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Anti-Vascular Endothelial Growth Factor Injection for Exudative Age-related Macular Degeneration in Patients with Vitreo-Macular Traction
The ability to detect and measure several autoantibodies (up to 100) in one sample makes this technology particularly appealing in the setting of autoimmune retinopathy; several antiretinal antibodies have been described as putative mediators of retinal degeneration, and many more remain to be discovered. We are in agreement that the use of multiplexing technology needs to be further explored in the testing for antiretinal antibodies; however, in this discussion it is important to highlight the various types of multiplexing technology that are available. The Luminex system is one of several commercially available bead-based multiplex assays.1 These systems employ fluorescent beads that are coupled to specific autoantigens. Following the addition of patient serum and a fluorochrome-coupled secondary antibody, dual-laser flow cytometry is used to detect and quantify the amount of bound autoantibody. Another system for multiplex testing is the line immunoassay (LIA),2 which is similar to immunoblotting except that there is no electrophoresis and blotting. Several autoantigens are applied to a solid matrix such as nitrocellulose, and each strip is then used in an identical manner to conventional immunoblotting. Computer-assisted imaging and densitometry can then be used to quantify the relative amount of bound autoantibody. Another novel high-throughput assay system is the luciferase immunoprecipitation system (LIPS).3,4 In this method, genes of antigens are fused to a luciferase reporter and then expressed in mammalian cells. The luciferasetagged fusion proteins are mixed with patient sera and then immunoglobulin-antigen complexes are captured by protein A/G. After washing, the amount of luciferase-antigen that is antibody bound is measured by light production. This assay system has been validated in the setting of several infectious diseases.3,5 Multiplex technologies that are in development and may hold promise in the future include autoantigen microarrays, microfluidics, and nanotechnology formats.2 In summary, many multiplex systems currently exist that may serve as novel tools for the detection and measurement of antiretinal antibodies. These systems offer several advantages over traditional assays for antiretinal antibody detection. The successful use of these systems in antibody detection for various autoimmune diseases suggests that this technology may be applicable in the setting of antiretinal antibody testing. However, as with more traditional assays, there is a need for standardization and internal validation of these assay systems prior to their use in the clinical diagnostic setting. We encourage the exploration of this technology in the detection and measurement of antiretinal antibodies, and look forward to seeing future reports of its potential utility. FARZIN FOROOGHIAN PETER D. BURBELO ROBERT B. NUSSENBLATT
Bethesda, Maryland VOL. 147, NO. 2
REFERENCES
1. Binder SR. Autoantibody detection using multiplex technologies. Lupus 2006;15:412– 421. 2. Fritzler MJ. Advances and applications of multiplexed diagnostic technologies in autoimmune diseases. Lupus 2006;15: 422– 427. 3. Burbelo PD, Ching KH, Mattson TL, et al. Rapid antibody quantification and generation of whole proteome antibody response profiles using LIPS (luciferase immunoprecipitation systems). Biochem Biophys Res Commun 2007;352: 889 – 895. 4. Burbelo PD, Goldman R, Mattson TL. A simplified immunoprecipitation method for quantitatively measuring antibody responses in clinical sera samples by using mammalian-produced Renilla luciferase-antigen fusion proteins. BMC Biotechnol 2005;5:22. 5. Ramanathan R, Burbelo PD, Groot S, et al. A luciferase immunoprecipitation systems assay enhances the sensitivity and specificity of diagnosis of Strongyloides stercoralis infection. J Infect Dis 2008;198:444 – 451.
