Narrative review: advances in ischemic optic neuropathy: classification, diagnosis tools, experimental models, and treatments

Introduction

Background

Ischemic optic neuropathy (ION) is an acute disorder resulting from the optic nerve’s impaired arterial blood supply, leading to ischemia and hypoxia, and ultimately damaging the optic nerve (1). The ischemic damage can occur anywhere along the optic nerve, from its intraocular segment to its intracranial transition into the optic chiasm. Clinically, ION is classified by the affected region and vascular pathology into anterior ION (AION), involving the optic nerve head (ONH), and posterior ION (PION), affecting the retrobulbar segment of the optic nerve (1). Furthermore, ION is divided into two categories according to its underlying cause. Non-arteritic ION (NA-AION) is frequently connected to vascular risk factors like hypertension, hyperlipidemia, diabetes mellitus, and obstructive sleep apnea, while arteritic ION is mainly linked to giant cell arteritis (GCA) (2).

ION is one of the main causes of blindness or severe visual impairment in older populations, with a yearly prevalence of 2.3 to 10.2 cases per 100,000 individuals aged 50 years or older (3-5). NA-AION alone affects 3.89 per 100,000 people (6). A 2024 systematic review and meta-analysis investigated the incidence and prevalence of ION in older adults, revealing higher rates in individuals aged 60 years and above compared to those aged 40–59 years (7). Clinically, ION presents as abrupt, painless vision loss with distinctive visual field (VF) defects (8). AION shows optic disc edema acutely, while PION often lacks fundoscopic signs, making diagnosis more difficult (9). ION symptoms are always comparable to those of other eye conditions. AION, for instance, can imitate glaucoma. A few months after getting AION, the optic nerve may begin to resemble a glaucomatous optic nerve in appearance, which includes eroded, atrophic, and pallid features, along with occasionally comparable vision field deficits (10,11). Additionally, AION also has similar symptoms to myelin oligodendrocyte glycoprotein antibody-associated disease optic neuritis. Both conditions can present with acute vision loss, optic disc edema, impaired color vision, and VF defects such as central or diffuse scotomas (12,13). Differential diagnosis is made more difficult by similarities. In conditions like arteritic AION (A-AION) due to GCA, immediate corticosteroid therapy is critical to prevent bilateral blindness (14). Diagnostic imaging, including optical coherence tomography (OCT), computed tomography (CT), magnetic resonance imaging (MRI), and fluorescein angiography (FA), supports differentiation and tracking disease progression (15,16).

Rationale and knowledge gap

Despite various interventions, treatment remains limited, especially for non-arteritic cases. Therapies like optic nerve sheath decompression and hyperbaric oxygen have shown minimal benefit (17). In addition to conventional treatments, the survival of retinal ganglion cells (RGCs) following ischemic injury is critical to visual prognosis, as RGCs are essential for vision but have limited regenerative capacity. When transient or permanent ischemia affects the optic nerve, it leads to axonal damage, RGC apoptosis, and irreversible vision loss (18-20). Because RGCs cannot regenerate effectively, their degeneration makes vision restoration extremely difficult (21). Thus, enhancing RGC survival remains a major treatment challenge. Various experimental animal models, particularly rodent models of NA-AION, have been used to investigate the mechanisms of RGC injury and to explore potential therapies. Current research targets neuroprotective and regenerative strategies to preserve RGCs and prevent further optic nerve damage. Although some approaches are in trials or experimental stages, none are approved for routine clinical use (22,23).

Objective

Although several reviews have addressed ION, challenges remain in understanding and managing this complex condition, particularly in non-arteritic cases. Recent developments in imaging, neuroprotective research, and animal modeling of ION have emerged since previous reviews. This review aims to provide a more comprehensive and up-to-date synthesis of current knowledge, integrating recent findings from both clinical and preclinical research. In particular, we highlight advances in imaging modalities, experimental models, and emerging neuroprotective strategies, with a special focus on preserving RGCs. This review aims to establish a solid theoretical foundation to support future advancements in the diagnosis and treatment of ION. We present this article in accordance with the Narrative Review reporting checklist (available at https://aes.amegroups.com/article/view/10.21037/aes-25-27/rc).

Methods

Relevant articles were identified through a literature search of PubMed and Web of Science databases for English-language publications from January 2020 to April 2025 (Table 1 and Table S1).

Classification of ION

Broadly, ION can be divided into AION and PION. AION results from ischemia of the ONH, primarily due to compromised circulation in the short posterior ciliary arteries (SPCAs), which supply its anterior segment (1). Ischemia in the retrobulbar region of the optic nerve, which is situated behind the optic disc, causes PION (Figure 1) (1).

