Nonarteritic anterior ischemic optic neuropathy: Epidemiology, pathogenesis, and etiologies

INTRODUCTION — Ischemic optic neuropathy is the most common optic nerve disorder in patients over age 50 years [1]. Ischemic optic neuropathy is generally categorized as anterior (affecting the optic disc) versus posterior (retrobulbar) and as arteritic versus nonarteritic. Anterior involvement is usual with both arteritic and nonarteritic ischemic optic neuropathy.

Nonarteritic anterior ischemic optic neuropathy (NAION) is the most common form of ischemic optic neuropathy. It is an idiopathic, ischemic insult of the optic nerve head characterized by acute, monocular, painless visual loss with optic disc swelling.

This topic will discuss the epidemiology, pathogenesis, and causes of NAION. The clinical features, diagnosis, treatment, and prognosis of NAION are discussed separately. Other forms of ischemic optic neuropathy and other optic neuropathies are discussed separately. (See "Nonarteritic anterior ischemic optic neuropathy: Clinical features and diagnosis" and "Nonarteritic anterior ischemic optic neuropathy: Prognosis and treatment" and "Clinical manifestations of giant cell arteritis" and "Optic neuropathies".)

VASCULAR ANATOMY — The optic nerve head (prelaminar and laminar portions) is supplied by 15 to 20 short posterior ciliary arteries that are derived from the ophthalmic artery and also by arterial branches from the anastomotic circle of Zinn-Haller [2-4]. The circle of Zinn-Haller itself is fed by the short posterior ciliary arteries, branches of pial arterial network, and choroidal vessels (figure 1).

This vascular supply may demonstrate distinct upper and lower halves consistent with altitudinal damage to the optic nerve head [5]. (See "Nonarteritic anterior ischemic optic neuropathy: Clinical features and diagnosis".)

The retina is supplied by the choroidal circulation and branches of the central retinal artery, both derived from the ophthalmic artery, a branch of the internal carotid artery. (See "Central and branch retinal artery occlusion", section on 'Vascular anatomy'.)

EPIDEMIOLOGY — NAION is the most common optic neuropathy in middle aged and older adult patients, and constitutes 94 percent of all anterior ischemic optic neuropathy cases [6]. The estimated annual incidence in the United States is 0.54 per 100,000 for all ages and 2.3 to 10.2 per every 100,000 persons older than 50 years, with similar rates in other countries [7-10]. There are approximately 6000 new cases annually.

NAION primarily occurs in older adults. The Ischemic Optic Neuropathy Decompression Trial (IONDT), a large prospective study population with age-defined entry criteria, reported a mean age of 66 years [7]. Other population-based studies report a mean age of 61 to 72 years [9,11]. NAION is considered unusual in patients under 45 years of age. However, in one case series of patients evaluated at a subspecialty clinic, 23 percent of individuals were less than 50 years old [12].

White individuals appear to be at higher risk than other ethnic groups [7,8]. NAION affects both sexes equally [7,8,13].

PATHOGENESIS — NAION is believed to result from acute ischemia to the optic nerve head. However, the precise mechanism leading to optic disc ischemia is unclear. There has been histopathologic documentation of infarction, but not vasculopathy in NAION [5,14,15]. Because retinal or cerebral emboli are rarely detected in the setting of NAION, embolism from cardiac or larger artery disease is believed to underlie few, if any, NAION [1,5]. In contrast to retinal ischemia, NAION is not associated with carotid occlusive disease [16,17].

Because of its strong association with age, diabetes, hypertension, and the known vascular supply of the optic nerve head, small arterial occlusive disease has been proposed as a mechanism of NAION. A magnetic resonance imaging study of 13 patients with NAION demonstrated a higher burden of white matter ischemic lesions compared with controls matched for age, hypertension, and diabetes [18]. However, a small artery vasculopathy affecting the optic nerve circulation has not been pathologically identified in NAION patients.

