmented paravenous retinochoroidal atrophy: a literature review supported by a unique case and insight. Eye (Lond) 2000;14:711–716.
R
occlusive nature of RV in ocular BD.5,6 Leakage from posterior retinal vessels may be seen before there are obvious ophthalmoscopic signs of vasculitis. Moreover, in many RV, vessels anterior to the equator are involved and cause peripheral leakage, ischemia, and neovascularization, which are difficult to detect clinically. In consequence, visualization of the peripheral retina could be essential to the diagnosis, monitoring, and treatment of RV in BD. Ultra-wide-field (UWF) imaging with Optos system has been recently introduced and provides 200° of photographic, autofluorographic, and angiographic views of the ocular fundus that may be helpful in the clinical management and treatment of RV.7 The principal aim of this study was to present and describe the potential benefits of UWF imaging in the management of RV associated to BD.
etinal vasculitis (RV) associated to Behçet disease (BD) is a sight-threatening condition that may be challenging to diagnose and treat. The prognosis for vision in patients with BD and recurrent posterior segment disease may be dismal, chiefly because of inflammatory retinal vein occlusions, peripheral retinal ischemia, and macular edema.1–4 Management decision of this condition is often based on the clinical appearance and angiographic behavior of retinal lesions and vasculature. Fundus fluorescein angiography (FA) is the gold standard to detect and monitor both leaky and
From the Uveitis Unit, Department of Ophthalmology, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain. None of the authors have any financial/conflicting interests to disclose. Reprint requests: Alfredo Adán, MD, PhD, Sabino de Arana, 1. 08028 Barcelona, Spain; e-mail: [email protected]
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2122 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
Patients and Methods We present a retrospective review of 38 eyes of 20 consecutive patients with Behçet RV attending the Uveitis Clinic of the Hospital Clinic of Barcelona who underwent UWF imaging between January 2012 and September 2013. Inclusion criteria were patients diagnosed with BD fulfilling the diagnostic criteria of the International Study Group8 who presented with active RV. The diagnosis of active RV was based on the presence of peripheral vascular sheathing with or without retinal infiltrates, vitritis, or anterior chamber inflammation. Exclusion criteria were significant media opacities, trauma, or any other macular or retinal disorders. The Hospital Clinic of Barcelona Institutional Review Board approved this study according to local and national institutional review board guidelines. After informed consent, each patient underwent standard clinical examination, followed by UWF scanning laser ophthalmoscope retinal imaging. Fundus autofluorescence (FAF) and FA were also performed when possible. New and established patients with BD were recruited by 2 co-investigators (M.M. and A.A.). Ultra-wide-field pseudocolor, FA, and FAF images were obtained with Optomap Panoramic 200Tx (Optos PLC, Scotland, United Kingdom). Basic operation is a scanning laser ophthalmoscope with 2 laser wavelengths scanning at 532 nm (green laser separation) and 633 nm (red laser separation). Images can be viewed separately or superimposed by specific software (Vantage V2; Optos PLC) to yield semirealistic color imaging. Excitation and detection wavelengths for FAF imaging were 532 nm and 540 nm to 800 nm, respectively. Fluorescein angiography was performed using intravenous injection of 5 mL of 10% sodium fluorescein. All retinal images and fluorescein angiograms were obtained by the same physician (J.R.F.). All images were reviewed independently by two reading center–certified retina specialists (M.M. and V.L.).
Results Twenty patients (38 eyes) were included, with mean age of 37.15 years (24–66 years) and a male (75%) preponderance. Ocular involvement was typically bilateral (90%). Table 1 shows the patients’ demographics, baseline treatments, and influence of UWF findings in patient management. Twenty patients (38 eyes) underwent UWF pseudocolor retinal imaging. The common characteristic UWF fundus findings in this study were vein sheathing in 38 eyes (100%) (Figure 1), vitreous cells in 28 eyes (73.7%), retinal infiltrates in 20 eyes (52.6%)
2014 VOLUME 34 NUMBER 10
(Figure 2), retinal haemorrhages in 19 eyes (50%), retinal vein occlusion in 6 eyes (15.8%), arteriolitis in 1 eye (2.6%), and retinal tear in 1 eye (2.6%). Ultra-wide-field FAF was performed in 18 patients (34 eyes), showing peripheral changes outside the posterior pole in 28 eyes (82.3%), multifocal hyperfluorescent spots in 19 eyes (55.9%) (Figure 3), multifocal hypofluorescent spots in 17 eyes (50%), and hypofluorescent lesions along retinal vessels in 7 eyes (20.6%) (Figure 4). Seventeen patients (33 eyes) underwent UWF FA, disclosing the following findings: vasculitis not clinically evident in 28 eyes (84.8%), diffuse vascular leakage in 25 eyes (75.7%) (Figure 5), peripheral retinal nonperfusion in 22 eyes (66.7%), optic disk leakage in 21 eyes (63.6%), macular leakage in 10 eyes (30.3%), macular edema in 9 eyes (27.3%), and retinal neovascularization in 3 eyes (9.1%) (Figure 6). Overall, UWF retinal imaging revealed additional information that caused a change of treatment in 16 of 20 patients (80%), as shown in Table 1. For instance, laser photocoagulation was performed in 4 eyes (10.5%) for severe peripheral retinal ischemia and/or retinal neovascularization demonstrated with UWF FA. Immunomodulatory treatment was modified because of UWF findings in 13 of 20 patients (65%). Therapy was modified when active new inflammatory retinal lesions appeared in UWF imaging or extensive areas of peripheral nonperfusion were identified.
