Clinical manifestations

Presentation and course

The typical clinical presentation of ischemic optic neuropathy (ION) is characterized by the sudden onset of vision loss in one eye in an older individual, with a reduction in visual acuity vision, peripheral visual field loss, or both. There will be a relative afferent pupillary defect except if both eyes are affected equally. In the acute stage, the ophthalmoscopic exam will show a segmentally or completely swollen optic disc in anterior ischemic optic neuropathy and a normal optic disc in posterior ischemic optic neuropathy. In the chronic stage, ophthalmoscopy will show a pale optic disc in both anterior and posterior forms. Key features to delineate arteritic from nonarteritic ischemic optic neuropathy are listed (Table 1). Further details are provided in the subsections below.

Table 1. Arteritic Versus Nonarteritic Anterior Ischemic Optic Neuropathy

Arteritic ischemic optic neuropathy (anterior or posterior). Depending on which arteries are affected, patients can have many symptoms. In addition to anterior or posterior ischemic optic neuropathy, which can affect both eyes simultaneously or sequentially, other ocular manifestations of giant cell arteritis include central and branch retinal artery occlusions, frequently accompanied by cotton wool spots and retinal hemorrhages. Patients with the vascular compromise to the ocular structures can experience episodes of temporary vision loss prior to the onset of permanent ocular ischemia. Diplopia and eye pain can occur due to ischemia of the extraocular muscles and other orbital structures. Constitutional symptoms suggestive of giant cell arteritis include headache, jaw claudication, scalp tenderness, weight loss, alopecia, fever, and depression. Multiple symptoms can occur simultaneously or stepwise due to the progressive involvement of other arteries. The progression can be rapid, and emergent treatment is necessary to reduce involvement of additional vascular beds.

Nonarteritic anterior ischemic optic neuropathy. Nonarteritic anterior ischemic optic neuropathy usually presents as acute painless vision loss in one eye, often noted upon awakening. Visual acuity may be preserved. Any pattern of visual field loss may occur, the most common being altitudinal loss involving all or a portion of the superior or inferior hemifield. In some cases, vision can decline further over the initial few weeks. In rare circumstances, vision loss can eventually involve both eyes, but simultaneous binocular involvement is rare.

A hyperemic optic disc is observed on funduscopic examination, usually accompanied by nerve fiber layer hemorrhages. The optic disc may be completely swollen or partially swollen in one or more quadrants with preservation of optic disc structure in non-swollen regions of the disc.

There is frequently little correlation between the degree of optic disc swelling and the amount of visual acuity or visual field loss. Patients with NAION commonly have a type of optic disc structure called the “disc at risk,” which is a small diameter optic disc with or without a small (less than 0.3) or absent cup in the center of the disc (14). This feature can be identified in the contralateral eye.

Nonarteritic posterior ischemic optic neuropathy. Although posterior ischemic optic neuropathy can occur in giant cell arteritis, it is more commonly encountered after systemic hypotension in severe hemorrhage or during renal dialysis, spinal, cardiac, and organ transplant surgery. In acute posterior ischemic optic neuropathy, the ophthalmic examination reveals visual acuity and/or visual field loss, an afferent pupillary defect (if unilateral or asymmetric), and a normal-appearing optic disc. Posterior ischemic optic neuropathy is a diagnosis of exclusion.

Prognosis and complications

Arteritic ischemic optic neuropathy. Vision recovery is rare. Prognosis relates to the underlying condition of giant cell arteritis. In the chronic phase of arteritic anterior ischemic optic neuropathy or arteritic posterior ischemic optic neuropathy, optic disc pallor is often accompanied by pathologic excavation of the disc, as axons and their supporting elements have been infarcted.

Nonarteritic anterior ischemic optic neuropathy. Typically, optic disc edema resolves within 2 to 3 months. Visual function stabilizes within three weeks.

