Despite years of clinical and basic science studies, the exact mechanism of NAION is still unknown. Briefly, the ultimate axonal degeneration and retinal ganglion cell apoptosis are comprehensive results of vascular ischemia (which causes anterior optic nerve edema), edema in a crowded disc (which causes compartment syndrome), and a subsequent cascade of vasogenic and cytotoxic factors[4, 12]. All these events ultimately lead to axonal degeneration and retinal ganglion cell apoptosis. Accordingly, potential therapeutic interventions targeting different parts of the pathogenic mechanism have been developed.
Histopathological and electron microscopic studies have shown that initial ischemia in the anterior optic nerve head is probably triggered by acute hypoperfusion of the vascular network originating from the short posterior ciliary arteries. Previous studies have reported that not only can EECP accelerate reperfusion of the poorly perfused cerebral microvasculature and retinal artery, increase the blood flow velocity of the ophthalmic artery, but it can also improve endothelial function and collateral angiogenesis[14–16.] Additionally, EECP is thought to be highly safe and well-tolerated in selected patients[7, 17]. Therefore, EECP was expected to be a safe and effective intervention in ocualr ischemic diseases. Previously, we reported in 16 NAION patients that visual acuity had improved from 0.92 to 0.40 (LogMAR) after EECP treatment (1 h daily for 12 days) . However, the study did not have a control group. Therefore, the current controlled study with detailed examinations and a long follow-up period was deemed necessary to further evaluate the safety and long-term benefits of EECP treatment for NAION.
Unfortunately, this study demonstrated no obvious long-term benefit of EECP treatment in NAION patients with NAION onset < 8 weeks, regarding visual function and risk of fellow eye involvement. During the treatment period, which was no less than the treatment durations in the previous EECP studies reporting promising results regarding angina[7, 17–19], the safety of EECP was confirmed.
IONDT reported that around 40% of NAION patients might spontaneously regain 3-line visual acuity, which might explain the paradox involving the current study and our previous study, as the improvement in our previous study was probably not attributable to EECP. There are few other studies on the effectiveness of EECP in NAION patients. One such study reported significant visual acuity improvement after EECP treatment in patients with carotid artery stenosis-related ocular ischemic diseases, including ischemic optic neuropathy (which includes more conditions than NAION), retinal artery occlusion, and ocular ischemic syndrome. The study did not include a control group and the curative rate for the ischemic optic neuropathy subgroup was not reported. Thus, the effectiveness of EECP of NAION has not been proven.
Among the therapies tested in NAION patients, aspirin and anticoagulants have been acted on thrombosis and both vasopressors and vasodilators have been proposed to be useful for regulating vasodynamic factors[6, 21–24]. Although they all aimed to resolve the initial triggers of disc edema, there was no visual function improvement from any of the treatments. Considering the results of the current study, we speculate that interventions targeting the pathophysiological factors that are relevant prior to disc edema might not be helpful for improving visual function. Once disc edema is triggered, a destructive closed loop may be formed by a cascade of events, including compartment syndrome with axonal and capillary compression, increased ischemia, increased release of cytotoxic factors, and vasogenic and cytotoxic disc edema[4, 25, 26]. Future interventions should pay more attention to disrupting this loop. Furthermore, novel NAION animal models have recently emerged, which will help researchers to evaluate new drugs.
As stated by Newman et al., one of the most important approaches regarding NAION management is to reduce the risk of fellow eye involvement. To protect against fellow eye involvement, potential etiological factors should be corrected first. As mentioned above, EECP can accelerate reperfusion and increase the blood flow velocity of the ophthalmic artery, which might improve the vascular circulation of the fellow eye and theoretically prevent fellow eye involvement. However, EECP did not show any protective effect regarding fellow eye involvement in this study. The rate of sequential attack during the 6-month follow-up period was relatively high (25–28%) compared to that in other studies (15–20%)[28, 29]. This might be explained by the fact that patients without fellow eye involvement can easily be lost to follow-up after stabilization of the visual acuity in the first eye. As a result, the rate of fellow eye involvement identified in this retrospective study might be much higher than the actual rate. As optic nerves are the nerve endings of the cerebrum, many consider NAION and intracranial cerebrovascular ischemic disease to be similarly related. Consequently, long-term aspirin use has also been recommended by some practitioners as a secondary prevention method, despite the controversy regarding the current evidence. A large randomized controlled trial is necessary to provide more credible evidence.
As a retrospective study, some limitations were inevitable in the current study. As the patients had chosen whether or not to undergo EECP treatment freely, this may have led to unrecognized bias, even though there were no significant differences regarding baseline characteristics (including the risk factors) between the two groups. Although there is no definite therapeutic window for NAION treatment, many studies have specified a 2-week window[9, 31, 32]. Most patients in current study had exceeded 2-week window at presentation. However, no differences were observed between the eight eyes underwent EECP within the 2-week therapeutic window and the 29 underwent EECP after this window. Thus, effort was devoted to improve the current frustrating situation regarding NAION treatment, but no significant effects were observed after EECP treatment.