Anti-Vascular Endothelial Growth Factor Injection for Exudative Age-related Macular Degeneration in Patients with Vitreo-Macular Traction EDITOR: I READ WITH INTEREST THE ARTICLE BY MOJANA AND
associates1 on the role of abnormal vitreomacular adhesion in age-related macular degeneration (AMD). Several authors, using ultrasound and optical coherence tomography (OCT), showed that there is a higher rate of vitreomacular adhesion in AMD.2– 4 Moreover, a high incidence of posterior vitreous attachment was intraoperatively observed by different authors.5 These data seem to suggest that the vitreous may play a role in the pathogenesis and/or progression of AMD. Different hypothesis have been formulated to explain the role of vitreomacular adhesion in AMD, focusing on both mechanical and biochemical factors.3 Based on the hypothesis that a local inflammation induced by AMD may be responsible for focal corresponding adhesion (potentially inducing tractional forces on the retina), the authors wished to determine the frequency of persistent hyaloid adherence to the posterior pole in patients with AMD, using high-resolution spectral-domain OCT.1 I am impressed with the image quality presented by the authors (even in a 3-dimensional configuration), and I congratulate with them for having clearly shown the vitreomacular traction (VMT) in the exudative AMD cases reported. It is interesting the higher incidence of tractional configuration of the attached posterior hyaloid in eyes with exudative AMD that the authors found in
CORRESPONDENCE
375
3. Ondes F, Yilmaz G, Acar MA, et al. Role of the vitreous in age-related macular degeneration. Jpn J Ophthalmol 2000;44: 91–93. 4. Krebs I, Brannath W, Glittenberg C, et al. Posterior vitreomacular adhesion: a potential risk factor for exudative agerelated macular degeneration? Am J Ophthalmol 2007;144: 741–746. 5. Lambert HM, Capone A, Aaberg TM, et al. Surgical excision of subfoveal neovascular membranes in age-related macular degeneration. Am J Ophthalmol 1992;113:257–262. 6. Querques G, Souied EH, Soubrane G. Macular hole following intravitreal ranibizumab injection for choroidal neovascular membrane due to age-related macular degeneration. Acta Ophthalmol Scand. Forthcoming.
their study compared with non-AMD eyes, and also the concentric configuration of the VMT to the choroidal neovascularization (CNV), suggesting a causal relationship. Based on these findings, the authors propose that persistent low grade of local inflammation in AMD patients (chronic disease), is likely to induce structural changes at the level of the vitreoretinal interface. The resulting anterior-posterior forces, present at the surface of the retina, may exacerbate the macular edema, which originally occurs secondary to the presence of leaking vessels in the CNV complex. In agreement with the authors, I also believe that there may be a subpopulation of CNV eyes that do not respond to anti-vascular endothelial growth factor (VEGF) therapy, in which VMT may play a component in the resistance to such therapy. Moreover, I believe that in these CNV eyes, additional and unusual complications related to the anti-VEGF injection may develop because of VMT. We recently reported on a patient with VMT and subfoveal CNV attributable to AMD, who developed macular hole following treatment with intravitreal injection of anti-VEGF.6 Since then, in our practice, we encountered several cases with preinjection evidence of VMT, in which a lamellar or full thickness macular hole developed following treatment with intravitreal injection of anti-VEGF. In these patients, several possible mechanisms may have induced the development of macular hole. The intravitreal injection may have induced vitreous incarceration, causing vitreoretinal traction leading to development of a macular hole. The anti-VEGF itself may have caused the macular hole by modulating the activity of the CNV and inducing contraction of the vascular membrane, leading to exacerbation of tangential traction on the overlying retina. I believe that, in CNV eyes with evidence of VMT, one should always consider not only the risk of resistance to anti-VEGF therapy but also additional and unusual complications, such as the development of lamellar or full-thickness macular hole, before treating by anti-VEGF injection. Considering all the aspects of treating CNV eyes with preexisting VMT, I wish to know the opinion of the authors in advocating primary epiretinal surgery in such eyes.
REPLY WE THANK DR QUERQUES FOR HIS INTEREST IN OUR ARTI-
cle. We appreciate his comments and insights and the issue he has raised. The evidence in our study that the vitreous plays a role in the pathogenesis of age-related macular degeneration (AMD) has recently been further supported.1 In a recent study, Chang and associates examined the ultrastructural correlates of spectral-domain optical coherence tomography (SD-OCT) findings in patients with vitreomacular traction syndrome (VMT). Interestingly, the adhesion between the vitreous and fovea in studied eyes was accompanied by fibrocellular proliferation along the exposed surfaces of the inner retina and the posterior surface of the vitreous. On OCT, each eye had an epiretinal membrane (ERM) under the detached perifoveal posterior vitreous detachment. This ERM appeared to course up the cone of attached vitreous and along the back surface of the posterior vitreous face.2 These findings suggest an augmented adhesion between the vitreous and the fovea. We also noted in our series an increased reflectivity and thickness of the partially detached hyaloid when VMT was present. We can speculate that the undergoing chronic inflammation associated with AMD may be partially responsible of an even increased cellular proliferation in this population of patients. Repeated intravitreal injections can indeed promote a complete vitreous detachment, but in cases of abnormal adhesion, the higher risk of focal retinal damage should definitely be considered. We believe that Dr Querques’ observation of macular hole development during anti-vascular endothelial growth factor (VEGF) treatment course is of interest and supports these findings; it deserves additional attention, particularly in a possible prospective neo-adjuvant surgical (or even pharmacological) approach to the vitreoretinal interface of these patients. We performed a cross-sectional and not a longitudinal study, but we also reported a case in which a focal VMT spontaneously released after intravitreal anti-VEGF administration. Because of the small number of cases treated with surgery in our study, we have not advocated surgery as first approach in
GIUSEPPE QUERQUES
Foggia, Italy
REFERENCES
1. Mojana F, Cheng L, Bartsch DU, et al. The role of abnormal vitreomacular adhesion in age-related macular degeneration: spectral optical coherence tomography and surgical results. Am J Ophthalmol 2008;146:218 –227. 2. Weber-Krause B, Eckardt U. [Incidence of posterior vitreous detachment in eyes with and without age-related macular degeneration. An ultrasonic study]. Ophthalmologe 1996;93: 660 – 665.