The Ischemic Optic Neuropathy Decompression Trial Research Group reported 42.7% overall spontaneous improvement of visual acuity of three lines or more (45). In a small study, optical coherence tomography imaging of the macula two weeks after presentation correlated with the ultimate visual outcome (22). Optic disc pallor occurs without pathologic optic cup excavation in the atrophic phase of NAION, presumably because of a lower degree of infarction than in arteritic anterior ischemic optic neuropathy.

The incidence of fellow eye involvement in NAION was 15% in one study (45). In contrast, another analysis showed a cumulative prevalence of NAION in the fellow eye of 30.6% (77). This can occur weeks to years after involvement of the affected eye, and the median time of onset was 1.2 years (77). Recurrent vision loss due to NAION in a previously affected eye is very rare but has been documented in persistent nocturnal hypotension attributed to ingestion of blood pressure medications in the evening (39).

Whether NAION is associated with a higher rate of subsequent cerebrovascular or cardiovascular events is unsettled. One study found an increased incidence of subsequent stroke (but not mortality) in patients with both hypertension and diabetes (38). A study based on a national health insurance database reported a doubling of the hazard ratio for ischemic stroke in individuals with NAION as compared to age- and gender-matched individuals without NAION (56). This finding persisted after accounting for vascular comorbidities. There is evidence of increased cerebral small vessel ischemic disease in these patients. A study of MRI of the brain in 63 patients with NAION revealed a significantly higher percentage of cerebral small vessel disease on MRI compared to controls matched for age, sex, and comorbidities (52). On the contrary, a review of the incidence of symptomatic stroke between 104 NAION patients and age-matched control subjects found no significant increase in the incidence of symptomatic stroke among NAION patients (28).

Clinical vignette

A 62-year-old man with well-controlled hypertension and a 30-pack-year smoking history awoke with “darkened,” impaired vision in the inferior visual field of the left eye three days prior to evaluation. He noted no headache, pain with eye movement, scalp or temporal tenderness, jaw claudication, malaise, anorexia, or unusual joint or muscle pain. He had no neurologic symptoms.

Examination revealed visual acuity of 20/20 in the right eye and 20/80 in the left eye. The temporal arteries were pulsatile and non-tender. There were no carotid bruits. A left afferent pupillary defect was present. The left optic disc demonstrated diffuse hyperemic edema, worse in the superior portion of the disc, with peripapillary flame hemorrhages and adjacent retinal arteriolar narrowing. No retinal arteriolar emboli were present. The remainder of the ophthalmologic examination was normal.

Quantitative perimetry revealed an inferior altitudinal visual field defect in the left eye. Erythrocyte sedimentation rate was 18 mm/hour. He was instructed to stop smoking and to continue aspirin, but no additional therapy was recommended.

Over the next week, visual acuity worsened to 20/100, with an associated slight increase in optic disc edema, followed by vision stabilization. By two months following onset of visual loss, the optic disc had become pale, especially in its superior half, with complete resolution of disc edema. By six months, visual acuity had improved to 20/60, but the visual field defect remained.

Biological basis

Etiology and pathogenesis

Arteritic ischemic optic neuropathy (anterior or posterior). The etiology of granulomatous vasculitis involves an environmental or infectious trigger in the context of systemic inflammation, primarily mediated by IL-6 (24). This leads to the activation of dendritic cells, arterial invasion by monocytes and T cells, and cytokine and chemokine release, causing further immune cell recruitment, vascular injury, and intimal hyperplasia and fibrosis as well as neoangiogenesis (89). Expansion of the diameter of the wall of the affected arteries by this inflammatory process in giant cell arteritis leads to a reduction in the size of the arterial lumen, which results in a reduction in arterial flow to the affected tissues downstream and an acute decrease or loss in perfusion when a thrombus lodges in the lumen. When the ophthalmic artery and its downstream branches are inflamed from giant cell arteritis, flow to the optic nerve, retina, choroid, and other ocular structures is reduced.

