Corticosteroid Therapy in Nonarteritic Anterior Ischemic Optic Neuropathy

Letters to the Editor a small signal of some benefit. A study with a larger patient cohort might detect a subgroup responsive to dalfampridine. Mark L. Moster, MD Robert C. Sergott, MD Department of Neuro-Ophthalmology, Wills Eye Hospital, Departments of Ophthalmology and Neurology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania Benjamin E. Leiby, PhD Department of Pharmacology and Experimental Therapeutics, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania Supported by Acorda Therapeutics. The authors report no other conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the full text and PDF versions of this article on the journal's Web site (www.jneuro-ophthalmology.com). Corticosteroid Therapy in Nonarteritic Anterior Ischemic Optic Neuropathy K upersmith et al (1) in their recent article stated that the conclusions of my study (2), showing beneficial effects of systemic corticosteroids in nonarteritic anterior ischemic optic neuropathy (NAION), was "inaccurate," and they listed several reasons for that. But if these authors had carefully read, with an unbiased mind, my detailed published rebuttals to those criticisms (3), they would have found that my conclusions were based on definite scientific evidence. This shows that their criticisms about my study are not valid. For more than 4 decades, I have found a built-in bias, without any scientific rationale, among neuroophthalmologists against the use of corticosteroid therapy in NAION, as is evident from the above and the following examples. In early 1970s, when I applied to the National Institutes of Health to run a multicenter clinical trial about the use of corticosteroids therapy in patients with NAION, the project was rejected on the grounds that there was "no scientific rationale for corticosteroid therapy in NAION." I have discussed that scientific rationale fully elsewhere (2,3). In justification of their comments, Kupersmith, Miller, and Levin cited 2 studies (4,5) showing no beneficial effects of corticosteroid therapy in NAION. But, as I have Letters to the Editor: J Neuro-Ophthalmol 2017; 37: 347-353 REFERENCES 1. Kupersmith MJ, Miller NR. A nonarteritic anterior ischemic optic neuropathy clinical trial: an industry and NORDIC collaboration. J Neuroophthalmol. 2016;36:231-234. 2. Dunn J, Blight A. Dalfampridine: a brief review of its mechanism of action and efficacy as a treatment to improve walking in patients with multiple sclerosis. Curr Med Res Opin. 2011;27:1415-1423. 3. Goodman AD, Brown TR, Edwards KR, Krupp LB, Schapiro RT, Cohen R, Marinucci LN, Blight AR. A phase 3 trial of extended release oral dalfampridine in multiple sclerosis. Ann Neurol. 2010;68:494-502. 4. Jones RE, Heron JR, Foster DH, Snelgar RS, Mason RJ. Effects of 4-aminopyridine in patients with multiple sclerosis. J Neurol Sci. 1983;60:353-362. 5. Bever CT Jr, Young D, Anderson PA, Krumholz A, Conway K, Leslie J, Eddington N, Plaisance KI, Panitch HS, Dhib-Jalbut S, Fossler MJ, Devane J, Johnson KP. The effects of 4-aminopyridine in multiple sclerosis patients: results of a randomized, placebo-controlled, double-blind, concentrationcontrolled, crossover trial. Neurology. 1994;44:1054-1059. 6. Horton L, Conger A, Conger D, Remington G, Frohman T, Frohman E, Greenberg B. Effect of 4-aminopyridine on vision in multiple sclerosis patients with optic neuropathy. Neurology. 2013;80:1862-1866. 7. Naismith RT, Tutlam NT, Trinkaus K, Lancia S. Phase II trial of dalfampridine to improve visual function in chronic optic neuritis due to MS. Ann Neurol. 2015;78(suppl 19):S66. 8. Iaci JF, Parry TJ, Huang Z, Finklestein SP, Ren J, Barrile DK, Davenport MD, Wu R, Blight AR, Caggiano AO. Dalfampridine improves sensorimotor function in rats with chronic deficits after middle cerebral artery occlusion. Stroke. 2013;44:1942-1950. pointed out (6), the study by Rebolleda et al (4), based on only 10 treated patients, was highly flawed, which invalidated its conclusion. Pakravan et al (5) treated 30 patients with high-dose intravenous corticosteroids, using a treatment protocol basically similar to that used in optic neuritis. But it is well established that etiologically NAION and optic neuritis are different diseases, and that simple fact and the study design used in this study invalidates their conclusion. In contrast, in my study, oral corticosteroid therapy (in 312 treated and 301 untreated patients) was used until optic disc edema resolved, that is, for about 8 weeks. Thus, comparing study designs and the numbers of patients in the 2 cited studies with those of my large study is like comparing apples and oranges. It is unfortunate that Kupersmith, Miller, and Levin apparently attach more importance to those 2 highly flawed studies supporting their bias than to my large, systematic, comprehensive study. Sohan Singh Hayreh, MD, MS, PhD, DSc, FRCS, FRCOphth Department of Ophthalmology and Visual Science, College of Medicine, University of Iowa, Iowa City, IA The author reports no conflicts of interest. 