It is estimated that the incidence of AION is about 8,000/year in the U.S.

The mechanism of injury for NAION used to be quite controversial. However, experts in the field have come to a consensus that most cases involve two main risk factors. The first is a predisposition in the form of a type of optic disc shape. The optic disc is where the axons from the retinal ganglion cells collect into the optic nerve. The optic nerve is the bundle of axons that carry the visual signals from the eye to the brain. This optic nerve must penetrate through the wall of the eye, and the hole to accommodate this is usually 20-30% larger than the nerve diameter. In some patients the optic nerve is nearly as large as the opening in the back of the eye, and the optic disc appears "crowded" when seen by ophthalmoscopy. A crowded disc is also referred to as a "disc at risk". While a risk factor, the vast majority of individuals with crowded discs do not experience NAION.

The second major risk factor involves more general cardiovascular risk factors. The most common are diabetes, hypertension and high cholesterol levels. While these factors predispose a patient to develop NAION, the most common precipitating factor is marked fall of blood pressure during sleep (nocturnal arterial hypotension)- that is why at least 75% of the patients first discover visual loss first on waking from sleep. These vascular risk factors lead to ischemia (poor blood supply) to a portion of the optic disc. The disc then swells, and in a crowded optic disc, this leads to compression and more ischemia.

Since both eyes tend to have a similar shape, the optometrist or ophthalmologist will look at the good eye to assess the anatomical predisposition. The unaffected eye has a 14.7% risk of NAION within five years.

A number of uncontrolled single case or small number of patient reports have associated NAION with use of oral erectile dysfunction drugs.

Perioperative PION patients have a higher prevalence of cardiovascular risk factors than in the general population. Documented cardiovascular risks in people affected by perioperative PION include high blood pressure, diabetes mellitus, high levels of cholesterol in the blood, tobacco use, abnormal heart rhythms, stroke, and obesity. Men are also noted to be at higher risk, which is in accordance with the trend, as men are at higher risk of cardiovascular disease. These cardiovascular risks all interfere with adequate blood flow, and also may suggest a contributory role of defective vascular autoregulation.

As illustrated by the risk factors above, perioperative hypoxia is a multifactorial problem. Amidst these risk factors it may be difficult to pinpoint the optic nerve’s threshold for cell death, and the exact contribution of each factor.

Low blood pressure and anemia are cited as perioperative complications in nearly all reports of PION, which suggests a causal relationship. However, while low blood pressure and anemia are relatively common in the perioperative setting, PION is exceedingly rare. Spine and cardiac bypass surgeries have the highest estimated incidences of PION, 0.028% and 0.018% respectively, and this is still extremely low. This evidence suggests that optic nerve injury in PION patients is caused by more than just anemia and low blood pressure.

Evidence suggests that the multifactorial origin of perioperative PION involves the risks discussed above and perhaps other unknown factors. Current review articles of PION propose that vascular autoregulatory dysfunction and anatomic variation are under-investigated subjects that may contribute to patient-specific susceptibility.

The most recognized cause of a toxic optic neuropathy is methanol intoxication. This can be a life-threatening event that normally accidentally occurs when the victim mistook, or substituted, methanol for ethyl alcohol. Blindness can occur with drinking as little as an ounce of methanol, but this can be counteracted by concurrent drinking of ethyl alcohol. The patient initially has nausea and vomiting, followed by respiratory distress, headache, and visual loss 18–48 hours after consumption. Without treatment, patients can go blind, and their pupils will dilate and stop reacting to light.

- Ethylene glycol, a component of automobile antifreeze, is a poison that is toxic to the whole body including the optic nerve. Consumption can be fatal, or recovery can occur with permanent neurologic and ophthalmologic deficits. While visual loss is not very common, increased intracranial pressure can cause bilateral optic disc swelling from cerebral edema. A clue to the cause of intoxication is the presence of oxalate crystals in the urine. Like methanol intoxication, treatment is ethanol consumption.

- Ethambutol, a drug commonly used to treat tuberculosis, is notorious for causing toxic optic neuropathy. Patients with vision loss from ethambutol toxicity lose vision in both eyes equally. This initially presents with problems with colors (dyschromatopsia) and can leave central visual deficits. If vision loss occurs while using ethambutol, it would be best to discontinue this medication under a doctor’s supervision. Vision can improve slowly after discontinuing ethambutol but rarely returns to baseline.

- Amiodarone is an antiarrhythmic medication commonly used for abnormal heart rhythms (atrial or ventricular tachyarrythmias). Most patients on this medication get corneal epithelial deposits, but this medication has also been controversially associated with NAION. Patients on amiodarone with new visual symptoms should be evaluated by an ophthalmologist.

