Though much has been learned about non-arteritic ischemic neuropathy since the earliest studies, no effective treatment is currently available. An update on research progress is highlighted.
Reviewed by Anthony C. Arnold, MD
Los Angeles-Though the research into non-arteritic ischemic optic neuropathy (NAION) has a long history, much progress remains to be achieved, explained Anthony C. Arnold, MD.
Dating back to 1924, three cases were described with severe arteriosclerosis and visual loss, visual field defects, optic disc edema, flame hemorrhages, and poor recovery.
A manuscript published in 1957 reported patients with “pseudopapillitis” characterized by edema, later atrophy of the optic nerve head, and fascicular perimetric defects that seemed to arise from an impaired vascular supply and not inflammation.
The first report in the English medical literature appeared in 1966, when Miller and Smith described 11 cases that were similar to giant cell arteritis (GCA) optic neuropathy, but the diagnoses of GCA were not confirmed.
Among this small series, the following characteristics were reported: 10 patients aged 52 to 68 years and one aged 46 years, the common presence of hypertension and diabetes, acute painless visual field loss, altitudinal or arcuate visual field loss, pale optic disc edema with hemorrhages that resolved in 3 to 4 weeks, poor visual prognosis, and no effective therapy.
Dr. Arnold described the progress that has been made in seven areas associated with NAION since 1966.
1) Location of the vasculopathy. The vasculopathy originally was speculated to be in the central artery of the optic nerve. This impairment caused the ischemic pseudovascular papillitis. Later reports focused on the short posterior ciliary artery circulation and choroid as being responsible for disc circulation and their impairment led to NAION.
“In the 1970s and 1980s, there was great controversy about the percentages of contributions from the short posterior ciliary arteries and from the choroidal circulation in supplying the blood flow to the optic disc,” said Dr. Arnold, professor and chief, neuro-ophthalmology division, Stein Eye Institute, University of California, Los Angeles.
Electron microscopic cast studies of the optic disc circulation have shown that some branches from the short posterior ciliary arteries supply the optic nerve, i.e., the paraoptic branches, and other branches supply the choroid.
“The studies suggested that the main supply of this portion of the optic nerve originated from the paraoptic branches of the ciliary arteries and not the choroid,” he said.
Early fluorescein angiography (FA) research suggested that the location of the optic disc in a watershed zone between distribution supplies of the ciliary arteries and the choroid might be a risk factor for the development of NAION, Dr. Arnold noted.
However, he and colleagues performed a follow-up FA study of NAION that showed that the watershed zone was commonly seen in both normal and ischemic discs. That study published in Am J Ophthalmology (1994;117:222-230) also showed that in 76% of cases, there was dramatically poor filling of the disc but the rest of the choroid usually filled normally, which was in contrast to patients with giant cell arteritis.
“This suggested that the location of the vasculopathy in NAION is not in either the short posterior ciliary artery or choroidal branches, but in the paraoptic branches and the tributaries of those in the microcirculation. This finding may have implications for the pathogenesis and future therapies, he noted.
2) Age at onset. Most early patients were reported to be over 50 years of age (average, 60 years), and most research suggested that NAION as unusual under age 50.
However, this no longer appears to be the case. Research in the early 2000s reported a sizable range (6.4% to 23.2%) of patients with NAION under the age of 50 years. Dr. Arnold’s 2013 study reported that 12.7% of a large series of NAION patients were less than 50 years, with some less than 40 years.
“The age at onset is not unusual under age 50 and this is something for physicians to keep in mind when younger-than-expected patients present with what looks like anterior ischemic neuropathy,” Dr. Arnold said.
3) Natural history. The previous belief about the natural disease history is that the affected eye had a poor visual prognosis and involvement of the fellow eye was estimated to occur in 30% to 40% of patients followed for 2 to 11 years.
More recent data suggests a better prognosis. In a large, multicenter, national clinical trial for NAION, the 6-month evaluation 42.7% of patients had a visual acuity improvement of three or more lines of vision.
Regarding involvement of the fellow eyes, a 1997 study found that 12% to 19% of fellow eyes were at risk of developing NAION at 5 years and this was later corroborated in the 2002 Ischemic Optic Neuropathy Decompression Study.