One hypothesis is that NAION results from transient hypoperfusion of the posterior ciliary arteries [5]. Fluorescein angiography in acute NAION shows delayed arterial filling, a finding that is not observed in cases of optic disc edema due to other etiologies [19,20]. Blood flow to the optic nerve head is maintained by autoregulatory mechanisms that include autonomic input to the blood vessels and release of vasoactive substances such as endothelin (vasoconstrictor) and nitric oxide (vasodilator). Disturbance in autoregulatory mechanisms may be induced by arteriosclerosis, vasospasm, and antihypertensive medications. In this setting, a critical fall of perfusion pressure in the capillaries supplying the optic nerve head may be caused either by a marked fall in blood pressure, a rise in the eye pressure, or blockage or sudden, severe narrowing of the internal carotid artery and/or ophthalmic artery (see 'Etiology and risk factors' below). Vasospasm has also been speculated to play a role [5,21,22].

Another theory is that NAION results from a process similar to that of a compartment syndrome. Some argue that the histopathologic characteristics of the injury, which, in some cases, included cavernous degeneration with substantial compression of adjacent normal axons by the degenerated nerve tissue, most favor this pathogenic mechanism [14,15]. Patients with NAION are believed to have a premorbid abnormality of optic disc structure (ie, a small cup with crowded optic nerve fibers) that predisposes them to NAION (see 'Ocular risk factors' below). The effects of structural crowding in the optic nerve head may lead to mechanical obstruction of axoplasmic flow causing axonal swelling and/or secondary compression of the microcirculation due to axoplasmic stasis [5]. The fact that a recurrence of NAION is uncommon in the same eye may support this hypothesis, as the atrophy that follows ischemic injury may relieve nerve fiber crowding [1].

Others have proposed that occlusion of tributaries of the central retinal vein is the initial event in NAION, which leads to optic nerve head edema and secondary arteriolar constriction causing an ischemic infarction of the optic nerve [23]. Purported risk factors such as sleep apnea and recumbent posture may cause an increase in venous pressure. Vasodilation of the central retinal artery causing a secondary obstruction of central retinal vein or its tributaries may also explain NAION occurring in association with prolonged hypotension, nocturnal hypotension, and use of phosphodiesterase-5 (PDE-5) inhibitors.

The most commonly proposed pathogenetic theory combines these mechanisms, proposing that insufficiency of the optic disc circulation causes ischemia and swelling of the optic nerve, which in the setting of a crowded optic nerve head leads to infarction.

ETIOLOGY AND RISK FACTORS — Most cases of NAION occur apparently spontaneously in the setting of one or more underlying atherosclerosis risk factors. In many case series and some case-control studies, several risk factors for NAION have been identified or suggested (table 1).

Atherosclerosis — Consistent with its presumed ischemic pathogenesis, atherosclerotic risk factors, smoking, hypertension, and diabetes have been associated with an increased risk of NAION; in the Ischemic Optic Neuropathy Decompression Trial (IONDT), one of these was present in 60 percent of patients [7]. Overall, systemic hypertension has been reported in 34 to 49 percent of patients, while diabetes is seen in 5 to 28 percent of patients [7,11,12,24-26]. NAION patients younger than 50 years old have a stronger association with diabetes, hypertension, and hypercholesterolemia than older patients [27-29].

Ischemic heart disease, hypercholesterolemia, stroke, tobacco use, and atherosclerosis have also been associated with NAION, but more variably [11,24-26,28-32].

Nocturnal hypotension — Twenty-four hour ambulatory blood pressure recordings demonstrate a physiologic drop in systemic blood pressure during sleep that normalizes on awakening in the morning. Some evidence suggests that this nocturnal arterial hypotension may play a role in the development of NAION [33-35]. Patients with NAION often discover vision loss upon awakening [36]. Patients with systemic hypertension and secondary impairment of autoregulation of the optic circulation may be particularly vulnerable to this putative complication of nocturnal hypotension [27,35].

Nocturnal blood pressure decreases may be exacerbated by antihypertensive medications, particularly when administered at night [37]. Implicated medications include beta-blockers (oral agents and eyedrops), calcium-channel blockers, angiotensin converting enzyme inhibitors, terazosin hydrochloride, amitriptyline, and other similar compounds [27,35,37,38]. However, marked nocturnal hypotension has also been recorded in patients not taking such medications.