- Tobacco exposure, most commonly through pipe and cigar smoking, can cause an optic neuropathy. Middle-aged or elderly men are often affected and present with painless, slowly progressive, color distortion and visual loss in both eyes. The mechanism is unclear, but this has been reported to be more common in individuals who are already suffering from malnutrition.

The predominant cause of nutritional optic neuropathy is thought to be deficiency of B-complex vitamins, particularly thiamine (vitamin B), cyanocobalamin (vitamin B) and recently copper Deficiency of pyridoxine (vitamin B), niacin (vitamin B), riboflavin (vitamin B), and/or folic acid also seems to play a role. Those individuals who abuse alcohol and tobacco are at greater risk because they tend to be malnourished. Those with pernicious anemia are also at risk due to an impaired ability to absorb vitamin B from the intestinal tract.

Optic neuritis typically affects young adults ranging from 18–45 years of age, with a mean age of 30–35 years. There is a strong female predominance. The annual incidence is approximately 5/100,000, with a prevalence estimated to be 115/100,000.

In ischemic optic neuropathies, there is insufficient blood flow (ischemia) to the optic nerve. The anterior optic nerve is supplied by the short posterior ciliary artery and choroidal circulation, while the retrobulbar optic nerve is supplied intraorbitally by a pial plexus, which arises from the ophthalmic artery, internal carotid artery, anterior cerebral artery, and anterior communicating arteries. Ischemic optic neuropathies are classified based on the location of the damage and the cause of reduced blood flow, if known.

- Anterior ischemic optic neuropathy (AION) includes diseases that affect the optic nerve head and cause swelling of the optic disc. These diseases often cause sudden rapid visual loss in one eye. Inflammatory diseases of the blood vessels, like giant cell arteritis, polyarteritis nodosa, Churg-Strauss syndrome, granulomatosis with polyangiitis, and rheumatoid arthritis can cause arteritic AIONs (AAION). The vast majority of AIONs are nonarteritic AIONs (NAION). The most common acute optic neuropathy in patients over 50 years of age, NAION has an annual incidence of 2.3-10.2/100,000. NAION presents as a painless loss of vision, often when awakening, that occurs over hours to days. Most patients lose the lower half of their visual field (an inferior altitudinal loss), though superior altitudinal loss is also common. The pathophysiology of NAION is unknown, but it is related to poor circulation in the optic nerve head. NAION is often associated with diabetes mellitus, elevated intraocular pressure (acute glaucoma, eye surgery), high cholesterol, hypercoagulable states, a drop in blood pressure (bleeding, cardiac arrest, peri-operative esp. cardiac and spine procedures), and sleep apnea. Rarely, amiodarone, interferon-alpha, and erectile dysfunction drugs have been associated with this disease.

- Posterior ischemic optic neuropathy is a syndrome of sudden visual loss with optic neuropathy without initial disc swelling with subsequent development of optic atrophy. This can occur in patients who are predisposed to AAION and NAION as described above as well as those who had cardiac and spine surgery or serious episodes of hypotension.

- Radiation optic neuropathy (RON) is also thought to be due to ischemia of the optic nerve that occurs 3 months to 8 or more years after radiation therapy to the brain and orbit. It occurs most often around 1.5 years after treatment and results in irreversible and severe vision loss, which may also be associated with damage to the retina (radiation retinopathy). This is thought to be due to damage to dividing glial and vascular endothelial cells. RON can present with transient visual loss followed by acute painless visual loss in one or both eyes several weeks later. The risk of RON is significantly increased with radiation doses over 50 Gy.

- There is also some evidence that interferon treatment (pegylated interferon with ribavirin) for hepatitis C virus can cause optic neuropathy.

Optic disc drusen are found clinically in about 1% of the population but this increases to 3.4% in individuals with a family history of ODD. About two thirds to three quarters of clinical cases are bilateral. A necropsy study of 737 cases showed a 2.4% incidence with 2 out of 15 (13%) bilateral, perhaps indicating the insidious nature of many cases. An autosomal dominant inheritance pattern with incomplete penetrance and associated inherited dysplasia of the optic disc and its blood supply is suspected. Males and females are affected at equal rates. Caucasians are the most susceptible ethnic group. Certain conditions have been associated with disc drusen such as retinitis pigmentosa, angioid streaks, Usher syndrome, Noonan syndrome and Alagille syndrome. Optic disc drusen are not related to Bruch membrane drusen of the retina which have been associated with age-related macular degeneration.

