Nonarteritic Anterior Ischemic Optic Neuropathy

Etiology

The optic nerve head can be subdivided into 4 regions—intraocular, prelaminar, lamina cribrosa, and retrolaminar regions. Blood supply to the optic nerve head is primarily through the short posterior ciliary arteries.[14] Pial branches and the peripapillary choroid contribute to the retrolaminar and prelaminar regions, respectively, but significant variation exists. The short posterior ciliary arteries are branches of the ophthalmic artery.[15] Multiple branches of the short posterior ciliary arteries form the circle of Zinn-Haller, which surrounds the optic nerve as it passes through the sclera via the lamina cribrosa. All blood supply, whether from pial branches, choroid, or ciliary arteries, is derived from the ophthalmic artery, whose branches these smaller vessels represent.

The pathophysiology of NAION is not entirely understood. Still, it is accepted that relative hypoperfusion of the optic nerve head and structural or other factors lead to edema and infarction of optic nerve fibers, most often in the superior half of the optic nerve head.[16] Several systemic and ocular risk factors are known to increase the risk of NAION, including a small optic nerve cup (disc-at-risk), optic disc drusen, systemic hypertension, diabetes mellitus, OSA, and the use of phosphodiesterase-5 inhibitors. Still, their exact roles in the mechanism are not yet fully understood.[17] Crowded discs or disc-at-risk are the most substantial risk factor for developing NAION. A disc-at-risk is characterized as an optic nerve head with a small diameter and cup-to-disc ratio, typically 0.2 or less. In a disc-at-risk, optic nerve head edema induced by ischemic injury is believed to cause compression of the axons within a smaller, rigid scleral tunnel. Similarly, optic disc drusen are believed to contribute to axonal compression within the tight confines of the optic nerve head. Hypertension, diabetes mellitus, hyperlipidemia, and smoking all contribute to the vascular causes of NAION, including arteriosclerosis of branches of the ophthalmic artery and intimal thickening of the short posterior ciliary arteries.[18] OSA has been recognized more recently as an independent risk factor for NAION, likely due to its effect on nocturnal blood pressure.

NAION is a multifactorial optic neuropathy characterized by sudden, painless visual loss resulting from ischemia of the anterior portion of the optic nerve head. The underlying etiology involves both systemic and local vascular factors that contribute to optic nerve hypoperfusion and subsequent axonal damage. A structured breakdown of its etiology is as follows:

Anatomical Predisposition (Disc-at-Risk)

• Patients with NAION typically have a small, crowded optic disc with a minimal or absent physiological cup.
• This configuration is termed a disc-at-risk and is commonly bilateral.
• In these discs, axons are tightly packed within a confined scleral canal. Any swelling due to ischemia precipitates a compartment syndrome, resulting in secondary compression and infarction of adjacent nerve fibers.[4]

Vascular Insufficiency

• The anterior optic nerve is supplied primarily by the short posterior ciliary arteries and peripapillary choroidal circulation.
• Transient or sustained hypoperfusion of these vessels is the fundamental event leading to ischemia.[19]
• Potential vascular mechanisms include:
  • Nocturnal hypotension (especially in patients on antihypertensives)
  • Impaired autoregulation of optic nerve head blood flow
  • Atherosclerotic narrowing or occlusion of short posterior ciliary arteries [20]

Systemic Vascular Risk Factors

Numerous systemic comorbidities have been strongly associated with NAION.

Table 1. Systemic Risk Factors and Mechanisms Associated with NAION

Abbreviation: NAION, nonarteritic anterior ischemic optic neuropathy.

Nocturnal Hypotension

• NAION often occurs upon awakening, suggesting that low nighttime blood pressure plays a key contributing factor.
• Excessive blood pressure reduction during sleep, particularly in patients treated with nighttime antihypertensive medications, may decrease perfusion pressure in the optic nerve head below the critical threshold.[21]

Medications and Drug-Related Factors

Some drugs have been implicated in NAION, especially in susceptible individuals.

Table 2. Medications Implicated in NAION and Their Proposed Mechanisms

Abbreviation: NAION, nonarteritic anterior ischemic optic neuropathy.

Hypercoagulable and Hemorheological Conditions

Although less common, hypercoagulable states can predispose patients to NAION, particularly in young patients or those without traditional vascular risk factors.[22] Examples include:

• Antiphospholipid antibody syndrome
• Protein C or S deficiency
• Hyperhomocysteinemia
• Elevated hematocrit/polycythemia vera
• Elevated plasma viscosity (e.g., Waldenström macroglobulinemia) [23]

Genetic Susceptibility

• Familial clustering has been reported in some studies, suggesting a possible genetic predisposition.
• Variants in genes related to thrombosis; vascular tone, such as endothelin; or mitochondrial function are being explored, but no definitive genetic marker has been identified to date.[24]

Ocular and Structural Factors

• Aside from disc crowding, other local anatomical or ocular features may contribute to NAION:
  • Shallow cup-to-disc ratio
  • Drusen of the optic nerve head
  • Elevated intraocular pressure (in a few cases)
  • Anterior segment surgeries (e.g., cataract surgery in rare cases can precipitate NAION—referred to as postoperative NAION) [25]

Bilateral Involvement

• Although NAION is initially unilateral, the second eye is affected in 15% to 25% of cases within 5 years.
• Patients with ongoing uncontrolled systemic risk factors are more likely to experience sequential involvement.

Differentiating from Arteritic Anterior Ischemic Optic Neuropathy

Distinguishing NAION from AAION is crucial, as it is a medical emergency caused by GCA.

Table 3. Key Clinical Differences Between NAION and AAION

Abbreviations: NAION, nonarteritic anterior ischemic optic neuropathy; AAION, arteritic anterior ischemic optic neuropathy; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein.

Table 4. Etiological Factors Contributing to NAION

Abbreviations: NAION, nonarteritic anterior ischemic optic neuropathy; OSA, obstructive sleep apnea; PDE5, phosphodiesterase-5.

The etiology of NAION is multifactorial, often involving an interplay between local anatomical predisposition and systemic vascular insults. Understanding these factors is crucial in both the diagnosis and prevention of further visual loss, especially in the fellow eye. A comprehensive approach to evaluation, including systemic workup, risk factor modification, and interprofessional collaboration, is necessary to optimize outcomes for patients with this potentially vision-threatening condition.[26]

Epidemiology

NAION is the most common cause of optic neuropathy in adults older than 50.[1] The prevalence of NAION in the United States has been estimated to be anywhere between 2.3 and 10.2 per 100,000. NAION is less common in Black individuals and is most prevalent in the Caucasian population, presumably because Black individuals tend to have a larger cup-to-disc ratio and are thus less likely to have small optic nerve cups, which is the most significant risk factor for developing NAION. NAION is the most common acute optic neuropathy in adults older than 50 and represents a significant cause of irreversible visual loss. Understanding its epidemiology provides valuable insights into its prevalence, risk profile, demographic distribution, and public health implications.[4]

Incidence and Prevalence

• The annual incidence of NAION in the United States is estimated to be 2.3 to 10.3 cases per 100,000 individuals aged 50 or older.
• NAION is more common than AAION, which occurs at a lower rate (approximately 0.36 per 100,000 per year).
• Global prevalence data show variability based on population demographics and underlying comorbidities. Higher rates are noted in populations with a higher burden of systemic vascular diseases, such as diabetes mellitus and hypertension.[27]

Age Distribution

• NAION predominantly affects individuals aged 50 or older, with the peak incidence between those aged 60 and 70.
• NAION is rare in individuals younger than 50 but has been reported in younger individuals, often associated with sleep apnea, migraine, or prothrombotic states.[28]

Gender Differences

• Most studies show a slight male predominance, although some report a near-equal gender distribution.
• Differential rates of systemic risk factors, such as cardiovascular disease and sleep apnea, may influence the gender distribution.[29]

Racial and Ethnic Variation

• High-quality data on racial differences in NAION epidemiology are limited.
• However, US studies suggest that the Caucasian population is more commonly affected, possibly due to a higher prevalence of disc-at-risk anatomy.
• Some studies suggest a lower prevalence in African American populations, which may relate to differences in optic disc morphology and vascular anatomy.[30]

Laterality and Bilaterality

• NAION is typically unilateral at presentation.
• However, 15% to 25% of patients develop NAION in the fellow eye within 5 years.
• The risk of bilateral involvement is higher in patients with poorly controlled systemic risk factors or those who continue to be exposed to triggering conditions, such as nocturnal hypotension.[4]

Recurrent Nonarteritic Anterior Ischemic Optic Neuropathy

• True recurrence in the same eye is rare but has been documented.
• Recurrence may occur in patients with persistent or worsening vascular risk profiles.[7]

Systemic Comorbidities (Epidemiological Correlation)

Several epidemiological studies have shown a strong association between NAION and systemic diseases.