One investigation found that patients with NAION had greater depressions in nocturnal blood pressure compared with controls, but this was not confirmed in another independent case series [27,39].

Prothrombotic risk factors — A number of case reports have described NAION occurring in individuals with coagulation abnormalities [40-45]. However, systematic studies have not defined a clear association for all coagulation abnormalities. As an example, elevated homocysteine levels have been found in some case series of patients with NAION [46-48], but not in others [49].

One small case-control study of 25 patients with NAION found increased odds of activated protein C resistance and factor V Leiden mutation (odds ratio [OR] 4.97, 95% CI 1.3-19.5) [50]. However, another case-control study of 61 patients with NAION did not find an association between the prothrombotic risk factors lupus anticoagulant, protein C or protein S, and antithrombin III, or prothrombotic polymorphisms in the genes for factor V, II, or methylenetetrahydrofolate reductase [26]. In a follow-up investigation in this population, a significant association between a platelet polymorphism involving the glycoprotein Ib-alpha gene and NAION was identified [51]. Patients carrying this allele were also more likely to have subsequent second eye involvement. It is speculated that this genetic change makes platelets more vulnerable to activation.

The results of a comprehensive battery of coagulation studies were compared in a group of 35 patients with NAION who were younger than 65 years and 70 age- and sex-matched healthy controls [52]. An abnormality was found in 51 percent of patients and 17 percent of controls. The most frequent abnormalities were an increased level of factor VIII and lipoprotein a. A family history of thromboembolism, age ≤55 years, and absence of cardiovascular risk factors were predictors of a coagulation abnormality.

Ocular risk factors — It is believed that an important risk factor for NAION is a small optic nerve head with a small or absent physiologic cup. In one case series, this finding was noted in 82 percent of patients [12]. Case-control studies have found a significantly smaller cup-to-disc ratio in the unaffected eye in patients with NAION [26,53-57]. Optic disc drusen is another disc anomaly that is believed to be associated with nerve fiber crowding and may predispose to NAION [12,58]. By contrast, the unaffected optic nerve head is normal-appearing in patients with arteritic anterior ischemic optic neuropathy [59].

The association between NAION and cataract surgery has been debated [60,61]. A number of cases of NAION occurring in the first hours to weeks after surgery have been reported [62,63]. One case series found that if NAION occurs after one cataract surgery, the risk in the other eye is as high as 30 to 50 percent after a subsequent surgery [64]. NAION has also been a reported complication following LASIK procedures [65,66]. It is suggested that a perioperative rise in intraocular pressure leads to decreased perfusion of the optic nerve head, but this is unproven.

NAION is infrequently associated with other ocular conditions including acute angle closure glaucoma [67], prolonged pressure on the eyeball from any cause, and marked optic disc edema.

Sleep apnea syndrome — An association has been proposed between NAION and obstructive sleep apnea syndrome (SAS). One case control study found evidence of SAS on polysomnography in 71 percent of 17 patients with NAION versus 18 percent of 17 control patients referred for evaluation of possible restless legs syndrome [68]. Another case series found that 89 percent of 27 consecutively diagnosed NAION patients had SAS on polysomnography, a prevalence almost five times higher than expected based on other community-based studies [69,70]. A screening questionnaire for SAS was employed in another case control study of 73 NAION patients [71]. Cases were somewhat more likely than controls to report symptoms and characteristics consistent with SAS (OR 2.62, 95% CI 1.03-6.6).

SAS may increase the risk of NAION by several potential mechanisms: impaired optic nerve head blood flow autoregulation secondary to repeated apnea, optic nerve vascular dysregulation secondary to SAS-induced arterial blood flow variations, and direct optic nerve damage due to prolonged hypoxia [68,72]. One case series report of three patients with NAION and SAS suggests that treatment of SAS may not prevent NAION [73]. SAS may also be associated with increased intracranial hypertension and the pseudotumor cerebri syndrome. (See "Idiopathic intracranial hypertension (pseudotumor cerebri): Epidemiology and pathogenesis", section on 'Pathogenesis'.)

