- Email: [email protected]
Intravitreal Injection of Autologous Plasmin Enzyme for Macular Edema Associated With Branch Retinal Vein Occlusion
Asia and Europe to better define the role of LOXL1 in the susceptibility to AMD.
AMD, the factors that explain why some individuals develop the more aggressive exudative AMD while others have the dry AMD type have not been definitively determined. The allele frequency of the T variant of LOXL1 SNP, rs1048661, in Lepre and associates’ study was not significantly different from that in our study. However, the 6 out of 22 cases of T/T homozygote in the exudative AMD cases had massive subretinal hemorrhages, that is, the more severe phenotype. Thus, our findings suggest that the LOXL1 locus could be a modifier for the growth of the choroidal neovascularization. We agree that the small sample size in our study was a limitation, as we stated in our manuscript, and we could not exclude the possibility of false positives. However, the purpose of our study was to investigate the association between the major AMD gene ARMS2 and the modifier gene in Japanese patients with dry AMD, exudative AMD, and polypoidal choroidal vasculopathy. We had hope that this study would shed light on the effect of this modifier locus on the genetics of AMD.
TIZIANA LEPRE RAFFAELLA CASCELLA FILIPPO MISSIROLI CECILIA DE FELICI FABIANA TAGLIA STEFANIA ZAMPATTI ANDREA CUSUMANO FEDERICO RICCI EMILIANO GIARDINA
Rome, Italy CHIARA MARIA EANDI
Torino, Italy GIUSEPPE NOVELLI
Rome, Italy, and Little Rock, Arkansas
REFERENCES
NOBUO FUSE TOSHIAKI ABE
1. Fuse N, Mengkegale M, Miyazawa A, et al. Polymorphisms in ARMS2 (LOC387715) and LOXL1 genes in the Japanese with age-related macular degeneration. Am J Ophthalmol 2011;151(3):550 –556. 2. Ricci F, Zampatti S, D’Abbruzzi F, et al. Typing of ARMS2 and CFH in age-related macular degeneration: case-control study and assessment of frequency in the Italian population. Arch Ophthalmol 2009;127(10):1368 –1372. 3. Rao KN, Ritch R, Dorairaj SK, et al. Exfoliation syndrome and exfoliation glaucoma-associated LOXL1 variations are not involved in pigment dispersion syndrome and pigmentary glaucoma. Mol Vis 2008;9(14)1254 –1262. 4. Ikegami H, Fujisawa T, Kawabata Y, et al. Genetics of type 1 diabetes: similarities and differences between Asian and Caucasian populations. Ann N Y Acad Sci 2006;1079:51–59. 5. Patterson K. 1000 GENOMES: a world of variation. Circ Res 2011;4;108(5):534-536.
Sendai, Japan KOHJI NISHIDA
Osaka, Japan
REFERENCES
1. Fuse N, Mengkegale M, Miyazawa A, et al. Polymorphisms in ARMS2 (LOC387715) and LOXL1 genes in the Japanese with age-related macular degeneration. Am J Ophthalmol 2011;151(3):550 –556. 2. Klaver CC, Kliffen M, van Duijn CM, et al. Genetic association of apolipoprotein E with age-related macular degeneration. Am J Hum Genet 1998;63(1):200 –206. 3. Seddon JM, Cote J, Page WF, Aggen SH, Neale MC. The US twin study of age-related macular degeneration: relative roles of genetic and environmental influences. Arch Ophthalmol 2005;123(3):321–327. 4. Seddon JM, George S, Rosner B, Klein ML. CFH gene variant, Y402H, and smoking, body mass index, environmental associations with advanced age-related macular degeneration. Hum Hered 2006;61(3):157–165. 5. Oshima Y, Ishibashi T, Murata T, Tahara Y, Kiyohara Y, Kubota T. Prevalence of age related maculopathy in a representative Japanese population: the Hisayama study. Br J Ophthalmol 2001;85(10):1153–1157.