There are several causes of toxic optic neuropathy. Among these are: ingestion of methanol (wood alcohol), ethylene glycol (automotive antifreeze), disulfiram (used to treat chronic alcoholism), halogenated hydroquinolones (amebicidal medications), ethambutol and isoniazid (tuberculosis treatment), and antibiotics such as linezolid and chloramphenicol. Tobacco is also a major cause of toxic optic neuropathy.

Ischemic optic neuropathy (ION) is the loss of structure and function of a portion of the optic nerve due to obstruction of blood flow to the nerve (i.e. ischemia). Ischemic forms of optic neuropathy are typically classified as either anterior ischemic optic neuropathy or posterior ischemic optic neuropathy according to the part of the optic nerve that is affected. People affected will often complain of a loss of visual acuity and a visual field, the latter of which is usually in the superior or inferior field.

When ION occurs in patients below the age of 50 years old, other causes should be considered. Such as juvenile diabetes mellitus, antiphospholipid antibody-associated clotting disorders, collagen-vascular disease, and migraines. Rarely, complications of intraocular surgery or acute blood loss may cause an ischemic event in the optic nerve.

Anterior ION presents with sudden, painless visual loss developing over hours to days. Examination findings usually include decreased visual acuity, a visual field defect, color vision loss, a relative afferent pupillary defect, and a swollen optic nerve head. Posterior ION occurs arteritic, nonarteritic, and surgical settings. It is characterized by acute vision loss without initial disc edema, but with subsequent optic disc atrophy.

Although there is no recognized treatment that can reverse the visual loss. Upon recent reports, optic nerve health decompression may be beneficial for a select group of patients with a gradual decline in vision due to ION.

AAION requires urgent and critical intervention with a very long course of corticosteroids to prevent further damage. While this treatment is in itself problematic, non-treatment leads to bilateral blindness and strokes.

There is much research currently underway looking at ways to protect the nerve (neuroprotection) or even regenerate new fibers within the optic nerve.

The optic nerve comprises axons that emerge from the retina of the eye and carry visual information to the primary visual nuclei, most of which is relayed to the occipital cortex of the brain to be processed into vision. Inflammation of the optic nerve causes loss of vision, usually because of the swelling and destruction of the myelin sheath covering the optic nerve.

The most common cause is multiple sclerosis or ischemic optic neuropathy (Blood Clot). Blood Clot that supplies the optic nerve. Up to 50% of patients with MS will develop an episode of optic neuritis, and 20-30% of the time optic neuritis is the presenting sign of MS. The presence of demyelinating white matter lesions on brain MRI at the time of presentation of optic neuritis is the strongest predictor for developing clinically definite MS. Almost half of the patients with optic neuritis have white matter lesions consistent with multiple sclerosis.

Some other common causes of optic neuritis include infection (e.g. Tooth Abscess in upper jaw, syphilis, Lyme disease, herpes zoster), autoimmune disorders (e.g. lupus, neurosarcoidosis, neuromyelitis optica), Pinch in Optic Nerve, Methanol poisoning, B12 deficiency and diabetes . Injury to the eye, which usually does not heal by itself.

Less common causes are: papilledema, brain tumor or abscess in occipitalregion, Cerebral trauma or hemorrhage, Meningitis Arachnoidal adhesions, sinus thrombosis, Liver Dysfunction or, Late Stage Kidney.

Arteritic anterior ischemic optic neuropathy (AAION or arteritic AION) is the cause of vision loss that occurs in temporal arteritis (aka giant cell arteritis). Temporal arteritis is an inflammatory disease of medium-sized blood vessels that happens especially with advancing age. AAION occurs in about 15-20 percent of patients with temporal arteritis. Damage to the blood vessels supplying the optic nerves leads to insufficient blood supply (ischemia) to the nerve and subsequent optic nerve fiber death. Most cases of AAION result in nearly complete vision loss first to one eye. If the temporal arteritis is left untreated, the fellow eye will likely suffer vision loss as well within 1–2 weeks. Arteritic AION falls under the general category of anterior ischemic optic neuropathy, which also includes non-arteritic AION. AION is considered an eye emergency, immediate treatment is essential to rescue remaining vision.

An exhaustive review article published in March 2009 described the latest information on arteritic and non-arteritic ischemic optic neuropathy, both anterior (A-AION and NA-AION) and posterior (A-PION, NA-PION, and surgical).

Those diseases understood as congenital in origin could either be specific to the ocular organ system (LHON, DOA) or syndromic (MELAS, Multiple Sclerosis). It is estimated that these inherited optic neuropathies in the aggregate affect 1 in 10,000

Of the acquired category, disease falls into further etiological distinction as arising from toxic (drugs or chemicals) or nutritional/metabolic (vitamin deficiency/diabetes) insult. It is worth mentioning that under-nutrition and toxic insult can occur simultaneously, so a third category may be understood as having a combined or mixed etiology. We will refer to this as Toxic/Nutritional Optic Neuropathy, whereby nutritional deficiencies and toxic/metabolic insults are the simultaneous culprits of visual loss associated with damage and disruption of the RGC and optic nerve mitochondria.