Figure 1 The anatomical position of damage in AION and PION. In AION, the injury occurs anterior to the lamina cribrosa, involving the optic nerve head. In PION, the damage is located posterior to the lamina cribrosa, affecting the retrobulbar segment of the optic nerve. AION, anterior ischemic optic neuropathy; PION, posterior ischemic optic neuropathy.

AION

AION accounts for 90% of ION cases. AION is classified into two main types: NA-AION and A-AION. Both types present with sudden, painless vision loss, though they have distinct underlying causes and pathophysiologies (24,25).

For adults over 50 years, NA-AION is the most frequent cause of optic nerve edema and optic neuropathy, a main cause of blindness in this population (26,27). Although the pathophysiology is not fully understood, NA-AION is widely believed to result from acute circulatory insufficiency of the ONH (27,28). The SPCAs, which are branches of the ophthalmic artery, provide the majority of the blood flow to the ONH (Figure 2). Several branches of SPCAs make up the circle of Zinn-Haller, which encircles the optic nerve as it travels through the lamina cribrosa and the sclera (29). When SPCAs are compromised, NA-AION may occur. Potential triggers include small optic nerve cup, embolization, venous occlusion, arteriosclerotic vascular blockage, vasospasm, nocturnal hypotension, and systemic hypoperfusion (30-32). Systemic disorders like diabetes, hypertension, atherosclerosis, cardiovascular disease, and sleep apnea increase the risk (33-35). Furthermore, smoking and certain medications—such as phosphodiesterase type 5 inhibitors (e.g., sildenafil, tadalafil), amiodarone, and interferon-alpha—have been associated with an increased risk of developing NA-AION (34,36).

Figure 2 Vascular supply for the optic nerve. The short posterior ciliary arteries, which are branches of the ophthalmic artery, provide the majority of the blood flow to the optic nerve head.

A-AION is an acute and often painful ophthalmic emergency that primarily affects elderly individuals and can result in permanent vision loss. Unlike the more common NA-AION, A-AION accounts for approximately 5–10% of AION cases (37,38). GCA and subsequent thrombosis of the SPCAs, especially the medial SPCA, are possible causes (39). Around 31% of the patients experience amaurosis fugax prior to permanent vision loss (40,41). Cavernous degeneration of Schnabel, an excavation of the ONH, may occur in the latter stage of AION. This characteristic usually manifests in the chronic stages of A-AION and is very rare in the NA-AION, occurring in only 2% of patients. Clinically, A-AION often presents with a relative afferent pupillary defect, peripapillary retinal hemorrhages, photophobia, color vision loss, while NA-AIO may be accompanied by ocular pain (1).

PION

PION is an uncommon but severe disease, which is usually caused by hypoperfusion or infarction in the pial capillary plexus (42). This capillary network receives blood supply from multiple sources, including branches of the ophthalmic artery, internal carotid artery, and vertebral-basilar system (37). There are three forms of PION, distinguished based on their etiology: non-arteritic PION (NA-PION) due to causes other than GCA, arteritic PION (A-PION), induced by GCA, and postoperative PION due to surgical treatment complications (43).

NA-PION is an uncommon ischemic disorder. Most studies thought that the pathophysiology was typically caused by retrobulbar optic nerve ischemia as a result of decreased perfusion pressure or poor autoregulation from a variety of non-ocular operations (44). For instance, a higher risk of NA-PION has been linked to brain procedures, especially those that are extensive or require significant blood loss. Systemic hypotension, anemia, and extended prone positioning are examples of intraoperative variables that might impair optic nerve perfusion and result in ischemic damage (43). Additionally, it typically happens when systemic vasculitis is present or has been identified. Common systemic diseases include arteriosclerosis, diabetes mellitus, and significant arterial hypotension (45). It must be noted that vascular changes associated with diabetes, such as basement membrane thickening, pericyte loss, and microvascular occlusions, may predispose to ischemic optic neuropathies. Such vascular changes are not limited to diabetes but also associated with other conditions such as atherosclerosis.

A-PION is often seen in older patients, although compared to A-AION, it happens far less frequently (46). It is characterized by abrupt, painless, acute monocular vision loss that is frequently accompanied by systemic symptoms of GCA, such as jaw claudication, scalp soreness, temporal headache, and polymyalgia rheumatica (47). Unlike A-AION, which has optic disc edema during the acute phase, it starts with a normal-looking optic disc and progresses to optic atrophy over weeks. Granulomatous inflammation of the medium and large arteries, particularly the posterior ciliary arteries, is linked to the pathophysiology of A-PION (48). This inflammatory process usually results in luminal occlusion, intimal hyperplasia, and endothelial damage (49).