REPLY WE THANK LEPRE AND ASSOCIATES FOR THEIR INTEREST IN
and comments to our recent article.1 Our study was a screening study for genes significantly associated with age-related macular degeneration (AMD). In Lepre and associates’ study, they typed 974 Italian subjects including 342 patients with diagnosis of AMD. With this large number, they had good statistical power to evaluate their findings. AMD is a complex disorder that is genetically associated with many susceptibility loci. Both genetic predisposition and environmental factors play important roles in the pathogenesis of AMD.2– 4 In Western countries, dry AMD is more common than the exudative type, but exudative AMD is more common in the Japanese.5 In addition, there are substantial differences in the disease phenotype and different frequencies of single nucleotide polymorphisms (SNPs) between these 2 groups. In multifactorial diseases, such as 326
AMERICAN JOURNAL
Intravitreal Injection of Autologous Plasmin Enzyme for Macular Edema Associated With Branch Retinal Vein Occlusion EDITOR: WE READ WITH SPECIAL INTEREST THE ARTICLE BY SAKUMA
and associates describing the results of intravitreal autoloOF
OPHTHALMOLOGY
AUGUST
2011
gous plasmin enzyme for macular edema in branch vein occlusion.1 Our clinical research has focused on the treatment of retinal disorders with autologous plasmin enzyme (APE) for the last 4 years. We have already published the favorable results obtained with APE in the management of diabetic macular edema and vitreomacular traction syndrome.2– 4 In our research we have also treated cases of macular edema secondary to branch vein occlusion where the vitreous was still attached to the retina, and this seemed to be the cause of the persistence of the edema or its worsening. We use a simplified and modified technique to obtain the plasmin 45 minutes before the injection3,5 compared to the technique used by Sakuma and associates. The concentrations of APE obtained by this simplified method are substantially lower than those obtained by the authors, but they appear to be effective in both inducing posterior vitreous detachment (PVD) and resolving macular edema (the amount of APE obtained with our method was 0.21 IU/0.2 mL on average, measured spectrophotometrically based on the lysis of a chromophoric agent [HD-NVA-CHA-lys-pN]).3 At the moment our experience includes 36 patients with a mean follow-up of 12 months. We observed improvement in visual acuity in 80.5% of patients (25) and 88.8% (34) displayed an important decrease in macular thickness after a single injection of APE. The results appeared to persist at least 6 months after only 1 intravitreal injection of APE. Biomicroscopy and optical coherence tomography confirmed a complete posterior detachment in 66.6% of patients (24). We find of interest the fact that both visual acuity and macular thickness improved even in the cases where PVD was not present. These data suggest that APE could work not only as a fibrinolytic agent and have other effects on the eye. No major side effects have been observed during the follow-up of our patients. We can conclude that APE was effective in the treatment of macular edema associated with branch vein occlusion in our patients, but further studies are needed to confirm its efficacy, actions, and safety. PATRICIA UDAONDO SALVADOR GARCIA-DELPECH DAVID SALOM MARIA GARCIA-POUS MANUEL DÍAZ-LLOPIS
Valencia, Spain
REFERENCES
1. Sakuma T, Mizota A, Inoue J, Takana M. Intravitreal injection of autologous plasmin enzyme for macular edema associated with branch retinal vein occlusion. Am J Ophthalmol 2010;150(6):876 – 882.
VOL. 152, NO. 2
2. Diaz-Llopis M, Udaondo P, Arevalo F, et al. Intravitreal plasmin without associated vitrectomy as a treatment for refractory diabetic macular edema. J Ocul Pharmacol Ther 2009;25(4):379 –384. 3. Díaz-Llopis M, Udaondo P, Cervera E, et al. Enzymatic vitrectomy by intravitreal autologous plasmin injection as initial treatment for macular epiretinal membranes and vitreomacular traction syndrome. Arch Soc Esp Oftalmol 2009; 84(2):91–100. 4. Diaz-Llopis M, Udaondo P, Garcia-Delpech S, Cervera E, Salom D, Quijada A. Enzymatic vitrectomy by autologous plasmin injection, as initial treatment for diffuse diabetic macular edema. Arch Soc Esp Oftalmol 2008;83(2):77– 84. 5. Rizzo S, Pellegrini G, Benocci F, Belting C, Baicchi U, Vispi M. Autologous plasmin for pharmacologic vitreolysis prepared 1 hour before surgery. Retina 2006;26(7):792–796.
