Dear Editor:

We read with great interest the recent commentary by Stewart et al [1] describing the evidence of the blood flow disturbances in the pathogenesis of the glaucomatous damage. Although I agree with some of the findings of this excellent review, there are some important points that should be addressed:
1.After reading this article, one may think that there is not evidence that ocular blood flow abnormalities are involved in the pathogenesis of the glaucomatous damage. Different studies, using different devices, point in the same general direction indicating that on average blood flow is decreased in some glaucoma patients, especially in primary open-angle glaucoma (POAG) patients and in patients that progress despite normalized intraocular pressure (IOP) [2]. Furthermore this decrease in blood flow is not confined to the eye alone [3].
2. Many different methods are being used to measure directly or calculate indirectly in vivo ocular blood flow. Although there is not still a single method that can provide all the relevant information in one reading, the development of newer techniques and their corrected use provides the potential for assessing blood flow in humans.
3. On the other hand, the Authors reveal the lack of evidence of a pathogenic link between glaucoma and impaired ocular blood flow. They asked for a long-term prospective study, that includes carefully selected patient groups, with similar baseline demographic and clinical characteristics, but with dissimilar baseline ocular hemodynamics. We published a paper that prospectively investigated the value of color Doppler imaging of the ophthalmic artery and short posterior ciliary arteries in the prognosis of disease progression in patients with POAG. [4] When baseline demographic and clinical characteristics were stratified according to whether the eyes progressed during the 3-year follow-up period, the only parameters to show significant differences were the resistivity index of the ophthalmic artery and the resistivity index of the short posterior ciliary arteries. Our study concluded that poor blood flow in the retrobulbar vessels is closely linked to visual field deterioration in POAG patients.

In conclusion, we think that the understanding of the role of ocular blood flow disturbances in the pathogenesis of glaucoma has improved greatly. We have evidence that ocular blood flow is altered independently from IOP or level of damage in patients with progressive glaucoma, which could represent a primary risk factor for disease progression. In looking forward, we need long-term prospective multicenter studies to evaluate both the impact of ocular blood flow in glaucoma and the benefit of improving ocular blood flow.

References

1. Stewart WC, Feldman R, Mychaskiw MA. Ocular blood flow in glaucoma: the need for further clinical evidence and patient outcomes research. Br J Ophthalmol. 2007; 91: 1263-1264.

2. Flammer J., Orgül S., Costa VP., et al. The impact of ocular blood flow in glaucoma. Prog Retin Eye Res 2002; 21: 359-393.

3. Gasser P, Flammer J. Blood-cell velocity in the nailfold capillaries of patients with normal-tension and high-tension glaucoma. Am J Ophthalmol. 1991; 111: 585-588.

4. Martinez A, Sanchez M. Predictive Value of Color Doppler Imaging in a Prospective Study of Visual Field Progression in Primary Open-Angle Glaucoma. Acta Ophthalmol Scand 2005; 83: 716-723.

Re: van Leeuwen R, Eijkemans MJC, Vingerling JR, Hofman A, de Jong PTVM, Simonsz HJ Risk of bilateral visual impairment in individuals with amblyopia: the Rotterdam study BJO 2007;91 (11): 1450

Josefin Nilsson The negative impact of amblyopia from a population perspective: untreated amblyopia almost doubles the lifetime risk of bilateral visual impairment. BJO 2007;91 (11): 1417

Dear Editor

It is not surprising that amblyopes are at higher risk of bilateral visual impairment since impaired visual functions of the fellow eye have been previously demonstrated. Leguire et al warned that “In future studies of amblyopia, whether in children or in adults, caution is advised in assuming that the nonamblyopic eye is normal because acuity is normal.” [2] Johnson found that both amblyopic and fellow eyes had central scotomata, even after apparently successful treatment, [3] and concluded that “ocular effects of amblyopia may not be strictly limited to the amblyopic eye.” [4] Anomalous optic discs, reduced axial lengths,[5] and anatomic abnormalities involving the axial length to optic disc area have been reported as present to different degrees in amblyopic and fellow eyes.[6,7] Moreover, amblyopia is commonly associated with systemic disorders such as prematurity and low birth weight[8] even in the absence of retinopathy. [9] These anatomic and functional factors put both eyes at risk makes them more susceptible to vision loss.

