- Email: [email protected]
Pulsar Perimetry in the Diagnosis of Early Glaucoma
4. Kondo N, Honda S, Ishibashi K, Tsukahara Y, Negi A. Elastin gene polymorphisms in neovascular age-related macular degeneration and polypoidal choroidal vasculopathy. Invest Ophthalmol Vis Sci 2008;49(3):1101–1105. 5. Neale BM, Fagerness J, Reynolds R, et al. Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC). Proc Natl Acad Sci U S A 2010;107(16):7395–7400.
higher in the exudative type of AMD and the polypoidal choroidal vasculopathy (PCV) groups than in the control group (exudative AMD vs control, P ⫽ 3.1 ⫻ 10⫺8; PCV vs control, P ⫽ 6.9 ⫻ 10⫺3). The distribution of ARMS2 SNPs in the AMD subjects in our study is in agreement with earlier findings. It has been suggested that the exudative type of AMD results from a defect in the elastic lamina in the Bruch membrane, which would then stimulate the development of a choroidal neovascularization (CNV). This was supported by the recent report that the elastic lamina of the Bruch membrane was more fragmented and less continuous in a LOXL1 knockout mouse. In addition, the CNVs induced by laser photocoagulation in these mice were grew more aggressively.3 It was suggested that the elastin gene (ELN) may be involved in the phenotypic expression of neovascular AMD and PCV.4 Nevertheless, the factors that underlie why some subjects develop the more aggressive exudative AMD, while others the dry AMD, are not well understood. Thus, the purpose of our study was to investigate the gene that influences the phenotype of the AMD and not the prevalence of AMD. It is correct that a recent genome-wide association study (GWAS) did not reveal a positive association between exudative AMD and LOXL1 gene locus mapped on 15q24.1,5 but in general GWAS cannot detect modifier genes. As for LOXL1 SNP rs1048661, the allele frequency of the T variant was not significantly different between cases with AMD from the controls (major allele frequency T ⫽ 0.620 in exudative AMD and T ⫽ 0.507 in controls). However, in the T/T homozygote in exudative AMD case, 6 out of 22 cases showed the massive subretinal hemorrhage due to neovascularization. Thus, there is the possibility that the LOXL1 locus could be a modifier locus affecting the integrity of the Bruch membrane and lead to more aggressive CNV growth. Again, we thank Drs Sakurada and Iijima for their interest and comments.
Pulsar Perimetry in the Diagnosis of Early Glaucoma EDITOR: IN A RECENTLY PUBLISHED ARTICLE,1 ZEPPIERI AND ASSOCI-
ates affirm that Pulsar perimetry shows lower sensitivity than other procedures for the diagnosis of glaucoma in cases where morphologic defect precedes functional defect (glaucomatous optic neuropathy; GON). However, the optic nerve head size of patients in the GON group is clearly larger (2.13 ⫾ 0.46 mm2) than that of normal reference subjects (1.81 ⫾ 0.51 mm2), which raises the suspicion that many patients in the GON group were not in fact glaucomatous. This suspicion is heightened by the fact that 43.7% of the group with ocular hypertension (OHT) presented an abnormal disc area, as shown in Figures 3 and 4. The influence of disc area in glaucoma is minimal or irrelevant, and larger disc area is known to be significantly associated with decreased specificity of Heidelberg Retina Tomograph (HRT) results.2 It is therefore evident that an abnormal appearance of the optic nerve head due to its size influenced the inclusion of false cases in the OHT group. It is highly likely that the same occurred with the inclusion of patients in the GON group, who presented much greater optic nerve head size and, therefore, more pronounced cupping. In addition, the “best cut-off” point selected by the authors in their receiver operating characteristic (ROC) curve analysis is, apparently, the point of greatest equilibrium between sensitivity and specificity. The choice of this cut-off point is important since some of the authors’ main conclusions are based on it. Unfortunately, it leads to some clearly biased and erroneous results. For example, in Tables 3 and 4,1 the cut-off point for the disc area yields a sensitivity of nearly 60% for the diagnosis of glaucoma, which is clearly untenable. It is widely accepted that the early diagnosis of glaucoma should be established using criteria of high specificity. If not, a large number of normal subjects would be erroneously considered as cases of suspected glaucoma and treated unnecessarily. This error is clearly more serious than delaying the diagnosis of suspected glaucoma, which should be periodically evaluated. A regularly monitored patient can easily be correctly treated as from an early phase of the disease.