Compared to patients with A-PION, individuals with postoperative PION are typically younger and often experience profound bilateral vision loss along with poorer visual outcomes (50,51). Numerous postoperative PION cases have been reported, typically linked to extended systemic surgical procedures such as radical neck dissection, venous graft in extremities, hip and nasal surgery, penetrating thoracoabdominal injury, and cataract surgery (52-54). Brain surgeries can also lead to PION due to cerebral edema, intraoperative hypotension, or vascular compromise—affecting the posterior optic nerve. Key contributors include orbital and periorbital edema, chemosis, anemia, hemodilution (from administering a large amount of intravenous fluids to compensate for the blood loss), severe and prolonged arterial hypotension, and, in rare cases, direct orbital compression by prone position (46,55). Obesity, male sex, obstructive sleep apnea, and the use of amiodarone or PDE-5 inhibitors are contributing factors to create complications that lead to postoperative PION (43). Obstructive sleep apnea has been associated with NA-AION and its recurrence, and treatment with continuous positive airway pressure (CPAP) may mitigate this risk.

Diagnosis of ION

The main differential diagnoses of ION include several other optic nerve and retinal conditions that can present with acute or subacute vision loss, optic disc swelling, or VF defects. Distinguishing ION from these conditions is crucial for appropriate management, as some require urgent intervention while others follow different treatment pathways. These can be differentiated based on imaging techniques such as CT, OCT, MRI and FA (Table 2) (10).

CT

CT is a non-invasive medical imaging technique that provides high-resolution cross-sectional images, aiding in the evaluation of bones, soft tissues, blood vessels, and organs (56). Although it is not a primary or gold standard diagnostic tool for ION, CT plays a crucial role in excluding alternative causes of optic nerve dysfunction. It is particularly useful in excluding compressive optic nerve lesions by tumors, trauma-related damage, or bony abnormalities of the orbit and optic canal (57). Furthermore, CT can detect vascular abnormalities, optic nerve swelling, edema, and intracranial hypertension, which are important for diagnosis of ION (58).

CT may show decreased perfusion in the ONH in AION patients (59). However, decreased ONH perfusion is not specific to AION, so further testing is needed to confirm the cause. PION is harder to detect on CT since the affected area lies deeper in the orbit, but perfusion deficits in the retrobulbar optic nerve can still be seen, especially in perioperative PION linked to systemic hypotension. These imaging patterns, along with clinical context, help distinguish AION from PION and other optic neuropathies.

OCT

OCT is a non-invasive imaging technique that revolutionizes the early diagnosis of central nervous system disorders. It is widely used for scanning and analyzing specific structures of the retina and ONH. It can give precise measures of the thickness of the retinal nerve fiber layer (RNFL), which can reveal atrophy or swelling of the nerves. Additionally, by analyzing the ganglion cell complex, OCT enables early detection of axonal damage, offering valuable prognostic insights into visual outcomes (60).

OCT and OCT angiography (OCT-A) have been used to identify vascular abnormalities contributing to the development and progression of ION and to characterize disease severity. For example, OCT frequently shows RNFL thickening in the affected eye relative to the other eye in the early stages of NA-AION. OCT can also detect subclinical edema in the unaffected eye, serving as an early warning sign of impending NA-AION and prompt timely intervention (16). As the disease enters the subacute phase, typically over the first 6 months, RNFL thickening rapidly, reflecting ongoing axonal loss (61). Long-term studies show no significant RNFL reduction between months 6 and 12, suggesting stabilization after the subacute phase. Many studies show that RNFL thinning is closely associated with the severity of VF defects and visual acuity (VA) loss. Compared to both the unaffected inferior sectors and healthy control eyes, RNFL thickness is significantly decreased in the corresponding superior quadrants and peripapillary sectors of eyes with the typical inferior altitudinal VF loss of NA-AION. Quantitative analysis shows VA decreases by about one Snellen line per 1.6 µm RNFL thickness loss. OCT’s value in measuring RNFL thickness has also been validated in NA-AION animal models, where peripapillary inner retinal thickness measured by OCT correlated well with histologic findings (62). This supports using OCT for early detection of optic disc edema, even when the swelling is subtle. Additionally, OCT enables monitoring of RNFL thinning over time, providing a non-invasive means to track disease progression and axonal loss. This helps r clinicians and patients understand the typical course, especially when optic disc pallor makes assessment difficult in later stages. OCT may also reveal additional retinal abnormalities, such as intraretinal and subretinal fluid, during the acute phase. For instance, Chapelle et al. reported that nearly 47% of NA-AION eyes had parafoveal or subfoveal fluid on OCT (62,63).

In contrast to NA-AION, OCT has not been widely utilized during either the acute or chronic phases of A-AION. To assess the choroidal vascular index in patients with both AAION and NA-AION, a recent study used ONH and macular OCT. While there was no discernible difference between NA-AION patients and healthy controls, the data indicated that A-AION patients had a considerably lower macular choroidal vascular index than those with NA-AION. Furthermore, A-AION had a considerably lower peripapillary choroidal vascular index than NA-AION, which is probably due to choroidal hypoperfusion caused by posterior ciliary artery vasculitis (64). OCT-A investigations in A-AION have revealed retinal peripapillary capillary defects that correlate with VF loss, similar to NA-AION (16). OCT findings in PION are generally similar to those in AION; however, AION typically presents with optic disc edema and more localized ONH changes, whereas PION affects the retrobulbar optic nerve and often lacks visible ONH abnormalities.