376
AMERICAN JOURNAL
OF
OPHTHALMOLOGY
FEBRUARY 2009
Bethesda, Maryland VOL. 147, NO. 2
REFERENCES
1. Binder SR. Autoantibody detection using multiplex technologies. Lupus 2006;15:412– 421. 2. Fritzler MJ. Advances and applications of multiplexed diagnostic technologies in autoimmune diseases. Lupus 2006;15: 422– 427. 3. Burbelo PD, Ching KH, Mattson TL, et al. Rapid antibody quantification and generation of whole proteome antibody response profiles using LIPS (luciferase immunoprecipitation systems). Biochem Biophys Res Commun 2007;352: 889 – 895. 4. Burbelo PD, Goldman R, Mattson TL. A simplified immunoprecipitation method for quantitatively measuring antibody responses in clinical sera samples by using mammalian-produced Renilla luciferase-antigen fusion proteins. BMC Biotechnol 2005;5:22. 5. Ramanathan R, Burbelo PD, Groot S, et al. A luciferase immunoprecipitation systems assay enhances the sensitivity and specificity of diagnosis of Strongyloides stercoralis infection. J Infect Dis 2008;198:444 – 451.
Anti-Vascular Endothelial Growth Factor Injection for Exudative Age-related Macular Degeneration in Patients with Vitreo-Macular Traction EDITOR: I READ WITH INTEREST THE ARTICLE BY MOJANA AND
associates1 on the role of abnormal vitreomacular adhesion in age-related macular degeneration (AMD). Several authors, using ultrasound and optical coherence tomography (OCT), showed that there is a higher rate of vitreomacular adhesion in AMD.2– 4 Moreover, a high incidence of posterior vitreous attachment was intraoperatively observed by different authors.5 These data seem to suggest that the vitreous may play a role in the pathogenesis and/or progression of AMD. Different hypothesis have been formulated to explain the role of vitreomacular adhesion in AMD, focusing on both mechanical and biochemical factors.3 Based on the hypothesis that a local inflammation induced by AMD may be responsible for focal corresponding adhesion (potentially inducing tractional forces on the retina), the authors wished to determine the frequency of persistent hyaloid adherence to the posterior pole in patients with AMD, using high-resolution spectral-domain OCT.1 I am impressed with the image quality presented by the authors (even in a 3-dimensional configuration), and I congratulate with them for having clearly shown the vitreomacular traction (VMT) in the exudative AMD cases reported. It is interesting the higher incidence of tractional configuration of the attached posterior hyaloid in eyes with exudative AMD that the authors found in
CORRESPONDENCE
375
3. Ondes F, Yilmaz G, Acar MA, et al. Role of the vitreous in age-related macular degeneration. Jpn J Ophthalmol 2000;44: 91–93. 4. Krebs I, Brannath W, Glittenberg C, et al. Posterior vitreomacular adhesion: a potential risk factor for exudative agerelated macular degeneration? Am J Ophthalmol 2007;144: 741–746. 5. Lambert HM, Capone A, Aaberg TM, et al. Surgical excision of subfoveal neovascular membranes in age-related macular degeneration. Am J Ophthalmol 1992;113:257–262. 6. Querques G, Souied EH, Soubrane G. Macular hole following intravitreal ranibizumab injection for choroidal neovascular membrane due to age-related macular degeneration. Acta Ophthalmol Scand. Forthcoming.
