• Neuro-Ophthalmology/Orbit

    Nonarteritic anterior ischemic optic neuropathy (NAION) has garnered attention of late in the popular media and in the ophthalmology community primarily because of its association with Sildenafil (Viagra).  NAION’s relationship to diabetic papillopathy and amiodarone are also topics of interest and controversy.  Diabetic papillopathy is felt by some to be a unique entity (Surv Ophthalmol. 2002;47:183-188), while others view it as a spectrum of NAION.  Similarly, many believe that amiodarone-associated optic neuropathy does even not exist.  This article will attempt to bring some clarity to the aforementioned matters.

    General Presentation of NAION

    Anterior ischemic optic neuropathty (AION) is divided into nonarteritic and arteritic (giant cell arteritis or temporal arteritis).  Most cases (94.7%) of AION are nonarteritic. NAION is the most common nonglaucomatous optic neuropathy of the middle-aged and elderly.  The incidence in the United States is as high as 10/100,000 with a slight male predominance.  It is most common in Caucasians with a mean age of 57-65 years, but NAION also occurs in younger patients with appropriate risk factors.

    Clinically, NAION patients have abrupt-onset visual loss, frequently upon waking.  The visual loss is typically painless, which helps differentiate between NAION and optic neuritis.  However, up to 12% of patients can experience periorbital pain.  Visual acuity may range from 20/20 to no light perception.  Like most optic neuropathies, color vision is decreased when central vision is affected and when there is a relative afferent pupillary defect (RAPD) in the involved eye.  The visual fields usually show an inferior altitudinal defect.  However, many other types of visual field defects have been noted. 

    By definition, the optic nerve is swollen acutely in NAION.  There may be focal or diffuse swelling corresponding to the visual field defect, and the optic nerve may be pale or hyperemic.  Peripapillary retinal hemorrhages off the disc are common (72%), but retinal and macular exudates that form a partial star mimicking neuroretinitis are less common.  NAION patients with macular edema seem to have a greater chance of visual improvement related to the resolution of the edema.

    Factors which produce vascular changes in the optic nerve head play a causative role in NAION.  These include hypertension, diabetes mellitus, elevated cholesterol and triglyceride levels, cigarette use, and hyperhomocysteinemia.  Nocturnal hypotension and disc autoregulatory abnormalities may also result in NAION and often present upon waking.  Taking blood-pressure lowering medications in the evening or at bedtime may exacerbate nocturnal hypotension.  While hypotension from spontaneous and surgical blood loss are likewise associated with NAION, the role of transiently elevated intraocular pressure (IOP) in the development of NAION after uncomplicated cataract surgery has been a topic of debate (Walsh & Hoyt’s Clinical Neuro-Ophthalmology. 2005:354).  Interferon alpha and optic disc drusen are also associated with NAION.

    Often, the most difficult thing to discuss with patients is the fact that fellow eye NAION occurs in 14.7% of patients.  If NAION is bilateral, it is usually nonsimultaneous.  The simultaneous variety is rare, but if it appears to be present, one should be suspicious of the diagnosis of NAION. 

    NAION and Erectile Dysfunction Drugs

    NAION has most often been reported in patients using erectile dysfunction drugs such as Sildenafil (Viagra) and tadalafil (Cialis) with preexisting risk factors for NAION like arterial hypertension, diabetes mellitus, and hyperlipidemia.  Most patients who experience visual loss while taking Viagra experience visual loss upon waking, as do most NAION patients who do not take Viagra.  In a recent article, Hayreh recommended that physicians advise patients against using erectile dysfunction drugs, if they possess cardiovascular risk factors, diabetes mellitus, are taking arterial hypotensive drugs, or have a previous history of NAION (J Neuroophthalmol. 2005;25:295-298).  Support for this position can be found in a retrospective, case-control study of 38 male patients with NAION who were matched via age and sex to 38 control patients without a history of NAION. 

    Employing interviewers who were cognizant of case status to administer a telephone questionnaire regarding patients’ past and current use of Viagra and/or Cialis, McGwin and associates found a statistically significant association between NAION and erectile dysfunction drugs in those patients with a history of myocardial infarction (Br J Ophthalmol. 2006:90;154-157).  A similar association was observed for those with a history of hypertension, though it lacked statistical significance.  Physicians prescribing erectile dysfunction medications to patients with myocardial infarction or hypertension should, therefore, warn them of the potential risk of developing NAION.