Table 5. Prevalence of Systemic Comorbidities in Patients with NAION

Abbreviation: NAION, nonarteritic anterior ischemic optic neuropathy.

OSA is notably underrecognized, but polysomnographic studies suggest a strong association with NAION due to repeated nocturnal hypoxemia and blood pressure fluctuations.

Time of Onset and Circadian Trend

• Approximately 70% to 80% of cases report sudden vision loss upon awakening, supporting the role of nocturnal hypotension in the pathogenesis of these conditions.
• This circadian pattern has prompted studies on the impact of nighttime antihypertensive medications in patients with NAION.[31]

Geographic Variation

• NAION occurs globally but shows regional variations in incidence, likely due to differing:
• Access to ophthalmic care and diagnostic tools
• Prevalence of vascular comorbidities
• Public health screening protocols [32]

• Extensive epidemiological studies from the United States, Japan, and the United Kingdom have reinforced the global burden of NAION, particularly among aging populations.

Risk of Second Eye Involvement

• Risk factors for second eye involvement include:
• Persistent uncontrolled systemic risk factors, such as diabetes mellitus and hypertension
• No treatment or correction of sleep apnea
• Presence of disc-at-risk in the fellow eye [7]

• The estimated 5-year cumulative risk of bilateral NAION is approximately 15% to 20%, with a higher risk observed in younger patients with underlying vasculopathy.

Table 6. Comparison of NAION, AAION, and Optic Neuritis

Abbreviations: NAION, nonarteritic anterior ischemic optic neuropathy; AAION, arteritic anterior ischemic optic neuropathy; OSA, obstructive sleep apnea.

Economic and Quality-of-Life Impact

• NAION significantly impacts daily functioning and quality of life, especially in individuals who lose vision in both eyes.
• Visual field defects and reduced contrast sensitivity impair activities, such as driving, reading, and work performance.
• Currently, there is no approved therapy to restore vision, making the prevention and control of risk factors essential.
• Recurrent cases or bilateral involvement increase the burden on healthcare systems and caregivers.

NAION is a relatively common optic neuropathy among the aging population and is often linked to systemic vascular comorbidities. The peak incidence of NAION in individuals older than 50, a strong association with nocturnal hypotension, and potential for bilateral involvement underscore the importance of early identification and modification of risk factors. Given the absence of definitive treatment, the epidemiological data support a preventive, interprofessional approach involving ophthalmologists, internists, sleep specialists, and primary care providers.[33]

Pathophysiology

As mentioned above, the exact pathophysiology of NAION remains unclear; however, the leading theory is that the hypoperfusion of short posterior ciliary arteries supplying the optic nerve head leads to localized edema of the involved axons.[34] In predisposed individuals—typically those with a small cup-to-disc ratio—the scleral canal through which the optic nerve passes into its intra-orbital compartment is small. Localized optic nerve head edema leads to a compartment syndrome, where the swelling is propagated by affecting the neighboring axons. This cascade eventually leads to severe axonal swelling or ischemia and apoptosis with functional loss of the affected axons. NAION results from a complex interplay of anatomical predisposition, vascular insufficiency, and secondary neural injury. NAION is characterized by acute ischemia of the optic nerve head, leading to rapid, painless monocular vision loss, typically upon awakening. Understanding its underlying pathophysiological mechanisms is crucial for both diagnosis and the development of preventive strategies.[35]

Anatomy of the Optic Nerve Head

The optic nerve head is primarily supplied by the short posterior ciliary arteries, which branch from the ophthalmic artery. These arteries form the paraoptic branches that perfuse the prelaminar and laminar regions of the optic nerve. The Zinn-Haller circle, an arterial circle formed by the anastomosis of short posterior ciliary arteries, plays a critical role in perfusing this region. Unlike other areas of the central nervous system, the optic nerve head lacks a significant collateral blood supply, making it vulnerable to ischemic insults.[36]

Disc-at-Risk and Crowded Optic Nerve Head

Disc-at-risk—a small, crowded optic disc with a small or absent physiologic cup— is the single most critical anatomical predisposition to NAION. Such a configuration limits space within the scleral canal, leading to mechanical crowding of axons. This anatomical feature is present in over 90% of patients with NAION and is frequently observed in the fellow eye as well. The disc-at-risk creates a milieu susceptible to compartment syndrome once edema develops. Even minor ischemia-induced swelling further compresses axons and microvasculature, perpetuating a vicious cycle of ischemia and axonal death.[37]

Hypoperfusion and Nocturnal Hypotension

Ischemia in NAION is believed to arise from hypoperfusion of the short posterior ciliary arteries, a process that can be exacerbated by systemic nocturnal hypotension commonly observed during sleep. Many cases of NAION occur upon awakening, thereby supporting this theory. Nocturnal hypotension is particularly pronounced in individuals on antihypertensive medications, especially beta-blockers or calcium channel blockers taken at bedtime. Combined with predisposing disc anatomy, a transient drop in perfusion pressure can result in a critical threshold of ischemia, triggering axoplasmic stasis, edema, and further compromise.[38]

Axoplasmic Flow Disruption and Edema

Once perfusion is compromised, axoplasmic flow within the ganglion cell axons is disrupted. This disruption results in intra-axonal swelling and accumulation of metabolic products, exacerbating the local edema. The optic nerve head, confined within the rigid lamina cribrosa and scleral canal, cannot accommodate this swelling, leading to:

• Compartment-like syndrome
• Compression of surrounding axons and capillaries
• Further reduction in local blood flow (ischemic vicious cycle) [39]

Apoptosis and Ganglion Cell Death

As ischemia progresses, ganglion cells and their axons undergo apoptosis. Histopathological studies demonstrate:

• Segmental infarction of the optic nerve head
• Swelling in the prelaminar and laminar zones
• Loss of retinal ganglion cells over time
• Demyelination and axonal dropout in affected regions

Eventually, this leads to optic disc pallor and permanent visual field deficits, typically characterized by altitudinal or arcuate patterns of loss. [40]

Role of Endothelial Dysfunction and Vascular Risk Factors

Many systemic diseases associated with NAION—such as diabetes mellitus, hypertension, and hyperlipidemia— contribute to endothelial dysfunction through the following:

• Decreased nitric oxide production
• Impaired autoregulation of blood flow
• Increased oxidative stress and vascular stiffness

These changes reduce the optic nerve's ability to autoregulate perfusion, especially under stress (e.g., during hypotension). Microvascular occlusion or sluggish flow further decreases oxygenation of the optic nerve head. Additionally, OSA leads to intermittent hypoxia, oxidative stress, and swings in blood pressure—all of which worsen optic nerve perfusion and increase the risk of NAION.[41]

