Pathology of Ischemic Optic Neuropathy

Ischemic optic neuropathy causes sudden, unilateral, painless vision loss. Bilateral simultaneous ION is rare and usually associated with systemic hypotension.^8,9  Anterior ION by definition is characterized by swelling of the optic disc. Nonarteritic anterior ION usually occurs in adults older than 45 years, while those with giant cell arteritis are, on average, older.¹  Other consistent findings in unilateral ION include a relative afferent pupillary defect and demonstrable visual field loss. Swollen optic discs in arteritic (Figure 1, A) and nonarteritic (Figure 1, B) anterior ION range in color from pallid to blush red. Given the high risk of second eye involvement in arteritic anterior ION and the effectiveness of systemic corticosteroids in preventing it, an expedited evaluation, including erythrocyte sedimentation rate, C-reactive protein, platelet count, and temporal artery biopsy, is indicated.¹  Other conditions can present with acute unilateral vision loss and a swollen optic disc, such as demyelinating optic neuritis or sarcoidosis, so a thorough medical evaluation is required. Posterior ION results in similar symptoms and clinical findings as anterior ION with the exception of disc edema.^8,9  Exclusion of giant cell arteritis is also crucial in the setting of posterior ION for the reasons stated above.

As based on clinical studies of arteritic and nonarteritic anterior ION, optic disc swelling regresses over an 8- to 12-week period, leaving a pale optic nerve (eg, optic atrophy).^1,10  Even though the retinal nerve fiber layer thins owing to loss of retinal ganglion cells (whose axons make up the optic nerve), excavation or cupping is relatively uncommon. When it does occur, it tends to follow arteritic anterior ION.^2,10 

Ischemic infarction of the retrolaminar optic nerve with variable involvement of laminar and prelaminar regions characterizes both arteritic and nonarteritic anterior ION.^1,7  Occlusion of inflamed short posterior ciliary arteries in cases of giant cells arteritis provides the most compelling evidence for the role these vessels play in anterior ION in general.^11,12  Clinicopathologic observations are complemented by anatomic studies that demonstrate the short posterior ciliary arteries are the main arterial supply to this region of the optic nerve.¹³ 

Few cases of common or idiopathic nonarteritic anterior ION have been examined histologically; those that have displayed little more than age-related vascular change of the posterior ciliary arteries.^7,14–16  This has led to a variety of hypotheses for circulatory insufficiency, including nocturnal hypotension and aberrant autoregulation.²  Thromboembolic occlusion of short posterior ciliary arteries results in the same histopathologic changes to the retrolaminar optic nerve as described in giant cell arteritis and nonarteritic ION.^7,17 

Clinical studies, such as fluorescein angiography and indocyanine green angiography, and Doppler flow techniques have provided little additional insight into the microvascular events that contribute to nonarteritic anterior ION. Carotid duplex scans have shown that carotid stenosis is not a risk factor. Neuroradiologic imaging has a role in diagnosing disorders that might mimic ION (such as demyelinating disease or lesions that compress the optic nerve) but cannot distinguish arteritic from nonarteritic anterior ION.^1,2,5 

Although IONs embrace a variety of causal pathways from embolic occlusion of short posterior ciliary arteries to severe systemic hypotension, the etiologies of the 2 most commonly diagnosed forms of anterior ION—common and giant cell arteritis—are unknown.

Giant cell arteritis is an antigen-driven, immune-mediated process with several genetic and epidemiologic features suggesting a connection to an infectious agent.⁶  Several hypotheses are being pursued, including one in which varicella-zoster virus triggers the inflammatory cascade.¹⁸ 

Information on the pathology of ischemic optic neuropathies has largely come from individual case reports. One large series involving 228 eyes is an exception but included 133 eyes (58%) that were classified as postischemic optic atrophy.⁷  Of the remaining cases, 26 (11%) displayed acute ischemic necrosis and 69 (30%) were diagnosed as cavernous degeneration, a morphologic variant of ION (see below). Clinical information was available for only 27 of 153 patients (18%), and was often incomplete.

The morphologic appearance of the optic nerve after ischemic injury depends on several variables including the severity of insult and the time interval after the vascular event. Although determining the age of cerebral infarcts, based on key microscopic changes of neurons, has been worked out,^19,20  the optic nerve differs from brain in several ways. It is an anatomically isolated white track with neural cell bodies (ie, retinal ganglion cells) located in the inner retina. This portion of retina is supplied by the central retinal artery, not the posterior ciliary arteries. The most reliable means by which to establish the time of ischemic injury before fixation comes from eyes removed by exenteration following fungal infection of the orbit. In some cases, mycotic thrombosis of the ophthalmic artery or its branches results in catastrophic vision loss and thus is a precise marker of when ischemic injury occurred (Figure 2). Unfortunately, few such cases have appeared in the literature.⁷ 

The characteristic features of acute infarction are loss of cells and edema. Neutrophils are rarely present. Later, macrophages populate the peripheral area of infarcted tissue (Figure 3). Severe ischemic injury results in profound cellular dropout, including loss of axons, myelin sheaths, and glial cells. Fibroblasts within pial septa are most resistant to ischemia, but their nuclei are usually small and pyknotic. Mucopolysaccharide is not present within infarcted tissue. The time frame when macrophages appear after infarction is poorly characterized. Coagulative necrosis is the defining feature of all forms of ION.