Renal failure — NAION has been reported in patients with renal failure on peritoneal or hemodialysis [74-80]. In contrast to other cases of NAION, children as young as 17 months are at risk [81-83]. A bilateral, but not necessarily symmetric, presentation is common.

Renal failure may contribute to the development of NAION via a number of mechanisms. The accelerated arteriosclerosis that occurs in patients with chronic renal failure may predispose patients to this complication. Most patients with NAION in this setting have either chronic hypotension or hypotensive episodes, usually related to dialysis. Anemia also appears to be a risk factor for NAION patients with renal failure [77]. Some speculate that a rise in intraocular pressure during hemodialysis may contribute to NAION; however, the effects of dialysis on intraocular pressure are disputed [83,84].

Volume replacement, along with restoration of blood pressure during hemodialysis, is reported to improve visual function in some patients [75,77,85].

Uremia is also speculated to produce a toxic optic neuropathy, characterized by a more slowly progressive vision loss, with decreased pupillary response and papilledema and improvement with dialysis [85,86].

Perioperative ischemic optic neuropathy — Perioperative ischemic optic neuropathy is a rare but potentially devastating complication of surgery and is the leading cause of postoperative blindness. (Other causes include retinal and cerebral ischemia [87-90].) In contrast to ischemic optic neuropathy occurring in other clinical settings, posterior rather than anterior ischemic optic neuropathy may be a more common postoperative complication, particularly in association with lumbar spine surgery and radical neck dissection [87]. (See "Posterior ischemic optic neuropathy", section on 'Perioperative PION'.)

Cardiopulmonary bypass (CABG) and spine surgeries are the procedures most often associated with NAION, but it has also been reported with many other surgeries, particularly bilateral radical neck dissection [91-95] and other chest, abdominal, neck, and orthopedic surgeries [96-99]. The incidence of ischemic optic neuropathy after CABG is reported between 0.06 and 0.5 percent [90,100-103] and after spine surgery is between 0.03 to 0.11 percent [3,89,90,104]. With other surgeries, it is a much less frequent complication, estimated at 0.0008 percent at one institution [105]. NAION may also occur after cataract and other eye surgeries. (See 'Ocular risk factors' above.)

Perioperative NAION usually presents with vision loss in the immediate postoperative period, after recovery from general anesthesia. Compared with other causes of NAION, the visual deficit is usually profound and often (in 53 to 66 percent) bilateral [87,90,101,106]. Because the erythrocyte sedimentation rate (ESR) and C-reactive protein can be elevated postoperatively in normal patients, these tests are not reliable in this setting to distinguish between arteritic ischemic optic neuropathy and NAION [107,108]. However, in the absence of presurgical symptoms that suggest giant cell arteritis, arteritic ischemic optic neuropathy in the postoperative setting is considered unlikely.

Risk factors for perioperative ischemic optic neuropathy include [87,88,90,91,96,98,100-104,106,107,109]:

●Severe prolonged arterial hypotension

●Hemodilution

●Use of vasoconstricting agents, pressor support

●Elevated pressor support

●Anemia

●Substantial blood loss, transfusion requirement

●Longer operation time

●Atherosclerotic risk factors

●Small optic cup, optic nerve crowding

Use of the head-down or prone position used in some spinal surgeries may also increase orbital venous pressure by increasing intra-abdominal and intra-thoracic pressure, and is suggested to be a risk factor for ischemic optic neuropathy in these patients [87-89,104,110,111]. Alternatively, direct ocular compression from the headrest can occur in prone position and has been implicated as a cause of optic nerve head ischemia [88,111,112]. Risk factors for ischemic optic neuropathy more specific to spine surgery are discussed in detail separately. (See "Posterior ischemic optic neuropathy" and "Posterior ischemic optic neuropathy", section on 'Perioperative PION'.)