Thrombotic and Prothrombotic Mechanisms

Although NAION is typically not embolic, hypercoagulable states and prothrombotic conditions may play a role in select younger patients. Potential underlying disorders include:

• Antiphospholipid antibody syndrome
• Protein C or S deficiency
• Hyperhomocysteinemia

In these patients, vascular occlusion may result from localized thrombus formation rather than hypoperfusion alone.[42]

Inflammatory Mediators and Blood-Optic Nerve Barrier Breakdown

Acute ischemic injury may also result in the release of inflammatory cytokines and disrupt the blood-optic nerve barrier, promoting local inflammation. Although NAION is nonarteritic, such inflammation may worsen axonal injury and contribute to subsequent gliosis and optic disc pallor. This low-grade inflammation is distinctly different from the florid granulomatous inflammation observed in AAION, where GCA plays a central role.[43]

Differential Perfusion Territories in Optic Nerve Head

NAION typically involves the superior or inferior arcuate regions of the optic nerve head, sparing the papillomacular bundle initially. This anatomical preference explains the common altitudinal visual field defects observed in NAION. The segmental vascular supply from the short posterior ciliary arteries contributes to this pattern. If only 1 or 2 branches are compromised, partial ischemia may occur, producing incomplete visual loss.[7]

Natural History and Secondary Degeneration

Over weeks to months, the initial swelling of the optic nerve resolves, often leaving behind optic disc pallor. Secondary degeneration of remaining axons and their target neurons in the lateral geniculate nucleus and visual cortex has been demonstrated in imaging and histopathological studies.

Importantly, vision rarely improves after initial loss; however, a small subset of patients may regain a few lines of acuity depending on the degree of axonal preservation and adaptive mechanisms, such as fixation shifts.

The pathophysiology of NAION involves a multi-hit mechanism, including:

• Anatomical predisposition (disc-at-risk)
• Acute perfusion failure, particularly during nocturnal hypotension
• Axoplasmic flow stasis and edema
• Compartment syndrome–like compression
• Apoptosis and irreversible optic nerve damage

Understanding these mechanisms underscores the importance of early identification of high-risk patients and highlights the need for preventive strategies, especially in managing nocturnal hypotension, sleep apnea, and systemic vascular risk factors. Although no proven treatment exists to reverse NAION, its pathophysiology guides both supportive care and future therapeutic targets, such as neuroprotection and vascular modulation.[44]

Histopathology

NAION represents a noninflammatory infarction of the anterior portion of the optic nerve head. Unlike its atheritic counterpart (AAION), NAION lacks the granulomatous inflammation typically associated with GCA. Instead, the histological hallmark is ischemic axonal injury, often secondary to compromised perfusion from the short posterior ciliary arteries. Postmortem and biopsy studies provide insight into the microscopic features observed during the acute and chronic phases of NAION.[4]

Gross Appearance

• In enucleated eyes or optic nerve specimens, the anterior portion of the optic nerve appears swollen in the acute phase and pale and atrophic in the chronic phase. 
• The optic disc shows sectoral pallor corresponding to the affected vascular territory.
• In advanced stages, the nerve fiber layer is thinned, and optic disc cupping is generally absent—a distinguishing feature from glaucomatous optic neuropathy.[45]

Acute Phase Histology (Within Days to Weeks)

• Edema and axoplasmic stasis are predominant features.
• Axons appear swollen and vacuolated.
• Axoplasmic flow is disrupted, leading to the accumulation of intracellular organelles and mitochondrial debris.
• No inflammatory infiltrate is observed, distinguishing NAION from arteritic etiologies.
• Mild perivascular edema and occasional microglial activation may be observed.
• The blood-optic nerve barrier may be mildly compromised, but no vasculitis or fibrinoid necrosis of vessels is found.
• Capillary congestion and ischemic necrosis of optic nerve axons are observed in the prelaminar and laminar regions.
• The optic nerve head capillaries may show attenuation due to compression by edematous axons.[46]

Subacute Phase (Weeks to a Few Months)

• Evidence of ongoing Wallerian degeneration is evident, involving the breakdown of the axonal cytoskeleton and the distal myelin sheath at the site of injury.
• Reactive astrocytosis begins with the proliferation of fibrous astrocytes attempting to fill the axonal void.
• Axonal dropout becomes more evident.
• Myelin basic protein staining shows fragmented or absent myelin sheaths in affected zones.
• Microglial activation continues, playing a role in clearing debris.
• Gliosis begins to replace the lost neural tissue, resulting in a fibrous scar in the anterior optic nerve.[47]

Chronic Phase (Months to Years)

• Optic nerve head atrophy is prominent.
• The affected sectors show a significant loss of ganglion cell axons.
• These areas appear pale and thinned histologically.
• Dense gliotic replacement is observed in previously infarcted zones.
• Loss of capillary density in the optic disc microvasculature is noted.
• Typically, there are no signs of ongoing inflammation or neovascularization.
• The retinal ganglion cell layer in the peripapillary retina also shows dropout, especially in regions corresponding to visual field loss.[48]

Immunohistochemical Findings

• Glial fibrillary acidic protein staining confirms the presence of reactive gliosis.
• CD68 immunostaining highlights activated microglia or macrophages involved in phagocytosis.
• Myelin stains, such as Luxol Fast Blue, show demyelination in affected axons.
• Neurofilament staining shows axonal degeneration.
• Vascular endothelial markers, such as CD31, may show reduced capillary perfusion areas without occlusion or thrombus formation.[49]

Table 7. Histopathological Differences Between NAION and AAION

Abbreviations: NAION, nonarteritic anterior ischemic optic neuropathy; AAION, arteritic anterior ischemic optic neuropathy; GCA, giant cell arteritis.

Summary of Key Histopathologic Features of Nonarteritic Anterior Ischemic Optic Neuropathy

• Axonal swelling and ischemic necrosis
• Absence of inflammatory infiltrates
• Wallerian degeneration and reactive gliosis
• Loss of ganglion cells and optic nerve axons
• No evidence of vasculitis or thromboembolic occlusion
• Predominant involvement of the anterior optic nerve head [50]

Clinical Correlation

Histopathological findings correlate with the following clinical features:

• Visual field loss, such as altitudinal defects, caused by sectoral axonal injury.
• Optic disc swelling followed by pallor as axonal loss ensues.
• Poor visual recovery due to irreversible axonal death and gliosis.
• Lack of inflammation explains the ineffectiveness of corticosteroids in most nonarteritic cases.

Histopathology of NAION reveals a noninflammatory ischemic optic neuropathy characterized by axonal degeneration, glial proliferation, and sectoral optic disc atrophy. These findings are crucial for distinguishing NAION from arteritic causes and underscore the pathogenesis rooted in microvascular compromise and structural disc anatomy rather than inflammatory occlusion. Postmortem studies remain the gold standard for confirming the diagnosis and understanding the irreversible nature of the optic nerve injury in NAION.[51]

Toxicokinetics

Although NAION is primarily a vascular and ischemic optic neuropathy, toxicokinetics—the study of how substances are absorbed, distributed, metabolized, and excreted—is relevant in understanding drug-induced optic neuropathies and their contribution to NAION-like presentations. Certain pharmacologic agents can alter optic nerve perfusion, impair mitochondrial function, or exacerbate preexisting vascular risk factors, thereby increasing the risk of NAION.[28]

Drug Absorption and Distribution

• Phosphodiesterase-5 (PDE5) inhibitors, such as sildenafil and tadalafil, have been linked to NAION-like events.
• These drugs alter vascular perfusion dynamics by causing systemic vasodilation, which can potentially lead to hypoperfusion of the short posterior ciliary arteries, especially in patients with a disc-at-risk.
• Peak plasma concentrations of sildenafil are reached within 1 hour of ingestion and are distributed widely across vascular tissues, including ocular circulation.

