Nonarteritic Ischemic Optic Neuropathy
What Are the Clinical Features for Typical Nonarteritic AION?
Anterior ischemic optic neuropathy (AION) is characterized clinically by the acute onset of usually unilateral visual loss. Although pain may occur in approximately 10% (range 8–30% in various series) of patients, the visual loss is typically painless. Middle-aged to older patients (usually older than 50) are the predominant populations at risk for AION. The ocular examination in these patients reveals the following: (1) ipsilateral visual acuity and visual field loss; (2) a relative afferent pupillary defect; and (3) edema of the optic nerve head with or without peripapillary hemorrhages (Arnold, 1994b; Feldon, 1999; Friedland, 1996; Gerling, 1998a,b; Grosvenor, 1993; Hattenhauer, 1997; Hayreh, 1990a, 1997a; Ischemic Optic Neuropathy Decompression Trial, 1995, 1996; Johnson, 1993, 1994a,b, 1996a,b; Kay, 1991; Lessell, 1999; Moro, 1990; Rizzo, 1991; Sawle, 1990). The presence of optic disc edema (anterior optic neuropathy) in the acute phase is essential for the diagnosis of AION to be made. Rarely, AION may present with asymptomatic disc edema without visual loss or field defect (Gordon, 1997) or be associated with macular edema (Tomsak, 1998). After resolution of the disc edema, the optic disc develops sector or diffuse pallor. The typical clinical features of nonarteritic (NA-AION) are outlined in Table 4–1.
The optic disc appearance may help differentiate AION from optic neuritis (ON), although there are overlapping features. Optic disc stereo photos were reviewed by masked observers (87 AION and 68 ON) (Warner, 1997). Altitudinal disc swelling was more than three times more common in AION than ON, although most discs were diffusely swollen. Most patients with AION had hemorrhages, whereas most ON cases did not. Almost all discs with ON had normal color or were hyperemic, and only 35% of discs with AION had pallid swelling. Pallid swelling was so rare in ON, however, that of discs with pallor, 93% had AION. Arterial attenuation was also much more typical of AION. AION was the clinical diagnosis in 82% of cases with altitudinal edema, 81% of the cases with disc hemorrhage, 93% of the cases with pallid edema, and 90% of the cases with arterial attenuation. A pale nerve with hemorrhage, regardless of type of edema, always represented AION (100%). A normal color nerve without hemorrhage reflected ON in 91% of the cases, increased from only 76% if hemorrhage was not considered. A hyperemic nerve with hemorrhage represented AION in 82% of cases, but if altitudinal edema was also present, AION incidence increased to 93%.
Age usually over 40 years
Unilateral variable loss of visual acuity and/or visual field
Visual field defects consistent with an optic neuropathy (e.g., central, cecocentral, arcuate, or altitudinal)
Optic disc edema (usually pallid edema) in the acute phase followed by optic atrophy that may be sector or diffuse
Relative afferent pupillary defect in unilateral or bilateral but asymmetric cases
Small cup and cup to disc ratio (less than 0.2) (Burde, 1993; Feldon, 1999; Lavin, 1994; Salomon, 1999a)
Often associated with underlying vasculopathic risk factors (e.g., hypertension, diabetes, smoking, ischemic heart disease, hypercholesterolemia) (Chung, 1994; Feldon, 1999; Hayreh, 1994; Salomon, 1999a)
Lack of premonitory symptoms (e.g., transient visual loss)
Usually visual loss remains static but may improve slightly or progress
End-stage optic disc appearance is segmental or diffuse pallor without significant cupping (unlike arteritic AION) (Danesh-Meyer, 2001)
Ischemic optic neuropathy (ION) without acute disc edema is referred to as posterior ischemic optic neuropathy (PION). PION is an atypical presentation of ION but it may occur in several conditions as listed in Table 4–2.
