Should Patients With Acute Central Retinal Artery Occlusion Be Treated With Intra-arterial t-PA?: Response

Letters to the Editor Should Patients With Acute Central Retinal Artery Occlusion Be Treated With Intraarterial t-PA?: Comment difference in visual outcome between the two groups in the EAGLE trial. Neil R. Miller, MD, FACS Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland I n their Point-Counterpoint article on whether to treat patients with acute central retinal artery occlusion (CRAO) with local intra-arterial fibrinolysis (LIF), both Dr Egan and Dr Van Stavern (1) appropriately reference the prospectively performed European Assessment Group for Lysis of the Eye (EAGLE) trial in which 84 subjects received either LIF (44 subjects) or "conservative" therapy (40 subjects). This trial found no difference in the degree of improvement in best-corrected visual acuity between the 2 groups (2). What neither author discusses in their otherwise excellent article is that all subjects in the EAGLE trial received 5 days of intravenous heparin in addition to either LIF or conservative treatment. In general, treatment with intravenous heparin for that period of time in patients with acute CRAO is not the standard of care in the United States. Indeed, it was not used in the study that we reported from Johns Hopkins (3) nor in several other studies from other countries that reported that patients with CRAO treated with LIF have better visual outcomes than patients treated conservatively (4,5). I am not suggesting that patients with acute CRAOs be treated with LIF nor that the results reported in the EAGLE Trial were invalid; however, I do wonder if 5 days (or more) of anticoagulation might have been the reason that there was no Should Patients With Acute Central Retinal Artery Occlusion Be Treated With Intraarterial t-PA?: Response W e thank Dr Miller for his comments and question about our Point-Counterpoint article. We agree that the use of intravenous anticoagulation may have played a role in the outcomes. However, time to treatment likely represents the larger factor in the lack of a statistical benefit between the 2 groups. Again extrapolating from acute stroke trial data, the International Stroke Trial failed to demonstrate a benefit of intravenous heparin started within 48 hours of onset over aspirin therapy when the increased risk of anticoagulationrelated hemorrhage was taken into account (1). Looking purely at recurrent ischemic stroke as a surrogate for clinical outcome in that trial, the benefit of intravenous heparin was 0.9% at 14 days. The 2015 Cochrane sys444 The author reports no conflicts of interest. REFERENCES 1. Egan RA, Van Stavern R. Should patients with acute central retinal artery occlusion be treated with intra-arterial t-PA? J Neuroophthalmol. 2015;35:205-209. 2. Schumacher M, Schmidt D, Jurklies B, Algal C, Wanke I, Schmoor C, Maier-Lenz H, Solymosi L, Brueckmann H, Neubauer AS, Wolf A, Feltgen N; EAGLE-Study Group. Central retinal artery occlusion: local intra-arterial fibrinolysis versus conservative treatment, a multicenter randomized trial. Ophthalmology. 2010;117:1367-1375. 3. Aldrich EM, Lee AW, Chen CS, Gottesman RF, Bahouth MN, Gailloud P, Murphy K, Wityk R, Miller NR. Local intraarterial fibrinolysis administered in aliquots for the treatment of central retinal artery occlusion. The Johns Hopkins Hospital experience. Stroke. 2008;39:1746-1750. 4. Weber J, Remonda L, Mattle HP, Koerner U, Baumgartner RW, Sturzenegger M, Ozdoba C, Koerner F, Schroth G. Selective intraarterial fibrinolysis of acute central retinal artery occlusion. Stroke. 1998;29:2076-2079. 5. Richard G, Lerche RC, Knospe V, Zeumer H. Treatment of retinal arterial occlusion with local fibrinolysis using recombinant tissue plasminogen activator. Ophthalmology. 1999;106:768-773. tematic review of early anticoagulant therapy in acute ischemic stroke revealed no benefit (2). Treatment with anticoagulants reduced recurrent stroke, deep vein thrombosis, and pulmonary embolism, but these reductions were offset by increased bleeding risk. When considering at time as an important factor, an open label, single center, randomized controlled trial of intravenous heparin (goal partial thromboplastin time 2-2.5 times greater than control for 5 d) vs placebo in 418 points treated within 3 hours of nonlacunar hemispheric stroke revealed somewhat similar outcomes when compared with the original NINDS trial (3,4). Only one of the studies included in the Cochrane review included patients who had been enrolled fewer than 12 hours from stroke onset. Renee B. Van Stavern, MD Stroke and General Neurology Sections, Washington University in St. Louis School of Medicine, St. Louis, Missouri Letters to the Editor: J Neuro-Ophthalmol 2015; 35: 444-446 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Letters to the Editor Robert A. Egan, MD Oregon Neurology, Tualatin, Oregon The author reports no conflicts of interest. REFERENCES 1. International Stroke Trial Collaborative Group. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous Reactive Oxygen Species in Mitochondrial Optic Neuropathies: Comment W e read with great interest the recent article by Leonard Levin (1), who emphasized the role of superoxide generation in several metabolic optic neuropathies, all characterized by cecocentral scotomas. He suggests that electrons spilled from the electron transport chain (e.g., in Leber hereditary optic neuropathy [LHON]), leads, in the presence of oxygen, to superoxide formation and that this can specifically signal retinal ganglion cell (RGC) death. Citing a variety of experiments, Levin makes a compelling argument that superoxide is not a consequence of cell death but a causative factor. We agree. Dr. Levin correctly interprets our mathematical model (2), which uses a nerve fiber layer stress index to predict the order of fiber loss (small to large and hence papillomacular bundle first). But Levin suggested that we believe this to be due to problems of bioenergetics. So a clarification is in order. We did not intend to suggest that lack of adenosine triphosphate (ATP) directly leads to RGC death. On the contrary, in our other article pertaining to this mathematical model, we emphasized ". . .that the mitochondria could use cell signaling systems to help initiate and promote apoptosis." and further that, "Reactive oxygen species (ROS) are not only the toxic by-products of oxygenation reactions but also a signaling system for mitochondria." (3) In LHON, these electrons probably spill from Complex I to produce ROS. As Dr. Levin points out, superoxide is the predominant ROS. Levin cited our work (3,4) in which we show that the smallest fibers of the optic nerve, beginning in the papillomacular bundle, are affected first, and then, in more severe cases, this proceeds like a wave to involve larger and larger fibers. Indeed true. But what is fascinating and remains unexplained is that the histological measurements show the affected sectors of LHON optic nerves (corresponding to areas that in normals contain smaller than average caliber axons) "were completely devoid of axons, with losses not limited to just the smallest. . ." (2). In other words, some sort of signal or effect must spread from the small and susceptible axons to Letters to the Editor: J Neuro-Ophthalmol 2015; 35: 444-446 heparin, both, or neither among 19 435 patients with acute ischaemic stroke. Lancet. 1997;349:1569-1581. 2. Sandercock PAG, Counsell C, Kamal AK. Anticoagulants for acute ischaemic stroke. Cochrane Database Syst Rev. 2008: CD000024. 3. Camerlingo M, Salvi P, Belloni G, Gamba T, Cesana BM, Mamoli A. Intravenous heparin started within the first 3 hours after onset of symptoms as a treatment for acute nonlacunar hemispheric cerebral infarctions. Stroke. 2005;36:2415- 2420. 4. The National Institute of Neurological Disorders and Stroke rtPA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333:1581-1587. their larger neighbors. This suggests a mass action effect such that a cascading event includes adjacent fibers regardless of their size. This cannot be explained by just bioenergetics. That the RGC injury arises in the unmyelinated retinal nerve fiber layer is no surprise, given that repolarization only occurs where there is no myelin. But again, this does not necessarily mean that the problem is a lack of ATP, as a bioenergetic problem may lead to compensatory changes that produce an abundance of ROS in the context of dysfunctional mitochondria (3). It should also be noted that although ROS may mediate apoptosis, ROS are also important and useful as intracellular signals. For example, LHON cybrid studies have shown that mitochondrial biogenesis is likely signaled by high ROS levels (5). Furthermore, although superoxide is a prominent member of the ROS family, this chemical is ephemeral. It is very reactive and thus changes quickly in time and space. Superoxide, therefore, is hard to pin down and be reliably measured in any experimental system. In the same issue of Journal of Neuro-Ophthalmology, Neil Miller (6) provides us with his thoughts on what a human clinical trial would need to test these hypotheses. Dr. Miller would like to see a clinical trial with an agent that not only ameliorates the optic neuropathy of LHON but also works in B-12 deficiency and ethambutol optic neuropathy. All other considerations aside, such a trial would be a challenge insofar as the treatment of B-12 deficiency and ethambutol toxicity is to supplement the former and discontinue the latter. And if an agent is added to that management, seeing the small additional therapeutic effect will not be easy. Rather, I would like to see any purported agents tried in a faithful animal model. Fortunately, this model now exists (7). Wallace's team introduced the human optic atrophy mtDNA ND6 P25L mutation into the mouse thus creating a genetically identical animal model of LHON. These mice went blind as demonstrated by a number of tests including electroretinograms and their small caliber axons were selectively lost in the optic nerves. Perhaps most importantly, in vitro analysis of the mice brains demonstrated ". . .decreased Complex I activity and increased ROS but no diminution of ATP production. Thus, LHON pathophysiology may result from oxidative stress." (7) It seems that in this, we all agree. And we are pleased that Dr. Levin stresses 445 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.