• Systemic corticosteroids, while used therapeutically, can cause fluid retention and hypertension, aggravating perfusion compromise in predisposed optic nerves.[52]

Metabolism and Mitochondrial Stress

• Certain mitochondrial toxins, such as ethambutol or linezolid, though more commonly associated with toxic optic neuropathies, can present with similar disc swelling and vision loss.
• These agents impair mitochondrial ATP synthesis, leading to axonopathy, particularly at the unmyelinated optic nerve head.
• Toxic accumulation in poorly perfused tissues, such as the lamina cribrosa zone, may mimic NAION histologically and functionally.[53]

Drug-Related Risk Enhancement

• Agents that lower systemic blood pressure, such as antihypertensives taken at night, may increase nocturnal hypotension and predispose patients with crowded discs to hypoperfusion-induced NAION.
• Vasoconstrictors, such as pseudoephedrine or ergots, may exacerbate vasospasm and reduce optic nerve head perfusion.[21]

Elimination and Accumulation

• Drugs with renal elimination, such as some antibiotics and PDE5 inhibitors, can accumulate in patients with renal insufficiency—a known NAION risk factor—and increase toxicity.
• Patients with impaired drug clearance may have prolonged systemic exposure, increasing the likelihood of optic nerve ischemia through systemic effects, such as hypotension or vascular dysregulation.[54]

Clinical Implications

• Understanding the toxicokinetics of medications helps identify iatrogenic contributors to NAION.
• Screening for recent drug exposure, especially vasodilators or mitochondrial toxins, is critical in the workup of acute optic neuropathy.
• Clinicians should be cautious when prescribing medications with ocular vascular adverse effects to patients with disc-at-risk anatomy—small, crowded optic disc—or preexisting vascular disease.[55]

In summary, although NAION is not classically a toxicologic condition, toxicokinetics plays a significant role in identifying and preventing drug-induced vascular insults to the optic nerve. Proper assessment of drug metabolism, systemic distribution, and elimination profiles can help mitigate risks in vulnerable populations.

History and Physical

Obtaining a detailed neuro-ophthalmological history is crucial, emphasizing the onset of visual loss, which is typically sudden in NAION and semi-acute in optic neuritis. Other associated symptoms should also be assessed. About 10% to 15% of patients with NAION experience pain in and around the eye but not with eye movements, whereas pain with eye movement is typical in optic neuritis. Typically, there are no other accompanying neurological symptoms. Medication history should specifically address the use of PD-5 inhibitors and antihypertensive medications—particularly when taken at night—as well as the use of amiodarone, which can be associated with the anterior optic neuropathy, whose presentation can be similar to NAION.[56]

A complete examination should be performed. Visual acuity can vary from 20/15 to no light perception, although inferior vision (hand motions or worse) is uncommon in NAION.[57] The RAPD should be present in all patients at presentation. All patients must have optic nerve head edema at presentation, which can persist for 4 to 6 weeks after onset. While it is present, visual acuity can continue to decline due to the compartment syndrome effect.[14] Formal visual field testing should be performed in each eye, as field abnormalities are typically nerve fiber bundle defects, with altitudinal defects being prevalent. This pattern may be due to the proposed semicircle organization of the short posterior ciliary arteries that supply the optic nerve head.[16] Peripapillary OCT invariably demonstrates thickening of the RNFL. The presence of the so-called disc-at-risk, characterized by a cup-to-disc ratio of 0.2 or less in the fellow eye, is observed in over 95% of patients with NAION. If it is not present, the diagnosis should be questioned.

Patient History

Obtaining a detailed history is essential for diagnosing NAION and differentiating it from AAION and other optic neuropathies.

Onset and course:

• Sudden, painless visual loss, typically in one eye, is the hallmark presentation.
• Patients often report vision loss upon waking, suggestive of nocturnal hypotension as a contributing factor.
• Visual loss may be noticed as a dark spot in the superior or inferior field, consistent with an altitudinal defect.
• The degree of visual impairment varies, ranging from mild blurring to profound loss.[56]

Associated symptoms:

• No pain is typically reported, unlike optic neuritis.
• No systemic symptoms, such as headache, jaw claudication, scalp tenderness, or polymyalgia, are present—essential to differentiate from AAION.
• No progression after initial days: NAION typically stabilizes within 2 to 3 days, unlike compressive or inflammatory neuropathies, which may worsen progressively.

Past ocular history:

• History of similar symptoms in the contralateral eye (observed in up to 15%-25% within 5 years).
• Prior optic disc edema or disc-at-risk (small cup-to-disc ratio) if previously documented.
• Refractive error: More common in hyperopic (farsighted) eyes due to small, crowded discs.[58]

Systemic and medical history:

• Assess for vascular risk factors, such as hypertension, diabetes mellitus, hyperlipidemia, OSA, ischemic heart disease, and smoking.
• Review medication history:
• Recent use of PDE5 inhibitors, such as sildenafil.
• Systemic hypotensive agents, especially when taken at bedtime.
• Evaluate for sleep apnea symptoms, such as loud snoring, daytime sleepiness, and apnea episodes.
• Absence of recent weight loss, fever, or temporal arteritis symptoms supports ruling out AAION.[59]

Physical Examination

Visual acuity:

• Commonly reduced in the affected eye (20/40 to counting fingers).
• A minority may maintain near-normal vision, depending on the extent of foveal involvement.

Pupillary examination:

• RAPD is a cardinal sign in cases of unilateral or asymmetric disease.
• Bilateral symmetric NAION may mask RAPD.[60]

Colour vision:

• Dyschromatopsia, also known as impaired color vision, is less severe than optic neuritis.
• Often disproportionate to the level of visual acuity loss.

Visual fields:

• Altitudinal visual field defect, typically more pronounced inferiorly than superiorly, is a classic example.
• Other patterns include arcuate, central, or diffuse depression.
• Automated perimetry, such as the Humphrey 24-2 test, is used for documentation.[61]

Fundus examination (dilated):

• The optic disc may appear swollen, either segmentally or diffusely, often accompanied by peripapillary flame-shaped hemorrhages.
• Unlike central retinal vein occlusion, venous congestion is absent.
• The disc may appear pale and edematous, with blurring of its margins.
• A small or absent physiologic cup (disc-at-risk) may be noted in the fellow eye.
• Hard exudates or macular edema are rare but possible.
• Optic disc edema typically resolves within 6 to 8 weeks, often followed by optic disc pallor.[8]

Intraocular pressure:

• Typically normal; elevated intraocular pressure (IOP) suggests other pathologies, such as anterior ischemic optic neuropathy, due to increased perfusion resistance.

Neurological and systemic examination:

• Generally unremarkable in NAION.
• In suspected cases of GCA, assess for:
• Tenderness over the temporal arteries
• Scalp tenderness
• Jaw claudication
• Constitutional symptoms, such as fever, weight loss, and fatigue
• Polymyalgia rheumatica symptoms, such as pain or stiffness, in the shoulders and hips [62]

Ancillary testing:

Recommended based on history and examination findings:

• Visual field testing (perimetry)
• OCT of the optic nerve head: Reveals disc edema and RNFL thickening acutely; later shows thinning.
• Fundus photography: Documents disc edema for follow-up.
• Fluorescein angiography (optional): May show delayed filling of prelaminar optic disc.
• Polysomnography: In patients with suspected sleep apnea.
• Blood work: ESR, CRP, CBC—especially to exclude GCA in patients older than 50.
• BP monitoring: Including postural drops to evaluate nocturnal hypotension.[63]

Table 8. Clinical Features of NAION

Abbreviations: NAION, nonarteritic anterior ischemic optic neuropathy; AAION, arteritic anterior ischemic optic neuropathy; RAPD, relative afferent pupillary defect; OSA, obstructive sleep apnea.