MRI

MRI is a non-invasive imaging modality that utilizes the body’s natural magnetic properties to generate high-resolution images of internal structures. In the context of ION, MRI is used for confirming the diagnosis and differentiating it from other types of optic neuropathies, as it offers greater precision and is considered the preferred imaging method (12). Additionally, by identifying the temporal artery’s wall thickening and contrast enhancement, MRI can be used to diagnose temporal arteritis (65). There are different kinds of MRI imaging modalities used for diagnosing and studying ION. These modalities provide different insights into the anatomical, functional, vascular, and metabolic changes associated with ION (Table 3). T1-weighted imaging (T1WI) and T2-weighted imaging (T2WI) focus on the anatomical assessment of the optic nerve and surrounding structures (66). Diffusion-weighted imaging (DWI), diffusion tensor imaging (DTI), and magnetization transfer imaging (MTI) assess acute ischemic changes, neurodegeneration, and fiber integrity (67,68). Magnetic resonance angiography (MRA) and perfusion-weighted imaging (PWI) evaluate blood supply and ischemic severity in the optic nerve. Magnetic resonance spectroscopy (MRS) analyzes optic nerve metabolism and neurodegeneration (69).

MRI plays a valuable role in evaluating A-AION, particularly in cases associated with GCA. One of the hallmark findings in A-AION is post-contrast enhancement of the ONH and perineural sheath on enhanced black-blood three dimensional (3D) T1WI, which shows inflammation and blood-nerve barrier breakdown (70). In contrast, T2WI may reveal increased signal intensity in the affected optic nerve due to edema in the acute phase, while chronic stages often show optic nerve atrophy with reduced T2 signal (71). Additionally, DWI frequently shows restricted diffusion in the optic nerve, with a corresponding reduction in apparent diffusion coefficient (ADC) values, which strongly suggests acute ischemic infarction. This feature is particularly useful in differentiating A-AION from optic neuritis, as the latter typically does not exhibit diffusion restriction. To assess the vascular involvement characteristic of GCA, MRA is often employed to detect occlusion or stenosis of the SPCAs or ophthalmic artery. High-resolution-contrast-enhanced MRI can noninvasively visualize mural thickening and enhancement of the superficial temporal artery wall, which is a diagnostic hallmark of GCA and shows strong agreement with histologic and clinical criteria (71). These advanced imaging techniques help differentiate A-AION from NA-AION, which generally lacks significant post-contrast enhancement or vascular occlusion. Therefore, guiding early intervention with corticosteroid therapy to prevent further visual deterioration. Conversely, MRI is less effective for diagnosing non-arteritic ION, as it rarely reveals definitive abnormalities of the optic nerve. For instance, signal alterations or contrast enhancement of the optic nerve are typically absent or subtle in MRI scans of NA-AION patients, making it difficult to detect with standard imaging techniques (72). As a result, its primary role in the evaluation of non-arteritic ION is to exclude other causes of optic neuropathy rather than to confirm the diagnosis (73).

AION is best visualized using T1WI, short tau inversion recovery (STIR), and MRA, as it involves the ONH. In contrast, PION mostly impacts the optic nerve’s retrobulbar region and is more effectively diagnosed using DWI, T2WI, and post-contrast T1WI. Among these, DWI is particularly important for detecting acute ischemic changes in PION that may not be evident on other sequences. Several case reports have highlighted the utility of DWI in identifying acute optic nerve infarction or ION following infection, surgery, or various inflammatory and non-inflammatory conditions (62). However, there is a significant chance of false-negative results when utilizing DWI to detect ischemia alterations along the optic nerve. Partial volume averaging effects from normal axial DWI recording and susceptibility artifacts from adjacent anatomical structures are contributing causes. Imaging should be obtained in the coronal plane with improved signal-to-noise ratio and increased spatial resolution, utilizing DTI to improve infarct detection.

FA

FA is an invasive imaging technique used to evaluate retinal and choroidal circulation in the optic nerve, helping detect vascular abnormalities, leakage, ischemia, and other retinal pathologies (74). The procedure involves intravenous injection of fluorescein dye, usually into an arm vein, which rapidly circulates through the ocular vasculature. Under blue light excitation, the dye emits yellow-green fluorescence, allowing a specialized camera to capture sequential images of blood flow through the retina and choroid at various phases (75).