Younger patients (less than 40 years of age) with diabetes (Inoue, 1997; Jacobson, 1997), migraine, severe hypertension including preeclampsia, or oral contraceptive use may also develop ION. We consider the development of ION in patients less than 40 years old to be an atypical presentation (Rinaldi, 1990). A clinical presentation of AION may occur in young patients without any known vasculopathic risk factors and has been termed AION of the young (AIONY). AIONY differs from typical AION in that recurrent attacks are more common than with typical NA-AION.
Atherosclerosis and arteriosclerosis (Sadda, 2001)
Severe hypotension or blood loss
Diabetes (Inoue, 1997)
Collagen vascular disorders (e.g., systemic lupus erythematosus)
Giant cell (temporal) arteritis (Sadda, 2001)
Infection (e.g., Aspergillus, herpes zoster)
Internal carotid artery occlusion or dissection (Biousse, 1998b; Kerty, 1999)
After surgical procedures (hypotension, anemia) (Sadda, 2001)
Thromboembolism (e.g., internal carotid artery disease)
Source: Lee, 1995a, 1996; Sadda, 2001.
Bilateral simultaneous involvement may occur in NA-AION (up to 15% of cases), but we consider this also an atypical finding. Giant cell arteritis (as well as other causes of a bilateral optic neuropathy) should be excluded in these cases (Hayreh, 1998).
Diabetic papillopathy is probably an atypical form of AION described in diabetics who present with minimal visual symptoms. This entity usually resolves in weeks to months. The clinical features of diabetic papillopathy are outlined in Table 4–3.
What Other Conditions Are Associated with Ischemic Optic Neuropathy?
ION has been reported in association with a number of systemic conditions listed in Table 4–4.
What Clinical Features Are Atypical for Anterior Ischemic Optic Neuropathy?
Patients with an atypical AION should undergo a complete evaluation to exclude other causes of an optic neuropathy (e.g., inflammatory infiltrative, compressive optic neuropathies). The clinical features that are atypical for AION are listed in Table 4–5.
Recurrence of NA-AION in the same eye is uncommon. Hayreh et al studied 594 consecutive patients with a diagnosis of NA-AION and found that recurrence occurred in the same eye in 45 patients (7.6%) with a median follow-up of 3.1 years (Hayreh, 2001b). Although it is uncommon for NA-AION to recur in the same eye, it may involve the fellow eye in 10 to 73% of cases (Boone, 1996). Beri et al evaluated 438 patients with AION (Beri, 1987); 388 had NA-AION and 50 had arteritic AION. The risk of bilateral involvement for the arteritic form was 1.9 times the risk for NA-AION. At 3 years, Beri et al calculated an incidence of bilateral NA-AION of 26% (Beri, 1987). In patients with bilateral disease, some authors have noted that the final outcome between eyes is similar for acuity, color vision, and visual fields (Boone, 1996). In another study, visual function in the second eye in patients with bilateral NA-AION correlated poorly with the first eye (WuDunn, 1997). In this study, older patients (> 50 years) with bilateral NA-AION retained better visual function in the second eye, whereas in younger patients the extent of visual loss in the second eye could not be predicted based on the visual loss in the first eye. Kupersmith et al also reported poor correlation of visual acuity and field defects in the second eye compared to the first involved eye (Kupersmith, 1997).
May be unilateral or bilateral (simultaneous or sequential)
May have relative afferent pupillary defect if unilateral or bilateral but asymmetric
May be associated with type I or type II diabetes
Disc swelling is mild to moderate and the disc is consistently hyperemic
Disc edema usually resolves within 1 to 10 months
Macular edema and capillary nonperfusion are frequent associated findings
Small cup-to-disc ratio in uninvolved fellow eyes (the “disc at risk”)
Significant (≥ 5 seconds) delay in fluorescein filling of all or a portion of the optic disc may occur
Minimal if any visual symptoms
May have enlarged blind spot or arcuate defect
Residual visual loss due to associated macular edema and retinopathy
Occasionally residual mild optic atrophy
Source: Arnold, 1997; Burde, 1993; Katz, 1990a; Regillo, 1995; Vaphiades, 2002.