In conclusion, obtaining a detailed history and performing a thorough physical examination are crucial for diagnosing NAION, excluding arteritic causes, and identifying modifiable systemic risk factors. A combination of clinical vigilance, fundoscopic findings, and targeted systemic assessment provides the foundation for timely diagnosis and management.

Evaluation

The diagnosis of NAION is clinical. All patients present with optic nerve edema, and over 97% of patients have a disc-at-risk in the fellow eye, with a cup-to-disc ratio of 0.2 or less. Patients with NAION may have a variety of visual field defects. However, many patients have an altitudinal defect supporting the notion that 2 separate semicircles of short posterior ciliary arteries supply the optic nerve's superior and inferior portions. Visual acuity can vary from 20/20 to no light perception, although very poor visual acuity is uncommon and should raise suspicion for GCA.[64] Although most patients with NAION are older than 50, many are younger, and young age at presentation does not exclude the diagnosis. However, demyelinating optic neuritis should be thought of and excluded in younger individuals.[18] Typically, in demyelinating optic neuritis, optic nerve head edema, if present, is mild, and the presence of peripapillary hemorrhages is rare, occurring in fewer than 5% of cases in the optic neuritis treatment trial. Pain with eye movements is distinctly uncommon in NAION, although pain in and around the eye can be present in up to 10% to 15% of patients. In contrast, it is present in up to 94% of patients with demyelinating optic neuritis. Suppose the differentiation between NAION and other optic neuropathies is difficult. In that case, magnetic resonance imaging of the orbits with gadolinium can be functional as it should be normal in all patients with NAION and almost always demonstrates enhancement of the optic nerve in post-contrast imaging in patients with inflammatory optic neuropathies.

The evaluation of NAION aims to confirm the diagnosis, exclude mimicking conditions—especially AAION—and assess for systemic risk factors that may contribute to the ischemic event. A structured, multidisciplinary evaluation is essential to guide appropriate management and secondary prevention.

Clinical Examination

Visual acuity testing:

• This testing helps establish the baseline and monitor progression or recovery.
• The visual acuity typically ranges from 20/20 to counting fingers, depending on the extent of optic nerve involvement.
• Visual acuity may improve over weeks in about 30% of patients.[4]

Pupillary eeflex evaluation:

• RAPD is typically present in unilateral or asymmetric disease.
• In bilateral cases, the defect may be masked, and careful comparison is needed.[65]

Colour vision testing:

• This testing is performed using Ishihara plates or the Farnsworth D-15 test.
• Dyschromatopsia is common but less pronounced than in optic neuritis.[66]

Fundus examination:

• Optic disc edema (segmental or diffuse) is evident in the acute phase of the disease.
• Flame-shaped hemorrhages may be present.
• The fellow eye may show a small cup-to-disc ratio (disc-at-risk).[28]

Visual field assessment:

• Humphrey visual field 24-2 or 30-2 is typically used.
• An inferior altitudinal scotoma is the most common defect.
• Other patterns include arcuate, central, or generalized depression.[67]

Optical Coherence Tomography

Optical coherence tomography of the optic nerve head:

• This imaging technique reveals increased RNFL thickness due to optic disc edema in the acute phase and RNFL atrophy in the chronic stage.

Optical coherence tomography of the macula:

• This imaging technique aids in ruling out coexisting macular pathology and in evaluating ganglion cell complex loss in chronic NAION.[68]

Fluorescein Angiography

• Fluorescein angiography is useful but not routinely performed.
• In NAION, it may show delayed or absent filling of the optic disc.
• This technique helps differentiate NAION from AAION, which typically has a more profound filling delay and choroidal nonperfusion.

Fundus Photography

• High-resolution color fundus photographs are useful for documenting optic disc edema and hemorrhages.
• These photographs facilitate comparison during follow-up and serve as valuable tools for teaching and teleophthalmology.[69]

Laboratory Workup

Although NAION is typically a clinical diagnosis, lab testing is crucial to exclude arteritic causes, particularly in older patients.[4]

• Erythrocyte sedimentation rate and C-reactive protein: These levels are normal in NAION, whereas elevated in AAION (suggestive of GCA).
• Complete blood count: Helps evaluate systemic inflammation or anemia.[70]
• Fasting blood glucose/HbA1c: To detect or assess control of diabetes mellitus.
• Lipid profile: Hyperlipidemia is a known risk factor for NAION.[71]
• Thrombophilia workup (in young patients):
  • Includes homocysteine, antiphospholipid antibodies, and protein C or S deficiency.
  • Performed selectively based on individual risk factors and clinical presentation.

• Polysomnography: Recommended in patients with symptoms suggestive of OSA, which is a significant risk factor.[72]

Neuroimaging

Magnetic resonance imaging of the brain and orbits with gadolinium contrast:

• Not required for every patient, but indicated when:
• The clinical picture is atypical, such as progressive vision loss and bilateral involvement at onset.
• Helps rule out compressive lesions, optic neuritis, or infiltrative diseases.
• Findings in NAION: Normal optic nerve or mild enlargement without enhancement.

Magnetic resonance angiography/computed tomography angiography:

• Considered when vascular compromise is suspected, such as carotid artery stenosis.
• Not routinely performed unless systemic ischemic symptoms exist.[73]

Temporal artery biopsy:

• Not indicated in NAION, but essential to exclude GCA in suspicious cases.
• Recommended when ESR/CRP is elevated or systemic symptoms, such as jaw claudication, scalp tenderness, or weight loss, are present.

Cardiovascular Risk Assessment

Because of the strong association between NAION and vascular comorbidities, cardiovascular evaluation is recommended:

• Blood pressure monitoring: Including nocturnal hypotension if suspected.
• Electrocardiogram and echocardiogram: If a cardioembolic source is considered.
• Carotid Doppler ultrasound: This test is especially useful in patients with bruits or a history of stroke.[74]

Diagnostic Criteria for NAION

Although no formal diagnostic criteria exist, the diagnosis is generally made based on the following combination:

Table 9. Clinical Criteria Supporting the Diagnosis of NAION

Abbreviations: NAION, nonarteritic anterior ischemic optic neuropathy; RAPD, relative afferent pupillary defect; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein.

Table 10. Key Features for Differentiating NAION from Other Causes

Abbreviations: NAION, nonarteritic anterior ischemic optic neuropathy; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; MRI, magnetic resonance imaging; CRAO, central retinal artery occlusion; BRAO, branch retinal artery occlusion.

The evaluation of NAION is comprehensive and multidisciplinary. Obtaining a detailed clinical history and performing a thorough ophthalmic examination remain the cornerstone of diagnosis, supported by visual field testing, OCT, and lab markers to rule out arteritic forms. Imaging and advanced systemic evaluations are reserved for atypical presentations or when other etiologies are suspected. Early and accurate assessment not only aids in patient counseling and visual prognosis but also facilitates the timely identification and modification of systemic risk factors, thereby helping to prevent further episodes in the fellow eye.[75]

Treatment / Management

Although numerous medications and treatment strategies have been investigated, none have proven effective. One of the very few randomized controlled clinical trials in neuro-ophthalmology evaluated optic nerve head decompression via vitrectomy for NAION and demonstrated that surgery was not beneficial and potentially harmful.[3] Intravitreal injections of bevacizumab and triamcinolone have been investigated, but with disappointing results.[76] Recently, a clinical trial evaluating the intravitreal injection of QRK207, a caspase-2 inhibitor that prevents apoptosis, in patients with recent (within 14 days of onset) onset of NAION did not demonstrate its efficacy and was stopped early. Currently, the only ongoing clinical trial involves subcutaneous injections of RPh201, an isolated botanical extract of gum mastic, in patients who have experienced the onset of NAION within 1 to 5 years before enrollment.(A1)

NAION poses a significant therapeutic challenge in ophthalmology. Despite being the most common acute optic neuropathy in adults older than 50, there is currently no universally accepted, evidence-based therapy that reliably improves visual outcomes. Therefore, management focuses primarily on identifying and modifying risk factors to prevent further visual loss, especially in the fellow eye, and providing patient education and support.