Nilsson’s editorial implies that lack of screening and treatment of amblyopia cause a lifelong handicap[10] and that treatment offer a significant cost / benefit gain.[11,12] These beliefs employed several unsupported assumptions. Among them is that treatment results in final visual acuity sufficient to perform all tasks and that untreated amblyopia has a financial handicap equivalent to workman’s compensation scales for loss of an eye. Actually, treatment of severe amblyopia rarely results in functionally useful vision.[13] PEDIG studies showed that approximately 25 percent of their treated patients had no or very limited improvement at the end of their initial observation period.[14,15] Initial successes were reduced by an anticipated 50 percent rate of recidivism.[16,17] Furthermore, the assumption that improved Snellen acuity reflects functional improvement is challenged by findings that reading speed is significantly less than normal even when final acuity was comparable with the controls. [18]

A retrospective demographic investigation concluded that “No functionally or clinically significant differences existed between people with and without amblyopia in educational outcomes, behavioral difficulties or social maladjustment, participation in social activities, unintended injuries (school, workplace, or road traffic accidents as driver), general or mental health and mortality, paid employment, or occupation based social class trajectories.”[19]

There is an absolute need for effective allocation of medical resources.[20] Increased bilateral vision impairment among people with initial anatomic ocular defects in both eyes must motivate efforts to prevent those prenatal conditions leading to impaired ocular anatomy.

Respectfully submitted, Philip Lempert, MD

References

1. van Leeuwen R, Eijkemans MJC, Vingerling JR, Hofman A, de Jong PTVM, Simonsz HJ Risk of bilateral visual impairment in individuals with amblyopia: the Rotterdam study BJO 2007;91 (11): 1450
2. Leguire LE, Rogers GL, Bremer DL Amblyopia: the normal eye is not normal. J Pediatr Ophthalmol Strabismus 1990;27(1):32-38
3. Johnson DA Relative scotomata in the "normal" eye of functionally patients. A scanning laser ophthalmoscope (SLO) micreperimetric study. Binocul Vis Strabismus Q. 2007;22(1):17-48.
4. Johnson DA The use of the scanning laser ophthalmoscope in the evaluation of amblyopia (an American Ophthalmological Society thesis). Trans Am Ophthalmol Soc. 2006;104:414-36.
5. Lempert P. Porter L. Dysversion of the optic disc and axial length measurements in a presumed amblyopic population J Amer Acad Ped Ophthalmol Strabismus 1998;2:207-213
6. Lempert P. Axial length – disc area ratio in esotropic amblyopia. Arch Ophthalmol 2003; 121:821-824
7. Lempert P The axial length / disc area ratio in anisometropic hyperopic amblyopia: A hypothesis for decreased unilateral vision associated with hyperopic anisometropia. Ophthalmology 2004:111:304-308
8. Holmström G, M el Azazi M, Kugelberg U Ophthalmological follow up of preterm infants: a population based, prospective study of visual acuity and strabismus Br J Ophthalmol 1999;83:143-150
9. O’Connor AR, Stephenson TJ, Johnson A, Tobin MJ, Ratib S, Moseley M, Fielder AR Visual function in low birthweight children . British Journal of Ophthalmology 2004: 88 (9): 1149 - 1153
10. Josefin Nilsson The negative impact of amblyopia from a population perspective: untreated amblyopia almost doubles the lifetime risk of bilateral visual impairment. BJO 2007;91 (11): 1417
11. Joish VN, Malone DC, Miller JM. A cost-benefit analysis of vision screening methods for preschoolers and school-age children. J AAPOS 2003;7:283-290
12. Membreno JH, Brown MM, Brown GC, Sharma S, Beauchamp GR. A cost- utility analysis of therapy for amblyopia.Ophthalmology. 2002;109(12):2265 -2271.
13. Ingram RM Amblyopia: the need for a new approach Brit J. Ophthalmol 1979:63:236-237
14. PEDIG A randomized trial of atropine vs. patching for treatment of moderate amblyopia in children. Arch Ophthalmol 2002;120:268-278
15. Pediatric Eye Disease Investigator Group. The course of moderate amblyopia treated with patching in children: experience of the amblyopia treatment study. Am J Ophthalmol. 2003;136(4):620-629
16. Simons K. Amblyopia characterization, treatment, and prophylaxis. Surv Ophthalmol. 2005;50(2):123-66
17. Rutstein RP, Fuhr PS Efficacy and stability of amblyopia therapy. Optom Vis Sci 1992;69(10):747-754
18.Stifter E, Burggasser G, Hirmann E, Thaler A, Radner W. Monocular and binocular reading performance in children with microstrabismic amblyopia. Br J Ophthalmol. 2005;89(10):1324-9
19. J S Rahi, P M Cumberland, and C S Peckham Does amblyopia affect educational, health, and social outcomes? Findings from 1958 British birth cohort BMJ 2006; 332: 820-825
20. Woolf SH Potential Health and Economic Consequences of Misplaced Priorities. JAMA 2007;197(5) 523-526