Discussion Retinal vasculitis represents an essential finding in BD and is a sign of sight-threatening disease. The treatment of Behçet RV usually requires immunosuppressive agents, which themselves may have lifethreatening side effects.9,10 Blockade of tumor necrosis factor a and treatment with interferon-a are effective in diminishing the severity of systemic BD, and reports on the effect on ocular disease are also encouraging.11,12 Hence, a thorough retinal assessment is essential in the decision-making process. In patients with active BDassociated RV, the presence and particularly the true extent of RV revealed by UWF imaging informed key decisions regarding the initiation and titration of immunosuppressive or biologic medications in our study. Overall, UWF retinal imaging revealed additional information that caused a change of management in 16 of 20 patients (80%) and enhanced disease monitoring in 11 of 20 patients (55%) in this study. Ultrawide-field imaging allowed clear documentation of peripheral retinal lesions and greatly simplified longitudinal comparisons for disease activity and progression.
Table 1. Demographics and Treatments Patient No.
Final Follow-up Treatment
Change in Management Because of UWF Findings
Sex
Laterality
1 2
66 34
M M
B B
PDN TCZ
PDN CZP
No Yes
3 4 5 6 7
24 45 30 32 30
M M F M F
U B U B B
ADA e2w ADA e4w PDN None PDN
ADA e2w ADA e2w PDN PDN CyA
No Yes No Yes Yes
8 9 10
40 38 46
M M F
B B B
IFX None PDN
11
29
F
B
CyA
12
43
M
B
ADA e4w
ADA e2w
Yes
13
29
M
B
GLM
Anti–IL-1b
Yes
14
37
M
B
None
PDN
Yes
15
35
F
B
PDN
Anti–IL-1b
Yes
16 17
34 35
M M
B B
PDN PDN
PDN + CyA PDN + CyA
Yes Yes
18
39
F
B
IFX
19
47
M
B
ADA e4w
20
30
M
B
None
IFX PDN + CyA PDN + laser photocoagulation IFX
IFX + laser photocoagulation ADA e2w PDN + CyA
No Yes Yes Yes
Yes Yes Yes
Reason for Change in Management Multiple retinal infiltrates in retinal periphery seen in UWF fundus photographs and multifocal hyperautofluorescent spots in UWF FAF Peripheral vascular leakage seen in UWF FA Peripheral RV seen in UWF FA Peripheral retinal infiltrates seen in UWF fundus photographs Peripheral RV seen in UWF FA Areas of capillary nonperfusion seen in FA Diffuse vascular leakage and vein sheathing seen in FA Multifocal hyperfluorescent spots observed in FAF Peripheral retinal infiltrates seen in UWF fundus photographs Peripheral retinal infiltrates seen in UWF fundus photographs Posterior and peripheral vascular leakage seen in FA Peripheral RV seen in UWF FA Multifocal hyper and hypoautofluorescent spots seen in FAF Areas of capillary nonperfusion seen in FA
ULTRA-WIDE-FIELD AND BEHÇET VASCULITIS MESQUIDA ET AL
Age
Baseline Treatment
Multifocal hyperautofluorescent spots observed in FAF Peripheral RV seen in UWF FA
B, bilateral; ADA, adalimumab; CyA, cyclosporine A; CZP, certolizumab pegol; e2w, every 2 weeks; e4w, every 4 weeks; F, female; IFX, infliximab; IL-1b, interleukin-1 beta; M, male; PDN, oral prednisone; TCZ, tocilizumab; U, unilateral; GLM, golimumab.
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2014 VOLUME 34 NUMBER 10
Fig. 1. Ultra-wide-field pseudocolor retinal images (A) showing retinal vein sheathing. Green laser light (red-free light) (532 nm) (B) highlights the anterior retinal structures and vasculature.