With respect to embolic and hemodynamic causes, this transient monocular visual loss ultimately occurs due to a temporary reduction in retinal artery, ophthalmic artery, or ciliary artery blood flow, leading to a decrease in retinal circulation which, in turn, causes retinal hypoxia. While, most commonly, emboli causing amaurosis fugax are described as coming from an atherosclerotic carotid artery, any emboli arising from vasculature preceding the retinal artery, ophthalmic artery, or ciliary arteries may cause this transient monocular blindness.

- Atherosclerotic carotid artery: Amaurosis fugax may present as a type of transient ischemic attack (TIA), during which an embolus unilaterally obstructs the lumen of the retinal artery or ophthalmic artery, causing a decrease in blood flow to the ipsilateral retina. The most common source of these athero-emboli is an atherosclerotic carotid artery. However, a severely atherosclerotic carotid artery may also cause amaurosis fugax due to its stenosis of blood flow, leading to ischemia when the retina is exposed to bright light. "Unilateral visual loss in bright light may indicate ipsilateral carotid artery occlusive disease and may reflect the inability of borderline circulation to sustain the increased retinal metabolic activity associated with exposure to bright light."

- Atherosclerotic ophthalmic artery: Will present similarly to an atherosclerotic internal carotid artery.

- Cardiac emboli: Thrombotic emboli arising from the heart may also cause luminal obstruction of the retinal, ophthalmic, and/or ciliary arteries, causing decreased blood flow to the ipsilateral retina; examples being those arising due to (1) atrial fibrillation, (2) valvular abnormalities including post-rheumatic valvular disease, mitral valve prolapse, and a bicuspid aortic valve, and (3) atrial myxomas.

- Temporary vasospasm leading to decreased blood flow can be a cause of amaurosis fugax. Generally, these episodes are brief, lasting no longer than five minutes, and have been associated with exercise. These vasospastic episodes are not restricted to young and healthy individuals. "Observations suggest that a systemic hemodynamic challenge provoke[s] the release of vasospastic substance in the retinal vasculature of one eye."

- Giant cell arteritis: Giant cell arteritis can result in granulomatous inflammation within the central retinal artery and posterior ciliary arteries of eye, resulting in partial or complete occlusion, leading to decreased blood flow manifesting as amaurosis fugax. Commonly, amaurosis fugax caused by giant cell arteritis may be associated with jaw claudication and headache. However, it is also not uncommon for these patients to have no other symptoms. One comprehensive review found a two to nineteen percent incidence of amaurosis fugax among these patients.

- Systemic lupus erythematosus

- Periarteritis nodosa

- Eosinophilic vasculitis

- Hyperviscosity syndrome

- Polycythemia

- Hypercoagulability

- Protein C deficiency

- Antiphospholipid antibodies

- Anticardiolipin antibodies

- Lupus anticoagulant

- Thrombocytosis

- Subclavian steal syndrome

- Malignant hypertension can cause ischemia of the optic nerve head leading to transient monocular visual loss.

- Drug abuse-related intravascular emboli

- Iatrogenic: Amaurosis fugax can present as a complication following carotid endarterectomy, carotid angiography, cardiac catheterization, and cardiac bypass.

Optic nerve damage is progressive and insidious. Eventually 75% of patients will develop some peripheral field defects. These can include nasal step defects, enlarged blind spots, arcuate scotomas, sectoral field loss and altitudinal defects. Clinical symptoms correlate to visibility of the drusen. Central vision loss is a rare complication of bleeding from peripapillar choroidal neovascular membranes. Anterior ischemic optic neuropathy (AION) is a potential complication.

Ocular causes include:

- Iritis

- Keratitis

- Blepharitis

- Optic disc drusen

- Posterior vitreous detachment

- Closed-angle glaucoma

- Transient elevation of intraocular pressure

- Intraocular hemorrhage

- Coloboma

- Myopia

- Orbital hemangioma

- Orbital osteoma

- Keratoconjunctivitis sicca

Many people of East Asian descent are prone to developing angle closure glaucoma due to shallower anterior chamber depths, with the majority of cases of glaucoma in this population consisting of some form of angle closure. Higher rates of glaucoma have also been reported for Inuit populations, compared to white populations, in Canada and Greenland.