REPLY WE APPRECIATE THE INTEREST EXPRESSED IN OUR ARTICLE1
by Udaondo and associates. We also believe that an intravitreal injection of autologous plasmin enzyme (APE) for some retinal disorders has been shown to be safe and effective. Udaondo and associates used a simplified and modified technique to obtain the plasmin 45 minutes before the injection. We also used the kit for the purification of APE that put the original principle1,2 to use (Sakuma T, et al. IOVS, 2006;47:ARVO E-Abstract 4684). The preparatory time for purification of APE is 120 minutes. But we can prepare the safe and highly purified APE, compared to the technique use by Udaondo and associates. The kit can purify about 1 IU of APE in 0.1 mL from 30 mL of autologous blood; samples are incubated for 48 hours to check for contamination before injection. In all vitreoretinal surgery, APE is not used immediately after diagnosing some retinal disorders. It is important to confirm whether surgeons can use APE for some retinal disorders with safety. We attempted to evaluate the benefit of APE-assisted vitrectomy in macular hole, diabetic macular edema, and vitreomacular traction syndrome.3–5 Almost all vitreous detachment is considered to be induced by APE (0.2 IU/0.1 mL). But APE (0.2 IU/0.1 mL) did not always work at strong adhesion between vitreous and retina and therefore we needed highly purified APE (1 IU/0.1 mL). As a result, posterior vitreous detachment (PVD) was confirmed in 88.5% of patients on an intravitreal injection of APE for branch retinal vein occlusion (BRVO).1 Visual acuity improved by 2 lines or more in 23 eyes (88.5%) and the retinal thickness was reduced in all eyes.1 Our observations also showed that 3 eyes without a PVD after the APE injection had good visual and retinal thickness recovery. Thus, we can conclude that the induc-
CORRESPONDENCE
327
AMD, the factors that explain why some individuals develop the more aggressive exudative AMD while others have the dry AMD type have not been definitively determined. The allele frequency of the T variant of LOXL1 SNP, rs1048661, in Lepre and associates’ study was not significantly different from that in our study. However, the 6 out of 22 cases of T/T homozygote in the exudative AMD cases had massive subretinal hemorrhages, that is, the more severe phenotype. Thus, our findings suggest that the LOXL1 locus could be a modifier for the growth of the choroidal neovascularization. We agree that the small sample size in our study was a limitation, as we stated in our manuscript, and we could not exclude the possibility of false positives. However, the purpose of our study was to investigate the association between the major AMD gene ARMS2 and the modifier gene in Japanese patients with dry AMD, exudative AMD, and polypoidal choroidal vasculopathy. We had hope that this study would shed light on the effect of this modifier locus on the genetics of AMD.
TIZIANA LEPRE RAFFAELLA CASCELLA FILIPPO MISSIROLI CECILIA DE FELICI FABIANA TAGLIA STEFANIA ZAMPATTI ANDREA CUSUMANO FEDERICO RICCI EMILIANO GIARDINA
Rome, Italy CHIARA MARIA EANDI
Torino, Italy GIUSEPPE NOVELLI
Rome, Italy, and Little Rock, Arkansas
REFERENCES
NOBUO FUSE TOSHIAKI ABE
1. Fuse N, Mengkegale M, Miyazawa A, et al. Polymorphisms in ARMS2 (LOC387715) and LOXL1 genes in the Japanese with age-related macular degeneration. Am J Ophthalmol 2011;151(3):550 –556. 2. Ricci F, Zampatti S, D’Abbruzzi F, et al. Typing of ARMS2 and CFH in age-related macular degeneration: case-control study and assessment of frequency in the Italian population. Arch Ophthalmol 2009;127(10):1368 –1372. 3. Rao KN, Ritch R, Dorairaj SK, et al. Exfoliation syndrome and exfoliation glaucoma-associated LOXL1 variations are not involved in pigment dispersion syndrome and pigmentary glaucoma. Mol Vis 2008;9(14)1254 –1262. 4. Ikegami H, Fujisawa T, Kawabata Y, et al. Genetics of type 1 diabetes: similarities and differences between Asian and Caucasian populations. Ann N Y Acad Sci 2006;1079:51–59. 5. Patterson K. 1000 GENOMES: a world of variation. Circ Res 2011;4;108(5):534-536.