Acute Phase Management

Observation

• For most cases of NAION, observation is the standard of care due to the lack of proven treatment to reverse optic nerve damage.
• About 30% to 40% of patients may experience some degree of spontaneous visual recovery within 6 months.
• Close follow-up is essential to monitor the disease's course and ensure that there is no progression or involvement in the fellow eye.[77]
(B3)

Systemic corticosteroids:

• The role of corticosteroids in NAION is controversial.
• A retrospective study by Hayreh suggested that oral prednisone (80 mg/d) initiated early may improve visual outcomes by reducing optic disc edema.
• However, this finding is not universally accepted, and no randomized controlled trials have confirmed its benefit.
• Risks, particularly in diabetics and hypertensives, should be carefully considered before initiating steroid therapy.[78]

Neuroprotective agents:

• No neuroprotective agent has shown proven benefit in NAION.
• Medications, such as brimonidine, used in glaucoma, have a theoretical benefit but lack clinical evidence in NAION.[79]
(A1)

Risk Factor Modification and Secondary Prevention

As NAION is strongly linked to systemic vascular risk factors, aggressive management is essential to reduce recurrence and protect the fellow eye.

Hypertension:

• Control blood pressure while avoiding nocturnal hypotension.
• Avoid aggressive antihypertensive therapy at bedtime.[80]

Diabetes mellitus:

• Optimize glycemic control to minimize microvascular ischemia.

Hyperlipidemia:

• Use of statins for low-density lipoprotein reduction may reduce vascular risk.

Obstructive sleep apnea:

• Strongly associated with NAION.
• Polysomnography should be considered in all patients with NAION.
• Continuous positive airway pressure (CPAP) therapy has shown potential to reduce the risk of fellow eye involvement.[81]

Smoking cessation

• Smoking is a modifiable risk factor that accelerates atherosclerosis and optic nerve ischemia.

Nocturnal hypotension:

• Nocturnal hypotension is implicated in the pathogenesis of NAION.
• Patients on beta-blockers, alpha-blockers, or long-acting antihypertensives should have their therapy reviewed.
• Twenty-four–hour ambulatory blood pressure monitoring should be considered in selected cases.[82]

Management of Fellow Eye Risk

• Patients with NAION have a 15% to 20% risk of developing NAION in the fellow eye.
• This risk increases with poorly controlled vascular comorbidities and OSA.
• Counseling and aggressive risk factor modification are crucial in reducing this risk.[37]

Investigational Therapies

Several treatments have been evaluated in clinical trials, although none have definitively proven beneficial.

Ischemic optic neuropathy decompression trial:

• This trial evaluated surgical optic nerve sheath decompression and found no benefit, along with potential harm from the procedure.[83]
(A1)

Intravitreal injections:

• Anti-VEGF agents, including bevacizumab or ranibizumab, are used off-label in some cases to reduce disc edema. However, supporting data are limited, and this approach is not considered standard of care.
• Intravitreal triamcinolone has been trialed to reduce inflammation and swelling, though evidence of benefit remains limited.

Neurotrophic factors and stem cell therapy:

• Neurotrophic factors and stem cell therapy remain in preclinical and early-phase research stages.
• Currently, there are no therapies with proven efficacy.[84]

Visual Rehabilitation and Support

Patients with significant visual loss require rehabilitation to maximize their remaining vision and maintain quality of life.

Low vision aids:

• Low vision aids such as magnifiers, telescopic lenses, and electronic reading devices can enhance visual function.
• Referral to a low vision specialist is recommended for individualized assessment and support.[10]
(A1)

Occupational therapy:

• This therapy helps patients adapt to vision loss for daily activities.

Psychological support:

• Sudden vision loss may lead to depression and anxiety.
• Psychological support, including counseling and participation in support groups, can be valuable.[85]

Table 11. Follow-Up Visits and Clinical Goals of NAION

Abbreviation: NAION, nonarteritic anterior ischemic optic neuropathy.

When to Refer

Referral to neuro-ophthalmology, internal medicine, or sleep medicine is appropriate in the following situations:

• Diagnostic uncertainty to rule out optic neuritis and compressive lesion
• Refractory or progressive vision loss
• Coexisting systemic conditions, including sleep apnea and stroke risk, that require coordinated management
• Need for low vision rehabilitation or psychological support

Emerging Therapies and Future Directions

Research is ongoing into potential interventions, including:

• Rho kinase inhibitors to improve perfusion
• Mitochondrial-targeted antioxidants to reduce axonal injury
• Gene therapy and regenerative medicine

Although these therapies are still in experimental stages, they represent future avenues for potentially altering the course of NAION.[86]

The management of NAION is multifaceted, focusing primarily on observation, modifying risk factors, and providing visual rehabilitation. Although acute interventions such as steroids and intravitreal therapies have been explored, their utility remains uncertain. Long-term care emphasizes the prevention of second eye involvement through the control of systemic diseases and the management of OSA. Interdisciplinary collaboration between ophthalmologists, internists, sleep medicine specialists, and rehabilitation services is critical for optimizing patient outcomes. Ongoing clinical trials may yield targeted therapies in the future, but until then, patient education and systemic control remain the cornerstones of care.[87]

Differential Diagnosis

In patients younger than 50, the primary differential diagnoses include demyelinating optic neuritis and antibody-mediated optic neuritis, such as those associated with aquaporin-4 and anti-myelin oligodendrocyte glycoprotein antibody.[88] Typically, patients with demyelinating optic neuritis experience pain with eye movements, reported in over 94% of cases. Peripapillary hemorrhages are uncommon, occurring in only 5% of affected individuals. Most importantly, visual function recovers in the vast majority of patients, in contrast to NAION, where visual acuity and visual field defect remain unchanged.[1] Patients with myelin oligodendrocyte glycoprotein–associated optic neuritis often have swollen optic nerves and hemorrhages on presentation. Still, they also have a good visual prognosis, with the majority recovering visual function as opposed to patients with NAION. All patients should also be asked about the use of amiodarone and dysfunction medications, as amiodarone can present with simultaneous or sequential optic neuropathy that resembles NAION but can improve following discontinuation of the drug. The use of phosphodiesterase inhibitors has been linked to the development of NAION. However, this association remains unclear, and decisions regarding discontinuation of these medications in patients with NAION should be individualized, considering factors such as the temporal relationship between NAION onset and phosphodiesterase inhibitor use, as well as the patient’s current visual status. In patients older than 50, GCA is the primary entity in the differential diagnosis. Therefore, all patients older than 60 presenting with a swollen optic nerve should have their inflammatory markers evaluated to rule out this potentially treatable condition. Patients with compressive optic neuropathies can sometimes present with a swollen optic nerve. Still, they typically have a slow onset of visual loss rather than an acute one, as observed in NAION.[89]

Table 12. Differential Diagnosis of Optic Neuropathies

Abbreviations: AAION, arteritic anterior ischemic optic neuropathy; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; CBC, complete blood count; MRI, magnetic resonance imaging; CT, computed tomography; MRV, magnetic resonance venography; HbA1c, hemoglobin A_1c, ACE, angiotensin-converting enzyme.

