Role of Nocturnal Arterial Hypotension in Nonarteritic Anterior Ischemic Optic Neuropathy

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. Letters to the Editor 1. It was pointed out that instead of comparing mean levels of blood pressure (BP) day vs. night, I used peak daytime levels and trough nighttime levels. My ABPM studies have shown that it is the fall in diastolic blood pressure which is of prime importance and not the mean BP (2,3). Calculation of mean BP is subject to a variety of potential inaccuracies including the accuracy by which the BP mean is obtained and physiologic fluctuations in BP that occur in the normal daily cycle. 2. Dr. Arnold comments that "the finding of Hayreh et al that patients using antihypertensive therapy and demonstrating lower nocturnal BP were at more risk for progressive NAION also is difficult to interpret from the data." My studies presented scientific data of a significant association between progressive visual field deterioration and nocturnal hypotension (2,3), particularly when patients took antihypertensive medications in the evening or at bedtime. 3. My data on the discovery of visual loss on awakening from sleep in patients with NAION varies greatly from the findings of the Ischemic Optic Neuropathy Decompression Trial (IONDT), where I found a 73% prevalence vs 42% in the IONDT (4,7). Actually, most of the remaining 27% of patients in my study could not rule out that visual loss occurred on awakening, so the frequency might actually be higher than 73%. In addition, I personally gathered all the historical information from my patients in contrast to the IONDT, in which historical data was primarily collected by technicians. Dr. Arnold's statement "a broader base of interviewers might result in less biased results" is illogical. Also, the criterion of visual loss occurring within 2 hours of awakening in IONDT was misleading. 4. Dr. Arnold mentions that "we have no data as to what constitutes a nocturnal or day level that increases risk, if such a level exists." NAION is a multifactorial disease caused by a combination of systemic and optic nerve head risk factors. Consequently, the degree of nocturnal hypotension required to precipitate NAION depends on the presence and severity of these risk factors, which shows marked individual variation. 5. It is stated that "we have no evidence that modifying blood pressure would have any beneficial effect in reducing risk of progression in the affected eye or risk of involvement of the fellow eye." In a study that I published on ipsilateral occurrence of NAION, the only significant risk factor for recurrence was nocturnal arterial hypotension (8). Letters to the Editor: J Neuro-Ophthalmol 2017; 37: 347-353 6. Finally, it is repeatedly stated that the pathogenesis of NAION is unknown. This is not entirely true. Rather, from my extensive study of this optic neuropathy, I have concluded that the pathogenesis of NAION is complex but not unknown (9). A comprehensive knowledge of optic nerve head blood supply and factors that influence blood flow in it is crucial to understand its pathogenesis. The pathogenesis of NAION proposed by Dr. Arnold (10) contains a series of scientific flaws to invalidate it, which I have discussed at length elsewhere (9). Sohan Singh Hayreh, MD, MS, PhD, DSc, FRCS, FRCOphth (Hon) Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, Iowa The author reports no conflicts of interest. REFERENCES 1. Cestari DM, Arnold A. Does nocturnal hypotension play a causal role in nonarteritic anterior ischemic optic neuropathy? J Neuroophthalmol. 2016;36:329-333. 2. Hayreh SS, Zimmerman MB, Podhajsky P, Alward WLM. Nocturnal arterial hypotension and its role in optic nerve head and ocular ischemic disorders. Am J Ophthalmol. 1994;117:603-624. 3. Hayreh SS, Podhajsky PA, Zimmerman B. Role of nocturnal arterial hypotension in optic nerve head ischemic disorders. Ophthalmologica. 1999;213:76-96. 4. Hayreh SS, Podhajsky PA, Zimmerman B. Non-arteritic anterior ischemic optic neuropathy - Time of onset of visual loss. Am J Ophthalmol. 1997;124:641-647. 5. Landau K, Winterkotn JMS, Mailloux LU, Vetter W, Napolitano B. 24-hour blood pressure monitoring in patients with anterior ischemic optic neuropathy. Arch Ophthalmol. 1996;114:570-575. 6. Hayreh SS, Zimmerman MB, Podhajsky P, Alward WLM. Nonarteritic anterior ischemic optic neuropathy: role of nocturnal arterial hypotension. Arch Ophthalmol. 1997;115:942-943. 7. Ischemic Optic Neuropathy Decompression Trial Study Group. Characteristics of patients with nonarteritic anterior ischemic optic neuropathy eligible for the Ischemic Optic Neuropathy Decompression Trial. Arch Ophthalmol. 1996;114:1366-1374. 8. Hayreh SS, Podhajsky PA, Zimmerman B. Ipsilateral recurrence of nonarteritic anterior ischemic optic neuropathy. Am J Ophthalmol. 2001;132:734-742. 9. Hayreh SS. Pathogenesis of classical non-arteritic anterior ischemic optic neuropathy. In: Ischemic Optic Neuropathies. Heidelberg, Germany: Springer Verlag, 2011:265-316. 10. Arnold AC. Pathogenesis of nonarteritic anterior ischemic optic neuropathy. J Neurooophthalmol. 2003;23:157-163. 351 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.