Hypertension (Feldon, 1999; Hayreh, 1990b, 1994b; Salomon, 1999b)
Diabetes mellitus (Feldon, 1999; Hayreh, 1994b; Inoue, 1997; Salomon, 1999b)
Arteriosclerosis, atherosclerosis, and ischemic heart disease (Hayreh, 1994b; Sadda, 2001; Salomon, 1999b)
Hypercholesterolemia (Salomon, 1999b)
Female carrier of Fabry’s disease (Abe, 1992)
Takayasu’s arteritis (Schmidt, 1997)
Carotid occlusion and dissection (Biousse, 1998a,b; Gotte, 2000; Kerty, 1999; Mokri, 1996; Rivkin, 1990; Strome, 1997)
Carotid artery hypoplasia (Horowitz, 2001)
Vasospasm (Hayreh, 1997a; Kaiser, 1996)
Acute blood loss or hypotension (Brown, 1994; Chun, 1997; Connolly, 1994; Cullinane, 2000; Hayreh, 1999; Lee, 1995b; Shaked, 1998; Teshome, 1999)
Systemic inflammatory response syndrome (survivors of severe injuries) (Culinane, 2000)
Postsurgical (Sadda, 2001; Williams, 1995)
Cardiopulmonary bypass procedures (Lund, 1994; Moster, 1998; Shapira, 1996; Spoor, 1991)
Lumbar spine surgery (Alexandrakis, 1999; Brown, 1994; Cheng, 2000; Dilger, 1998; Katz, 1994; Lee, 1995b; Loftman, 1996; Myers, 1997; Roth, 1997; Smith, 1996; Stevens, 1997)
Radical neck dissection (Fenton, 2001; Kirkali, 1990; Marks, 1990; Nawa, 1992; Schnobel, 1995; Wilson, 1991)
Leg vein bypass surgery (Remigio, 2000)
Mitral valve surgery
Nasal surgery (intranasal anesthetic) (Savino, 1990)
Radical prostatectomy (Williams, 1999)
Liver transplant (Janicki, 2001)
After treatment for malignant hypertension (Connolly, 1994)
Hemodialysis (Connolly, 1994)
Nocturnal hypotension (Hayreh, 1994b, 1997c, 1999; Landau, 1996)
Surgical (nonhypotensive or nonanemic)
Cataract surgery (McCulley, 2001; Perez-Santonja, 1993)
Laser in situ keratomileusis (LASIK) (Cameron, 2001; Cornblath, 2002; Lee, 2000)
Secondary intraocular lens implantation
After lower lid blepharoplasty (Good, 1999)
After general surgery without significant blood loss
Herpes zoster (Atmaca, 1992; Borruat, 1992; Kothe, 1990; Lexa, 1993)
Recurrent herpes labialis (Johnson, 1996b)
Staphylococcal cavernous sinus thrombosis
Acquired immune deficiency syndrome (AIDS)
Elevated titers of IgG antibodies to Chlamydia pneumoniae (Weger, 2002)
Inflammatory disorders (Coppetto, 1992)
Churg-Strauss disease (Acheson, 1993; Kattah, 1994; Sehgal, 1995; Vitali, 1996)
Mixed connective tissue disease
Relapsing polychondritis (Massry, 1995)
Sjögren’s syndrome (Mochizuki, 2000; Rosier, 1995)
Systemic lupus erythematosus (Siatkowski, 2001)
HLA-B27 associated anterior uveitis and ankylosing spondylitis (Tham, 2001)
Hyperopia (Katz, 1993)
Optic disc drusen (Lee, 2002; Liew, 1999)
Elevated intraocular pressure (Kalenak, 1991; Katz, 1992)
Acute angle-closure glaucoma (Slavin, 2001)
Anemia (e.g., iron deficiency anemia) (Golnik, 1990; Kacer, 2001)
Hyperhomocysteinemia (Kawasaki, 1999; Pianka, 2000; Weger, 2001)
Antiphospholipid antibodies (Aziz, 2000; Galetta, 1991; Ohte, 1995; Reino, 1997; Rosier, 1995)
Antiphospholipid antibodies with factor V Leiden mutation (Srinivasan, 2001)
Activated protein C resistance (Worrall, 1997)