Peripheral vein sheathing and retinal infiltrates that denote disease activity were clearly detected with UWF pseudocolour imaging in this study. Green laser and red laser separation images also provided additional informative value in our patients. Green laser light (red-free light) (532 nm) highlights the anterior retinal structures and retinal vasculature and was especially useful in the visualization and quantification of lesions in the retina secondary to RV. Even in patients with significant vitritis, we were able to obtain high-definition images to inform our therapeutic decisions and enhanced disease monitoring. In following-up patients in our series, wide-angle images facilitated detection of peripheral lesions, their true extensions, and assessment of the response to treatment.
Fig. 2. Ultra-wide-field pseudocolor images in a 34-year-old male patient with BD with bilateral active retinal vasculitis and retinal infiltrates (A and B). Green laser light (red-free light) (532 nm) images (C and D) highlighted peripheral retinal infiltrates in both eyes.
Fluorescein angiography is an essential tool in the management of patients with BD because it allows the documentation of important clinical findings, such as dye leakage from the papillary and retinal capillaries, vascular wall staining, retinal vein occlusion, cystoid macular edema, vascular remodeling as a result of capillary nonperfusion, areas of retinal ischemia as a result of occlusive vasculitis, and retinal and/or optic disk neovascularization. The degree of background retinal and optic disk vascular leakage as assessed by FA at times of clinical activity or quiescence is critical to make therapeutic decisions in BD. Moreover, signs of RV may be difficult to detect clinically as demonstrated in several of our cases where vasculitis was only discovered with the aid of UWF FA. Our study has shown that UWF FA may disclose peripheral and
ULTRA-WIDE-FIELD AND BEHÇET VASCULITIS MESQUIDA ET AL
2125
Fig. 3. Ultra-wide-field retinal images (A and B) showing retinal infiltrates, vitreous haze, and retinal vasculitis in a 37-year-old male patient with active BD. Ultrawide-field FAF images revealed multiple hyperfluorescent spots in retinal periphery (C and D). These abnormalities were more visible with FAF rather than UWF pseudocolor imaging.
posterior changes such as fluorescein leakage from retinal capillaries in 84.8% patients, even with no visual loss or abnormal fundus findings. In consequence, UWF FA seems to evaluate precisely the early and
subclinical retinal involvement. Peripheral retinal nonperfusion was demonstrated in 66.7% of the eyes. Our results suggest that the absence of macroscopic changes in the retina does not preclude ischemic peripheral
Fig. 4. Ultra-wide-field retinal imaging (A), FA (B), and FAF (C) of a 48-year-old patient with BD and suspected pigmented paravenous retinochoroidal atrophy, showing multiple chorioretinal atrophic hypofluoresent lesions adjacent to retinal vessels and surrounding the optic disk.
2126 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
2014 VOLUME 34 NUMBER 10
Fig. 5. Fundus images of a 30-year-old male patient with BD with retinal infiltrates visible in UWF pseudocolor imaging (A) unnoted in conventional 30° fundus photographs (B). UWF FA disclosed diffuse vascular leakage in posterior pole and peripheral retinal vessels, optic disk leakage, and macular edema (C) that led to treatment switch. Vascular leakage was visualized only partially in conventional FA (D).
abnormalities in Behçet RV. In consequence, UWF FA is a very helpful tool for determining whether the vasculitis has an occlusive nature and for quantifying the true extent of the capillary nonperfusion. Areas of
Fig. 6. Ultra-wide-field fundus imaging (A) showing retinal vasculitis and vitritis in a 39-year-old woman with active BD. Ultra-wide-field FA (B) disclosed severe and extensive peripheral capillary nonperfusion, vascular leakage, and optic disk leakage. The true extent of the peripheral retinal ischemia was difficult to detect with conventional 30° FA (C). Ultra-wide-field FA disclosing peripheral retinal nonperfusion and neovascularization in a 46-year-old female patient with BD (D). The ischemia region had been previously treated with laser photocoagulation. However, an area of capillary nonperfusion that had not been treated was then photocoagulated because of UWF FA findings.
