Non-Arteritic Anterior Ischemic Optic Neuropathy (NAION)
Ischemia of the optic nerve can occur in different anatomical locations and can have a myriad of etiologies. It is helpful to classify these syndromes by location and etiology (if known) since their presenting signs and symptoms as well as treatment and prognosis will vary. By definition, anterior ischemic optic neuropathy (AION) involves the 1mm segment of the optic nerve head, also known as the optic disc, and results in visible disc swelling. AION has two varieties. The first is non-arteritic (NAION) and the second is arteritic (AAION) and is almost always associated with giant cell arteritis. Posterior ischemic optic neuropathy (PION) encompasses those conditions that result in ischemia to any portion of the optic nerve posterior to the optic disc. By definition, PION will not cause disc edema.
The vast majority of cases of NAION are idiopathic but some specific etiologies have been reported to be associated with NAION although in all of the cases, no causal relationship has been definitively established.
Sleep Apnea Syndrome (SAS)
There have been case series that have demonstrated a possible association between SAS and NAION . The best evidence comes from a case-control study of 17 consecutive patients with NAION who were compared to 17 age and sex matched controls. In this study, 71% of the patients with NAION met criteria for SAS compared to 18% of controls . Since this association has been discovered, several retrospective cohort studies looking at national health insurance databases have found a significantly higher risk of NAION development in patients with SAS, even after controlling for confounding variables. It is unclear how SAS can cause NAION but it is hypothesized that apneic spells might result in acute increases in blood pressure, intracranial pressure or nocturnal hypoxemia which could cause optic nerve edema and ischemia .
The interferons are a group of glycoproteins with complex antiviral, antitumor, and antiangiogenic activities. In 1995 Purvin reported the development of acute bilateral, sequential vision loss, likely from NAION, in 2 patients taking interferon alpha for malignant neoplasms . It has been hypothesized that interferon alpha might cause an NAION by depositing immune complexes in the optic disc circulation that leads to ischemia . Since her original report in 1995, there have been a handful of additional reports of a possible association although a causal relationship has not been definitively established .
Sildenafil is an effective treatment for erectile dysfunction (ED) by inhibiting phophodiesterase type 5 (PDE5), an enzyme that regulates blood flow in the penis. Therapeutic doses of these medications used to treat ED can cause systemic hypotension. It has been hypothesized that these medications might exaggerate the physiologic nocturnal hypotension resulting in ischemia to the optic nerve head and compartment syndrome in susceptible patients with small cup to disk ratios . Additionally, these medications might interfere with the autoregulation of blood flow thereby decreasing perfusion to the optic nerve head . This association remains very controversial and multiple prospective studies have been conducted and shown an increased risk of NAION development in patients with exposure to PDE5-inhibitors. However, a systematic review and meta-analysis found no significant association between NAION and PDE5-inhibitor use after analyzing 5 original articles, indicating a need for more prospective clinical studies.
Optic Disc Drusen
Optic disc drusen might increase the risk of developing NAION by theoretically contributing to the “crowded” optic nerve in discs with small cup to disc ratios. There are anecdotal reports of NAION occurring in patients with optic disc drusen but a causal relationship has not been proved .
The vast majority of cases of AION are non-arteritic . NAION affects between 2.3 and 10.3 people per 100,000 individuals per year making it the most common cause of acute optic neuropathy in patients over the age of 50.  There are approximately 6000 new cases per year and Caucasians account for nearly 95% of cases . Men and women are nearly equally affected and the mean age at symptom onset varies between 57 and 65 years depending on which study you read . However, one retrospective study demonstrated 23% of patients with NAION were less than 50 years old .
The pathophysiology of NAION is controversial and no one mechanism had been definitively demonstrated. It is presumed to result from a circulatory insufficiency, or infarct, within the retrolaminar portion of the optic nerve head that is supplied by the short posterior ciliary arteries (SPCA). This presumption is based upon indirect evidence from atypical forms of NAION . Additional fluorescein and indocyanine studies have shown delayed optic disc filling in the prelaminar layers of the optic disc with normal choroidal circulation suggesting that the vasculopathy is located in the para-optic branches of the SPCA after their branching from the choroidal branches rather than in the short ciliary arteries themselves . Optical coherence tomography angiography (OCTA) performed in patients with NAION also confirmed the presence of microvascular changes in cases of patients with acute optic disc edema. The cause of optic disc edema is unclear but there is general agreement that the final common pathway leads to a compartment syndrome from axonal edema in a structurally crowded optic disc  resulting in apoptotically induced retinal ganglion cell death . Many mechanism have been presumed to be involved in the optic disc edema and it is worthwhile to explore them in a little more details.