Sendai, Japan KOHJI NISHIDA
Osaka, Japan
REFERENCES
1. Fuse N, Mengkegale M, Miyazawa A, et al. Polymorphisms in ARMS2 (LOC387715) and LOXL1 genes in the Japanese with age-related macular degeneration. Am J Ophthalmol 2011;151(3):550 –556. 2. Klaver CC, Kliffen M, van Duijn CM, et al. Genetic association of apolipoprotein E with age-related macular degeneration. Am J Hum Genet 1998;63(1):200 –206. 3. Seddon JM, Cote J, Page WF, Aggen SH, Neale MC. The US twin study of age-related macular degeneration: relative roles of genetic and environmental influences. Arch Ophthalmol 2005;123(3):321–327. 4. Seddon JM, George S, Rosner B, Klein ML. CFH gene variant, Y402H, and smoking, body mass index, environmental associations with advanced age-related macular degeneration. Hum Hered 2006;61(3):157–165. 5. Oshima Y, Ishibashi T, Murata T, Tahara Y, Kiyohara Y, Kubota T. Prevalence of age related maculopathy in a representative Japanese population: the Hisayama study. Br J Ophthalmol 2001;85(10):1153–1157.
REPLY WE THANK LEPRE AND ASSOCIATES FOR THEIR INTEREST IN
and comments to our recent article.1 Our study was a screening study for genes significantly associated with age-related macular degeneration (AMD). In Lepre and associates’ study, they typed 974 Italian subjects including 342 patients with diagnosis of AMD. With this large number, they had good statistical power to evaluate their findings. AMD is a complex disorder that is genetically associated with many susceptibility loci. Both genetic predisposition and environmental factors play important roles in the pathogenesis of AMD.2– 4 In Western countries, dry AMD is more common than the exudative type, but exudative AMD is more common in the Japanese.5 In addition, there are substantial differences in the disease phenotype and different frequencies of single nucleotide polymorphisms (SNPs) between these 2 groups. In multifactorial diseases, such as 326
AMERICAN JOURNAL
Intravitreal Injection of Autologous Plasmin Enzyme for Macular Edema Associated With Branch Retinal Vein Occlusion EDITOR: WE READ WITH SPECIAL INTEREST THE ARTICLE BY SAKUMA
and associates describing the results of intravitreal autoloOF
OPHTHALMOLOGY
AUGUST
2011
gous plasmin enzyme for macular edema in branch vein occlusion.1 Our clinical research has focused on the treatment of retinal disorders with autologous plasmin enzyme (APE) for the last 4 years. We have already published the favorable results obtained with APE in the management of diabetic macular edema and vitreomacular traction syndrome.2– 4 In our research we have also treated cases of macular edema secondary to branch vein occlusion where the vitreous was still attached to the retina, and this seemed to be the cause of the persistence of the edema or its worsening. We use a simplified and modified technique to obtain the plasmin 45 minutes before the injection3,5 compared to the technique used by Sakuma and associates. The concentrations of APE obtained by this simplified method are substantially lower than those obtained by the authors, but they appear to be effective in both inducing posterior vitreous detachment (PVD) and resolving macular edema (the amount of APE obtained with our method was 0.21 IU/0.2 mL on average, measured spectrophotometrically based on the lysis of a chromophoric agent [HD-NVA-CHA-lys-pN]).3 At the moment our experience includes 36 patients with a mean follow-up of 12 months. We observed improvement in visual acuity in 80.5% of patients (25) and 88.8% (34) displayed an important decrease in macular thickness after a single injection of APE. The results appeared to persist at least 6 months after only 1 intravitreal injection of APE. Biomicroscopy and optical coherence tomography confirmed a complete posterior detachment in 66.6% of patients (24). We find of interest the fact that both visual acuity and macular thickness improved even in the cases where PVD was not present. These data suggest that APE could work not only as a fibrinolytic agent and have other effects on the eye. No major side effects have been observed during the follow-up of our patients. We can conclude that APE was effective in the treatment of macular edema associated with branch vein occlusion in our patients, but further studies are needed to confirm its efficacy, actions, and safety. PATRICIA UDAONDO SALVADOR GARCIA-DELPECH DAVID SALOM MARIA GARCIA-POUS MANUEL DÍAZ-LLOPIS
Valencia, Spain
REFERENCES
1. Sakuma T, Mizota A, Inoue J, Takana M. Intravitreal injection of autologous plasmin enzyme for macular edema associated with branch retinal vein occlusion. Am J Ophthalmol 2010;150(6):876 – 882.
