Journal of Neuro-Ophthalmology:
Current Concepts in the Diagnosis, Pathogenesis, and Management of Nonarteritic Anterior Ischemic Optic Neuropathy
Miller, Neil R MD
Department of Neuro-Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
The author reports no conflict of interest.
Address correspondence to Neil R. Miller, MD, Department of Neuro-Ophthalmology, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287; E-mail: firstname.lastname@example.org
Anterior ischemic optic neuropathy (AION) is the second most common cause of optic nerve-related permanent visual loss in adults after glaucoma. There are 3 types of AION: nonarteritic, perioperative, and arteritic. In this editorial, I will consider only nonarteritic AION (NAION), the most common form, about which surprisingly little is known regarding pathogenesis or treatment.
Most cases of NAION occur in patients older than 55 years, with men and women being affected equally. Most have underlying systemic vascular disease, although this may be undiagnosed at the time of onset. The majority of cases of NAION are sporadic, but familial cases have also been reported (1). The prevalence of NAION in the United States has been reported to be between 3 and 10 per 100,000 (2).
NAION usually presents with painless unilateral loss of acuity, visual field, or both. Eye pain is unusual, and pain on eye movement is extremely rare (3). Visual acuity is variable, ranging from 20/15 to no light perception. Any visual field defect can be present, but the most common is an arcuate or altitudinal defect. A relative afferent pupillary defect is always present if the condition is unilateral, and there is no optic nerve or retinal disease in the fellow eye. The affected optic disc is typically swollen and hyperemic, with the hyperemia distinguishing it from the pale swelling that is typical of the arteritic form of AION. Peripapillary flame-shaped hemorrhages are almost always present.
Although there are exceptions (4), NAION occurs almost exclusively in patients with a typical morphology of the optic disc, that of a very small central cup (<0.3 cup-to-disc diameter), and may itself be smaller than normal (5). This appearance has been termed the “disc-at-risk.” In addition, patients almost always have systemic vascular risk factors, such as hypertension, hypercholesterolemia, diabetes mellitus, or a combination of these disorders (5,6). Other associations have been suggested or identified, including nocturnal hypotension, anemia, hyperhomocysteinemia, obstructive sleep apnea syndrome, and some coagulopathies (7). In addition, NAION may occur after various ocular and nonocular surgeries (6,8-10).
A number of medications have been associated with the development of individual cases of NAION. Some, such as pegylated interferon-alpha, appears to be related to the development of NAION in only a few isolated cases (11,12); however, more controversial is the relationship of NAION to the use of erectile dysfunction drugs (EDDs) and the cardiac medication amiodarone (13-16).
The current EDDs, sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra), are phosphodiesterase-5 inhibitors. Because they cause peripheral vasodilation and thus systemic hypotension, particularly in older individuals whose erectile dysfunction is related to systemic vascular disease or its treatment, it is reasonable to hypothesize that these drugs could induce NAION. Indeed, a number of cases of NAION have occurred that have been temporally related to the use of EDDs (17,18). In addition, several challenge cases have been reported; i.e., cases in which transient blurred vision occurred on several occasions following the ingestion of one of these drugs, eventually followed by permanent visual loss and clinical evidence of NAION. Nevertheless, fewer than 100 cases of NAION have been reported in patients taking an EDD compared with more than 50 million prescriptions having been written. I agree with those who recommend that any male patient who develops apparent NAION be asked about the use of EDDs (in private!) and that any patient who asks about using EDDs have careful disc assessment and be told about the low but potential risk of NAION, particularly if he has a disc-at-risk (19).