“We now know better what will happen and the percentages, at least in the 5-year range, are lower than 30% to 40%,” Dr. Arnold said.
However, age makes a dramatic difference in the involvement of the fellow eyes. Patients under age 50 years had fellow eye involvement at a much faster rate and in high percentages of patients, with the involvement occurring in some in as little as 6 months (range, 6 to 13 months) after diagnosis of the first eye.
4) Risk factors. The first investigators who studied NAION reported that hypertension, hyperlipidemia, diabetes, and smoking as the risk factors, with diabetes considered the most important.
Two additional risk factors have been identified in more current research: sleep apnea, a well-known vasculopathic disorder, and use of phosphodiesterase-5 (PDE5) inhibitors.
Recent studies of sleep apnea from 2002 to 2013 have reported that substantial numbers of patients with NAION had obstructive sleep apnea (range, 56% to 89%).
“More and more data are indicating that obstructive sleep apnea is a significant risk factor for NAION,” Dr. Arnold said. “Sleep apnea is something we look for routinely.”
Regarding the effects of PDE5 inhibitors, in 2005 a series of 14 patients were reported to have developed NAION following treatment with the drugs. All patients had at least one vasculopathic risk factor and all had crowed discs. NAION developed in all cases with 36 hours of dosing. At least 100 cases have now been reported.
Adverse effects from PDE5 inhibitors are plausible, according to Dr. Arnold, because with vasodilation the blood pressure and perfusion pressure decrease, with local optic nerve head vasodilation the venous system in the nerve might compress and exacerbate a compartment syndrome in the disc and result in an infarct, and with vasodilation in the optic disc normal autoregulation is impaired.
A recent study of PDE5 exposure conducted by Pfizer showed that the risk of NAION increased by about double within five half-lives of taking a PDE5 inhibitor.
However, a claims database study of filled PDE5 prescriptions found no correlation between the drug and development of NAION.
5) Optic disc appearance. The affected optic discs were described previously as pallid and possibly segmental or with flame hemorrhages. Now the affected eye is known to be hyperemic with surface telangiectasia, possibly segmental and often with flame hemorrhages. Severe pallor in a swollen disc is associated with giant cell arteritis.
The appearance of the fellow eyes was not discussed until the mid-1970s to 1982 when discs with small physiologic cups were mentioned. In the mid-1980s, many eyes were seen to have no cups.
“This appearance may well be a pathogenetic factor in NAION,” Dr. Arnold said.
6) Spectrum of ischemia. Sohan Hayreh, MD, believed that ischemia of the optic disc is not an all-or-nothing phenomenon.
Optic nerve ischemia can be present without optic nerve dysfunction (pre-NAION edema); ischemia with reversible dysfunction is associated with diabetic papillopathy; and ischemia with irreversible optic nerve dysfunction with NAION.
Dr. Arnold and colleagues confirmed Dr. Hayreh’s hypothesis in 2013 with FA, demonstrating poor filling of an edematous optic disc before visual loss in pre-NAION.
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7) Treatment. When NAION was first being investigated, no treatments were available. While numerous agents have been attempted, there still is no treatment currently available.
Dr. Arnold described rodent and primate models of NAION that are useful for identifying processes amenable to therapy. Intravitreal neuroprotection is one such avenue.
A clinical pilot study of intravitreal erythropoietin in 2011 found that about 55% of patients gained 3 or more lines of vision.
The QPI-1007 study (Quark Pharmaceuticals) of a synthetic siRNA anti-apoptotic agent was found to be effective in axotomy and crush models and is being studies for intravitreal use. The randomized, sham-controlled clinical study is ongoing.
“Even now, NAION remains the ophthalmologist’s dilemma,” Dr. Arnold said. “However, we have more information now than when the original research was published.”
Anthony C. Arnold, MD
This article was adapted from Dr. Arnold’s presentation of the William F. Hoyt Lecture at the 2015 meeting of the American Academy of Ophthalmolgy. Dr. Arnold has no financial interest in the subject matter.