their study compared with non-AMD eyes, and also the concentric configuration of the VMT to the choroidal neovascularization (CNV), suggesting a causal relationship. Based on these findings, the authors propose that persistent low grade of local inflammation in AMD patients (chronic disease), is likely to induce structural changes at the level of the vitreoretinal interface. The resulting anterior-posterior forces, present at the surface of the retina, may exacerbate the macular edema, which originally occurs secondary to the presence of leaking vessels in the CNV complex. In agreement with the authors, I also believe that there may be a subpopulation of CNV eyes that do not respond to anti-vascular endothelial growth factor (VEGF) therapy, in which VMT may play a component in the resistance to such therapy. Moreover, I believe that in these CNV eyes, additional and unusual complications related to the anti-VEGF injection may develop because of VMT. We recently reported on a patient with VMT and subfoveal CNV attributable to AMD, who developed macular hole following treatment with intravitreal injection of anti-VEGF.6 Since then, in our practice, we encountered several cases with preinjection evidence of VMT, in which a lamellar or full thickness macular hole developed following treatment with intravitreal injection of anti-VEGF. In these patients, several possible mechanisms may have induced the development of macular hole. The intravitreal injection may have induced vitreous incarceration, causing vitreoretinal traction leading to development of a macular hole. The anti-VEGF itself may have caused the macular hole by modulating the activity of the CNV and inducing contraction of the vascular membrane, leading to exacerbation of tangential traction on the overlying retina. I believe that, in CNV eyes with evidence of VMT, one should always consider not only the risk of resistance to anti-VEGF therapy but also additional and unusual complications, such as the development of lamellar or full-thickness macular hole, before treating by anti-VEGF injection. Considering all the aspects of treating CNV eyes with preexisting VMT, I wish to know the opinion of the authors in advocating primary epiretinal surgery in such eyes.
REPLY WE THANK DR QUERQUES FOR HIS INTEREST IN OUR ARTI-
cle. We appreciate his comments and insights and the issue he has raised. The evidence in our study that the vitreous plays a role in the pathogenesis of age-related macular degeneration (AMD) has recently been further supported.1 In a recent study, Chang and associates examined the ultrastructural correlates of spectral-domain optical coherence tomography (SD-OCT) findings in patients with vitreomacular traction syndrome (VMT). Interestingly, the adhesion between the vitreous and fovea in studied eyes was accompanied by fibrocellular proliferation along the exposed surfaces of the inner retina and the posterior surface of the vitreous. On OCT, each eye had an epiretinal membrane (ERM) under the detached perifoveal posterior vitreous detachment. This ERM appeared to course up the cone of attached vitreous and along the back surface of the posterior vitreous face.2 These findings suggest an augmented adhesion between the vitreous and the fovea. We also noted in our series an increased reflectivity and thickness of the partially detached hyaloid when VMT was present. We can speculate that the undergoing chronic inflammation associated with AMD may be partially responsible of an even increased cellular proliferation in this population of patients. Repeated intravitreal injections can indeed promote a complete vitreous detachment, but in cases of abnormal adhesion, the higher risk of focal retinal damage should definitely be considered. We believe that Dr Querques’ observation of macular hole development during anti-vascular endothelial growth factor (VEGF) treatment course is of interest and supports these findings; it deserves additional attention, particularly in a possible prospective neo-adjuvant surgical (or even pharmacological) approach to the vitreoretinal interface of these patients. We performed a cross-sectional and not a longitudinal study, but we also reported a case in which a focal VMT spontaneously released after intravitreal anti-VEGF administration. Because of the small number of cases treated with surgery in our study, we have not advocated surgery as first approach in
GIUSEPPE QUERQUES
Foggia, Italy
REFERENCES
1. Mojana F, Cheng L, Bartsch DU, et al. The role of abnormal vitreomacular adhesion in age-related macular degeneration: spectral optical coherence tomography and surgical results. Am J Ophthalmol 2008;146:218 –227. 2. Weber-Krause B, Eckardt U. [Incidence of posterior vitreous detachment in eyes with and without age-related macular degeneration. An ultrasonic study]. Ophthalmologe 1996;93: 660 – 665.
376
AMERICAN JOURNAL
OF
OPHTHALMOLOGY
FEBRUARY 2009