Amiodarone was developed in the 1960s for treatment of angina but now is used as a first-line drug for atrial fibrillation in patients with left ventricular dysfunction and congestive heart failure. Although it has long been known that ocular symptoms, most frequently seeing blue-green rings or halos around lights, occur in 1%-11% of patients, it was not until 1987 that it was suggested that patients taking amiodarone had an increased risk of developing NAION compared with the normal population (20). Subsequently, numerous case reports, case series, and pathology reports have linked amiodarone to the development of NAION, which usually is insidious in onset and bilateral, with resolution of disc swelling slower than the typical NAION. On the other hand, the author of a large prospective study concluded that at commonly used clinical doses, amiodarone either never or infrequently causes bilateral visual loss from NAION. Although it may be that some patients taking amiodarone do not recognize that they have developed visual loss or that the ophthalmologists caring for them ascribe visual loss in these vasculopaths to other causes, such as cataracts or macular degeneration, it seems clear that if amiodarone causes an optic neuropathy, the visual loss in such cases is not particularly severe. In any event, I agree with the recommendation that any patient who develops NAION be asked if he or she is taking amiodarone, that anyone taking amiodarone who develops an anterior optic neuropathy be told of the possible association between the drug and NAION, and that the patient's cardiologist and/or primary care provider be contacted and told of the possible association, at which point a decision to stop or continue drug can be made by the physician and patient (14).
Whatever its cause, NAION is characterized histologically by ischemia at the level of the prelaminar/laminar portions of optic nerve supplied by the circle of Zinn-Haller via short posterior ciliary arteries. Thus, this is not a disorder of large or medium-sized vessels but rather small-caliber vessels such as arterioles or capillaries (5).
About 40% of patients who develop NAION will experience a spontaneous improvement in visual function, with visual acuity being more likely to improve than visual field. As this occurs, the disc swelling resolves, and the disc becomes pale but not cupped as it does in arteritic NAION.
Patients in whom NAION occurs are at risk for subsequent cerebrovascular and cardiovascular events (e.g., transient ischemic attack, stroke, myocardial infarction) and their associated mortality. Many have an increased number of white matter lesions in the brain compared with age-matched controls (21). Thus, patients in whom the diagnosis is made should be told to undergo a complete physical examination, and their primary care provider should be notified of the occurrence of the condition and its systemic prognosis. Patients should be evaluated for systemic vascular disorders and treated appropriately. Because of the potential role of nocturnal hypotension in the development of NAION, patients with hypertension should be told to take their antihypertensive drug in the morning or during the day, not at night.
There is a small risk for recurrent NAION in the same eye (3%-5%) and a variable risk of NAION in the fellow eye (15%-25%) over the subsequent 5 years. It has been suggested that aspirin may reduce the risk of NAION in the fellow eye (22), but no controlled clinical trials have been performed testing this hypothesis, in large part because of the wide usage of aspirin and aspirin-containing products and the number of patients who would have to be followed over time to determine the efficacy of the drug.
The treatment of NAION is one of the most controversial and contentious issues surrounding the condition (23,24). At one time, it was suggested that optic nerve sheath fenestration (ONSF) was beneficial in patients experiencing progressive loss of visual function from NAION, but both retrospective series (25) and a controlled clinical trial to test this hypothesis failed to produce any evidence of such a benefit (26). The latter study actually found that patients treated with ONSF fared worse from a visual standpoint than those who were not treated.
The primary medications used for the treatment of NAION are corticosteroids, both as an intravitreal injection (27-29) and by systemic administration (29). While the results of these are controversial, many physicians now at least discuss this potential treatment with patients who experience acute NAION. Other drugs have been suggested to be potentially beneficial in small primarily nonrandomized case series. These include intravitreally injected bevacizumab (28,30), even though use of this agent has been associated with the development of NAION in patients treated for wet macular degeneration (31). A particularly exciting new drug that was found to be associated with an improved visual outcome in a small but double-masked prospective study is erythropoietin. This drug appears to have neuroprotective properties apart from its effects on the hematopoietic system.
It seems clear that some patients develop a condition that looks ophthalmoscopically like typical NAION but is unassociated with any visual dysfunction (32-34). In these cases of “incipient NAION,” the disc swelling resolves spontaneously and never recurs in 50%, resolves and then recurs symptomatically in 25%, and progresses to symptomatic NAION in the remaining 25%.
The previous lack of an animal model of NAION has hampered efforts to determine the optimum treatment of the condition; however, there now exist both murine and primate models of the condition (35). Although the method used to create AION in these models may be quite different from the pathogenesis of the human form (36), they nevertheless provide a platform on which to test treatment options. I am hopeful that the coming years will provide more information regarding pathogenesis, prevention, and treatment of NAION.
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