    The natural history of NAION is that 42.7% of patients improve 3 or more Snellen lines of visual acuity in 6 months.  At 24 months of follow-up, 31% of patients experience 3 or more Snellen lines of visual acuity improvement.  NAION rarely affects the same eye more than once (6.4%), perhaps because when the optic nerve infarcts, axons in the scleral canal are less tightly packed and have less mechanical obstruction and microcirculatory compromise.  This, in effect, increases the small cup-to-disc ratio, which many believe is a primary risk factor for NAION.  While Hayreh disagrees and feels that the “disc at risk” is a secondary risk factor for NAION (J Neuroophthalmol. 2005;25:295-298), physicians should nevertheless look for a small optic cup or no cup (“disc at risk”) in the fellow eye.  Moreover, Lee and Newman feel it is reasonable to include this as one of the predisposing factors in NAION when discussing erectile dysfunction drugs (Am J Ophthalmol. 2005;140:707-708). 

    Differentiating Between NAION, Diabetic Papillopathy, and Amiodarone-Associated Optic Neuropathy

    Diabetic papillopathy is a syndrome in which young juvenile diabetics develop optic disc edema with minimal optic nerve impairment and good visual prognosis.  Some categorize diabetic papillopathy as a subset of NAION, while others define it as a separate entity.  Diabetic papillopathy is unique in that it is commonly bilateral at presentation, has good prognosis of central vision, is not followed by dramatic optic atrophy, and may have prominent surface telangiectatic change of the optic nerve head without neovascularization.  The amount of optic nerve edema may range from minimal edema to florid swelling with capillary telangiectasias and nerve fiber hemorrhages and cystoid macular edema with or without a macular star.  The duration of the optic disc edema may be prolonged, but it usually lasts for less than 1 year with some improvement of optic nerve swelling within 3 months. 

    Diabetic papillopathy affects a younger age group than NAION, which usually afflicts patients older than 40 years of age.  In diabetic papillopathy, the age of patients typically ranges between 19 and 79 years with an average patient age of 50 years.  Visual acuity can sometimes be as poor as 20/400 in a minority of patients.  Furthermore, unlike NAION patients, clinically significant macular edema is present in nearly two-thirds of eyes affected by diabetic papillopathy, and a minority of patients have an RAPD.   Intravitreal (Am J Ophthalmol. 2004;137:1151-1153) and periocular (Eye. 2005;19:45-51) injection of corticosteroids has recently been reported to be effective in the management of diabetic papillopathy.

    Amiodarone-associated optic neuropathy is a topic of controversy, because many ophthalmologists feel that this entity does not exist.  In the most compelling cases, patients have large cup-to-disc ratios with an insidious onset of bilateral, simultaneous optic disc edema that usually resolves over several months.  This is very different from NAION.  Before entertaining the diagnosis of amiodarone-associated optic neuropathy, other etiologies for bilateral, simultaneous optic disc edema must be considered.  These include papilledema, bilateral optic neuritis, giant cell arteritis, and diabetic papillopathy. 

    Given the fact that amiodarone is routinely used for many short-term and long-term cardiac disorders that are potentially life threatening, communication with a cardiologist is imperative before discontinuing use of the drug. 

    Diagnosis and Treatment of NAION

    NAION only requires neuroimaging, if it is atypical in presentation (e.g., bilateral or prolonged disc swelling or orbital signs such as proptosis or chemosis).  Otherwise, a directed interview and serum blood studies can complete the testing.  A reasonable work-up may include an erythrocyte sedimentation rate, cholesterol, triglycerides, serum glucose, metabolic panel, and complete blood count and homocysteine (selected patients).  Patients older than 50 years should be evaluated for giant cell arteritis.

    Therapeutically, control of vasculopathic risk factors may be important to avoid fellow eye involvement.  Newman et al concluded that a history of diabetes and poor acuity (20/200 or worse) was associated with fellow eye involvement (Am J Ophthalmol. 2002;134:317-328).  Meanwhile, Hayreh et al identified nocturnal arterial hypotension as a risk factor for ipsilateral recurrence of NAION (Am J Ophthalmol. 2001;132:734-742).  

    Therapies specifically directed at improving the involved eye have been unrewarding.  A 3-week course of levodopa within 45 days of onset of symptoms has been shown to improve vision in recent onset NAION (Ophthaomology. 2000;107:521-523).  However, this study has been criticized (Ophthalmology 2000;107:1431-1433), and the therapy remains controversial and is not generally recommended.  Aspirin has been proposed to reduce second eye NAION.  However, the therapeutic value of aspirin is also controversial and probably affords no benefit.  Despite this, many physicians prescribe a daily 81 mg aspirin.


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    Author Disclosure

    The author states that he has no financial relationship with the manufacturer or provider of any product or service discussed in this article or with the manufacturer or provider of any competing product or service. This work, however, was supported in part by an unrestricted grant from the organization Research to Prevent Blindness, Inc. in New York.