Few microscopic studies have used techniques other than basic histochemical stains. Investigations into the relationship of necrosis and apoptosis have not been explored in human specimens, nor have markers for mediators of postischemic inflammation.

Cavernous degeneration of the optic nerve (also known as Schnabel cavernous degeneration) is considered a morphologic variant of ION.⁷  The condition is relatively common, having been described in 2.1% of eyes at autopsy and nearly 1% of eyes removed with uveal melanoma.^21,22  Despite its prevalence in laboratory specimens, cavernous degeneration has not been diagnosed clinically, making it a pathologic curiosity more than a nosologic entity. Although found in cases of arteritic and nonarteritic ION, cavernous degeneration is often reported as an incidental finding in patients with chronic glaucoma and uveal melanoma.^21–24  The absence of clinical history of sudden vision loss in some cases with well-documented ocular records have added to the mystery surrounding the condition.^23,24 

Cavernous degeneration is usually found in the immediate retrolaminar region of the optic nerve. Distinctive histologic features include large empty spaces (ie, caverns) filled with faintly staining mucopolysaccharide sensitive to hyaluronidase (Figure 4).^21–24  No tissue other than a few naked nuclei can be found within areas of spongiform degeneration. Pial septa when present are widely separated. The cavernous spaces can be large enough at times to see on gross inspection of the nerve, and the unaffected portion of the nerve appears compressed. Remaining optic nerve will typically display varying degrees of chronic atrophy characterized by relative collapse of nerve bundles and thickening of pial septa. In eyes with glaucoma, the disc is cupped. Some have compared the tissue changes to a lacunar infarct.²² 

The source of hyaluronic acid in cavernous degeneration is controversial. An early hypothesis that vitreous was forced into the optic nerve by elevated intraocular pressure has been discredited.²³  In adults, hyaluronic acid is normally found around myelin sheaths in the retrolaminar nerve, but it diminishes with age.²³  It is virtually absent in eyes with chronic open-angle glaucoma.²⁵  For reasons that remain unclear, hyaluronic acid accumulates in the so-called cavernous spaces for which the condition is named.^21,22,25 

Few disorders are mistaken histologically for ischemic necrosis of the optic nerve, although several conditions can mimic cavernous degeneration. Infiltration of silicone oil into the optic nerve is common in blind eyes removed after oil was used for surgical tamponade of the retina. In these cases, globules of oil, both free and within macrophages, are found in many ocular tissues, particularly retina and optic nerve.²⁶  The globules are variable in size, ranging from several micrometers to more than 30 micrometers. Uncommonly, the oil droplets can coalesce to mimic cavernous degeneration of the optic nerve.²⁷  The distinction from cavernous degeneration starts with gross inspection of the cut surface of the eye. The colorless oil that fills the vitreous is visibly and tactilely evident. Histologically, tissues in contact with oil have a Swiss-cheese appearance from intracellular and extracellular droplets of oil. There is usually a mild macrophage response to silicone oil (Figure 5).

Hydropic axonal degeneration of the optic nerve is described in eyes with elevated intraocular pressure or hypotony. It is thought that obstruction of axoplasmic flow causes axons to swell acutely, giving rise to microvesicular changes.²⁸  Clear round to oval spaces are seen on both sides of the lamina cribrosa, ranging in size from several micrometers to roughly 15 micrometers (Figure 6). The spaces fail to stain with histologic dyes.²⁸  The empty spaces are substantially smaller and more uniform in diameter than those in cavernous degeneration. They run parallel to axon bundles, do not bow fibrous septa outward, and contain no mucin.

There is too little information on the early histologic changes of acute demyelinating optic neuritis as a manifestation of multiple sclerosis or neuromyelitis optica for definitive guidance in the differential diagnosis of ION. From autopsy findings in acute demyelinating disease, the spinal cord and optic chiasm reveal patches of demyelination and axonal degeneration associated with necrosis and cavitation.^29,30  Inflammation is inconspicuous. Although necrosis has been reported in these locations, it is attributed to ischemia from compartmental compression.³⁰  Given the rarity of ION and acute demyelinating optic neuritis as anatomic specimens, both diagnoses should be arrived at with careful clinical correlation.

The pathogeneses of the most common IONs (arteritic and nonarteritic anterior ION) are incompletely understood. Optic nerves with recent ischemic injury are uncommon specimens in pathology laboratories, usually encountered at autopsy or found in eyes or orbits removed surgically for other reasons. Careful inspection of regional vasculature including ophthalmic artery and posterior ciliary arteries is required to exclude known causes of vascular occlusion. Determining the age of infarction in hours or days involves clinical input, as the microscopic features lack sufficient precision in dating circulatory events. The scarcity of optic nerve specimens with ION has left gaps in clinical-morphologic correlation, including the roles that postinflammatory mediators and apoptosis play in the evolution of ischemic injury.