Optic Disc Anatomy
Up to 97% of patients with NAION have small optic discs with small or absent optic cups. Acutely, it can be difficult to determine the cup/disc ratio because of optic nerve edema and the clinician should note the cup/disc ratio in the fellow eye. It is typically less than 0.3 and these discs are referred to as a “disc at risk”. The role of the small cup/disc ratio is unclear but there are probably contributory mechanical effects of the small cup/disc ratio in the pathogenesis of NAION. A crowded disc can exacerbate chronic mechanical obstruction to axoplasmic flow resulting in secondary compression and ischemia. An inhibition in axoplasmic flow can inhibit critical neurotrophins leading to additional ganglion cell death .
The optic nerve head efficiently autoregulates blood flow . Flow is normally maintained constant despite variations in perfusion pressure and intraocular pressure under various metabolic conditions and different diseases can impair the optic nerve’s ability to autoregulate its blood flow . Systemic hypertension, arteriosclerosis, vasospasm or medications may reduce the autoregulatory capacity of the optic disc . Vasoactive substances might be released in response to ischemia that influence the autonomic control of blood vessels. Intravitreal and intravenous injections of endothelin-1 have been shown to decrease optic nerve head blood flow and produce chronic optic disc ischemia in rabbits . Hayreh has postulated that the release of endogenous serotonin may contribute to optic nerve ischemia by vasoconstricting arterioles and impairing autoregulation.
There are normal nocturnal fluctuations in blood pressure and Hayreh has theorized that nocturnal systemic hypotension may contribute to NAION. Patients with chronically altered optic disc autoregulation, from such diseases as systemic hypertension and atherosclerosis, might be susceptible to exaggerated decreases in nocturnal blood pressure. This effect might be exacerbated in patients treated with aggressive antihypertensive therapy, especially if taken right before bedtime .
Levin et al. believe the clinical and pathological evidence does not support arterial occlusion in NAION and they have theorized that NAION might result from venous insufficiency that occurs from closure of tributary venules receiving blood from optic nerve capillaries that drain into the central retinal vein posterior to the optic nerve head . They argue that NAION does not have the clinical characteristics of an arterial disease. AAION causes a pallid edema that ultimately resolves leaving significant excavation and atrophy of the disc whereas NAION typically exhibits normal or hyperemic edema that resolves leaving relatively preserved disc substance . Disc hemorrhages are seen less commonly in AAION and central retinal artery occlusion but are more common in NAION and central retinal vein occlusion. NAION causes less severe vision loss than AAION and they believe this is akin to less severe neuronal damage from cerebral venous disease. Furthermore, the choroidal circulation is typically affected in AAION due to posterior ciliary artery occlusion (and sometimes ophthalmic artery) and occlusion of this artery in the monkey results in choroidal circulation changes . The infarct in NAION does not fit the vascular bed of any known artery,  and as I discussed earlier, fluorescein angiography demonstrates normal choroidal filling and mildly delayed arterial filling of only the prelaminar disc .
Vasculopathic Risk Factors
NAION is presumed to result from vascular insufficiency but there is no clear association of well-known risk factors for ischemic small vessel disease and NAION. Lipohyalinosis is suspected in the pathogenesis of NAION but no histopathologic confirmation has been demonstrated . In the IONDT, 60% of NAION patients had at least one vasculopathic risk factor with hypertension (47% and diabetes (24%) being most common . Smoking does not seem to be an independent risk factor .
Patients with NAION will typically have some or all of the signs of an optic neuropathy including decreased visual acuity, dyschromatopsia, an RAPD, a swollen optic nerve with splinter hemorrhages and a visual field defect.