To differentiate between A-AION and NA-AION, FA is especially useful in evaluating choroidal and optic disc perfusion (76). FA usually indicates partial or delayed optic disc capillary filling in the early phase of AION, which is indicative of impaired posterior ciliary artery perfusion (77). In the late phase, disc leakage and hyperfluorescence are commonly observed due to inflammation and vascular permeability. While A-AION frequently exhibits choroidal hypoperfusion and severe disc leakage, which are signs of GCA, FA may exhibit segmental hypofluorescence with modest disc leakage in NA-AION (78). However, because the ischemia in PION takes place posterior to the visible optic disc, FA results are frequently normal. Therefore, FA is more effective in diagnosing AION than PION, as the PION often needs MRI or clinical correlation for confirmation.

Animal models for research

The axons of RGCs make up most of the optic nerve, which is essential for visual function. However, RGCs are incapable of regeneration and functional restoration following injury. The complex and inhibiting conditions exist within their environment. Intrinsic breakdowns in regeneration, and the geometric tortuosity that provides a physical impediment to axon growth are some of the elements that make regenerating optic nerve axons difficult (21). The most effective method for developing prospective therapies to regenerate RGCs is through animal studies.

NA-AION animal models

To better understand the pathogenesis of NA-AION and evaluate potential neuroprotective therapies, researchers have developed a variety of rodent and primate models that closely mimic the human condition. The rodent NA-AION model (rNA-AION) replicates many clinical features of the disease. In this model, a photosensitive dye like Rose Bengal dye is intravenously injected into the sedated animal. A custom plano-concave contact lens (7 mm for rats, 5 mm for mice, 3-mm-thick) allows retinal visualization and keeps the eye steady when it is in front of a slit lamp for laser induction. The intraocular region of the ON is exposed to a 532-nm laser (500 µm for rats and 300 µm for mice) for 12 seconds, sparing the rest of the retinal capillary bed (Figure 3) (79). The low-intensity laser light activates the dye, damaging ON capillaries without thermal injury. However, excessive laser fluence can lead to unintended damage, including retinal burns or central retinal vessel occlusion (80). This model replicates key pathological features of NA-AION, such as RGC apoptosis, compartment syndrome followed by axonal collapse, and ONH edema. The rNA-AION model has proven valuable for evaluating potential therapeutic strategies, with several interventions demonstrating neuroprotective effects when administered either as early treatments or pre-treatments (81,82). Recent research employing this model has demonstrated that CNTF therapy in conjunction with SARM1 inhibition results in a long-lasting, synergistic neuroprotective effect in ION (83).

Figure 3 Experimental setup of the rNA-AION model. (A) Inject a 1 mL/kg mixture comprising 80 mg/mL ketamine and 4 mg/mL xylazine intraperitoneally to anesthetize the animal. (B) Dilate the pupils with 1% tropicamide and apply 0.5% proparacaine for topical anesthesia. (C) Place a drop of 1% methylcellulose inside a custom-designed contact lens, then position the lens on the eye. (D) Inject 1 mL/kg of Rose Bengal dye intravenously via the tail vein and allow circulation for 30 seconds. (E) Position the animal’s head at a 45° angle to align the eye perpendicularly to the laser beam and activate the laser. (F) The low intensity 532 nm laser generates dye-induced superoxide radicals within the ON capillaries, initiating localized ischemic injury without thermal damage. ON, optic nerve; rNA-AION, rodent non-arteritic anterior ischemic optic neuropathy model.

Rhesus monkeys have also been used to develop an NA-AION model, offering significant anatomical advantages due to their closer similarity to humans—including the presence of a macula, a well-defined lamina cribrosa, and optic nerve sheath structures. The steps are similar to rNA-AION model, despite the mouse and primate having different anatomy. In the primate model, a standard glasser contact lens replaces the custom-designed lens used in rodents, and laser parameters are adjusted accordingly. Specifically, a 532 nm laser is applied at 200 mW for 8.5 seconds with a 1.2 mm spot size to induce focal ischemic injury (84). This primate model enables more clinically relevant investigations into disease mechanisms and therapeutic interventions.

A-AION animal models

All currently available A-AION models simulate acute or subacute ischemic injury to the ON, rather than replicating the underlying medium-sized arterial inflammation of true A-AION. Developing reliable animal models remains particularly challenging, as A-AION is driven by systemic vasculitis rather than localized ischemia. Accurately modeling this immune-mediated vascular pathology requires systemic immune activation, which is difficult to achieve consistently in animals. Nevertheless, several experimental approaches have provided valuable, though limited, insights into its pathogenesis.