Decreased concentrations of protein C, protein S, or antithrombin III (Bertram, 1995)
G-6-PD deficiency syndrome
Lipid abnormalities (Giuffre, 1990; Talks, 1995)
Sickle cell trait and disease (Perlman, 1994)
Thrombocytopenic purpura (Killer, 2000)
Embolic (Horton, 1995)
Acute intermittent porphyria
Bacille Calmette-Guérin (BCG) vaccination
Cardiac valvular disease (Hayreh, 1994a)
Cavernous sinus thrombosis (Gupta, 1990)
Cervical discopathies and vasospasm
Gastrointestinal ulcers (Hayreh, 1994a)
Graves’ disease (Dosso, 1994)
Human lymphocyte antigen-A29 (Johnson, 1993)
Interferon-alfa treatment (Purvin, 1995; Tang, 1995)
Sumatriptan for migraine (Chiari, 1994)
Omeprazole for gastric ulcer treatment (Schönhofer, 1997)
Amiodarone (Mäntyjärvi, 1998)
Oxymetazoline nasal spray (nasal decongestant) (Fivgas, 1999)
Sildenafil (Viagra) (Cunningham, 2001; Egan, 2000; Pomeranz, 2002)
Lymphoma and sepsis (Guyer, 1990)
Migraine (Chiari, 1994)
Radiation necrosis (Kawasaki, 1998; Parsons, 1994)
Renal failure and uremia (Haider, 1993; Korzets, 1998; Winkelmayer, 2001)
Smoking (Chung, 1994; Johnson, 1994b; Talks, 1995)
Trauma (Gadkari, 1990)
After trans-Atlantic airplane journey (Kaiserman, 2002)
Familial AION (Sadun, 1996)
Age younger than 40 years
Bilateral simultaneous onset
Visual field defect not consistent with an optic neuropathy (e.g., bitemporal hemianopsia, homonymous hemianopsia)
Lack of optic disc edema in the acute phase
Lack of relative afferent pupillary defect
Large cup to disc ratio (Parsa, 1998)
End-stage optic disc appearance of cupped disc (present in 2% of patients with nonarteritic-AION vs. 92% of patients with arteritic AION) (Danesh-Meyer, 2001)
Lack of vasculopathic risk factors
Presence of premonitory symptoms of transient visual loss (amaurosis fugax)
Progression of visual loss beyond 2 to 4 weeks
Recurrent episodes in the same eye
Anterior or posterior segment inflammation (e.g., vitreous cells)
The visual loss in NA-AION is usually acute and remains relatively static, but may spontaneously improve in up to 42.7% of patients (Aiello, 1992; Barrett, 1992; IONDT, 1995; Movsas, 1991; Rizzo, 1991). In up to 25% of patients, visual loss may be progressive over several weeks. In our opinion, gradual and progressive visual loss should prompt further evaluation, including neuroimaging, to exclude other causes of a continuing optic neuropathy (e.g., optic nerve sheath meningioma).
What Is the Evaluation and Treatment for AION?
Patients with typical features of AION (e.g., acute onset, unilateral visual loss, ipsilateral optic disc edema, older/aged patient) do not require neuroimaging (class II–III, level B). The major entity that must be excluded in AION is giant cell arteritis (GCA) (see Chapter 5). An erythrocyte sedimentation rate (and/or C-reactive protein) and other appropriate evaluation for GCA should be considered in cases of AION in patients over age 50 (class II, level B). Patients with atypical features (Table 4–5) should be evaluated for other etiologies of an optic neuropathy (see Chapter 1).