Human autopsy studies have demonstrated ischemic necrosis of the prelaminar, laminar, and retrolaminar portions of the optic nerve, along with infiltration of the short posterior ciliary arteries by lymphocytes, macrophages, plasma cells, and multinucleated giant cells. Discontinuity of the internal elastic lamina is frequently seen in histological sections of the affected artery. Segments of the arteries, in some cases, have shown occlusion of the lumen by inflammatory thickening of the wall of the artery with or without thrombotic occlusion (61).

Nonarteritic anterior ischemic optic neuropathy. The mechanism by which NAION occurs is not well understood. The most common hypothesis proposes that insufficiency of the optic disc arterial circulation, probably through the build-up of atherosclerotic plaque or structural changes in the wall of the posterior ciliary end-artery branches of the ophthalmic artery in vasculopathic patients, exacerbated by structural "crowding" of the optic disc, eventually crosses a threshold beyond which inadequate perfusion produces irreversible axonal damage (05). Repetitive cycles of ischemia, axonal swelling, compression of blood vessels due to compartment syndrome, and further ischemia may lead to progressive nerve damage and eventual retinal ganglion cell death by apoptosis. Hayreh believes that NAION occurs in the setting of nocturnal hypotension, which leads to inadequate arterial perfusion to the optic disc in the short posterior ciliary branch end-arteries and circle of Zinn-Haller surrounding the optic disc, making this a disease of small-caliber arterioles and capillaries rather than the large- or medium-sized vessels affected by giant cell arteritis. Fluorescein angiography in NAION has shown segmental filling delay of the optic disc and adjacent peripapillary choroid, suggesting impairment of flow at the level of the short posterior ciliary arteries (34). In contrast, the peripapillary choroidal filling was not consistently delayed compared to control subjects. One study showed that flow velocities in the ophthalmic arteries on the side of the eyes with NAION were significantly decreased compared with those on the side of the unaffected eye (100). Common and internal carotid intima-media thickness was significantly greater on the NAION side than on the contralateral side.

Another theory is that there is the inadequate autoregulatory capacity of the arterial perfusion of the optic nerve in the setting of microvascular diseases, such as hypertension, diabetes, and atherosclerosis, or secondary to the effects of medications on autoregulation, such as erectile dysfunction drugs. Increased levels of endothelin-1 have been identified in patients with NAION (97; 96). One study suggested that sleep apnea may act as a permissive risk factor by affecting vascular endothelium in vasculopathic patients (03). A venous etiology for NAION has also been proposed (57). In this model, ischemia to the optic disc is preceded by venous congestion, leading to optic disc edema. Once optic disc edema occurs, cycles of ischemia and compression lead to further damage. The observation supports this theory that many patients have asymptomatic optic disc elevation prior to the onset of vision loss from NAION.

On rare occasions, NAION can occur in several members of the same family, suggesting there may be a hereditary form of this disease. A familial form of NAION has been identified in which some of these individuals carry the mitochondrial mutation G4132A (26; 37).

A review of the histopathologic features in 193 eyes with NAION confirmed infarction in the prelaminar, laminar, and postlaminar regions of the optic disc (53). Cavernous degeneration of the optic nerve was noted in 36% of eyes, with mucopolysaccharide deposition in over half, frequently distorting the remaining intact nerve fibers. This finding supports the hypothesis of secondary damage of axons caused by swelling of adjacent axons. However, no consistent abnormalities were noted in the vessels within the optic disc, which belies the theory that structural damage to the arteries prior to the onset of vision loss is important.

Rodent and primate models for this disease have been developed, utilizing laser-activated rose bengal induction of microvascular thrombosis (10; 19). Use of animal models has demonstrated that a cascade of molecular changes at the level of the optic nerve axons leads to optic nerve ischemia and apoptosis, and different molecules will decrease the degree of axonal damage when applied to the optic nerve in vivo either prior to or at the time of onset of axonal ischemia. For example, intravitreal anti-NOGO antibody preserved axonal structure and optic nerve function measured by electrophysiology (50), whereas prostaglandin J2 had similar effects and additionally decreased optic disc edema (64). Studies are needed to determine whether combining agents with different mechanisms could have a synergistic effect.