The only documented A-AION animal model involves acute, partial rupture of the long posterior ciliary arteries (LPCAs) or SPCAs, which contribute to the primate arterial circle of Zinn-Haller. In this primate model, several SPCAs are ligated at their scleral entry points, causing segmental SPCA circulation loss (Figure 4). This interruption leads to choroidal hypoperfusion and reduced cilioretinal artery flow, as these vessels are supplied by the choroidal circulation. The resulting segmental disruption of axonal transport triggers ONH edema. Intravenous FA reveals segmental choroidal perfusion loss extending to the optic disc, consistent with both clinical A-AION and the early post-induction phase in the model. Thus, the SPCA-A-AION model closely mimics the proposed mechanism of human A-AION (85). However, its use is limited: it has only been developed in nonhuman primates, making it expensive and ethically challenging. These constraints limit experimental frequency and hinder its broader application in therapeutic research (80).

Figure 4 Schematic diagram of the primate A-AION model. Ligation of multiple SPCAs at their entry points into the sclera leads to segmental choroidal ischemia, disrupting the blood supply to the optic nerve head and surrounding structures. A-AION, arteritic anterior ischemic optic neuropathy; SPCA, short posterior ciliary artery.

Previous nonhuman primate models of ON stroke have been developed through surgical ablation of the major arteries supplying the ON and posterior segment of the eye. This approach generates a model that more closely resembles A-AION, as it also results in concomitant retinal and choroidal infarction, mimicking the vascular compromise seen in human disease (86). By employing an implanted minipump to release endothelin-1 continuously, another model that mimics the characteristics of A-AION has been developed in rabbits (87). Despite the fact that glaucomatous alterations have been the main association of this model, some observed effects—such as early RGCs loss, axonal and myelin degeneration in the ON, and marked reduction in ON blood flow—overlap with the pathophysiology of A-AION, at least in rabbits (80). Attempts to develop rodent models of A-AION have been hindered by significant anatomical differences. Rodents have significantly smaller eyes and fewer PCAs supplying the outer retina compared to primates. As a result, larger regions of the posterior circulation are dependent on a limited number of vessels. Consequently, occlusion of a single PCA in rodents often results in widespread ischemia, including extensive retinal and choroidal infarction, rather than localized ON ischemia. This anatomical constraint has prevented successful replication of A-AION in rodent models through PCA ablation. As a result, no reliable or specific rodent models for A-AION currently exist (88).

PION animal models

Until recently, it was challenging to replicate human PION in animal models due to the complexity and location of the optic nerve lesions. However, researchers have developed a mouse model that closely mimics human PION. In this model, erythrosin B, a type II photosensitizer, is administered intravenously. Upon exposure to light, erythrosin B generates reactive singlet oxygen species that induce peroxidation of vascular endothelial cells, causing vascular damage. After dye administration, a laser beam with a 532 nm wavelength is directed at the exposed segment of the optic nerve. The laser is applied for 90 seconds at an average intensity of 16 W/cm², activating the dye to create localized endothelial damage. This results in vasogenic edema and the formation of occlusive thrombi within the microvasculature of the optic nerve, thereby inducing focal ischemia in the targeted region (89). This model is the first to effectively simulate human PION, as it displays key pathological features, such as focal edema, axonal loss, glial activation, ballooned myelin sheaths, cavernous degeneration, and delayed RGC death. This model substantially resembles the pathophysiology of human NA-PION by producing local thrombosis and vasogenic edema, despite the fact that ischemia is caused by peroxidative endothelium damage caused by singlet oxygen produced from erythrosine B (90).

Treatment

The underlying pathophysiological mechanisms of ION—particularly the disruption of ONH perfusion and resultant ischemia—are shared across its various subtypes. As a result, the therapeutic approaches to ION often overlap, regardless of the specific classification. Broadly, treatments can be categorized into several major types, including pharmacologic interventions, surgical treatment, neuroprotective strategies, and supportive therapies tailored to specific clinical contexts, such as postoperative PION.

Pharmacologic treatments

Corticosteroids

Corticosteroids are commonly used due to their well-established anti-edematous and anti-inflammatory properties (91). Since GCA is the main cause of A-AION and A-PION, effective management of these conditions involves addressing the underlying GCA. High-dose corticosteroids are the main treatment for A-ION. These steroids reduce capillary permeability and accelerate the resolution of optic disc edema, alleviating compression on the capillaries and axons. This increases ONH blood flow and axon survival (92). The standard regimen typically involves acute intravenous methylprednisolone to rapidly reduce inflammation and protect the unaffected eye, followed by a gradual tapering of oral prednisone (93). The typical dosing protocol consists of intravenous methylprednisolone at 1 g/kg/day for three days, followed by oral prednisolone at 1 mg/kg/day for 4 to 6 weeks. The dosage is subsequently tapered based on clinical markers such as erythrocyte sedimentation rate and C-reactive protein levels (93). Tapering corticosteroids requires a gradual and careful approach to avoid flare-ups. Recommendations for tapering are as follows: reducing the dose by 10 mg/month until a daily dose of 20 mg is reached, after which the dose is reduced by 5 mg/month, and then by 1 mg/month until 10 mg/day is achieved (39). However, long-term treatment for A-AION as a manifestation of GCA involves continued corticosteroid use over several months or even years. Corticosteroids are associated with well-known side effects, including gastritis, hypertension, osteoporosis, insulin resistance, steroid-induced myopathy, and psychiatric issues (94). To minimize steroid exposure and its associated side effects, alternative treatments such as methotrexate, tocilizumab, abatacept, tumor necrosis factor alpha (TNF-α) inhibitors, and prostaglandin E1 (PGE1) have been explored (95-99).