NOBUO FUSE TOSHIAKI ABE
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 e551. 2. Fritsche LG, Loenhardt T, Janssen A, et al. Age-related macular degeneration is associated with an unstable ARMS2 (LOC387715) mRNA. Nat Genet 2008;40(7):892– 896. 3. Yu HG, Liu X, Kiss S, et al. Increased choroidal neovascularization following laser induction in mice lacking lysyl oxidaselike 1. Invest Ophthalmol Vis Sci 2008;49(6):2599 –2605.
500
AMERICAN JOURNAL
OF
OPHTHALMOLOGY
SEPTEMBER
2011
Tables 3 and 4 indicate that, for a specificity of 95%, Pulsar proved more sensitive than frequency doubling technology (FDT), even in the GON group, and much more sensitive than GDx, a procedure less dependent on disc area3 that theoretically should show early alterations in patients with GON. At this level of specificity, the results obtained with HRT, although probably subject to diagnostic bias, are not significantly better than those obtained with Pulsar. Given these considerations, the authors’ affirmation of GON patients’ being an exception regarding the advantages of Pulsar perimetry for the early diagnosis of glaucoma is probably misguided. MANUEL GONZALEZ DE LA ROSA
Santa Cruz de Tenerife, Spain
REFERENCES
1. Zeppieri M, Brusini P, Parisi L, Johnson CA, Sampaolesi R, Salvetat ML. Pulsar perimetry in the diagnosis of early glaucoma. Am J Ophthalmol 2010;149(1):102–112. 2. Saito H, Tsutsumi T, Araie M, Tomidokoro A, Iwase A. Sensitivity and specificity of the Heidelberg Retina Tomograph II Version 3.0 in a population-based study: the Tajimi Study. Ophthalmology 2009;116(10):1854 –1861. 3. Laemmer R, Horn FK, Viestenz A, Juenemann AG, Mardin CY. Influence of optic disc size on parameters of retinal nerve fiber analysis with laser scanning polarimetry. Graefes Arch Clin Exp Ophthalmol 2006;244(5):603– 608.
REPLY WE THANK PROF GONZALES DE LA ROSA FOR THE COM-
ments regarding our paper.1 Agreement on issues among different laboratories can sometimes be problematic. When reputable laboratories disagree, it is usually not because one is right and the other is wrong. Rather, it is because there are differences in the manner in which each group views the problem, how they interpret the items under investigation, their prior experience, and the results of other investigators. We believe that our system of evaluating the merit and validity of scientific and clinical research is fair and provides the best current method of determining whether a research project is worthy of publication or not. Additionally, we believe in other factors in conducting research: 1) results by the inventor are usually better than those obtained by others who have no conflict of interest; 2) collaboration with others is advantageous; 3) critical peer review is a fair and just means of evaluating research; and 4) disagreements among different laboratories can be positive. Experiments and results are more powerful and compelling than arguments. Prof Gonzales de la Rosa raised the suspicion that many patients with glaucomatous optic neuropathy (GON) were false positives, considering the greater optic disc size VOL. 152, NO. 3
compared to normals (2.13 vs 1.81 mm2). The average optic disc size based on the Heidelberg Retina Tomograph (HRT) database is 1.6 to 2.6 mm2; thus differences within this range are probably unlikely to bias the inclusion criteria. Moreover, GON was based on masked consensus grading by expert graders (all experienced senior glaucoma specialists), with adjudication by a third, and all GON eyes showed at least 1 typical glaucomatous sign. The relationship between optic disc size and glaucoma is complex. It is quite common to find greater disc areas in glaucoma and GON groups compared to controls in glaucoma studies.2– 4 Larger optic discs increase the likelihood of diagnosis.5 Studies