Nonarteritic posterior ischemic optic neuropathy. Posterior ischemic optic neuropathy is thought to result from impaired perfusion of blood from the pial plexus to the retrobulbar portion of the optic nerve (35). Most cases not associated with surgery occur in the context of vasculopathic risk factors, such as diabetes, hypertension, and hypercholesterolemia. In perioperative cases it is hypothesized that a combination of blood loss and hypotension under general anesthesia leads to inadequate perfusion of one or both optic nerves during surgery and to vision loss that patients recognize within 24 to 48 hours after surgery. A large, multicenter, case-controlled study of perioperative ischemic optic neuropathy after spinal fusion surgery assessed risk factors associated with vision loss, including obesity, male sex, Wilson frame use, longer anesthesia duration, greater estimated blood loss, and decreased percent colloid administration (85). These results, along with medical claims-based studies demonstrating an association between perioperative ischemic optic neuropathy, obesity, transfusion, and carotid artery stenosis (93; 92), suggest patient positioning and hemodynamic contributions to this condition.

Autopsy studies of patients with cardiac or cerebrovascular disease have shown that the pial vessels supplying the retrobulbar optic nerve may show atherosclerotic changes. Some of these patients also show infarcts of the retrobulbar optic nerve (44). This supports the hypothesis that posterior ischemic optic neuropathy could be caused by atherosclerosis in some cases. Histopathology of the optic nerve obtained from a patient with posterior ischemic optic neuropathy that occurred from profound hypotension and anemia with no underlying vascular disease showed infarction of the retrolaminar portion of the optic nerve (49). Pial vessels might be subject to compression due to local edema from hypoxia. Most patients with posterior ischemic optic neuropathy have no abnormalities on fluorescein angiography, indicating that the posterior ciliary arteries are not involved.

Animal models for posterior ischemic optic neuropathy have been developed (115). Hemodilution and head-down tilt induce functional optic nerve changes and optic nerve swelling in rats (91). It is hoped that these models will identify mechanisms of ischemic injury to the optic nerve and lead to a paradigm for testing different treatment strategies for the disease.

Epidemiology

Arteritic anterior ischemic optic neuropathy. Incidence has been reported at 0.36 per 100,000 population (48). It occurs exclusively in older individuals, with cases rarely seen under age 50. There is no gender predisposition, but the disease occurs more frequently in white people than in black or Hispanic individuals.

Nonarteritic anterior ischemic optic neuropathy. This is the most common acute optic neuropathy in patients older than 50 years of age, with an estimated annual incidence in the United States of 2.3 to 10.2 per 100,000, resulting in up to 6000 new cases each year (48). The incidence of NAION in the population with crowded optic discs is unknown.

The risk factors commonly associated with NAION are age, male gender, white race, and diabetes with end-organ involvement (16). A study demonstrated that the majority of NAION patients are white, followed by Black and Asian races. (07). Systemic hypertension has been documented in up to 49% of patients with NAION, with diabetes being present in up to 25% (38; 46). Carotid occlusive disease itself does not appear to be directly associated with anterior ischemic optic neuropathy in most cases (30).

NAION occasionally is recognized as the cause of vision loss after cataract surgery and LASIK. Patients with a previous history of NAION had a 4-fold increased risk of developing NAION in the fellow eye after cataract surgery in one study (54). However, one study suggested no association (70).

There has been substantial interest in the possible role of additional risk factors for ischemic optic neuropathy, particularly in younger patients or patients who do not have hypertension, diabetes, or hyperlipidemia. Hyperhomocysteinemia has been implicated in premature vascular disease in coronary, cerebral, and peripheral arteries, and there is limited evidence that it may increase the risk for retinal artery occlusion (81). However, studies of patients with NAION reporting homocysteine levels and mutations of the methylene tetrahydrofolate reductase gene have shown conflicting results (12; 32). Another study suggests elevated plasma homocysteine levels are associated with NAION (31). Prothrombotic risk factors such as protein C, protein S, and antithrombin III deficiency have not been demonstrated to correlate with the development of ischemic optic neuropathy (98). However, there is a case report of NAION in a patient with both antiphospholipid syndrome and the factor V Leiden mutation (106). A retrospective study of Factor V Leiden mutation in patients with NAION demonstrated a 25% occurrence in a sample of 25 (76).