In contrast to A-AION, the role of corticosteroids in NA-AION remains controversial. The rationale for their use in NA-AION is based on the hypothesis that corticosteroids may reduce optic disc edema and limit secondary damage from inflammatory mediators and oxidative stress. By alleviating tissue swelling, they could potentially improve perfusion to the ischemic ONH (100). However, this hypothesized mechanism has not been definitively proven, and the clinical benefits remain uncertain. According to recent systematic reviews, systemic corticosteroid treatment does not significantly enhance VA or VF outcomes in NA-AION patients (101). Consequently, the efficacy of intravitreal corticosteroid administration in NA-AION is still under debate and requires further investigation through controlled clinical studies.

Other pharmacologic treatments

To lower the probability of recurrence in the affected eye and the involvement of the other eye in patients with NA-AION, aspirin has been studied as a primary treatment drug as well as a preventive measure. Although current evidence does not conclusively demonstrate a significant benefit of aspirin in either treatment or prevention, it continues to be recommended by many clinicians. This is largely due to the association of NA-AION with systemic vascular risk factors, for which aspirin’s antiplatelet effects may offer broader cardiovascular protection (4,102).

The FDA has approved tocilizumab, a monoclonal antibody that targets the interleukin-6 (IL-6) receptor, to treat GCA (103). Multiple studies have demonstrated its effectiveness in controlling GCA and its potential as a steroid-sparing agent. For example, Quartuccio et al. (2024) reported in a real‑world cohort of 112 newly diagnosed GCA patients that by month 6, 16.1% of those receiving weekly tocilizumab achieved sustained glucocorticoid-free remission—compared to 0% in the methotrexate group (P=0.001). By month 12, 64.5% of tocilizumab-treated patients remained steroidfree versus only 11.1% on methotrexate (P<0.001) (103,104). However, most of these studies cover relatively short timeframes and do not fully address the long-term safety required for lifelong management of GCA to prevent vision loss from A-AION. Additionally, the use of tocilizumab is associated with potential adverse effects, including cytopenias, upper respiratory tract infections, bronchitis, and hepatotoxicity (2). Despite these concerns, tocilizumab remains a promising adjunct in the treatment of A-AION and may be considered as a steroid-sparing therapy, particularly during periods where corticosteroid reduction is desired, provided patients are monitored closely for side effects (95).

A strong vasodilator, PGE1 may, in theory, aid in reestablishing circulation through the PCAs and preventing ischemia damage to the ONH (105). Intravenous administration of PGE1 has been reported to improve vision rapidly in a case of NA-PION during its acute ischemic phase (106). Furthermore, one study demonstrated that combining PGE1 with initial high-dose corticosteroid therapy in patients with A-AION led to improvements in VA, which remained stable during follow-up evaluations (107). However, these findings are based on a limited sample size, and larger, controlled studies are needed to more definitively assess the efficacy and safety of PGE1 in the management of ION.

Surgical treatments

Several surgical approaches have been explored for ION, particularly for NA-AION (108). One such intervention is optic nerve head sheath decompression (ONHSD), which involves creating one or more fenestrations in the optic nerve sheath to allow cerebrospinal fluid to escape. In order to potentially save reversibly damaged axons, this method attempts to lower perineural pressure, lessen the “compartment syndrome” effect, and enhance vascular perfusion and axonal transport at the level of the ONH (109). Early reports suggested possible visual function improvement, and ONHSD gained global attention as a potential treatment for various types of NA-AION. However, a large, two-year controlled study found no significant visual benefit—and in some cases, potential harm—leading to the eventual abandonment of the procedure (1).

In contrast to the surgical exploration in NA-AION, postoperative PION remains particularly challenging, as no effective treatment currently exists to restore vision once the damage has occurred (110). Unlike NA-AION, where surgical intervention was trialed, the management of postoperative PION focuses almost entirely on prevention. This form of PION is often associated with major surgical procedures, and its risk is influenced by patient-specific factors such as anemia, prolonged prone positioning, hypotension, obesity, and utilizing tools such as the Wilson frame (53). Preventive strategies during surgery include minimizing operative time, avoiding systemic hypotension, ensuring adequate fluid replacement and oxygenation, and avoiding pressure on the orbit and globe, especially in the dependent head position (93).