have reported that large optic discs may be more susceptible to glaucomatous damage based on biomechanical properties.6 Our comment regarding the fair diagnostic ability of Pulsar in GON eyes was based on area under the receiver operating characteristic curve (ROC) values in different groups and not with other instruments. We are not in agreement with Prof Gonzales de la Rosa’s view that “it is widely accepted that the early diagnosis of glaucoma should be established using criteria of high specificity.” This may be true for population screening, but not in patients with suspect glaucoma where high sensitivity may be preferred over excellent specificity. In summary, we stand by our published results and are confident that our collaborative efforts, acceptance through the peer review process, and comments from other laboratories are supportive of this work. However, we also encourage other laboratories and investigators who have no direct or indirect financial or other conflicting interest in this device to pursue further research in this area. In this view, we believe that this can serve as a challenge and an opportunity for other investigators to pursue issues related to Pulsar perimetry. MARCO ZEPPIERI
Udine, Italy, and Portland, Oregon PAOLO BRUSINI
Udine, Italy CHRIS A. JOHNSON
Portland, Oregon, and Iowa City, Iowa MARIA LETIZIA SALVETAT
Udine, Italy
REFERENCES
1. Zeppieri M, Brusini P, Parisi L, Johnson CA, Sampaolesi R, Salvetat ML. Pulsar perimetry in the diagnosis of early glaucoma. Am J Ophthalmol 2010;149(1):102–112. 2. Tuulonen A, Airaksinen PJ. Optic disc size in exfoliative, primary open angle, and low-tension glaucoma. Arch Ophthalmol 1992;110(2):211–213. 3. Healey PR, Mitchell P. Optic disk size in open-angle glaucoma: The Blue Mountains Eye Study. Am J Ophthalmol 1999;128(4):515–517.
CORRESPONDENCE
501
higher in the exudative type of AMD and the polypoidal choroidal vasculopathy (PCV) groups than in the control group (exudative AMD vs control, P ⫽ 3.1 ⫻ 10⫺8; PCV vs control, P ⫽ 6.9 ⫻ 10⫺3). The distribution of ARMS2 SNPs in the AMD subjects in our study is in agreement with earlier findings. It has been suggested that the exudative type of AMD results from a defect in the elastic lamina in the Bruch membrane, which would then stimulate the development of a choroidal neovascularization (CNV). This was supported by the recent report that the elastic lamina of the Bruch membrane was more fragmented and less continuous in a LOXL1 knockout mouse. In addition, the CNVs induced by laser photocoagulation in these mice were grew more aggressively.3 It was suggested that the elastin gene (ELN) may be involved in the phenotypic expression of neovascular AMD and PCV.4 Nevertheless, the factors that underlie why some subjects develop the more aggressive exudative AMD, while others the dry AMD, are not well understood. Thus, the purpose of our study was to investigate the gene that influences the phenotype of the AMD and not the prevalence of AMD. It is correct that a recent genome-wide association study (GWAS) did not reveal a positive association between exudative AMD and LOXL1 gene locus mapped on 15q24.1,5 but in general GWAS cannot detect modifier genes. As for LOXL1 SNP rs1048661, the allele frequency of the T variant was not significantly different between cases with AMD from the controls (major allele frequency T ⫽ 0.620 in exudative AMD and T ⫽ 0.507 in controls). However, in the T/T homozygote in exudative AMD case, 6 out of 22 cases showed the massive subretinal hemorrhage due to neovascularization. Thus, there is the possibility that the LOXL1 locus could be a modifier locus affecting the integrity of the Bruch membrane and lead to more aggressive CNV growth. Again, we thank Drs Sakurada and Iijima for their interest and comments.