Whether phosphodiesterase inhibitors used for erectile dysfunction or pulmonary hypertension cause NAION is unsettled. Cases of NAION associated with use of phosphodiesterase inhibitors have been documented (84; 83). In these case series, cup-to-disc ratios were small in all patients, and most patients had typical risk factors for NAION, such as hypertension, diabetes, and hyperlipidemia. FDA-mandated prospective studies of individuals who used PDE-5 inhibitors in the month prior to NAION demonstrated increased odds of NAION among those who used PDE-5 inhibitors within five half-lives prior to their NAION event (15).

Cases of NAION associated with amiodarone use have been documented, but a causal link has never been firmly established (74). In many cases, unilateral or bilateral optic disc edema may be present for weeks or months before vision loss occurs. Vision loss can be abrupt or insidious (79). Improvement in visual field loss or visual acuity has been documented with the discontinuation of amiodarone, raising the question of whether this form of optic neuropathy is truly NAION (36; 66; 65).

Obstructive sleep apnea is common in patients with NAION, though a causal relationship has not been established (69; 09; 111). A meta-analysis showed obstructive sleep apnea could be a risk factor for NAION (116).

A single-center retrospective case series of five patients with high-altitude-associated NAION was reported. These patients exhibited a progressive course of vision loss after initial onset and severe thinning of retinal nerve fiber layer (RNFL) (59).

Optic disc drusen are calcified deposits located in optic nerve head. According to several studies, optic disc drusen has been proposed as the independent risk factor of NAION. NAION patients with optic disc drusen more often had no vascular risk factors as compared to NAION patients without optic disc drusen (94). Additionally, the prevalence of optic disc drusen in young NAION patients (50 years or younger) was significantly higher than in the general population (29).

Retinal vein occlusion and age-related macular degeneration are associated with NAION (16).

Several case reports described NAION associated with COVID-19 or COVID-19 vaccination. Although the pathogenesis is not well understood, it is speculated that the immune-mediated response or direct ischemic events secondary to virus-associated endotheliopathy contributed to the impaired microvascular network of the optic nerve head (71; 75; 112).

A prospective comparative study showed that three or more injections of intravitreal anti-VEGF was considered as a risk factor for developing NAION in diabetic patients (18).

Posterior ischemic optic neuropathy. This is rare, with an incidence no higher than 0.087% (13). The age of patients with posterior ischemic optic neuropathy associated with surgery is younger than that related to vascular risk factors or giant cell arteritis (95). The incidence of posterior ischemic optic neuropathy associated with spine surgery but not cardiac surgery decreased between 1998 and 2013 (93; 92).

In a large, multicenter, case-controlled study of perioperative ischemic optic neuropathy after spinal fusion surgery, risk factors associated with vision loss included obesity, male sex, Wilson frame use, longer anesthesia duration, greater estimated blood loss, and decreased percent colloid administration (85). In medical claims-based studies, ischemic optic neuropathy during cardiac surgery was associated with carotid artery stenosis and degenerative eye conditions (92) and ischemic optic neuropathy during spinal fusion surgery was associated with older age, male gender, obesity, and transfusion (93).

Prevention

Nonarteritic anterior ischemic optic neuropathy. There are no data regarding what extent improved control of vascular risk factors after diagnosis of NAION might decrease the risk or severity of NAION in the fellow eye. On the other hand, it is thought that overly aggressive control of hypertension may increase the risk of recurrence in the same eye or involvement of the second eye, possibly because of the resulting nocturnal hypotension.