Dear Editor,

We appreciated the paper by Iriyama et al.[1] The authors have investigated the role of anti vascular endothelial growth factor (VEGF) antibodies on retinal ganglion cells in rats. It is an interesting and relevant paper considering the clinical use of anti-VEGF antibodies in a variety of ocular conditions.[2] However, there are a couple of issues that require further clarification.

The authors demonstrate, in figure 1, that bevacizumab (AvastinTM; Genentech Inc. San Francisco, CA) is unable to bind to murine VEGF and they provide evidence by doing Western blot on rat ocular tissue (retina and choroid) using anti-rat VEGF antibody (R&D systems, Minneapolis) and bevacizumab. Membranes were developed using rabbit anti mouse IgG and anti-goat IgG. Authors demonstrate that only anti rat VEGF antibody was able to detect rat VEGF and not bevacizumab. Although the authors have not mentioned it in their paper, the anti-rat VEGF antibody that the authors used is raised in goat according to the information provided by the source. It justifies the use of anti-goat secondary antibody. It is not clear why and where they used anti-mouse IgG. On the other hand, bevacizumab is a humanized antibody and it should be detected by anti-human IgG 3, which was not used by the authors. This might explain why they could not detect bevacizumab binding with rat VEGF. Consistent with this argument, Bock et al. in a recent paper[4] have been able to show that bevacizumab binds to murine VEGF. They used a similar technique (Western blot), and by using anti-human IgG were able to detect bevacizumab bound to the murine VEGF. They further confirmed their results using additional techniques such as ELISA (again utilizing anti-human IgG) and surface Plasmon resonance (BIAcore assay).

Also, the figure legend of Figure 2 does not match the figure, nor does the legend for Figure 4. It seems figures have switched.

Rajesh K Sharma, MD, PhD

Kakarla V Chalam, MD, PhD, MBA, FACS

Department of Ophthalmology
University of Florida, College of Medicine
Jacksonville FL

References

1. Iriyama A, Chen YN, Tamaki Y et al. Effect of anti-VEGF antibody on retinal ganglion cells in rats. Br.J.Ophthalmol. 2007;91:1230-3.

2. Aggio FB, Farah ME, Silva WC et al. Intravitreal bevacizumab for exudative age-related macular degeneration after multiple treatments. Graefes Arch.Clin.Exp.Ophthalmol. 2006.

3. Heiduschka P, Fietz H, Hofmeister S et al. Penetration of bevacizumab through the retina after intravitreal injection in the monkey. Invest Ophthalmol.Vis.Sci. 2007;48:2814-23.