Neuroprotective treatments

Recent advances in experimental therapies for ION have increasingly focused on neuroprotection, aiming to enhance RGC survival following ischemic injury. A range of approaches has been explored in both preclinical and early clinical studies. Several neurotrophic factors and molecular agents have demonstrated potential for neuroprotective effects. These include Norrin, pigment epithelium-derived factor (PEDF), glial cell line-derived neurotrophic factor (GDNF), vascular endothelial growth factor (VEGF), nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF), all of which play roles in neuronal survival and regeneration (111).

Furthermore, in NA-AION animal models, agents such as astaxanthin, G-CSF, omega-3 fatty acids, and rho-kinase inhibitors have been shown to reduce RGC apoptosis (112-114). Some have progressed to early clinical trials. For example, G-CSF exerts antiapoptotic effects via the TAF9-P53-TRIAP1-CASP3 pathway (115). A pilot trial evaluating intravitreal G-CSF (60 µg/0.1 mL) within 2 weeks of NA-AION onset showed temporary BCVA improvement at one month, though the effect diminished, with no significant long-term benefit (116). This suggests the treatment is safe but transient, highlighting the need for larger trials. Additional neuroprotective agents like brimonidine, erythropoietin, and citicoline have also reduced oxidative stress and RGC apoptosis in models (117,118). Another strategy targets sterile alpha and TIR motif-containing 1 (SARM1), a key protein in axonal degeneration. Combined SARM1 inhibition and CNTF treatment yielded synergistic neuroprotection and improved RGC survival in ischemic models (83). Other promising avenues under investigation include mesenchymal stem cell transplantation and optic nerve regeneration techniques, which may help restore visual function by replacing or repairing damaged neural tissue (119). Mitochondrial support therapies—such as coenzyme Q10, nicotinamide, M01, and resveratrol—may further enhance cellular resilience by mitigating mitochondrial dysfunction (120,121).

Despite encouraging preclinical data and initial human trials, the translation of these findings into clinical practice remains limited. Most human studies suffer from small sample sizes, short follow-up durations, or a lack of control groups. Therefore, carefully planned and extensive clinical trials are necessary to confirm the long-term advantages, safety, and effectiveness of these neuroprotective techniques (122).

Strengths and limitations

The key strengths of this review are: (I) integration of clinical and experimental evidence to provide readers with a multidimensional perspective on IONs; (II) how modern diagnostic modalities enhance the accurate differentiation of ION subtypes; (III) the emphasis on animal models, which have facilitated mechanistic studies and therapeutic exploration. We also note the ongoing challenges in developing models that more closely mimic human disease. This review has several limitations: (I) being a narrative rather than systematic review with a potential for selection bias; (II) anatomical and physiological differences between experimental models and human pathology also restrict the direct applicability of preclinical findings and; (III) finally, given the rapidly evolving nature, some recent findings may have been inadvertently omitted.

Conclusions

ION is one of the main causes of abrupt vision loss, primarily affecting middle-aged and elderly populations. It is classified into AION and PION, each with a distinct vascular pathophysiology. AION primarily results from impaired circulation in the SPCAs, while PION involves ischemia in the pial capillary plexus. Accurately diagnosing ION is essential for prompt and effective management; however, it remains challenging due to symptom overlap with other forms of optic neuropathy. Advanced imaging techniques, such as OCT, have enhanced our understanding of ONH and retinal microvascular changes. MRI and DWI provide further insights, especially for detecting posterior ION, where direct visualization is more difficult. CT plays a more limited role but can help rule out compressive or traumatic causes of optic neuropathy. Animal models play a crucial role in understanding ION and developing potential therapeutic strategies. Although the types and number of models are limited, different models have been established to mimic NA-AION, A-AION, and PION. Despite extensive research, effective treatment options for ION remain limited. High-dose corticosteroids are the primary therapy for A-AION, as they can reduce inflammation and prevent further ischemic damage. However, for NA-AION and PION, no proven treatment can restore vision once damage occurs. Efforts to improve RGC survival are crucial, given their limited regenerative capacity. Current research focuses on neuroprotection, vascular perfusion improvement, and stem cell therapy, but these remain largely experimental.

In conclusion, ION remains a complex and challenging condition with no definitive cure. Advances in imaging, experimental models, and neuroprotective strategies offer hope for future breakthroughs. Further research is needed to develop effective animal models and treatments that can halt progression and restore vision in affected patients.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://aes.amegroups.com/article/view/10.21037/aes-25-27/rc

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Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://aes.amegroups.com/article/view/10.21037/aes-25-27/coif). S.K.B. serves as an unpaid editorial board member of Annals of Eye Science from August 2024 to December 2026. W.L. received grants from NIH, DOD and Alzheimer’s foundation, Research to Prevent Blindness, but not related to work presented in the manuscript. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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