VOL. 152, NO. 2
2. Diaz-Llopis M, Udaondo P, Arevalo F, et al. Intravitreal plasmin without associated vitrectomy as a treatment for refractory diabetic macular edema. J Ocul Pharmacol Ther 2009;25(4):379 –384. 3. Díaz-Llopis M, Udaondo P, Cervera E, et al. Enzymatic vitrectomy by intravitreal autologous plasmin injection as initial treatment for macular epiretinal membranes and vitreomacular traction syndrome. Arch Soc Esp Oftalmol 2009; 84(2):91–100. 4. Diaz-Llopis M, Udaondo P, Garcia-Delpech S, Cervera E, Salom D, Quijada A. Enzymatic vitrectomy by autologous plasmin injection, as initial treatment for diffuse diabetic macular edema. Arch Soc Esp Oftalmol 2008;83(2):77– 84. 5. Rizzo S, Pellegrini G, Benocci F, Belting C, Baicchi U, Vispi M. Autologous plasmin for pharmacologic vitreolysis prepared 1 hour before surgery. Retina 2006;26(7):792–796.
REPLY WE APPRECIATE THE INTEREST EXPRESSED IN OUR ARTICLE1
by Udaondo and associates. We also believe that an intravitreal injection of autologous plasmin enzyme (APE) for some retinal disorders has been shown to be safe and effective. Udaondo and associates used a simplified and modified technique to obtain the plasmin 45 minutes before the injection. We also used the kit for the purification of APE that put the original principle1,2 to use (Sakuma T, et al. IOVS, 2006;47:ARVO E-Abstract 4684). The preparatory time for purification of APE is 120 minutes. But we can prepare the safe and highly purified APE, compared to the technique use by Udaondo and associates. The kit can purify about 1 IU of APE in 0.1 mL from 30 mL of autologous blood; samples are incubated for 48 hours to check for contamination before injection. In all vitreoretinal surgery, APE is not used immediately after diagnosing some retinal disorders. It is important to confirm whether surgeons can use APE for some retinal disorders with safety. We attempted to evaluate the benefit of APE-assisted vitrectomy in macular hole, diabetic macular edema, and vitreomacular traction syndrome.3–5 Almost all vitreous detachment is considered to be induced by APE (0.2 IU/0.1 mL). But APE (0.2 IU/0.1 mL) did not always work at strong adhesion between vitreous and retina and therefore we needed highly purified APE (1 IU/0.1 mL). As a result, posterior vitreous detachment (PVD) was confirmed in 88.5% of patients on an intravitreal injection of APE for branch retinal vein occlusion (BRVO).1 Visual acuity improved by 2 lines or more in 23 eyes (88.5%) and the retinal thickness was reduced in all eyes.1 Our observations also showed that 3 eyes without a PVD after the APE injection had good visual and retinal thickness recovery. Thus, we can conclude that the induc-
CORRESPONDENCE
327