NAION is a perplexing disorder. No treatment is effective, visual improvement is unimpressive,² and the pathophysiology is unknown.³ A feature common to patients with NAION is a crowded optic disc, the structure through which 1 200 000 axons from the retina converge before passing through the sclera toward targets in the brain. Swelling within the confines of a tight disc can lead to a compartment syndrome^4-5 in which cycles of swelling and ischemia reciprocate until infarction ensues. But what causes the initial swelling? Despite the lack of clinical and pathological evidence, the predominantly held assumption is that edema is precipitated by occlusion of microvascular arteriolar branches of 1 or more short posterior ciliary arteries within the optic nerve from systemic or local hypotension. However, the clinical and pathological evidence (detailed later) does not support arterial occlusion in NAION.

Furthermore, there are several unusual features of NAION that distinguish it from several other ischemic disorders of the visual system. For example, patients often have asymptomatic disc edema for weeks to months before visual loss ensues.⁶ There is some association with the use of phosphodiesterase-5 inhibitor drugs for erectile dysfunction, although this is controversial. Another example is that NAION only rarely recurs in the same eye.

We believe that the reason the etiology of NAION has been enigmatic is a misplaced focus on arterial insufficiency. Instead, we hypothesize that in many cases NAION is precipitated by venous insufficiency, with venous congestion causing initial disc edema. The creation of a compartment syndrome and subsequent cytotoxic and vasogenic (interstitial) edema cause infarction and tissue loss. We discuss how this reframing of NAION pathophysiology explains many of the clinical and pathological features of the disease. Finally, we describe testable implications for diagnosis and treatment.

NAION OFTEN DOES NOT HAVE CLINICAL CHARACTERISTICS OF AN ARTERIAL DISEASE

NAION DOES NOT HAVE PATHOPHYSIOLOGICAL CHARACTERISTICS OF AN ARTERIAL DISEASE

The vascular bed of the occlusion in AAION often includes the choroidal circulation as a result of posterior ciliary artery vasculitis. Occlusion of a posterior ciliary artery in the monkey results in choroidal circulation changes.⁸ In contrast, the infarct in NAION does not fit the vascular bed of any known artery,⁵ and fluorescein angiography in NAION demonstrates normal choroidal filling and mildly delayed arterial filling of the anterior (prelaminar) disc alone.⁹ The pathological findings of NAION also do not resemble those of a lacunar stroke¹⁰ in that there is no evidence of lipohyalinosis.¹¹

RISK FACTORS FOR NAION ARE NOT SPECIFIC TO ARTERIAL DISEASE

HYPOTHESIS: NAION IS A PRIMARY VENOUS OCCLUSIVE DISEASE

The degree of visual impairment of NAION shows a similar pattern to venous occlusive disease of the central nervous system. As with cerebral infarction secondary to venous occlusion, the degree of permanent damage in NAION is variable and is often milder than that seen with arterial infarction.¹⁶ Pathologically, experimentally, and radiologically, there is early cytotoxic edema followed by vasogenic edema along with capillary hemorrhages not dissimilar to those seen with NAION.^17-21

What can initiate occlusion of CRV tributaries? Increased venous pressure from sleep apnea²² or recumbency during sleep may contribute to a cascade of events leading to NAION. Vasodilation of the CRA can compress the CRV and its tributaries within their shared sheath. This mechanism would explain NAION in the setting of prolonged hypotension, nocturnal hypotension, shock, or phosphodiesterase-5 inhibitor erectile dysfunction drugs, all of which are characterized by arterial dilation. Finally, upstream venous congestion such as cavernous sinus thrombosis²³ or ligation of the jugular vein²⁴ can cause NAION, but this occurs rarely, probably because of collateral venous drainage from the CRV.

We are not suggesting that NAION is due to occlusion of the CRV but rather that it results from closure of tributary venules that receive blood from optic nerve capillaries and drain into the CRV posterior to the surface of the optic nerve head. In contrast, the clinical picture of CRV occlusion (CRVO) probably reflects occlusion of the CRV anteriorly and resultant hemorrhage and leakage of capillaries within the retina that drain into retinal veins. Decreased venous outflow within the anterior optic nerve would not be expected to cause the hemorrhagic retinal findings of CRVO or delayed retinal venous filling because there are significant collateral venous drainage pathways from the retina. In fact, posterior venous occlusion in CRVO is associated with less retinopathy than anterior occlusion,²⁵ and ligating the CRV as it exits the optic nerve does not cause retinal hemorrhage.²⁶ Cilioretinal artery occlusion, which often occurs in conjunction with CRVO, may be the result of a congested CRV causing secondary cilioretinal artery compression, the converse of the mechanism we suggest for cases of NAION induced by CRA vasodilation.²⁷

VENOUS INSUFFICIENCY EXPLAINS SEVERAL IDIOSYNCRATIC FEATURES OF NAION

The first feature is premonitory asymptomatic disc edema. Some patients have weeks to months of asymptomatic disc edema, which either worsens and becomes symptomatic or spontaneously resolves.⁶ It is likely that this phase involves venous congestion of the anterior optic nerve but without frank infarction (ie, cytotoxic and vasogenic edema).

The second is possible association with the use of the phosphodiesterase-5 inhibitor erectile dysfunction drugs. These produce erections partly by vasodilating arteries that fill cavernous venous spaces to systolic blood pressure, secondarily blocking venous outflow and thereby causing venous engorgement. We suggest that the same mechanism in the anterior optic nerve, where the CRA and CRV share a common adventitial sheath, could cause NAION in those patients with discs at risk. Prolonged arterial dilation within the fibrous sheath would decrease optic nerve drainage to the CRV via its tributaries. Although the association between the erectile dysfunction drugs and NAION is controversial,²⁸ there is at least 1 case with multiple rechallenge episodes.²⁹

Third is the high incidence of NAION in diabetes, particularly in younger patients. Although diabetes predisposes to both arterial and venous disease, it also is associated with capillary endothelial leakage and would be expected to produce more vasogenic edema for a given amount of venous pressure elevation.

TESTABLE IMPLICATIONS

If venous occlusion preceded optic nerve infarct in NAION, we would also predict that decreasing venous congestion would decrease the subsequent optic nerve tissue loss. Most patients with NAION are seen after the infarction has occurred, but some have long-standing premonitory disc edema and would be candidates for abortive therapy. One approach would be to decrease venous congestion using the same therapy considered for priapism, blocking nitric oxide.³¹ This would not be expected to prevent NAION from arterial infarction.

In summary, we suggest that NAION has been challenging to elucidate and recalcitrant to treat because of the focus on arterial ischemia, when the problem is more likely of venous origin in many cases. We propose that if experimental studies confirm this hypothesis, then anterior venous ischemic optic neuropathy could become a more precise designation for many cases of what has hitherto been called NAION.

AUTHOR INFORMATION

Submitted for Publication: December 11, 2007; final revision received March 4, 2008; accepted March 10, 2008.

Financial Disclosure: Dr Levin served as a paid consultant for attendance at a 1-day advisory board meeting sponsored by Pfizer in October 2005 on NAION and will be one of the investigators in a planned noninterventional observational clinical study of phosphodiesterase-5 inhibitor drugs in NAION sponsored by Pfizer. He also has served or serves as a consultant to Alcon, Allergan, Biogen, Eyetech, Danube, Fovea, Inspire, Novartic, Ovation, Merck, Pfizer, Santen, Serono, and Teva on areas unrelated to the subject of this article.

Additional Contributions: Anthony Arnold, MD, Neil Miller, MD, Harry Quigley, MD, and Peter Savino, MD, provided helpful comments on previous versions of the manuscript.