retinal ischemia and neovascularization were easily identified in the present series, aiding targeted laser photocoagulation. Indeed, laser photocoagulation was performed in 4 eyes (10.5%) for severe peripheral
ULTRA-WIDE-FIELD AND BEHÇET VASCULITIS MESQUIDA ET AL
retinal ischemia or neovascularization demonstrated with UWF FA. In our experience, UWF FA disclosed the true extent, nature, and severity of RV and informed key decisions regarding the initiation of biologic medications or shortening their dose regimen. Our findings are similar to those reported by Leder et al13 and suggest that UW FA can provide relevant information in the management of RV. Although recently Reznicek et al14 reported the diagnostic value of wide-field FAF in patients with noninfectious posterior uveitis, to date, there are no reports on the use of FAF imaging in Behçet uveitis. Eighteen patients (34 eyes) of our series underwent UWF FAF. In this case series, UWF FAF images revealed significantly more specific information regarding number and extension of retinal abnormalities than color imaging. Different degrees of alteration on the level of the retinal pigment epithelium, with consecutive changes in lipofuscin distribution may not be visible on color fundus images but are more reliable being detected with FAF. The most frequent FAF finding in our series was the presence of multiple hyperfluorescent spots in the retinal periphery in 28 eyes (82.3%). These abnormalities were more visible with FAF rather than with UWF pseudocolor imaging. Our findings suggest that active RV also induces retinal epithelium alterations in the retinal periphery. In consequence, FAF abnormalities could be frequent in Behçet uveitis and are readily revealed by UWF FAF imaging, manifesting with distinct patterns. For evaluating and monitoring those, FAF imaging adds to the clinical fundus examination in our patients. Multiple chorioretinal atrophic hypofluoresent lesions adjacent to retinal veins were seen in two eyes of one of our patients. Perivascular retinal pigmentary changes have not been previously described in BD. Our case presented with similar findings to those described in pigmented paravenous retinochoroidal atrophy.15 This is a rare disorder of unknown origin characterized by bone corpuscle pigmentation accumulation along the distribution of the retinal veins. It seems likely that there are cases of paravascular inflammation or vasculitis associated with well-known conditions (e.g., BD). Our patient at the time of diagnosis presented with active RV. In summary, our results suggest that the UWF technology may be important to detect inflammation early and to follow treatment in patients with BD RV. This technology may lead investigators to change their assessment of the severity or stability of the disease activity and therefore alter management of the patients. Additional studies, including longitudinal evaluations, are needed to determine whether these findings, or the
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subsequent management alterations, may be able to improve patients’ outcomes. Key words: Behçet uveitis, retinal vasculitis, ultrawide-field imaging, fluorescein angiography, fundus autofluorescence. Acknowledgment The authors are very grateful to Professor Andrew Dick for his critical reading of the present article. References 1. Takeuchi M, Hokama H, Tsukahara R, et al. Risk and prognostic factors of poor visual outcome in Behcet’s disease with ocular involvement. Graefes Arch Clin Exp Ophthalmol 2005; 243:1147–1152. 2. Tugal-Tutkun I, Onal S, Altan-Yaycioglu R, et al. Uveitis in Behçet disease: an analysis of 880 patients. Am J Ophthalmol 2004;138:373–380. 3. Evereklioglu C. Current concepts in the etiology and treatment of Behçet disease. Surv Ophthalmol 2005;50:297–350. 4. Deuter CM, Kötter I, Wallace GR, et al. Behçet’s disease: ocular effects and treatment. Prog Retin Eye Res 2008;27: 111–136. 5. Yu HG, Kim MJ, Oh FS. Fluorescein angiography and visual acuity in active uveitis with Behçet disease. Ocul Immunol Inflamm 2009;17:41–46. 6. Atmaca LS, Sonmez PA. Fluorescein and indocyanine green angiography findings in Behçet’s disease. Br J Ophthalmol 2003;87:1466–1468. 7. Campbell JP, Leder HA, Sepah YJ, et al. Wide-field retinal imaging in the management of noninfectious posterior uveitis. Am J Ophthalmol 2012;154:908–911. 8. The International Study Group for Behçet’s Disease. Evaluation of diagnostic (“classification”) criteria in Behçet’s disease —towards internationally agreed criteria. Br J Rheumatol 1992;31:299–308. 9. Toker E, Kazoko glu H, Acar N. High dose intravenous steroid therapy for severe posterior segment uveitis in Behçet’s disease. Br J Ophthalmol 2002;86:521–523. 10. Taylor SR, Singh J, Menezo V, et al. Behçet disease: visual prognosis and factors influencing the development of visual loss. Am J Ophthalmol 2011;152:1059–1066. 11. Okada AA, Goto H, Ohno S, Mochizuki M; Ocular Behçet’s Disease Research Group of Japan. Multicenter study of infliximab for refractory uveoretinitis in Behçet disease. Arch Ophthalmol 2012;130:592–598. 12. Perra D, Alba MA, Callejas JL, et al. Adalimumab for the treatment of Behçet’s disease: experience in 19 patients. Rheumatology (Oxford) 2012;51:1825–1831. 13. Leder HA, Campbell JP, Sepah YJ, et al. Ultra-wide-field retinal imaging in the management of non-infectious retinal vasculitis. J Ophthalmic Inflamm Infect 2013;3:30. 14. Reznicek L, Kernt M, Seidensticker F, et al. Autofluorescence in posterior uveitis. Ophthalmology 2012;119:1712–1713. 15. Murray AT, Kirkby GR. Pigmented paravenous retinochoroidal atrophy: a literature review supported by a unique case and insight. Eye (Lond) 2000;14:711–716.
