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Show EDITORIAL Intravitreal Triamcinolone or Bevacizumab for Nonarteritic Anterior Ischemic Optic Neuropathy: Do They Merit Further Study? Shalom E. Kelman, MD Nonarteritic anterior ischemic optic neuropathy ( NAION) remains a major cause of sudden loss of vision in elderly individuals. The results of the Ischemic Optic Neuropathy Compression Trial ( IONDT) ( 1) demonstrated that optic nerve sheath decompression not only did not produce better visual outcomes than occurred in the nonintervention group but also was actually harmful. The study also denned for the first time the natural history of the disease. At 6 months, 42% of the patients in the nonintervention group experienced significant clinical improvement ( doubling of the visual angle). A most unexpected and important result of the IONDT was the determination of second eye involvement with NAION. Before the IONDT, reports had suggested that second eye involvement occurred in up to 45% of patients. The IONDT demonstrated a rate of close to 15% over 5 years ( 2). At the time of a first eye involvement with NAION when a terribly anxious patient asks " What will happen to my other eye?" we can now answer with confidence that the risk of involvement of the second eye is relatively low. Even so, second eye involvement may render the patient visually disabled. Our sense of frustration and desperation with this subgroup of patients strongly motivates a search for new innovative treatments. Although there is much hope regarding the contribution of stem cells, the benefits of this approach are unlikely be realized for 20- 30 years. We desire a treatment that we can use in the very near future. In this issue of the Journal, Kaderli et al ( 3) report improved visual acuity and rapid reduction in optic disc edema after intravitreal injection of triamcinolone in 4 eyes of patients with NAION. Bennett et al ( 4) reported similarly impressive results in a single patient with NAION after intravitreal injection of bevacizumab. As pointed out by the authors of both reports, the small sample and lack of concurrent controls limit the conclusions. Nevertheless, small studies of this nature are hypothesis- generating and ought to serve as a stimulant to larger and better- designed trials. Is there a plausible rationale for the benefit of either agent in NAION? Kaderli et al ( 3) propose that by reducing optic disc edema through corticosteroids, " the vicious cycle of ischemia, edema, and compartment syndrome" may be ameliorated. They also suggest that the corticosteroid anti- inflammatory effect may be beneficial on the basis of limited histopathologic data. Unfortunately, the science to support these hypotheses is weak. The pathophysiology of NAION remains poorly understood. There is very limited pathologic material available to determine whether there is an inflammatory component in NAION. Bennett et al ( 4) postulated that acute expression of vascular endothelial growth factor ( VEGF) may cause harmful optic disc edema and pointed out that inhibition of VEGF signaling has reduced cerebral edema and tissue injury in a mouse stroke model. Maryland Neuroophthalmology, LLC, Department of Ophthalmology, University of Maryland School of Medicine, Baltimore, Maryland. Address correspondence to Shalom E. Kelman, MD, Maryland Neuroophthalmology, LLC, 1777 Reisterstown Road, Suite 234, Baltimore, MD 21208; E- mail: skelman( S), comcast. net J Neuro- Ophthalmol, Vol. 27, No. 3, 2007 161 J Neuro- Ophthalmol, Vol. 27, No. 3, 2007 Editorial Before we consider embarking on a large scale, expensive clinical trial using one or the other of these agents in NAION, it is worth recalling the process we went through in generating the IONDT, of which I was the lead investigator. In the late 1980s, optic nerve sheath decompression for NAION seemed to work but the rationale was weak. In 1987, I visited Robert Sergott, MD, in Philadelphia to observe his performance of optic nerve sheath decompression surgery on 2 patients with papilledema from idiopathic intracranial hypertension ( pseudotumor cerebri). In 1988, Dr. Sergott and his colleagues published favorable results with use of this procedure in the management of papilledema ( 5). I soon started performing the procedure, and after achieving successful outcomes in many patients with papilledema, I became a strong advocate. In 1989, Sergott et al ( 6) published the lead article in Archives of Ophthalmology showing that 12 of 14 patients with progressive NAION ( characterized by reported worsening over at least 7 days) improved after undergoing optic nerve sheath decompression, whereas only 1 of 3 patients with sudden, nonprogressive visual loss improved after this type of surgery. They noted that in a control group with nonprogressive NAION, only 2 of 15 eyes demonstrated spontaneous improvement. They concluded that optic nerve sheath decompression benefited patients with progressive NAION but not those with acute, nonprogressive NAION. After reading this report, Michael Elman, MD, a retinal surgeon with a strong background in clinical trial design, and I began to offer the procedure to selected patients with NAION. We published our favorable results in a group of 7 patients ( 7), cautioning that the natural history was still unknown and suggesting that the improvement was not limited to the progressive form of NAION. Dr. Elman and I took our idea of a multicenter randomized trial of optic nerve sheath decompression in NAION to Dr. Sergott in recognition of his pivotal role in applying optic nerve sheath decompression to NAION. He declined to participate, stating that he lacked the clinical equipoise necessary to proceed with a randomized clinical trial. He believed that the literature supported his impression that spontaneous improvement was very rare and that his experience with the procedure demonstrated significant rates of improvement. Under the circumstances, he could not ethically submit his patients to random trial assignment. We developed a plan that would ultimately lead to funding for a multicenter clinical trial. Letters were sent to neuro- ophthalmologists requesting that they perform chart reviews of their patients with NAION. Based on these chart reviews, we were able to arrive at an estimate of the spontaneous improvement rate and the prevalence of the