349 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Letters to the Editor REFERENCES 1. Kupersmith MJ, Miller NR, Levin LA. New treatments in NeuroOphthalmology: the role for evidence. J Neurophthalmol. 2017;37:1-2. 2. Hayreh SS, Zimmerman MB. Non-arteritic anterior ischemic optic neuropathy: role of systemic corticosteroid therapy. Graefes Arch Clin Exp Ophthalmol. 2008;246:1029-1046. 3. Hayreh SS. Ischemic optic neuropathies-where are we now? Graefes Arch Clin Exp Ophthalmol. 2013;251:1873-1884. 4. Rebolleda G, Pérez-López M, Casas-Llera P, Contreras I, MuñozNegrete FJ. Visual and anatomical outcomes of non-arteritic Corticosteroid Therapy in Nonarteritic Anterior Ischemic Optic Neuropathy: Response W e thank Dr. Hayreh for the opportunity to continue the discussion on this most important topic- namely, the need for Level I evidence in medicine to assess potential therapies. We recognize and appreciate Dr. Hayreh's contributions to the understanding of nonarteritic anterior ischemic optic neuropathy (NAION), and we are sorry that he seems to have misinterpreted our commentary as a personal attack. Our editorial is an unbiased evaluation of the issue of steroid treatment of NAION and, more importantly, a plea for well-designed, prospective clinical trials that collect and analyze meaningful data and come to an evidence-based conclusion regarding the efficacy of a potential therapy. These trials must include masking and randomization, for without them, the conclusions could be flawed. Even when unintended, bias from study subjects and investigators are known contaminants. Uncontrolled cases series, no matter how many patients are included, are still simply large series, and physicians should be cautious in interpreting the results of such studies, as the studies do not follow the accepted principles for conduct- Role of Nocturnal Arterial Hypotension in Nonarteritic Anterior Ischemic Optic Neuropathy I was interested to read the discussion of the role of nocturnal arterial hypotension in nonarteritic anterior ischemic optic neuropathy (NAION) (1). Since my studies were the first to raise this issue (2-4), I believe that a number of comments are in order. It was stated that my 24-hour ambulatory blood pressure monitoring (ABPM) studies (2,3) in patients with NAION had no control group and, therefore, the "data had significant limitations." I have discussed at length why it is impossible to have a valid control group in such a study (2), given the fact 350 anterior ischemic optic neuropathy with high-dose systemic corticosteroids. Graefes Arch Clin Exp Ophthalmol. 2013;251:255-260. 5. Pakravan M, Sanjari N, Esfandiari H, Pakravan P, Yaseri M. The effect of high-dose steroids, and normobaric oxygen therapy, on recent onset non-arteritic anterior ischemic optic neuropathy: a randomized clinical trial. Graefes Arch Clin Exp Ophthalmol. 2016;254:2043-2048. 6. Hayreh SS. Treatment of non-arteritic anterior ischemia optic neuropathy with high-dose systemic corticosteroid therapy. Graefes Arch Clin Exp Ophthalmol. 2013;251:1029-1030. ing clinical trials. Uncontrolled data are useful for generating hypotheses and exploring new concepts, but they should be viewed only as pilot or preliminary information on which to base controlled clinical trials. We recommend that, given his expertise in this area, Dr. Hayreh attempt once again to perform a prospective trial of steroid therapy for NAION using the methodology that all trials of investigational agents require to properly test a hypothesis. Mark J. Kupersmith, MD Icahn School of Medicine at Mount Sinai and New York Eye and Ear Infirmary, New York, New York Neil R. Miller, MD Johns Hopkins School of Medicine and Wilmer Eye Institute, Baltimore, Maryland Leonard A. Levin, MD, PhD McGill University Faculty of Medicine, Montreal, Canada University of Wisconsin, Madison, Wisconsin The authors report no conflicts of interest. that NAION is a multifactorial disease with many systemic and optic nerve head risk factors. Hence, a true control population would have to be matched for systemic and optic nerve head factors in addition to age and sex. My studies, in fact, had an important built-in reliable control, because patients with nocturnal hypotension, compared with those without it, had a significant association with progression of visual field deterioration in NAION. The ABPM study in 24 patients with NAION by Landau et al (5) has been cited as contradictory to my findings regarding nocturnal arterial hypotension in NAION. I have discussed at length the flaws in that study which invalidate its conclusions (6). Anthony Arnold, MD, raised a number of concerns regarding the data from my studies. Following are my responses. Letters to the Editor: J Neuro-Ophthalmol 2017; 37: 347-353 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.