Pertinent Studies and Ongoing Trials

Ischemic Optic Neuropathy Decompression Trial

• Design: Randomized controlled trial.
• Objective: To assess the efficacy of optic nerve sheath decompression surgery in NAION.
• Findings: The trial concluded that surgical decompression provided no visual benefit and may be harmful. Nearly 32% of patients in the surgical group lost ≥3 lines of vision, compared to 23% in the observation group.
• Impact: This pivotal study discouraged surgical interventions for NAION and emphasized the importance of conservative management and control of vascular risk factors.[9]

Nonarteritic Anterior Ischemic Optic Neuropathy Treatment Trial Using Brimonidine

• Design: Multicenter randomized controlled trial.
• Objective: To test whether brimonidine, a neuroprotective alpha-2 agonist, improved outcomes.
• Outcome: No statistically significant improvement in visual acuity or visual field compared to placebo.
• Conclusion: The study did not support the use of brimonidine as an effective treatment for acute NAION.[28]

RPh201 (Human Placental Extract) Trial

• Phase: Phase 2a clinical trial.
• Objective: To assess the safety and efficacy of RPh201, a novel bioactive compound, in improving visual function in patients with NAION.
• Results: Preliminary data indicated a mild improvement in visual acuity in some patients.
• Current status: Further larger-scale studies are needed to validate results.[90]

Optic Nerve Head Topography Studies (Optical Coherence Tomography–Based Trials)

• Purpose: To study structural changes in the optic nerve head and RNFL post-NAION using OCT and OCT-A.
• Findings: Peripapillary capillary dropout and RNFL thinning are common and correlate with visual outcomes.[91]
• Impact: Help refine prognosis and follow-up strategies in NAION.

Neuroprotective Agent Trials (Citicoline and Erythropoietin)

• Design: Small-scale pilot studies.
• Focus: Evaluate whether agents such as citicoline and erythropoietin may promote optic nerve recovery.
• Preliminary data: Indicate possible benefit in visual field preservation and axonal support.
• Status: Awaiting larger randomized controlled trials.[92]

Obstructive Sleep Apnea and Continuous Positive Airway Pressure Intervention Studies

• Context: OSA is a known risk factor for NAION.
• Design: Observational and interventional studies assessing the role of CPAP therapy in preventing second eye involvement.
• Findings: Some evidence suggests that patients using CPAP are less likely to develop NAION in the fellow eye.
• Implication: Sleep studies and OSA management may become part of comprehensive NAION care.[93]

Treatment Planning

Acute Phase Management (First Few Days to Weeks)

Although there is no proven therapy to reverse visual loss in NAION, the primary focus of acute management is on limiting further ischemic injury, optimizing vascular health, and ruling out arteritic causes.

Observation

• Visual acuity often stabilizes within 6 to 8 weeks.
• Up to 43% of patients exhibit spontaneous visual improvement without intervention, according to the natural history data from the IONDT.
• No progressive visual loss beyond 2 to 3 weeks unless recurrent or the fellow eye becomes involved.[28]

Exclusion of Arteritic Anterior Ischemic Optic Neuropathy

• In patients older than 50, immediate evaluation of ESR, CRP, and platelet count is essential to rule out GCA, particularly if any of the following are present:
• Systemic symptoms such as jaw claudication and scalp tenderness
• Markedly elevated ESR/CRP
• Chalky white disc edema
• Marked vision loss (no light perception)
• Temporal artery tenderness [94]

Systemic Risk Factor Management

• Blood pressure: Nocturnal hypotension should be avoided by reviewing antihypertensive medications and adjusting dosing to prevent reduced perfusion during sleep.
• Diabetes and glycemic control: Tight regulation reduces endothelial dysfunction and ischemic burden.
• Dyslipidemia: Statins should be initiated if low-density lipoprotein >100 mg/dL according to the American College of Cardiology/American Heart Association guidelines.
• Smoking cessation: Smoking cessation is strongly advised due to vasoconstrictive and atherosclerotic effects.
• Sleep apnea evaluation:
• Polysomnography is indicated for patients with snoring, obesity, or excessive daytime sleepiness.
• CPAP therapy improves vascular health and may reduce the risk of recurrence.[95]

Role of Aspirin

• Aspirin (81-325 mg/d) has been proposed to reduce the incidence of second eye involvement.
• Small retrospective studies have shown a modest benefit, but large-scale trials remain inconclusive.
• Aspirin may be considered, unless contraindicated, especially if other atherothrombotic risk factors are present.

Corticosteroid Therapy (Controversial)

• In small nonrandomized studies by Hayreh et al, early administration of oral prednisone (80 mg/d, tapered over 4 to 6 weeks) within 2 weeks of onset has been shown to reduce disc edema and achieve a modest visual improvement.
• No randomized clinical trials exist; corticosteroids are not the standard of care. A thorough risk-benefit analysis should be discussed with the patient.[96]

Visual Rehabilitation

Low vision services:

• A referral to low vision specialists is generally recommended when a patient's best-corrected visual acuity remains <6/24
• Low vision aids include magnifiers, high-contrast materials, and field enhancement devices.

Occupational and vocational therapy:

• This therapy is recommended for patients with bilateral or career-threatening involvement.
• Includes mobility training, assistive technology integration, and psychological counseling.[10]

Prevention of fellow eye involvement:

• The risk of second eye involvement is approximately 15% to 24% over 5 years and may be higher in patients with untreated systemic conditions.
• Strict control of all modifiable risk factors, such as hypertension, diabetes mellitus, dyslipidemia, and OSA, is paramount.
• Antihypertensive regimens should be adjusted to prevent nocturnal hypotension and maintain adequate perfusion pressure during sleep.

Experimental and Investigational Approaches

Neuroprotective agents:

• Agents such as brimonidine and citicoline targeting apoptosis pathways are under investigation.
• Currently, it is not standard care.[97]

Intravitreal therapy:

• Anti-VEGF agents (e.g., ranibizumab): Some reports suggest resolution of disc edema and structural improvement; however, there is no proven functional benefit.
• Intravitreal corticosteroids (e.g., triamcinolone): Evidence remains limited and inconclusive.
• Intravitreal therapy is generally reserved for clinical trials or off-label use in select, non-resolving cases.[98]

Surgical interventions:

• Optic nerve sheath fenestration and vitrectomy have shown no benefit in NAION and may be harmful.
• The IONDT definitively discouraged the use of surgical decompression.

Counseling and Patient Education

• Prognosis: Up to 43% of patients may experience partial recovery, whereas others remain stable or experience worsening of their condition.
• Recurrence: Recurrence in the same eye is rare, but the risk to the fellow eye should be discussed.
• Driving and legal blindness: Guidance should be provided on the implications of monocular vision loss.
• Support networks: Referrals to patient advocacy and psychological support groups should be made when appropriate.

Follow-Up Protocol

• Initial follow-up: Weekly for 2 to 3 weeks to monitor disc edema and rule out progression.
• Systemic evaluation: Collaborative care with primary physicians, endocrinologists, and sleep specialists.
• Fellow eye surveillance: Patients should be educated on early symptoms of involvement.[99]

Toxicity and Adverse Effect Management

Although NAION itself is a noninflammatory ischemic optic neuropathy, its management may involve pharmacological agents and systemic risk control therapies that can lead to adverse effects. Proper identification and mitigation of these adverse effects are crucial in a multidisciplinary approach.

Corticosteroid-Related Toxicities

Corticosteroids are often used off-label in selected early cases of NAION. However, their use requires careful consideration due to potential adverse effects.

• Adverse Effects:
  • Hyperglycemia
  • Hypertension
  • Immunosuppression
  • Mood changes
  • Steroid-induced glaucoma or cataract (ocular)

•  Management:
  • Use the lowest effective dose for the shortest time
  • Monitor blood glucose and blood pressure
  • Coordinate care with endocrinology in patients with diabetes mellitus
  • Avoid use in patients with uncontrolled systemic conditions [100]

Antiplatelet (Aspirin) Therapy

• Adverse Effects:
  • Gastrointestinal irritation or bleeding
  • Increased bleeding risk, particularly in older patients

•  Management:
  • Use enteric-coated formulations
  • Consider gastroprotective agents, such as proton pump inhibitors
  • Monitor regularly for signs of gastrointestinal bleeding [101]

Systemic Risk Factor Management

Comprehensive management may include statins, antihypertensives, and hypoglycemics. Each class carries specific toxicity risks requiring tailored oversight.

