Non-Arteritic Anterior Ischemic Optic

Neuropathy (NAION)
Original article
Dean Cestari, M.D.
contributed by:
Aaron M. Miller, MD, MBA, FAAP, Andrew Go Lee, MD, Dean Cestari, M.D., Mark J.
All contributors:
Kupersmith, MD and Stacy L Pineles, M.D.
Assigned editor: Dean Cestari, M.D.
Review: Assigned status Up to Date by Stacy L Pineles, M.D. on August 10, 2015.

Contents
[hide]

 1 Disease Entity
o 1.1 Disease
o 1.2 Etiology
 1.2.1 Sleep Apnea Syndrome (SAS)
 1.2.2 Medications
 1.2.3 Optic Disc Drusen
o 1.3 Risk Factors
o 1.4 Pathophysiology
 1.4.1 Optic Disc Anatomy
 1.4.2 Autoregulation
 1.4.3 Nocturnal hypotension
 1.4.4 Venous Insufficiency
 1.4.5 Vasculopathic Risk Factors
 2 Diagnosis
o 2.1 Signs
 2.1.1 Visual Acuity
 2.1.2 Color Vision
 2.1.3 Pupils
 2.1.4 Visual Fields
 2.1.5 Optic disc and retinal appearance
o 2.2 Symptoms
o 2.3 Clinical diagnosis
o 2.4 Laboratory test
o 2.5 Differential diagnosis
 3 Management
o 3.1 Medical therapy
 3.1.1 Thrombosis
 3.1.2 Disc edema
 3.1.3 Compartment Syndrome
o 3.2 Prognosis
 4 Additional Resources
 5 References

Disease Entity [edit source]

Disease [edit source]

Ischemia of the optic nerve can occur in different anatomical locations and can have a myriad of etiologies. It is
helpful to classify these syndromes by location and etiology (if known) since their presenting signs and symptoms
as well as treatment and prognosis will vary. By definition, anterior ischemic optic neuropathy (AION) involves the
1mm segment of the optic nerve head, also known as the optic disc, and results in visible disc swelling. AION has
two varieties. The first is non-arteritic (NAION) and the second is arteritic (AAION) and is almost always
associated with giant cell arteritis. Posterior ischemic optic neuropathy (PION) encompasses those conditions
that result in ischemia to any portion of the optic nerve posterior to the optic disc. By definition, PION will not
cause disc edema.

Etiology [edit source]

The vast majority of cases of NAION are idiopathic but some specific etiologies have been reported to be
associated with NAION although in all of the cases, no causal relationship has been definitively established.

Sleep Apnea Syndrome (SAS)[edit source]

There have been case series that have demonstrated a possible association between SAS and NAION 47, 48.
The best evidence comes from a case-control study of 17 consecutive patients with NAION who were compared
to 17 age and sex matched controls. In this study, 71% of the patients with NAION met criteria for SAS compared
to 18% of controls 47. It is unclear how SAS can cause NAION but it is hypothesized that apneic spells might
result in acute increases in blood pressure, intracranial pressure or nocturnal hypoxemia which could cause optic
nerve edema and ischemia 47.

Medications[edit source]
The interferons are a group of glycoproteins with complex antiviral, antitumor, and antiangiogenic activities. In
1995 Purvin reported the development of acute bilateral, sequential vision loss, likely from NAION, in 2 patients
taking interferon alpha for malignant neoplasms 49. It has been hypothesized that interferon alpha might cause
an NAION by depositing immune complexes in the optic disc circulation that leads to ischemia 49-51. Since her
original report in 1995, there have been a handful of additional reports of a possible association although a
causal relationship has not been definitively established 52 53, 54.
Sildenafil is an effective treatment for erectile dysfunction (ED) by inhibiting phophodiesterase type 5 (PDE5), an
enzyme that regulates blood flow in the penis. Therapeutic doses of these medications used to treat ED can
cause systemic hypotension. It has been hypothesized that these medications might exaggerate the physiologic
nocturnal hypotension resulting in ischemia to the optic nerve head and compartment syndrome in susceptible
patients with small cup to disk ratios 55. Additionally, these medications might interfere with the autoregulation of
blood flow thereby decreasing perfusion to the optic nerve head 55. This association remains very controversial
and a prospective study has been conducted and has shown that the patients at risk for ED agents had prior
NAION is 55a.

Optic Disc Drusen[edit source]

Optic disc drusen might increase the risk of developing NAION by theoretically contributing to the “crowded” optic
nerve in discs with small cup to disc ratios. There are anecdotal reports of NAION occurring in patients with optic
disc drusen but a causal relationship has not been proved 56, 57, 58, 59, 60, 61.