Toxic optic neuropathy refers to the ingestion of a toxin or an adverse drug reaction that results in vision loss from optic nerve damage. Patients may report either a sudden loss of vision in both eyes, in the setting of an acute intoxication, or an insidious asymmetric loss of vision from an adverse drug reaction. The most important aspect of treatment is recognition and drug withdrawal.

Among the many causes of TON, the top 10 toxins include:

- Medications

- Ethambutol, rifampin, isoniazid, streptomycin (tuberculosis treatment)

- Linezolid (taken for bacterial infections, including pneumonia)

- Chloramphenicol (taken for serious infections not helped by other antibiotics)

- Isoretinoin (taken for severe acne that fails to respond to other treatments)

- Ciclosporin (widely used immunosuppressant)

- Acute Toxins

- Methanol (component of some moonshine, and some cleaning products)

- Ethylene glycol (present in anti-freeze and hydraulic brake fluid)

Metabolic disorders may also cause this version of disease. Systemic problems such as diabetes mellitus, kidney failure, and thyroid disease can cause optic neuropathy, which is likely through buildup of toxic substances within the body. In most cases, the cause of the toxic neuropathy impairs the tissue’s vascular supply or metabolism. It remains unknown as to why certain agents are toxic to the optic nerve while others are not and why particularly the papillomacular bundle gets affected.

Severe ipsilateral or bilateral carotid artery stenosis or occlusion is the most common cause of ocular ischemic syndrome. The syndrome has been associated with occlusion of the common carotid artery, internal carotid artery, and less frequently the external carotid artery. Other causes include:

- Takayasu's arteritis

- Giant cell arteritis

- Severe ophthalmic artery occlusion, due to thromboembolism.

- Surgical interruption of anterior ciliary blood vessels supplying the eye, particularly during extensive strabismus surgery on 3 or more rectus muscles, leading to an anterior segment ischemic syndrome.

No clear evidence indicates vitamin deficiencies cause glaucoma in humans. It follows, then, that oral vitamin supplementation is not a recommended treatment for glaucoma. Caffeine increases intraocular pressure in those with glaucoma, but does not appear to affect normal individuals.

Over many years, glaucoma has been defined by an intraocular pressure of more than 20 or 20 mm Hg. Incompatible with this (now obsolete) definition of glaucoma was the ever larger number of cases that have been reported in medical literature in the 1980s and 1990s who had the typical signs of glaucomatous damage, like optic nerve head excavation and thinning of the retinal nerve fiber layer, while these patients had an IOP that would generally have been regarded as "normal". It is now widely estimated that a larger percentage of patients with primary open-angle glaucoma (POAG) are suffering from normal tension glaucoma: probably half of all POAG patients in Europe and the majority of POAG patients in East Asia. Among Americans of Japanese descent, for instance, the prevalence of NTG is about four times as high as the prevalence of the "classical glaucoma" with an IOP of 22 mm Hg and higher. The pillar of the current understanding of normal tension glaucoma is a reduced IOP tolerance of the retinal ganglion cells and the cells in the optic nerve head - an IOP of, for example, 17 or 19 mm Hg that would not affect a healthy eye leads to damage in the eye of an NTG patient.

In many patients, normal tension glaucoma is common in individuals with a generalized reduced perfusion of organs and certain body tissues. A low blood pressure - whether consistently low or with sudden pressure drops - is associated with NTG as are conditions like Flammer syndrome and obstructive sleep apnea. Flammer syndrome has been attributed to increase the likelihood of ganglion cell damage in normal tension glaucoma patients with disc hemorrhages as a characteristic clinical sign. Besides race (Japanese) and low blood pressure, the female gender is also a risk factor.

Papilledema (or papilloedema) is optic disc swelling that is caused by increased intracranial pressure. The swelling is usually bilateral and can occur over a period of hours to weeks. Unilateral presentation is extremely rare. Papilledema is mostly seen as a symptom resulting from another pathophysiological process.

In intracranial hypertension, the optic disc swelling most commonly occurs bilaterally. When papilledema is found on fundoscopy, further evaluation is warranted due to the fact that vision loss can result if the underlying condition is not treated. Further evaluation with a CT or MRI of the brain and/or spine is usually performed. Recent

research has shown that point-of-care ultrasound can be used to measure optic nerve sheath diameter for detection of increased intracranial pressure and shows good diagnostic test accuracy compared to CT. Thus, if there is a question of papilledema on fundoscopic examination or if the optic disc cannot be adequately visualized, ultrasound can be used to rapidly assess for increased intracranial pressure and help direct further evaluation and intervention. Unilateral papilledema can suggest a disease in the eye itself, such as an optic nerve glioma.