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Show Letters to the Editor Intravitreal Triamcinolone Acetonide Injection in a Rodent Model of Anterior Ischemic Optic Neuropathy: Comment I read with great interest the recent article from Pereira et al (1) which detailed a trial of an intravitreal triamcinolone acetate (IVTA) injection in the rodent model of anterior ischemic optic neuropathy (rNAION). The group demonstrated no significant difference between the IVTA group and controls. I suggest that significant differences in the pathophysiology of the rNAION model and human nonarteritic ischemic neuropathy, NAION, make this model challenging for testing the therapeutic potential of steroids. The rNAION model establishes optic nerve ischemia using intravenous rose bengal and subsequent laser; Pereira et al used 532-nm diode laser to cause selective ischemia of the optic nerve head (ONH). This rNAION model does demonstrate many functional and histological similarities with NAION (2). Histological analysis of the ONH in the rNAION model demonstrates a significant reduction in the filling of optic nerve capillaries. This ischemic lesion results in a protracted optic disc swelling, demonstrated with biomicroscopic images here (2). The rNAION model should be thought of as a homolog to end-stage NAION, irreversible ONH ischemia, and cell loss. It is for this reason that steroids are unlikely to have a therapeutic effect. Much of the pathophysiology of NAION remains in question, but it is undoubtedly a multifactorial process that manifests as small vessel circulatory insufficiency of the ONH (3). It is believed that this vascular insufficiency, at least in its beginnings, is transient (4). ONH edema and a subsequent compartment syndrome are likely to play a role in exacerbating the ischemia with smaller and more crowded optic nerves being particularly vulnerable (3). Furthermore, ONH edema has been shown to precede visual loss in NAION (4). Rather than viewing ONH edema as a downstream effect of ON infarction, as it is in rNAION, one must consider it part of the initial pathophysiology and therefore a potential therapeutic target. The role of IVTA in the treatment of NAION remains controversial. Studies to date using IVTA have been small; however, some groups have shown modest benefits (5). The evidence for oral steroids is more robust (5). The proposed Intravitreal Triamcinolone Acetonide Injection in a Rodent Model of Anterior Ischemic Optic Neuropathy: Response W e would like to thank Dr. Harvey for his interest in our study titled “Intravitreal triamcinolone acetonide injection in a rodent model of anterior ischemic optic neuropathy” (1). He points out the limitations of using a rodent model to Letters to the Editor: J Neuro-Ophthalmol 2019; 39: 545-547 mechanism of action of steroids is to speed up the resolution of ONH edema and thus re-establish ONH blood supply (5). If true, this mechanism of action makes the rNAION model used in the study by Pereira et al a challenging choice. The structural damage caused to the ONH capillaries in the rNAION model is likely irreversible. ONH ischemia will ensue, despite reestablishment of blood supply to these vessels. Furthermore, ONH edema in the rNAION model resolves by 5 days, compared with the much longer time course seen in humans (2). This suggests significant differences in the role ONH edema plays in the pathophysiology of the disease in rNAION and NAION. NAION is a poorly understood and severe optic neuropathy for which we have few therapeutic options. One of the difficulties with NAION research in humans is its rapid progression, which makes the therapeutic window extremely small. For this reason, animal models present an exciting opportunity to test potential treatments. However, the rNAION model may represent a choice that has challenges for investigating the therapeutic potential of steroids in NAION. Joshua P. Harvey, MA (Oxon), BM, BCh Ophthalmology Department, King's College Hospital, London, United Kingdom The author reports no conflicts of interest. REFERENCES 1. Pereira LS, Ávila MP, Salustiano LX, Paula AC, Arnhold E, McCulley TJ. Intravitreal triamcinolone acetonide injection in a rodent model of anterior ischemic optic neuropathy. J Neuroophthalmol. 2018;38:561–565. 2. Bernstein SL, Johnson MA, Miller NR. Nonarteritic anterior ischemic optic neuropathy (NAION) and its experimental models. Prog Retin Eye Res. 2011;30:167–187. 3. Arnold AC. Pathogenesis of nonarteritic anterior ischemic optic neuropathy. J Neuroophthalmol. 2003;23:157–163. 4. Hayreh SS, Zimmerman MB. Incipient nonarteritic anterior ischemic optic neuropathy. Ophthalmology. 2007;114:1763–1772. 5. Atkins EJ, Bruce BB, Newman NJ, Biousse V. Treatment of nonarteritic anterior ischemic optic neuropathy. Surv Ophthalmol. 