Risk Factors [edit source]

The vast majority of cases of AION are non-arteritic 1. NAION affects between 2.3 and 10.3 people per 100,000
individuals per year making it the most common cause of acute optic neuropathy in patients over the age of 50. 2,
3 There are approximately 6000 new cases per year and Caucasians account for nearly 95% of cases 3. Men
and women are nearly equally affected and the mean age at symptom onset varies between 57 and 65 years
depending on which study you read 1, 4, 5, 6. However, one retrospective study demonstrated 23% of patients
with NAION were less than 50 years old 7.

Pathophysiology [edit source]

The pathophysiology of NAION is controversial and no one mechanism had been definitively demonstrated. It is
presumed to result from a circulatory insufficiency, or infarct, within the retrolaminar portion of the optic nerve
head that is supplied by the short posterior ciliary arteries (SPCA). This presumption is based upon indirect
evidence from atypical forms of NAION 19, 20, 21, 22, 23, 24, 25. Additional fluorescein and indocyanine studies
have shown delayed optic disc filling in the prelaminar layers of the optic disc with normal choroidal circulation
suggesting that the vasculopathy is located in the para-optic branches of the SPCA after their branching from the
choroidal branches rather than in the short ciliary arteries themselves 15, 26. The cause of optic disc edema is
unclear but there is general agreement that the final common pathway leads to a compartment syndrome from
axonal edema in a structurally crowded optic disc 27 resulting in apoptotically induced retinal ganglion cell death
24. Many mechanism have been presumed to be involved in the optic disc edema and it is worthwhile to explore
them in a little more details.

Optic Disc Anatomy[edit source]

Up to 97% of patients with NAION have small optic discs with small or absent optic cups. Acutely, it can be
difficult to determine the cup/disc ratio because of optic nerve edema and the clinician should note the cup/disc
ratio in the fellow eye. It is typically less than 0.3 and these discs are referred to as a “disc at risk”. The role of the
small cup/disc ratio is unclear but there are probably contributory mechanical effects of the small cup/disc ratio in
the pathogenesis of NAION. A crowded disc can exacerbate chronic mechanical obstruction to axoplasmic flow
resulting in secondary compression and ischemia. An inhibition in axoplasmic flow can inhibit critical
neurotrophins leading to additional ganglion cell death 28, 29, 30, 31, 32.

Autoregulation[edit source]
The optic nerve head efficiently autoregulates blood flow 33. Flow is normally maintained constant despite
variations in perfusion pressure and intraocular pressure under various metabolic conditions and different
diseases can impair the optic nerve’s ability to autoregulate its blood flow 34, 33. Systemic hypertension,
arteriosclerosis, vasospasm or medications may reduce the autoregulatory capacity of the optic disc 34, 35.
Vasoactive substances might be released in response to ischemia that influence the autonomic control of blood
vessels. Intravitreal and intravenous injections of endothelin-1 have been shown to decrease optic nerve head
blood flow and produce chronic optic disc ischemia in rabbits 36, 37. Hayreh has postulated that the release of
endogenous serotonin may contribute to optic nerve ischemia by vasoconstricting arterioles and impairing
autoregulation 35.

Nocturnal hypotension[edit source]

There are normal nocturnal fluctuations in blood pressure and Hayreh has theorized that nocturnal systemic
hypotension may contribute to NAION. Patients with chronically altered optic disc autoregulation, from such
diseases as systemic hypertension and atherosclerosis, might be susceptible to exaggerated decreases in
nocturnal blood pressure. This effect might be exacerbated in patients treated with aggressive antihypertensive
therapy, especially if taken right before bedtime 38.

Venous Insufficiency[edit source]

Levin et al. believe the clinical and pathological evidence does not support arterial occlusion in NAION and they
have theorized that NAION might result from venous insufficiency that occurs from closure of tributary venules
receiving blood from optic nerve capillaries that drain into the central retinal vein posterior to the optic nerve head
39. They argue that NAION does not have the clinical characteristics of an arterial disease. AAION causes a
pallid edema that ultimately resolves leaving significant excavation and atrophy of the disc whereas NAION
typically exhibits normal or hyperemic edema that resolves leaving relatively preserved disc substance 40. Disc
hemorrhages are seen less commonly in AAION and central retinal artery occlusion but are more common in
NAION and central retinal vein occlusion. NAION causes less severe vision loss than AAION and they believe
this is akin to less severe neuronal damage from cerebral venous disease. Furthermore, the choroidal circulation
is typically affected in AAION due to posterior ciliary artery occlusion (and sometimes ophthalmic artery) and
occlusion of this artery in the monkey results in choroidal circulation changes 41. The infarct in NAION does not
fit the vascular bed of any known artery, 25 and as I discussed earlier, fluorescein angiography demonstrates
normal choroidal filling and mildly delayed arterial filling of only the prelaminar disc 15.