Further laboratory studies to investigate the presence of a hypercoagulable state could be considered in patients with NA-AION who do not have the typical risk factors, such as older age, diabetes, hypertension, or tobacco use, or in young patients with bilateral or recurrent attacks of NA-AION, but the data are conflicting (class III, level C). Some authors have recommended that laboratory tests for a hypercoagulable state in the following patients: (1) young (less than age 45 years) patients with NA-AION; (2) NA-AION without a small cup to disc ratio (“disc at risk”) in the fellow eye; (3) bilateral simultaneous NA-AION; (4) recurrent NA-AION in the same eye; (5) NA-AION in a patient with a previous history or family history of recurrent thrombotic events (Lee, 1999) (class III, level U). Hyperhomocysteinemia was discovered in two of 12 nondiabetic patients with NA-AION before the age of 50 years (Kawasaki, 1999). Both of these two patients had experienced NA-AION in both eyes with recurrent episodes (class III).
Unfortunately, although corticosteroids (systemic, retrobulbar, sub-Tenons), anticoagulation, dipyridamole, acetazolamide, hemodilution, vasodilators, vasopressors, atropine, norepinephrine, diphenylhydantoin, and hyperbaric oxygen have been tried in the past, there is no proven therapy for NA-AION (Arnold, 1996; Wolfe, 1993). The natural history of NA-AION in the past has been difficult to define. In the Ischemic Optic Neuropathy Decompression Trial (IONDT), there was an unexpectedly high rate of spontaneous (three or more lines from baseline at 6 months) improvement of 42.7% (class I, level A). This rate is higher than that noted in the literature on AION before 1989 (less than 10%). In the literature since then, visual improvement rates as high as 33% have been reported (Arnold, 1994b; Rizzo, 1991; Yee, 1993).
We believe that any future treatments for NA-AION will have to prove better than the natural history data of the IONDT. Most previously published reports on treatment for NA-AION are limited by retrospective design, nonstandardized methods of data collection or measurement, small sample sizes, and variable (usually relatively short) lengths of follow-up.
Medical control of underlying hypertension, diabetes, and other presumed etiologic vasculopathic risk factors (such as smoking cessation) has been recommended (Chung, 1994; Hayreh, 1994b), but no well-controlled data on the efficacy of such measures in reducing fellow-eye involvement exist (class III, level C). In addition, overaggressive control of arterial hypertension may be potentially dangerous in patients in whom acute and/or nocturnal hypotension is an underlying etiology for NA-AION (Hayreh, 1994b) (class III, level U). Patients with malignant hypertension in whom the blood pressure is lowered too rapidly may also be at risk for the precipitation of NA-AION in the fellow eye.
Are Additional Studies (e.g., Noninvasive Carotid Doppler Studies, Cardiac Studies, Neuroimaging) Warranted in Patients with NA-AION?
Although Guyer et al reported a significantly higher incidence of cerebrovascular and cardiovascular disease in 200 patients with idiopathic AION (Guyer, 1985, 1988), Hayreh et al have found no increased risk for subsequent cerebrovascular or cardiovascular disease (Hayreh, 1994b). Some authors have found no increased incidence of generalized cerebral vascular disease on magnetic resonance imaging (MRI) of the head in nine patients with NA-AION, but Arnold et al reported an increased number of central nervous system white matter lesions on brain MRI in patients with NA-AION (Arnold, 1995). Fry et al found no significant difference in carotid stenosis in 15 patients with AION versus controls (Fry, 1993). Several authors have reported no significant association between AION and extracranial carotid artery occlusive disease. AION has rarely been attributed to embolic disease (Horton, 1995). We do not perform additional noninvasive evaluation of the carotid or cardiac systems in patients with NA-AION unless there are other signs of carotid disease, such as ocular ischemic syndrome or retinal emboli, or a history of transient or persistent focal neurologic deficits (Horton, 1995) (class III, level U). We also consider MR angiography in patients with NA-AION with associated ipsilateral head or neck pain to evaluate for carotid artery dissection (Biousse, 1998a,b). Neuroimaging studies of the head are not indicated in patients with typical unilateral NA-AION (Arnold, 1995) (class II–III, level B).