There is no proven prophylactic treatment for NAION. Although aspirin reduces the incidence of stroke in patients at risk, data regarding its role in decreasing the severity of NAION and reducing the incidence of fellow eye involvement after the initial episode do not demonstrate a clear-cut beneficial effect (08). One study suggested that larger doses of aspirin (325 mg daily) might be more effective than lower doses (100 mg daily) in preventing second eye involvement (99), but the numbers of patients in each group were small. Patients who use PDE-5 inhibitors with NAION in one eye should be counseled regarding the risk in the other eye (82). A prospective study demonstrated nonadherence with sleep apnea treatment in patients with prior NAION and severe sleep apnea associated with an increased risk of second eye involvement (02). Further studies are required to determine the role of the institution of continuous positive airway pressure or other treatment.

Perioperative ischemic optic neuropathy. In ischemic optic neuropathy associated with surgical procedures, particularly spinal surgery, prophylaxis is directed at avoiding large drops in blood pressure, significant blood loss, perioperative anemia, prolonged surgery, and pressure on the orbit and globe if the patient is in the prone position. A preoperative risk factor scoring system for perioperative ischemic optic neuropathy in spinal fusion surgery has been proposed. The highest estimated absolute and relative risk was for a man, aged 40 to 64 years, with obstructive sleep apnea (102). Additional risk factors identified from predictive model are hypertension, chronic anemia, and carotid artery stenosis (72). However, some cases of postoperative ischemic optic neuropathy occur despite such precautions.

Differential diagnosis

Anterior ischemic optic neuropathy (arteritic and nonarteritic). Anterior ischemic optic neuropathy (arteritic and nonarteritic) must be differentiated from other optic neuropathies with disc swelling, including idiopathic optic neuritis (particularly in patients under 50 years of age), syphilitic or sarcoid-related optic nerve inflammation, infiltrative optic neuropathies, anterior orbital lesions producing optic nerve compression, asymmetric papilledema due to elevated intracranial pressure, and idiopathic forms of optic disc edema, including diabetic papillopathy and papillophlebitis. Optic neuritis may resemble ischemic optic neuropathy with regard to timing of onset, pattern of visual field loss, and optic disc appearance; however, in most cases, the patient's older age, the lack of pain with eye movement, the character of the disc edema (pale or segmental), and the presence of flame hemorrhages makes the distinction clear.

Occasionally, ancillary testing such as fluorescein angiography, ultrasonography, or MRI of the optic nerve may be helpful in differentiation. Fluorescein angiography may show delayed optic disc filling in optic disc ischemia, whereas the timing of filling is normal in papillitis (06). MRI is typically normal in ischemia, whereas enhancement is usually seen in optic neuritis (88). Another study found that diffusion-weighted imaging and postcontrast enhancement of the intraorbital optic nerve are more likely to present in optic neuritis, and post-contrast enhancement of the optic disc without diffusion-weighted imaging signal is highly specific for NAION (01). A recent MRI study showed that optic nerve enhancement pattern and distribution of white matter lesions could be helpful in differentiation between anterior ischemic optic neuropathy and optic neuritis (80). Enhancement of the optic nerve head, also known as the “central bright spot” sign, is characteristic of anterior ischemic optic neuropathy.

Optic nerve inflammation associated with syphilis or sarcoidosis often is associated with other intraocular inflammatory signs, such as uveitis, which should prompt further testing. Orbital lesions producing disc edema usually are associated with gradually progressive visual loss, but occasionally onset is more rapid. The detection of signs of orbital disease, including mild proptosis, lid abnormalities, or eye movement abnormalities, may indicate the need to perform neuroimaging to detect orbital inflammation or tumor, such as optic nerve sheath meningioma. However, in most cases, such testing is not required. Atypical features for NAION include the age of fewer than 40 years, pain, lack of vasculopathic risk factors, bilateral simultaneous onset, recurrent attacks, macular star, and lack of disc edema improvement within four weeks (11).