disease. Power calculations could now be performed, and we arrived at an estimate of the number of patients we would need to demonstrate a statistically significant effect of treatment. As a result of these chart reviews, we suspected that the natural history was better than had been reported and that the published reports were not rigorous. During the 1990 American Academy of Ophthalmology meeting in Atlanta, Dr. Elman and I locked ourselves in our hotel rooms to write a National Eye Institute ( NEI) grant proposal. At that meeting, I engaged in a heated debate with Sohan S. Hayreh, MD, who animatedly asserted that the scientific rationale for sheath decompression was flawed. ( He later published his opposition to the rationale for surgery in NAION in a letter to the editor [ 8]). Despite being disheartened by the rebuke of one of the world's leading authorities on NAION, we continued our work. We were propelled by a sense that a clinical trial undertaken soon after sheath decompression was gaining popularity would be the most effective way to prevent dissemination of a potentially harmful intervention. The NEI accepted our proposal on the first try, an almost miraculous occurrence. Our hard work and preparation had paid off, but the truly difficult part of running a clinical trial had just begun. Twenty- five clinical centers were selected and training began. Surgeons studied videotapes on the surgical procedure, clinical coordinators received training on vision testing, and a manual of operations was developed. Eventually the clinical centers were certified and up and running, and our first patient was enrolled in October of 1992, a short 34 months after optic nerve sheath decompression was first reported as a treatment for NAION. Enrollment was highly successful. But within 24 months of entering the first patient, the Data and Safety Monitoring Committee halted the study after 244 patients had been randomly assigned. The data had demonstrated that surgery was not beneficial and perhaps harmful, even in patients with progressive disease. Most unexpectedly, the natural history arm demonstrated improvement of vision in 42% of patients who had not undergone surgery at 6 months ( 1). Subsequent follow- up in the second phase of the study demonstrated a 5- year rate of second eye involvement of only 15% ( 2). As noted by Leonard Levin, MD, in an accompanying editorial to the initial report ( 9), " the barn door was closed in time." What are the implications of the IONDT for another multicenter clinical treatment trial of NAION? Power calculations can now be carried out with better precision based on the IONDT data. These calculations depend on the expected magnitude of the treatment effect relative to the spontaneous improvement rate. Given the relative large spontaneous improvement rate found in the IONDT, much larger numbers of patients will be needed to demonstrate a modest effect of a new intervention. On the other hand, if the intervention is expected to produce a dramatic improvement in function, fewer patients will be needed. 162 © 2007 Lippincott Williams & Wilkins Editorial J Neuro- Ophthalmol, Vol. 27, No. 3, 2007 The magnitude of the effect that intravitreal triamcinolone or bevacizumab has on visual outcomes will determine the feasibility of the study. If the results of the small studies of intravitreal triamcinolone or bevacizumab reported here are reproducible and the magnitude of improved visual acuity and rapidity of resolution of the disc edema can be substantiated in further pilot studies, then power calculations may demonstrate the feasibility of a multicenter clinical treatment trial. One important difference between then and now is the possibility of testing these interventions in an animal model. The rodent model ( 10,11) and, more recently, the primate model of NAION ( 12) have been developed to the point that putative interventions such as intravitreal corticosteroid or anti- VEGF injections can be tested before human trials are begun. This approach would not unduly delay the introduction of a promising new treatment. On the other hand, if animal models fail to demonstrate any potential benefit, patients will be spared another clinical trial with negative results. REFERENCES 1. The Ischemic Optic Neuropathy Decompression Trial Research Group. Optic nerve decompression surgery for nonarteritic anterior ischemic optic neuropathy ( NAION) is not effective and may be harmful. JAMA 1995; 273: 625- 32. 2. Newman NJ, Scherer R, Langenberg P, et al. The fellow eye in NAION: report from the ischemic optic neuropathy decompression trial follow- up study. Am J Ophthalmol 2002; 134: 317- 28. 3. Kaderli B, Avci R, Yucel A, et al. Intravitreal triamcinolone improves recovery of visual acuity in nonarteritic anterior ischemic optic neuropathy. J Neuroophthalmol 2007; 27: 164- 68. 4. Bennett JL, Thomas S, Olson JL, et al. Treatment of nonarteritic anterior ischemic optic neuropathy with intravitreal bevacizumab. J Neuroophthalmol 2007; 27: 238^ 0. 5. Sergott RC, Savino PJ, Bosley TM. Modified optic nerve sheath decompression provides long- term visual improvement for pseudotumor cerebri. Arch Ophthalmol 1988; 106: 1384- 90. 6. Sergott RC, Cohen MS, Bosley TM, et al. Optic nerve decompression may improve the progressive form of nonarteritic ischemic optic neuropathy. Arch Ophthalmol 1989; 107: 1743- 54. 7. Kelman SE, Elman Ml Optic nerve sheath decompression for nonarteritic ischemic optic neuropathy improves multiple visual function measurements. Arch Ophthalmol 1991; 109: 667- 71. 8. Hayreh SS. The role of optic nerve sheath fenestration in management of anterior ischemic optic neuropathy. Arch Ophthalmol 1990; 108: 1063- 5. 9. Levin LA. Clarifying the treatment of nonarteritic anterior ischemic optic neuropathy. JAMA 1995; 273: 666- 7. 10. Bernstein SL, Guo Y, Kelman SE, et al. Functional and cellular responses in a novel rodent model of anterior ischemic optic neuropathy. Invest Ophthalmol Vis Sci 2003; 44: 4153- 62. 11. Bernstein SL, Guo Y, Slater BJ, et al. Neuron stress and loss following rodent anterior ischemic optic neuropathy in double-reporter transgenic mice. Invest Ophthalmol Vis Sci 2007; 48: 2304- 10. 12. Bernstein SL, Chen C, Miller NR, et al. A primate model of nonarteritic anterior ischemic optic neuropathy ( pNAION). Invest Ophthalmol Vis Sci 2007; 48: E- Abstract 4410. 163 |