Vasculopathic Risk Factors[edit source]

NAION is presumed to result from vascular insufficiency but there is no clear association of well-known risk
factors for ischemic small vessel disease and NAION. Lipohyalinosis is suspected in the pathogenesis of NAION
but no histopathologic confirmation has been demonstrated 42, 43. In the IONDT, 60% of NAION patients had at
least one vasculopathic risk factor with hypertension (47% and diabetes (24%) being most common 44, 45.
Smoking does not seem to be an independent risk factor 46.
Diagnosis [edit source]

Signs [edit source]

Patients with NAION will typically have some or all of the signs of an optic neuropathy including decreased visual
acuity, dyschromatopsia, an RAPD, a swollen optic nerve with splinter hemorrhages and a visual field defect.

Visual Acuity[edit source]

Visual acuity may vary widely but no light perception is exceptionally rare and when present, should make the
clinician suspect AAION or another diagnosis. Much of what we know about the range of visual acuities comes
from the IONDT. In this study, 49% of patients had an initial visual acuity of 20/64 or better and 66% had 20/200
or better. 12. Others have demonstrated that in patients seen within two weeks of symptom onset, nearly 50% of
patients will have visual acuity 20/30 or better 13.

Color Vision[edit source]

Acquired loss of color vision, dyschromatopsia, is a very sensitive sign of optic nerve dysfunction. Unlike optic
neuritis, the degree of dyschromatopsia in NAION is typically proportional to visual acuity loss 14. However,
altitudinal and quadrantic defects are commonly seen in NAION and in these cases there is often sparing of color
vision likely due to sparing of central fibers involved in central vision.

Pupils[edit source]
Despite loss of vision in one eye, the pupils will be round and symmetric. There will be no anisocoria (something
often confused by medical students and neurology residents). A relative afferent pupillary defect will be present
as long as the contralateral eye is normal.

Visual Fields[edit source]

Any visual field defect relating to optic nerve damage can occur. Nearly 25% of patients will have central
scotomas but the majority of patients will have an altitudinal field loss, inferior being most common 9.

Optic disc and retinal appearance[edit source]

As mentioned earlier, optic disc edema is always present in the acute phase of NAION (the reason will be
discussed in the section under Pathophysiology) and comes in two varieties, diffuse or segmental. Segmental
(typically altitudinal) is more common but it does not consistently correspond to the accompanying area of visual
field loss 15. The edema is typically hyperemic and rarely pallid. Pallid edema is common in AAION and should
alert the clinician to the possibility of giant cell arteritis. Peripapillary splinter hemorrhages are seen in nearly
three-quarters of patients 12 and its presence can sometimes help to differentiate NAION from optic neuritis
since they will be present in 5-15% of patients with optic neuritis 16, 17. Retinal exudates are uncommon but both
hard and soft exudates were reported in up to 7% of patients in the IONDT 12 and the retinal arterioles can be
focally narrowed in the peripapillary region in two-thirds of patients 18.

Symptoms [edit source]

The classic description of patients with NAION presenting with acute, painless unilateral vision loss that is often
described as a blurring or cloudiness of vision, often inferiorly, has been expanded. Although the majority of
patients do not have accompanying pain, headache or periocular pain is reported in 8-12% of patients, which can
make it difficult to differentiate from optic neuritis 8, 9, 10. Patients with NAION report loss of vision that occurs
over hours to days. Hayreh et al. have reported that over two-thirds of patients notice vision loss upon awakening
which suggests that nocturnal arterial hypotension may be critically involved in the pathophysiology of NAION 11.
However this was not confirmed by the ischemic optic neuropathy decompression trial (IONDT) 12.

Clinical diagnosis [edit source]

The diagnosis of NAION is a clinical one. In patients who present with the typical history of acute, painless,
unilateral vision loss and who have the classic findings on examination including a hyperemic and swollen optic
nerve with peripapillary splinter hemorrhages and a fellow eye with a small cup to disc ratio, no additional testing
is required.

Laboratory test [edit source]

If the review of systems is positive for GCA then laboratory tests including ESR, CRP and platelets should be
obtained and a temporal artery biopsy should be performed to exclude GCA. Some clinicians will obtain these
inflammatory markers in any patient over the age of 50 years who presents with an NAION but it varies from
clinician to clinician depending on their level of suspicion and clinical experience. Additional laboratory tests for
hypercoagulable states can be considered in patients under 50 with additional personal or family history of early
or unexplained thrombosis. Neuroimaging is not necessary in typical cases but MRI of the brain and orbits with
gadolinium should be obtained in cases with significant pain, especially pain with ipsilateral eye movement, to
exclude optic neuritis and multiple sclerosis. Neuroimaging should also be obtained in any patient exhibiting an
atypical course including those with prolonged disc edema or progressive and/or recurrent visual loss more than
two months after their initial presentation to exclude inflammatory or compressive lesions.