• Statins toxicity:
  • Toxicity: Myopathy, liver enzyme elevation
  • Management: Monitor liver function tests; switch agent if needed

• Antihypertensive overcorrection:
  • Risk: Nocturnal hypotension is a risk for the second eye NAION
  • Management: Avoid bedtime dosing; monitor blood pressure over 24 hours

• Diabetic medications:
  • Risk: Hypoglycemia with tight control
  • Management: Titrate cautiously with ophthalmic input [102]

Continuous Positive Airway Pressure in Sleep Apnea

CPAP is often recommended to reduce recurrence in sleep apnea–related NAION.

• Adverse effects:
  • Discomfort, nasal congestion, and poor compliance

•  Management:
  • Nasal saline sprays or humidifiers
  • Reassurance and titration of pressure settings
  • Sleep specialist collaboration [103]

Intravitreal Therapy (Experimental)

Intravitreal therapy is used rarely or off-label; it includes anti-VEGF agents and steroids.

• Risks:
  • Endophthalmitis
  • IOP elevation
  • Retinal detachment

•  Management:
  • Strict asepsis during injection
  • Post-injection monitoring
  • Timely intervention for any complications

Patient Education and Monitoring

• Patients should be educated on the potential adverse effects of systemic and ocular medications.
• Patients should be encouraged to promptly report symptoms, such as eye pain, visual loss, or systemic adverse reactions.
• Regular follow-up and interdisciplinary coordination—particularly with primary care physicians, endocrinologists, and sleep medicine specialists—are essential for safe and effective long-term management.[104]

Staging

Table 13. Clinical Staging of NAION

Abbreviations: NAION, nonarteritic anterior ischemic optic neuropathy; OCT, optical coherence tomography; RNFL, retinal nerve fiber layer.

• There is no formal TNM or ICD staging for NAION; this classification helps in prognostication and treatment timing.
• Visual field defects, most commonly inferior altitudinal, help track progression or recurrence.
• OCT and visual field monitoring are essential at all stages to assess optic nerve damage and manage the risk to the contralateral eye.[46]

Prognosis

The natural progression of NAION has been described in the optic nerve decompression treatment trial. This trial showed that one-third of patients regain 3 or more lines of vision at 2-year follow-up, 30% lose 3 or more lines of vision at 2 years, and the remainder demonstrate unchanged visual acuity.[105] In practice, most patients likely maintain their vision after the resolution of acute optic nerve head edema, and the improvement observed was secondary to their learned ability to fixate around their scotomas. The prognosis of NAION remains variable and often discouraging due to the lack of definitive treatment. Outcomes are largely determined by the extent of initial optic nerve damage, systemic vascular risk factors, and the anatomical predisposition of the optic disc.

Visual Acuity and Field Outcomes

• Initial vision loss: Most patients experience sudden, painless vision loss, typically worse in the inferior visual field. At presentation:
• Approximately 45% to 50% have visual acuity worse than 6/60.
• Approximately 30% to 40% present with altitudinal or arcuate visual field defects.

• Visual recovery:
• Approximately 30% to 45% of patients experience some degree of spontaneous improvement in visual acuity, typically within the first 6 to 12 weeks. Proper visual recovery beyond this time is rare.
• Approximately 20% to 25% of patients may show some worsening in visual function after initial presentation.
• Visual field defects are generally more persistent than visual acuity loss.

• Stabilization: The disease process stabilizes within 2 to 3 months in most patients. Once optic disc swelling resolves and optic atrophy sets in, further improvement is unlikely.[88]

Fellow Eye Involvement

• Risk of second eye involvement: Approximately 15% to 25% of patients develop NAION in the fellow eye within 5 years.
• The risk increases in patients with uncontrolled systemic conditions such as hypertension, diabetes mellitus, hyperlipidemia, and nocturnal hypotension.
• The presence of a disc-at-risk in the fellow eye—a small, crowded optic disc with a small cup-to-disc ratio—further predisposes to bilateral involvement.[7]

Predictors of Poor Visual Outcome

• Poor baseline visual acuity worse than 6/60.
• Presence of a RAPD and severe disc edema.
• Systemic vasculopathies, such as diabetes mellitus and hypertension.
• Optic disc hemorrhages at presentation.
• Nocturnal hypotension, particularly in patients on antihypertensives at bedtime.
• Sleep apnea syndrome, associated with repetitive nocturnal ischemia.[106]

Impact on Quality of Life

• Even with preserved central visual acuity, persistent visual field defects, particularly inferior altitudinal scotomas, can severely impact reading, mobility, driving, and daily functioning.
• Psychological morbidity, including depression and anxiety, is higher in visually impaired patients with NAION.
• Fear of second eye involvement contributes to significant patient anxiety and lifestyle limitations.[107]

Long-Term Considerations

• No established therapy reverses the optic nerve damage once NAION has occurred.
• The mainstay of management is secondary prevention:
• Rigorous control of systemic vascular risk factors, such as blood pressure, glucose, and lipids.
• Evaluation for sleep apnea and appropriate intervention.
• Avoidance of nocturnal hypotension, such as adjustment of antihypertensive medications.
• Patient education regarding symptom monitoring and the need for urgent review if the fellow eye becomes affected.

NAION has a guarded prognosis with limited recovery of visual function in most patients. Although some experience partial improvement in acuity, visual field deficits typically persist. The risk of fellow eye involvement underscores the importance of modifying systemic risk factors. Early diagnosis, close monitoring, and interdisciplinary care involving neurologists, cardiologists, and sleep specialists can help mitigate further visual loss and improve patient quality of life.[12]

Complications

Ischemic optic neuropathies lead to atrophy of the optic nerve in 1 or both eyes and can lead to permanent blindness. NAION primarily affects vision but can lead to several direct and indirect complications. These complications not only affect the patient's visual prognosis but also impact their quality of life and overall systemic health. The complications can be grouped into ocular, systemic, and psychosocial domains.[28]

Table 14. Ocular Complications of NAION

Abbreviation: NAION, nonarteritic anterior ischemic optic neuropathy.

Systemic Complications (Indirect)

• Undiagnosed systemic vascular disease: NAION may be the first manifestation of undetected conditions such as diabetes mellitus, hypertension, hyperlipidemia, or nocturnal hypotension.
• Sleep apnea syndrome: Often underdiagnosed; untreated OSA increases the risk of recurrent or bilateral NAION.
• Medication-related risks: Use of nocturnal antihypertensives or PDE-5 inhibitors may exacerbate hypotension and precipitate NAION.[108]

Psychosocial and Functional Complications

• Reduced quality of life: Difficulty reading, driving, and navigating, especially with visual field loss.
• Depression and anxiety: Fear of blindness, uncertainty about recovery, and lifestyle limitations contribute to psychological distress.
• Occupational impact: Visual impairment may restrict work capacity in visually demanding jobs, especially those requiring bilateral vision.[109]

Complications from Misdiagnosis

• Inappropriate steroid use: Mislabeling NAION as AAION (GCA) may lead to unnecessary corticosteroid exposure and its systemic adverse effects.
• Delay in systemic workup: Overlooking the vascular component can lead to delayed cardiologic or neurologic evaluation and secondary prevention.

Although NAION itself is a noninflammatory ischemic event, its complications are primarily the result of permanent optic nerve damage and associated systemic comorbidities. Timely diagnosis, thorough systemic evaluation, and effective patient counseling are crucial to minimize long-term visual and systemic complications.[78]