Visual acuity may vary widely but no light perception is exceptionally rare and when present, should make the clinician suspect AAION or another diagnosis. Much of what we know about the range of visual acuities comes from the IONDT. In this study, 49% of patients had an initial visual acuity of 20/64 or better and 66% had 20/200 or better. . Others have demonstrated that in patients seen within two weeks of symptom onset, nearly 50% of patients will have visual acuity 20/30 or better.
Acquired loss of color vision, dyschromatopsia, is a very sensitive sign of optic nerve dysfunction. Unlike optic neuritis, the degree of dyschromatopsia in NAION is typically proportional to visual acuity loss. However, altitudinal and quadrantic defects are commonly seen in NAION and in these cases there is often sparing of color vision likely due to sparing of central fibers involved in central vision.
Despite loss of vision in one eye, the pupils will be round and symmetric. There will be no anisocoria (something often confused by medical students and neurology residents). A relative afferent pupillary defect will be present as long as the contralateral eye is normal.
Any visual field defect relating to optic nerve damage can occur. Nearly 25% of patients will have central scotomas but the majority of patients will have an altitudinal field loss, inferior being most common.
Optic disc and retinal appearance
As mentioned earlier, optic disc edema is always present in the acute phase of NAION (the reason will be discussed in the section under Pathophysiology) and comes in two varieties, diffuse or segmental. Segmental (typically altitudinal) is more common but it does not consistently correspond to the accompanying area of visual field loss . The edema is typically hyperemic and rarely pallid. Pallid edema is common in AAION and should alert the clinician to the possibility of giant cell arteritis. Peripapillary splinter hemorrhages are seen in nearly three-quarters of patients  and its presence can sometimes help to differentiate NAION from optic neuritis since they will be present in 5-15% of patients with optic neuritis . Retinal exudates are uncommon but both hard and soft exudates were reported in up to 7% of patients in the IONDT and the retinal arterioles can be focally narrowed in the peripapillary region in two-thirds of patients .
The classic description of patients with NAION presenting with acute, painless unilateral vision loss that is often described as a blurring or cloudiness of vision, often inferiorly, has been expanded. Although the majority of patients do not have accompanying pain, headache or periocular pain is reported in 8-12% of patients, which can make it difficult to differentiate from optic neuritis. Patients with NAION report loss of vision that occurs over hours to days. Hayreh et al. have reported that over two-thirds of patients notice vision loss upon awakening which suggests that nocturnal arterial hypotension may be critically involved in the pathophysiology of NAION. However this was not confirmed by the ischemic optic neuropathy decompression trial (IONDT).
The diagnosis of NAION is a clinical one. In patients who present with the typical history of acute, painless, unilateral vision loss and who have the classic findings on examination including a hyperemic and swollen optic nerve with peripapillary splinter hemorrhages and a fellow eye with a small cup to disc ratio, no additional testing is required.
If the review of systems is positive for GCA then laboratory tests including ESR, CRP and platelets should be obtained and a temporal artery biopsy should be performed to exclude GCA. Some clinicians will obtain these inflammatory markers in any patient over the age of 50 years who presents with an NAION but it varies from clinician to clinician depending on their level of suspicion and clinical experience. Additional laboratory tests for hypercoagulable states can be considered in patients under 50 with additional personal or family history of early or unexplained thrombosis. Neuroimaging is not necessary in typical cases but MRI of the brain and orbits with gadolinium should be obtained in cases with significant pain, especially pain with ipsilateral eye movement, to exclude optic neuritis and multiple sclerosis. Neuroimaging should also be obtained in any patient exhibiting an atypical course including those with prolonged disc edema or progressive and/or recurrent visual loss more than two months after their initial presentation to exclude inflammatory or compressive lesions. It has been hypothesized that OCTA may be useful in diagnosing and predicting the severity of NAION based upon the blood flow to the optic disc, however studies have shown conflicting results about the utility of this imaging.
The most critically important entity to differentiate is AAION secondary to GCA because of the increased frequency of bilateral vision loss as well as cardiac and neurologic complications. The other main differential diagnosis is optic neuritis which can be secondary to multiple sclerosis.