Posterior ischemic optic neuropathy. Posterior ischemic optic neuropathy is a diagnosis of exclusion and needs to be differentiated from other retrobulbar optic neuropathies, such as infectious and noninfectious optic neuritis, as well as traumatic, compressive, hereditary, or toxic optic neuropathies. History, examination, laboratory testing, and neuroimaging serve to distinguish these entities.

Presumed perioperative posterior ischemic optic neuropathy should be differentiated from other causes of postoperative vision loss, such as central retinal artery occlusion, which should show a cherry red spot on ophthalmoscopic examination.

Diagnostic workup

Arteritic ischemic optic neuropathy (anterior or posterior). A tentative diagnosis of arteritic disease may be made based on typical clinical symptoms in conjunction with elevation of the erythrocyte sedimentation rate or c-reactive protein, and these tests should be performed in all patients with a clinical suspicion of giant cell arteritis. This includes elderly patients with suggestive systemic symptoms, as well as patients with suspicious ophthalmological findings such as profound visual loss, pallid disc edema, the presence of retinal ischemia in addition to the optic nerve swelling, and a normal-sized cup in the unaffected eye. Most cases of active giant cell arteritis show marked elevation of erythrocyte sedimentation rate (mean 70 mm/hour, often more than 100 mm/hour) and CRP. The erythrocyte sedimentation rate may be normal in up to 16% of these patients; however, the erythrocyte sedimentation rate normally rises with age, with 60 mm/hour not unusual in patients over 70 and without arteritis. Elevation of the erythrocyte sedimentation rate is nonspecific, confirming only the presence of any active inflammatory process.

Orbit MRI helps distinguish other causes of acute optic neuropathy in posterior cases. Arteritic anterior ischemic optic neuropathy may demonstrate optic nerve enhancement on MRI (55). Restricted diffusion of the optic disc and/or nerve was more frequently seen on MRI within five days after the onset of visual symptoms associated with anterior ischemic optic neuropathy (73). A study using 3-tesla high-resolution vessel wall MRI showed that enhancement of ophthalmic artery, optic nerve sheath complex, posterior ciliary, or extracranial arteries could be used to distinguish between arteritic and nonarteritic anterior ischemic optic neuropathy (68).

Doppler ultrasound of superficial vessels (eg, temporal and axillary arteries) is useful as a noninvasive adjunct to biopsy. Presence of the halo sign was found to be as sensitive and nearly as specific as temporal artery biopsy in one large study (60), whereas a metaanalysis found that sensitivity and specificity of AAION ultrasonic findings were 68% and 81%, respectively, compared to biopsy (87). High-resolution MRI of the superficial temporal artery had a sensitivity of 91% and specificity of 78% compared to biopsy in a recent meta-analysis, with significantly higher specificity using 3D high-resolution MRI than 2D (117). Imaging of the large vessels (eg, aorta) using MRI or PET can also help confirm the initial diagnosis or monitoring for relapsing disease (113).

A positive temporal artery biopsy confirms the diagnosis of giant cell arteritis. This procedure is recommended in any case of ischemic optic neuropathy in which arteritis is suspected based on the severity of ocular involvement, associated systemic symptoms, or elevated inflammatory markers. A biopsy length of 1 to 3 cm has been recommended to avoid missing skip lesions (21; 62). A positive biopsy provides support for long-term systemic corticosteroid therapy, frequently maintained for at least one year with concern about its attendant systemic complications.

Nonarteritic anterior ischemic optic neuropathy. This is a clinical diagnosis, and imaging is not routinely done for anterior ischemic optic neuropathy. It is usually negative in uncomplicated nonarteritic anterior ischemic optic neuropathy when performed. Hypotensive nonarteritic anterior ischemic optic neuropathy and nonarteritic anterior ischemic optic neuropathy associated with cavernous sinus venous thrombosis may demonstrate restricted diffusion (114; 20). A meta-analysis demonstrated that peripapillary capillary density, nerve fiber layer thickness, and macular ganglion cell complex thickness measured by optical coherence tomography angiography are reduced in NAION but exhibit significant heterogeneity (58).