4. Bock F, Onderka J, Dietrich T et al. Bevacizumab as a potent inhibitor of inflammatory corneal angiogenesis and lymphangiogenesis. Invest Ophthalmol.Vis.Sci. 2007;48:2545-52.

Dear Editor

I read with interest the article by Pedroza-Seres M and associates who assessed the pathogenic roles of peripheral CD57+ natural killer T (NKT) cell in pars planitis.[1] The authors compared the frequencies of CD57+ NKT cell in peripheral blood between pars planitis patients and healthy controls, and then evaluated the effector-related surface molecules and functions of CD57+ NKT cells derived from patients. The authors conclude that CD57+ NKT cell subsets may function as memory-effector T cells during pars planitis immunopathogenesis. My experience of using similar methods to investigate the phenotypes and functions of CD8^brightCD56+ T cells in Behçet uveitis supports the notion that NK-typed CD8+ T cells play an effector role in chronic uveitis.[2] I would like to offer my opinion to their interpretation of experimental results.

I observed that CD8^bright CD56+ cells in peripheral blood were composed of more than 95% TCRαβ cells and that CD8^dimCD56+ cells consisted of natural killer cells and γδTCR+ cells.[2,3] Because the authors used the different gate of CD8 expression in figure 1 and 3, it is possible to overestimate the frequencies of peripheral CD8+CD57+ T cells including CD8^dim populations. Likewise CD56+ cells, CD8^dimCD57+ cells may not be TCRαβcells, which require confirmation of TCR expression. As shown in Figure 4 and Table 3, the authors found that CD57+CD8+ T cells significantly produced IL-4 after nonspecific stimulation. However, these results are not compatible with the idea that terminally differentiated NK-typed CD8+ T cells are polarized to produce cytokines, like CD56+CD8+ T cells.[2] Apoptosis of ex vivo CD57+CD8+ T cells may contribute to these findings because of smaller cell counts after stimulation (thick lines). The authors described that stimulared or unstimulated immune cells were used for intracellular staining of perforin. Because CD8+CD56+ T cells shed the preformed intracellular perforin after in vitro stimulation, the authors should measure the amounts of intracellular perforin in unstimulated cells.

I agree with the authors that NK-typed CD8+ T cells exert potent effector functions over conventional CD8+ T cells. CD56+ T cells are recruited into eye, particularly in Behçet uveitis, which are different from other etiologies of uveitis.[3] Moreover, these cells show phenotypical or functional changes after immunosuppresive treatments.[4] However, I did not observe upregulation of CD56+ T cells in aqueous or peripheral blood in patients with intermediate uveitis.[3] The specific roles of CD57+CD8+ T cells in pars planitis pathogenesis are not definite because the authors did not evaluate phenotypical or functional differences of CD57+CD8+ T cells according to the disease activity or compare their results with other etiologies of uveitis. Therefore, further investigations are needed to identify the pathogenic roles of CD57+CD8+ T cells in pars planitis.

References

1. Pedroza-Seres M, Linares M, Voorduin S, et al. Pars planitis is associated with an increased frequency of effector-memory CD57+ T cells. Br J Ophthalmol 2007;91:1393-8.

2. Ahn JK, Chung H, Lee DS, Yu YS, Yu HG. CD8^brightCD56+ T cells are cytotoxic effectors in patients with active Behçet's uveitis. J Immunol 2005;175:6133-42.

3. Yu HG, Lee DS, Seo JM, et al. The number of CD8+ T cells and NKT cells increases in the aqueous humor of patients with Behçet's uveitis. Clin Exp Immunol 2004;137:437-43.

4. Ahn JK, Park YG, Park SW, et al. Combined low dose cyclosporine and prednisone down-regulate natural killer cell-like effector functions of CD8^brightCD56+ T cells in patients with active Behçet's uveitis. Ocul Immunol Inflamm 2006;14:267-275.