2010;55:47–63. investigate anterior ischemic optic neuropathy (AION). We are in agreement that animal models will always fall short of studying human disease. However, they are often the most appropriate first step. There is no question that rodents have different responses to tissue injury than do primates. We also agree that, unlike AION in humans, the current animal models of AION, both rodent and nonhuman primate, are potentially different from human AION. With all animal models, we know 545 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Letters to the Editor exactly when damage occurred; however, with humans, we do not know when damage began—only when symptoms were first detected. Positive studies are of most value. If drug studies in rodents and other lower animals (e.g., rodents, rabbits, and hamsters) work, then we have a basis on which to test drugs in nonhuman primates or, in some cases, directly in humans. However, if they do not work, we still do not know with certainty that they would not work in humans. Such negative studies do have value in that they serve as essential building blocks, providing direction for future studies and at times justification for funding. Dr. Harvey voices several specific concerns. He asserts that laser-induced optic AION should be viewed as “a homolog” to end-stage AION. This presumption may or may not be accurate. But, even if accurate, our findings would still suggest that steroids lack benefit at this stage of disease, which may be at or shortly after appreciation of visual symptoms. He further argues that edema may play a role in the pathophysiology of AION, at different phases of the disease, and in some cases, preceding infarction. This likely is correct, and it is possible that steroids could have benefit in a subset of patients, specifically those with progressive axonal ischemia related to secondary compartmental compression. As we stated in our discussion section, we agree that our findings do not negate the possibility that steroids may have benefit in all or possibly a subset of human patients. In closing, we agree with Dr. Harvey that findings in a rodent model of AION far from perfectly parallel human disease. However, it would be unwise to assume animal studies such as this are entirely without value. They are, in many cases, the most appropriate initial step. We maintain that our data are sufficient to exclude a significant impact of intravitreal triamcinolone, with a final intravitreal concentration of 1 mg/mL, on retinal ganglion cells number in rodent eyes with nonarteritic ischemic optic neuropathy (NAION). Our findings do not exclude the possibility that anti- Diplopia and Giant Cell Arteritis W e read with interest the article by Ross et al that discussed 27 patients with diplopia and giant cell arteritis (GCA) (1). We contribute the perspective of 40 additional patients with diplopia and biopsy-proven GCA, based on our recent retrospective study of 1,666 subjects who underwent consecutive temporal artery biopsy for suspected GCA at 12 medical centers that did not contribute to the Ross paper (2). Diplopia-related data were available on 1,593 patients, of whom 137 (8.6%) had diplopia. We did not differentiate subjects with transient diplopia from those with constant diplopia. Of 392 patients with biopsy-proven GCA, 40 (10.2%) had diplopia. The characteristics of the subjects with diplopia and biopsy-proven GCA vs. those with a negative temporal 546 inflammatory therapy may be beneficial in all or in subsets of human patients with NAION. A detailed account of our study's limitations and implications comprises the bulk of the discussion section of the article (1). We are hopeful that these data will benefit future the design of more focused studies. Luciano S. Pereira, MD, PhD Marcos Pereira Ávila, MD, PhD Department of Ophthalmology, Universidade Federal de Goiás, Goiânia, Brazil Luciana X. Salustiano, MD, PhD Department of Pathology, Universidade Federal de Goiás, Goiânia, Brazil Alcio C. Paula, MD, PhD Department of Ophthalmology, Universidade Federal de Goiás, Goiânia, Brazil Emmanuel Arnhold, PhD Department of Statistics, Universidade Federal de Goiás, Goiânia, Brazil Timothy J. McCulley, MD The Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland The authors report no conflicts of interest. REFERENCE 1. Pereira LS, Ávila MP, Salustiano LX, Paula AC, Arnhold E, McCulley TJ. Intravitreal triamcinolone acetonide injection in a rodent model of anterior ischemic optic neuropathy. J Neuroophthalmology 2018:38;561–565. artery biopsy are shown in Table 1. Patients with diplopia and GCA had statistically significant greater age, jaw claudication, vision loss, erythrocyte sedimentation rate, C-reactive protein, and platelet levels than patients with diplopia and a negative temporal artery biopsy. Notwithstanding, on multivariable logistic regression model of the 1,201 subjects with complete data, diplopia was not a statistically significant predictor for biopsy-proven GCA (P = 0.659; Table 2). This result did not change with multiple imputation missing data analysis. Edsel B. Ing, MD, MPH Department of Ophthalmology, University of Toronto, Toronto, Canada Letters to the Editor: J Neuro-Ophthalmol 2019; 39: 545-547 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. |