In patients undergoing radical neck dissection, increased orbital venous pressure may result from internal jugular vein ligation and lead to decreased arterial perfusion pressure at the optic nerve head [91,92,113]. Avoidance of simultaneous internal jugular vein ligation has been suggested to prevent this complication after radical neck dissection; however, staging the neck dissection does not appear to afford protection [91,93].

Efforts to rapidly correct hemodynamic derangements are recommended and may mitigate the severity of permanent vision loss, but there are no controlled observations to corroborate this as a treatment [88,89]. Similarly, avoidance of perioperative anemia with early transfusion has been suggested to prevent perioperative NAION, but a critical threshold of anemia or hypotension has not been identified [88,104,106].

Medications

Phosphodiesterase-5 inhibitors — The phosphodiesterase-5 (PDE-5) inhibitors sildenafil, vardenafil, and tadalafil are generally prescribed to treat male sexual dysfunction. Several reports link these drugs with NAION [114-121]. One study estimated an OR for the increased risk associated with PDE-5 inhibitors to be 2.4 (95% CI 1.3-4.2) [120]. It is not possible for observational studies to prove causation, and patients with sexual dysfunction often have vascular risk factors that are also associated with NAION [114,122,123]. In one case-control study, PDE-5 inhibitor prescription was not associated with NAION after controlling for diabetes, hypertension, and vascular disease [124]. As an exception, one case report describes NAION occurring in a child prescribed sildenafil for pulmonary hypertension [125].

While the relationship between these medications and NAION is unproven, the US Food and Drug Administration (FDA) has issued a warning regarding a possible association with NAION [126]. We suggest that patients with risk factors for NAION (eg, cardiovascular risk factors, sleep apnea, on antihypertensive drugs, history of prior NAION) be counseled against the use of these medications.

A causal relationship is suggested by the close temporal proximity of drug administration and symptom onset in many of these cases [120]. One case report in particular is compelling in describing multiple episodes of transient visual field loss, each episode occurring after taking tadalafil [127]. After a fifth dose, the patient experienced persistent monocular vision loss with clinical findings consistent with NAION. Two other cases have been described in which sequential symptoms were associated with drug rechallenge [114,128]. Another study examined visual fields in five healthy volunteers after taking sildenafil; one patient developed bilateral superior and inferonasal visual field depression [129]. At least two case reports document bilateral simultaneous NAION in patients taking PDE-5 inhibitors [117,119].

The mechanism by which PDE-5 inhibitors might cause NAION is not known. Some studies, although not others, suggest that in normal adults, these agents cause retinal vasodilation and increased optic nerve perfusion [130-133]. It is possible that in patients with microvascular disease and impaired autoregulation, these agents might cause a "shunting" of blood flow away from these vessels and induce ischemia [122]. In one case-control study, PDE-5 inhibitors were a risk factor for NAION only in the setting of comorbid cardiovascular disease or hypertension [134]. Another possible mechanism by which these drugs might be associated with NAION is their hypotensive effect, which, when they are used in the evening hours, could exacerbate nocturnal hypotension [122]. (See 'Nocturnal hypotension' above.)

A phase IV observational case-crossover study to assess whether PDE-5 inhibitors trigger NAION is ongoing [135]. The results of this study will provide useful data on the safety of these compounds and of patients at risk who should avoid their use.

Interferon-alpha — Interferon-alpha is used in the treatment of chronic hepatitis, as well as certain malignancies. NAION has been reported as an uncommon complication of interferon-alpha treatment [136-142]. NAION in these case reports tends to be bilateral and sequential, and may recur after restarting the medication. Clinical course is variable, with some patients improving after discontinuation of therapy. Possible pathogenic mechanisms include interferon-induced systemic hypotension, an immune complex deposition within the optic disc circulation, or another cytokine-mediated inflammatory reaction of the blood vessels.

Amiodarone — An association between amiodarone and NAION is uncertain [143]. Amiodarone has also been suggested to cause a toxic optic neuropathy, although this remains unproven as well. An optic neuropathy related to direct toxic effects of the drug is suspected in patients who have a more insidious onset of vision loss with slow progression and simultaneous bilateral involvement, features that are atypical of NAION [143-145]. (See "Optic neuropathies", section on 'Drugs and toxins' and "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring", section on 'Optic neuropathy'.)

