We are grateful to Dr McLeod1 for the interest that he has shown in our paper.2 Rather, then there being a conspiracy to increase the confusion within central retinal artery occlusion (CRAO), our study demonstrates that the disease is incompletely understood. In particular, we disagree with Dr McLeod that the retinal penumbra lasts for more than 24 h. Retinal and cerebrovascular ischaemia share a number of common pathophysiological features and is reflected by the recent extended definition of stroke involving retinal as well as cerebral ischaemia.3
In vitro experiments show that when neuronal cells are deprived of oxygen, that within 5 s, there is evidence of neuronal dysfunction. Within 10 s, cell death occurs. The elegant experiment of Astrup et al4 demonstrated that the penumbra is a function of collateral perfusion and that if there was no resolution of the occlusion, then eventually the penumbra would fail, and infarction would be permanent.
In cerebral stroke using perfusion imaging, various groups have demonstrated that the ischaemic penumbra may persist beyond 24 h. However, randomised controlled trials of reperfusion therapy in acute stroke have demonstrated on that in the majority of individuals, the ischaemic penumbra only extends out to 4.5 h and at maximum, 6 h.5, 6
The misperceptions that the retinal penumbra persists for 24 h, initially backed up by observational data, led to the design of two randomised controlled trials that recruited individual with central retinal artery occlusion of beyond 6 h. The EAGLE study recruited subjects up to 19 h of symptom onset,7 while our group conducted a randomised controlled trial of intravenous tPA given to individuals within 24 h of symptom onset.8 Both of these randomised controlled trials were negative studies, however, a signal was seen in individuals who receive tPA within 6 h of symptom onset.8 This mirrors the retinal tolerance time demonstrated in Hayreh’s animal experiments of 4 h.9
Conversely, if the thrombus that initially caused a retinal artery occlusion resolves such that retinal perfusion is restored, then the symptoms will be invariably improved leading to a transient central retinal artery occlusion.
Nevertheless, we agree with Dr McLeod that the classical clinical features of central retinal artery occlusion remain more or less the same, but that various findings may give a clue as to the time of the onset or alternatively the presence of partial occlusion. These are important points given that for randomised controlled trials on the treatment of CRAO are to succeed, then individuals need to be recruited within the shortest time possible.
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Varma DD, Cugati S, Lee AW, Chen CS . A review of central retinal artery occlusion: clinical presentation and management. Eye 2013; 27: 688–697.
Easton JD, Saver JL, Albers GW, Alberts MJ, Chaturvedi S, Feldmann E et al. Definition and Evaluation of Transient Ischemic Attack: A Scientific Statement for Healthcare Professionals From the American Heart Association/American Stroke Association Stroke Council; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Nursing; and the Interdisciplinary Council on Peripheral Vascular Disease: the American Academy of Neurology affirms the value of this statement as an educational tool for neurologists. Stroke 2009; 40: 2276–2293.
Astrup J, Symon L, Branston NM, Lassen NA . Cortical evoked potential and extracellular K+ and H+ levels at critical levels of brain ischemia. Stroke 1977; 8: 51–57.
Hacke W, Kaste M, Bluhmki E, Brozman M, Dávalos A, Guidetti D et al. Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke. N Engl J Med 2008; 359: 1317–1329.
Sandercock P, Wardlaw JM, Lindley RI, Dennis M, Cohen G, Murray G et al. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial. Lancet 2012; 379: 2352–2363.
Feltgen N, Neubauer A, Jurklies B, Schmoor C, Schmidt D, Wanke J et al. Mutlicenter study of the European Assessment Group for Lysis in the Eye (EAGLE) for the treatment of central retinal artery occlusio: design issues and implications. EAGLE study report no. 1. Graefes Arch Clin Exp Ophthalmol 2006; 244: 950–956.
Chen CS, Lee AW, Campbell B, Lee T, Paine M, Fraser C et al. Efficacy of intravenous tissue-type plasminogen activator in central retinal artery occlusion: report from a randomized, controlled trial. Stroke 2011; 42: 2229–2234.
Hayreh SS, Zimmerman MB, Kimura A, Sanon A . Central retinal artery occlusion. Retinal survival time. Exp Eye Res 2004; 78: 723–736.
The authors declare no conflict of interest.
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Lee, A., Chen, C., Cugati, S. et al. Reply: ‘Central retinal artery occlusion and cerebral stroke’. Eye 27, 1422–1423 (2013). https://doi.org/10.1038/eye.2013.216
Evidence for an enduring ischaemic penumbra following central retinal artery occlusion, with implications for fibrinolytic therapy
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