Nonarteritic posterior ischemic optic neuropathy. Neuroimaging of the optic nerves/orbit and brain is usually performed in these circumstances to rule out another mechanism of optic nerve injury. It will be normal in most cases of posterior ischemic optic neuropathy, although restricted diffusion in the orbital segment of the optic nerves has been demonstrated.

Management

Arteritic ischemic optic neuropathy (anterior or posterior). If giant cell arteritis is suspected and visual symptoms and/or other indications of cranial ischemia are present, early steroid therapy is critical to avoid irreversible vision loss and should be instituted immediately; confirmation by temporal artery biopsy should be done as soon as possible and ideally within two weeks of treatment initiation. High dose intravenous methylprednisolone at 500 mg to 1 g per day for the first 3 to 5 days is most often recommended, particularly when the patient is seen in the acute phase because this mode of therapy probably produces higher blood levels of medication more rapidly than oral therapy and has been demonstrated to improve visual outcomes (17; 41). After that, oral prednisone at doses up to 100 mg daily is administered in follow-up and tapered slowly.

Tocilizumab, an anti-IL-6 receptor antibody, was shown by the GiACTA trial to reduce cumulative steroid doses in both patients with the new onset and relapsing giant cell arteritis, increase the likelihood of sustained remission with a 26- or 52-week taper, and lengthen the time to first flare (110; 108; 109). The American College of Rheumatology/Vasculitis Foundation recommends treatment with tocilizumab along with oral glucocorticoids over oral glucocorticoids alone and the addition of another biologic such as abatacept (CTLA4-Ig) or methotrexate if clinical remission is not achieved (62). The European League Against Rheumatism recommends using tocilizumab as adjunctive therapy in patients with refractory or relapsing disease or an increased risk of steroid-associated complications (42).

Frequent monitoring of systemic and ophthalmic manifestations, fundus examination, and laboratory indicators of inflammation, such as the ESR and CRP, should be performed after the diagnosis of giant cell arteritis has been established. Partnership with a rheumatologist can help manage medical therapy.

Nonarteritic anterior ischemic optic neuropathy. No treatment has been demonstrated to decrease the loss of visual acuity or visual field effectively. Various treatments that have been suggested include optic nerve sheath decompression (45; 47), optic neurotomy (103; 104), vitrectomy (67), intravitreal injection (51; 86; 90), aspirin, anticoagulants, antiplatelet agents, vasodilators, vasopressors, prostaglandin E1 (107), intraocular pressure-lowering agents, steroids, diphenylhydantoin, erythropoietin (78), and levodopa (27; 43). A Cochrane review found no evidence that optic nerve decompression surgery is beneficial in NAION (23).

The controversy over treatment with steroids is far from settled. These should theoretically be helpful because optic disc swelling contributes to the vicious cycle of compartment syndrome, leading to more swelling, and steroids reduce vasogenic edema. Hayreh and colleagues reported improvement of visual acuity in patients with moderate visual loss (visual acuity 20/70 or worse) who received treatment with oral prednisolone within two weeks of onset (40). Unfortunately, the nonrandomized methodology limits the generalizability of the finding because a substantial number of patients with NAION have spontaneous improvement. A randomized control trial examining the effectiveness of oral steroids in nondiabetic NAION patients did not demonstrate improvement in visual outcome (101). However, oral steroids were associated with faster resolution of optic disc edema and improved electrophysiologic measures. A retrospective study of intravitreal triamcinolone found that injection within 15 days of symptom onset led to improvement of visual acuity and visual field at six months (25).

Clinical trials for novel acute treatments are in process. Intravitreal small interfering ribonucleic acid (siRNA) is an emerging neuroprotective treatment for NAION. By inhibiting caspase-2, siRNA prevents the apoptosis cascade of neurons (105). However, this randomized study is closed. The current treatment strategy focuses on the identification and alteration of possible risk factors identified on an individual case basis.

Nonarteritic posterior ischemic optic neuropathy. There are no proven treatments.