Pulsar Perimetry in the Diagnosis of Early Glaucoma EDITOR: IN A RECENTLY PUBLISHED ARTICLE,1 ZEPPIERI AND ASSOCI-
ates affirm that Pulsar perimetry shows lower sensitivity than other procedures for the diagnosis of glaucoma in cases where morphologic defect precedes functional defect (glaucomatous optic neuropathy; GON). However, the optic nerve head size of patients in the GON group is clearly larger (2.13 ⫾ 0.46 mm2) than that of normal reference subjects (1.81 ⫾ 0.51 mm2), which raises the suspicion that many patients in the GON group were not in fact glaucomatous. This suspicion is heightened by the fact that 43.7% of the group with ocular hypertension (OHT) presented an abnormal disc area, as shown in Figures 3 and 4. The influence of disc area in glaucoma is minimal or irrelevant, and larger disc area is known to be significantly associated with decreased specificity of Heidelberg Retina Tomograph (HRT) results.2 It is therefore evident that an abnormal appearance of the optic nerve head due to its size influenced the inclusion of false cases in the OHT group. It is highly likely that the same occurred with the inclusion of patients in the GON group, who presented much greater optic nerve head size and, therefore, more pronounced cupping. In addition, the “best cut-off” point selected by the authors in their receiver operating characteristic (ROC) curve analysis is, apparently, the point of greatest equilibrium between sensitivity and specificity. The choice of this cut-off point is important since some of the authors’ main conclusions are based on it. Unfortunately, it leads to some clearly biased and erroneous results. For example, in Tables 3 and 4,1 the cut-off point for the disc area yields a sensitivity of nearly 60% for the diagnosis of glaucoma, which is clearly untenable. It is widely accepted that the early diagnosis of glaucoma should be established using criteria of high specificity. If not, a large number of normal subjects would be erroneously considered as cases of suspected glaucoma and treated unnecessarily. This error is clearly more serious than delaying the diagnosis of suspected glaucoma, which should be periodically evaluated. A regularly monitored patient can easily be correctly treated as from an early phase of the disease.
NOBUO FUSE TOSHIAKI ABE
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 e551. 2. Fritsche LG, Loenhardt T, Janssen A, et al. Age-related macular degeneration is associated with an unstable ARMS2 (LOC387715) mRNA. Nat Genet 2008;40(7):892– 896. 3. Yu HG, Liu X, Kiss S, et al. Increased choroidal neovascularization following laser induction in mice lacking lysyl oxidaselike 1. Invest Ophthalmol Vis Sci 2008;49(6):2599 –2605.
500
AMERICAN JOURNAL
OF
OPHTHALMOLOGY
SEPTEMBER
2011
Tables 3 and 4 indicate that, for a specificity of 95%, Pulsar proved more sensitive than frequency doubling technology (FDT), even in the GON group, and much more sensitive than GDx, a procedure less dependent on disc area3 that theoretically should show early alterations in patients with GON. At this level of specificity, the results obtained with HRT, although probably subject to diagnostic bias, are not significantly better than those obtained with Pulsar. Given these considerations, the authors’ affirmation of GON patients’ being an exception regarding the advantages of Pulsar perimetry for the early diagnosis of glaucoma is probably misguided. MANUEL GONZALEZ DE LA ROSA
Santa Cruz de Tenerife, Spain
REFERENCES
1. Zeppieri M, Brusini P, Parisi L, Johnson CA, Sampaolesi R, Salvetat ML. Pulsar perimetry in the diagnosis of early glaucoma. Am J Ophthalmol 2010;149(1):102–112. 2. Saito H, Tsutsumi T, Araie M, Tomidokoro A, Iwase A. Sensitivity and specificity of the Heidelberg Retina Tomograph II Version 3.0 in a population-based study: the Tajimi Study. Ophthalmology 2009;116(10):1854 –1861. 3. Laemmer R, Horn FK, Viestenz A, Juenemann AG, Mardin CY. Influence of optic disc size on parameters of retinal nerve fiber analysis with laser scanning polarimetry. Graefes Arch Clin Exp Ophthalmol 2006;244(5):603– 608.
