Nonarteritic AION

General

Most common form of AION.

Numbers

2.3 and 10.3 people per 100,000 individuals per year

Most common cause of acute optic neuropathy in patients over the age of 50.

There are approximately 6000 new cases per year and Caucasians account for nearly 95% of cases [23].

>50 yrs

10% of cases are in people over age 45.

M:F 1:1

Aetiology

Idiopathic mostly

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)

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

Medications

Interferons

It has been hypothesized that interferon alpha might cause an NAION by depositing immune complexes in the optic disc circulation that leads to ischemia

Sildenafil

Effective treatment for erectile dysfunction (ED) by inhibiting phophodiesterase type 5 (PDE5), an enzyme that regulates blood flow in the penis.
Sildenafil can cause

Systemic hypotension → 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
Problems with autoregulation of blood flow thereby decreasing perfusion to the optic nerve head

Optic Disc Drusen

Abnormal deposition of protein and calcium found in the optic nerve.
Might increase the risk of developing NAION by theoretically contributing to the “crowded” optic nerve in discs with small cup to disc ratios.

Pathophysiology

Not caused by inflammation of the arteries but

A drop in blood pressure to such a degree that blood supply to the optic nerve is decreased;
Increased intraocular pressure
Narrowed arteries
Increased blood viscosity
Decreased blood flow to the optic nerve

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).

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 [39] resulting in apoptotically induced retinal ganglion cell death

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

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”.
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

Autoregulation

The optic nerve head efficiently autoregulates blood flow.
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
Systemic hypertension, arteriosclerosis, vasospasm or medications may reduce the autoregulatory capacity of the optic disc
Vasoactive substances might be released in response to ischemia that influence the autonomic control of blood vessels.

Nocturnal hypotension

There are normal nocturnal fluctuations in blood pressure → 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

Venous Insufficiency

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

Reasons is because 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
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
The infarct in NAION does not fit the vascular bed of any known artery
Fluorescein angiography demonstrates normal choroidal filling and mildly delayed arterial filling of only the prelaminar disc [35].

Vasculopathic Risk Factors

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
In the ischemic optic neuropathy decompression trial (IONDT), 60% of NAION patients had at least one vasculopathic risk factor with hypertension (47% and diabetes (24%) being most common

Smoking does not seem to be an independent risk factor [58].

Clinical features

Symptoms

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.
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

Loss of vision that occurs over hours to days.
>2/3 of patients notice vision loss upon awakening which suggests that nocturnal arterial hypotension may be critically involved in the pathophysiology of NAION

Examination

Signs

Optic neuropathy including decreased visual acuity, dyschromatopsia, an RAPD, a swollen optic nerve with splinter hemorrhages and a visual field defect.

Visual Acuity

May vary widely
49% of patients had an initial visual acuity of 20/64 or better and 66% had 20/200 or better
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

Color Vision

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

Pupils

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

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

Fundoscopy

Optic disc and retinal appearance

Optic disc edema is always present in the acute phase of NAION

2 types

Segmental (typically altitudinal)

Is more common
But it does not consistently correspond to the accompanying area of visual field loss
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

3/4 patients
Its presence can sometimes help to differentiate NAION from optic neuritis since they will be present in 5-15% of patients with optic neuritis

Retinal exudates

Are uncommon but both hard and soft exudates were reported in up to 7% of patients in the IONDT
And the retinal arterioles can be focally narrowed in the peripapillary region in two-thirds of patients [65].

Clinical diagnosis

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

Coag to check for hypercoagulable states can be considered in patients under 50 with additional personal or family history of early or unexplained thrombosis.

Radiology

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.

It has been hypothesized that OCT-A may be useful in diagnosing and predicting the severity of NAION based upon the blood flow to the optic disc, however studies have shown conflicting results about the utility of this imaging[37][38][69].

Differential diagnosis

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

Medical therapy

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

Thrombosis

There is very little data in the form of case reports looking at the effectiveness of anti-platelet agents and anticoagulants.

Disc edema

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.
Early treatment of NAION with prednisone might be effective still awaiting studies to prove

Compartment Syndrome

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

Prognosis

Vision can worsen over the 2 week period following initial presentation and typically stabilizes by 2 months.

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

Other studies have reported observing recovery of at least 3 Snellen acuity lines in 13% - 42.7% of patients

In general,

The prognosis for visual recovery is better for younger patients
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%

Involvement of the fellow eye ranges from 15% to 24% over 5 years

A systematic review and meta-analysis

Attempted to find a predictive determination of visual acuity in patients with sequential bilateral NAION and found that it is impossible to definitively determine visual outcomes in patients based on their initial presentation.
It also found that the use of preventive measures after the first event do not have any effect on stopping development of NAION in the contralateral eye