There is no effective treatment for NAION. Although not proven, small vessel arterial occlusion with subsequent disc edema that results in a compartment syndrome in a “crowded” disc is one of the presumed etiologies of NAION. Different treatment modalities have been tried to help limit the pathological cascade initiated by these two conditions
There is very little data in the form of case reports looking at the effectiveness of anti-platelet agents and anticoagulants. Botelho et al. in a retrospective case-controlled study looked at visual outcome in 23 patients being treated with aspirin before and during the course of NAION and compared them to 55 NAION patients who did not use aspirin. They found no difference in initial or final visual acuity as well as initial and final mean deviation on automated perimetry between the two groups . Aftab et al. performed a prospective pilot study examining the use of anticoagulation in patients who presented within 4 weeks of onset of acute NAION. They showed that there was a higher proportion of patients in whom visual acuity improved when taking anticoagulation. However, this study was limited by a small sample size and lack of a control group. There are no reports in the English literature looking at the effectiveness of anticoagulation in NAION patients .
As described earlier, optic disc edema from NAION likely contributes to a compartment syndrome in “crowded” discs and contributes to axonal damage as well as retinal ganglion cell apoptosis. Corticosteroids are known to be highly effective in reducing vasogenic but not cytotoxic edema. Hayreh recently reported 613 consecutive patients seen between 1973 and 2000. Patients were given the option of being treated with prednisone or not. In patients treated within two weeks, the median time to resolution of optic disc edema was 6.8 weeks compared with 8.2 weeks in untreated patients (P<0.0001). In both groups the visual acuity and visual fields continued to improve up to 6 months. At 6 months, patients treated within 2 weeks with initial visual acuity of 20/70 or worse had visual acuity improvement in 69.8% compared to 40.5% in untreated patients (P=0.001). Nearly forty percent of treated patients had an improvement in their visual field defects at 6 months compared to 24.5% of untreated patients (p=0.005). Hayreh et al. concluded that early treatment of NAION with prednisone 80mg improves visual acuity and visual field defects . However as Atkins et al point out, these patients were not randomized and the untreated group had more vascular risk factors making it difficult to interpret these results . Further, the examiner was not masked to the treatment assignment. In 2018, Saxena et al. performed the first true double-blinded RCT examining the effectiveness of oral corticosteroids in treatment of non-diabetic NAION. While they noticed a larger improvement in BCVA at 6 months in the steroid group (P=0.02), there was no significant difference in the final BCVA between treatment groups. They also noticed subtly improved structural recovery, with the steroid group having a faster resolution of optic disc edema, but it appears these structural changes are clinically insignificant. Currently, there is one industry sponsored randomized trial using a synthetic RNA to block caspase 2, an enzyme in the apoptosis cycle. Patients with acute NAION are being studied to determine whether this agent will be an effective neuroprotective therapy (see NORDICclinicaltrials.com for details).
The IONDT was a randomized, single-masked, multicenter trial examining the safety and efficacy of optic nerve decompression surgery compared with careful observation alone in patients with NAION. The authors concluded that not only is optic nerve decompression surgery ineffective, it might be harmful and the study was abandoned early based upon overwhelming initial data.
Vision can worsen over the 2 week period following initial presentation and typically stabilizes by 2 months. In Hayreh’s review looking at the natural history of visual outcome in NAION, approximately 50% of patients had a visual acuity of 20/30 or better and nearly one-quarter were 20/200 or worse. 41% of patients seen within two weeks of symptom onset who had 20/70 or worse showed improvement at 6 months. Two years after the initial visit, there was worsening in 9% of eyes with initial visual acuity of 20/60 or better and in 18% of those with visual acuity of 20/70 or worse . Other studies have reported observing recovery of at least 3 Snellen acuity lines in 13% - 42.7% of patients . In general, the prognosis for visual recovery is better for younger patients. Vision in the affected eye will typically stabilize within two months. Progression or recurrence more than two months after initial presentation should bring the diagnosis of NAION into question and should prompt a re-evaluation. Reported episodes of recurrence in the affected eye range from 3% to 8% . Involvement of the fellow eye ranges from 15% to 24% over 5 years  . A systematic review and meta-analysis attempted to find a predictive determination of visual acuity in patients with sequential bilateral NAION and found that it is impossible to definitively determine visual outcomes in patients based on their initial presentation. It also found that the use of preventive measures after the first event do not have any effect on stopping development of NAION in the contralateral eye.
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