Differential diagnosis [edit source]

The most critically important entity to differentiate is AAION secondary to GCA because of the increased
frequency of bilateral vision loss as well as cardiac and neurologic complications. The other main differential
diagnosis is optic neuritis which can be secondary to multiple sclerosis.

Management [edit source]

Medical therapy [edit source]

There is no effective treatment for NAION. Although not proven, small vessel arterial occlusion with subsequent
disc edema that results in a compartment syndrome in a “crowded” disc is one of the presumed etiologies of
NAION. Different treatment modalities have been tried to help limit the pathological cascade initiated by these
two conditions 67

Thrombosis[edit source]
There is very little data in the form of case reports looking at the effectiveness of anti-platelet agents and
anticoagulants. Botelho et al. in a retrospective case-controlled study looked at visual outcome in 23 patients
being treated with aspirin before and during the course of NAION and compared them to 55 NAION patients who
did not use aspirin. They found no difference in initial or final visual acuity as well as initial and final mean
deviation on automated perimetry between the two groups 68. There are no reports in the English literature
looking at the effectivenenss of anticoagulation in NAION patients 67.

Disc edema[edit source]

As described earlier, optic disc edema from NAION likely contributes to a compartment syndrome in “crowded”
discs and contributes to axonal damage as well as retinal ganglion cell apoptosis. Corticosteroids are known to
be highly effective in reducing vasogenic but not cytotoxic edema. Hayreh recently reported 613 consecutive
patients seen between 1973 and 2000. Patients were given the option of being treated with prednisone or not. In
patients treated within two weeks, the median time to resolution of optic disc edema was 6.8 weeks compared
with 8.2 weeks in untreated patients (P<0.0001). In both groups the visual acuity and visual fields continued to
improve up to 6 months. At 6 months, patients treated within 2 weeks with initial visual acuity of 20/70 or worse
had visual acuity improvement in 69.8% compared to 40.5% in untreated patients (P=0.001). Nearly forty percent
 of treated patients had an improvement in their visual field defects at 6 months compared to 24.5% of untreated
patients (p=0.005). Hayreh et al. concluded that early treatment of NAION with prednisone 80mg improves visual
acuity and visual field defects 69. However as Atkins et al point out, these patients were not randomized and the
untreated group had more vascular risk factors making it difficult to interpret these results 67. Further, the
examiner was not masked to the treatment assignment. Currently, there is one industry sponsored randomized
trial using a synthetic RNA to block caspase 2, an enzyme in the apoptosis cycle. Patients with acute NAION are
being studied to determine whether this agen will be an effective neuroprotective therapy (see
NORDICclinicaltrials.com for details).

Compartment Syndrome[edit source]

The IONDT was a randomized, single-masked, multicenter trial examining the safety and efficacy of optic nerve
decompression surgery compared with careful observation alone in patients with NAION. The authors concluded
that not only is optic nerve decompression surgery ineffective, it might be harmful and the study was abandoned
early based upon overwhelming initial data 44, 45.

Prognosis [edit source]

Vision can worsen over the 2 week period following initial presentation and typically stabilizes by 2 months. In
Hayreh’s review looking at the natural history of visual outcome in NAION, approximately 50% of patients had a
visual acuity of 20/30 or better and nearly one-quarter were 20/200 or worse. 41% of patients seen within two
weeks of symptom onset who had 20/70 or worse showed improvement at 6 months. Two years after the initial
visit, there was worsening in 9% of eyes with initial visual acuity of 20/60 or better and in 18% of those with visual
acuity of 20/70 or worse 13. Other studies have reported observing recovery of at least 3 Snellen acuity lines in
13% - 42.7% of patients 9, 44, 45, 62-64. In general, the prognosis for visual recovery is better for younger
patients 7. Vision in the affected eye will typically stabilize within two months. Progression or recurrence more
than two months after initial presentation should bring the diagnosis of NAION into question and should prompt a
re-evaluation. Reported episodes of recurrence in the affected eye range from 3% to 8% 5, 65. Involvement of
the fellow eye ranges from 15% to 24% over 5 years 66.

Additional Resources [edit source]

 American Academy of Ophthalmology. Non arteritic anterior ischemic optic neuropathy Practicing
Ophthalmologists Learning System, 2017 - 2019 San Francisco: American Academy of Ophthalmology, 2017.

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