REPLY WE THANK PROF GONZALES DE LA ROSA FOR THE COM-
ments regarding our paper.1 Agreement on issues among different laboratories can sometimes be problematic. When reputable laboratories disagree, it is usually not because one is right and the other is wrong. Rather, it is because there are differences in the manner in which each group views the problem, how they interpret the items under investigation, their prior experience, and the results of other investigators. We believe that our system of evaluating the merit and validity of scientific and clinical research is fair and provides the best current method of determining whether a research project is worthy of publication or not. Additionally, we believe in other factors in conducting research: 1) results by the inventor are usually better than those obtained by others who have no conflict of interest; 2) collaboration with others is advantageous; 3) critical peer review is a fair and just means of evaluating research; and 4) disagreements among different laboratories can be positive. Experiments and results are more powerful and compelling than arguments. Prof Gonzales de la Rosa raised the suspicion that many patients with glaucomatous optic neuropathy (GON) were false positives, considering the greater optic disc size VOL. 152, NO. 3
compared to normals (2.13 vs 1.81 mm2). The average optic disc size based on the Heidelberg Retina Tomograph (HRT) database is 1.6 to 2.6 mm2; thus differences within this range are probably unlikely to bias the inclusion criteria. Moreover, GON was based on masked consensus grading by expert graders (all experienced senior glaucoma specialists), with adjudication by a third, and all GON eyes showed at least 1 typical glaucomatous sign. The relationship between optic disc size and glaucoma is complex. It is quite common to find greater disc areas in glaucoma and GON groups compared to controls in glaucoma studies.2– 4 Larger optic discs increase the likelihood of diagnosis.5 Studies have reported that large optic discs may be more susceptible to glaucomatous damage based on biomechanical properties.6 Our comment regarding the fair diagnostic ability of Pulsar in GON eyes was based on area under the receiver operating characteristic curve (ROC) values in different groups and not with other instruments. We are not in agreement with Prof Gonzales de la Rosa’s view that “it is widely accepted that the early diagnosis of glaucoma should be established using criteria of high specificity.” This may be true for population screening, but not in patients with suspect glaucoma where high sensitivity may be preferred over excellent specificity. In summary, we stand by our published results and are confident that our collaborative efforts, acceptance through the peer review process, and comments from other laboratories are supportive of this work. However, we also encourage other laboratories and investigators who have no direct or indirect financial or other conflicting interest in this device to pursue further research in this area. In this view, we believe that this can serve as a challenge and an opportunity for other investigators to pursue issues related to Pulsar perimetry. MARCO ZEPPIERI
Udine, Italy, and Portland, Oregon PAOLO BRUSINI
Udine, Italy CHRIS A. JOHNSON
Portland, Oregon, and Iowa City, Iowa MARIA LETIZIA SALVETAT
Udine, Italy
REFERENCES
1. Zeppieri M, Brusini P, Parisi L, Johnson CA, Sampaolesi R, Salvetat ML. Pulsar perimetry in the diagnosis of early glaucoma. Am J Ophthalmol 2010;149(1):102–112. 2. Tuulonen A, Airaksinen PJ. Optic disc size in exfoliative, primary open angle, and low-tension glaucoma. Arch Ophthalmol 1992;110(2):211–213. 3. Healey PR, Mitchell P. Optic disk size in open-angle glaucoma: The Blue Mountains Eye Study. Am J Ophthalmol 1999;128(4):515–517.
CORRESPONDENCE
501