Not all case series distinguish between patients with a clinical presentation that suggests NAION versus those that are more consistent with a toxic neuropathy [146,147]. Another source of confusion is that patients taking amiodarone frequently have ischemic cardiac disease and therefore share risk factors with NAION [148]. Hence, the apparent relationship may represent confounding rather than causation. Because of the uncertainty surrounding the association, some suggest that for patients taking amiodarone who develop an optic neuropathy, the dose of amiodarone be lowered and/or discontinued if therapeutic alternatives exist [144-146].

Sympathomimetics — Case reports of NAION have been reported in which the onset of symptoms appeared to be related to the use of amphetamine or other sympathomimetic agent [149-151]. These agents are also associated with stroke and other cardiovascular complications. (See "Clinical diagnosis of stroke subtypes", section on 'Other risk factors'.)

Others

Blood loss — Vision loss in the setting of acute blood loss is often bilateral, but can be asymmetric and even strictly unilateral. When NAION occurs in this setting, the most frequent sources of bleeding are gastrointestinal tract in men and the uterus in women [152-155]. NAION has also been reported to be a complication of trauma requiring massive volume resuscitation [156,157].

Migraine — A few case reports have documented NAION occurring in migraineurs during an episode of migraine [158,159]. Vasospasm may underlie such cases [21,22].

Carotid dissection — An ischemic optic neuropathy is a rare complication of carotid dissection, occurring in 3 to 4 percent of cases, always in the setting of other clinical signs and symptoms [160,161]. In contrast to atherosclerotic carotid disease, which is not believed to be associated with NAION, carotid dissection can cause abrupt rather than slowly progressive carotid occlusion and loss of distal perfusion.

Genetic factors — Families with a strong predisposition to NAION have been described [118,162,163]. These cases are somewhat atypical. A survey of 79 individuals with NAION revealed a family history of NAION in a first-degree relative in four [164]. Investigators have sought to associate the mitochondrial mutations associated with Leber hereditary optic neuropathy (LHON) with NAION. None of the affected individuals among three families with NAION had one of the major LHON mutations [162]. These were also not observed in another investigation of 19 patients without known family history [165]. However, in the latter study and in another family with NAION, intermediate or secondary LHON mutations were more common in NAION patients compared with controls [163,165].

Metabolic factors — One study found elevated plasma homocysteine and lipoprotein(a) levels, as well as low vitamin B6 levels in 85 patients with new-onset NAION compared with 107 healthy controls, suggesting that these factors may increase the risk for developing NAION [166].

Infection — Several case reports have documented varicella zoster infection in association with ischemic optic neuropathy in patients who were suspected of having giant cell arteritis [167-170]. Whether the virus can also trigger an inflammatory optic neuropathy and whether it plays a pathogenic role in the development of temporal arteritis remains under investigation.

SUMMARY — Nonarteritic anterior ischemic optic neuropathy (NAION) is an idiopathic, ischemic insult of the optic nerve head and is the most common form of optic neuropathy in older adults.

●Older White adults (greater than 45 to 50 years) are most at risk of NAION. Men and women are affected approximately equally. (See 'Epidemiology' above.)

●NAION is believed to result from vascular insufficiency of the optic nerve head. While atherosclerotic risk factors are prevalent in these patients, an underlying vasculopathy involving the optic nerve circulation has not been defined. A possible alternative or contributory mechanism involves a compartment syndrome affecting the optic nerve head. (See 'Pathogenesis' above.)

●Most cases of NAION occur apparently spontaneously in older adults with vascular risk factors (diabetes, hypertension). (See 'Atherosclerosis' above.)

●A small optic cup, implying optic nerve fiber crowding, is a common finding in the fellow eye in patients with NAION and is believed to place individuals at risk for NAION. (See 'Ocular risk factors' above.)

●NAION has been described in other clinical settings that are believed to play a role in its onset in specific cases (table 1). (See 'Etiology and risk factors' above.)