Resident Short Review
Pathology of Ischemic Optic Neuropathy
Hershel R. Patel, MD, MS; Curtis E. Margo, MD, MPH
 Ischemic optic neuropathy (ION) describes a state of
hypoxic injury of the optic nerve. Clinically, ION is
divided into anterior and posterior forms defined by the
presence or absence of optic disc swelling, respectively.
It is further classified as arteritic when secondary to
vasculitis, and nonarteritic when not. The site of vascular
occlusion for anterior ION from giant cell arteritis is the
short posterior ciliary arteries, but mechanical vascular
obstruction does not play a role in most nonarteritic
cases. Histologically, ION is characterized by axon and
glial necrosis, edema, and a sparse mononuclear re-
sponse. Like other ischemic injuries, the morphologic
alternations in the nerve are time dependent. A variant of
ION called cavernous degeneration (of Schnabel) fea-
tures large cystic spaces filled with mucin. Several
conditions can histologically mimic cavernous degener-
ation of the optic nerve. The scarcity of cases of ION
examined histologically has contributed to an incomplete
understanding of its pathogenesis.
(Arch Pathol Lab Med. 2017;141:162–166; doi:
10.5858/arpa.2016-0027-RS)
I schemic optic neuropathy (ION) refers to infarction of any
portion of the optic nerve from the chiasm to optic nerve
head. Clinically, it is divided into anterior and posterior
forms by the presence or absence of swelling of the optic
nerve head, respectively.1 Both forms are further classified
into arteritic when secondary to vasculitis and nonarteritic
when caused by other entities. Nearly all cases of arteritic
ION are due to giant cell arteritis. The pathogenesis of
nonarteritic anterior ION is unsettled, but the clinical
diagnosis encompasses several distinct, albeit uncommon,
sources of injury including thromboembolism, systemic
hypotension, and atherosclerotic vascular occlusion.2 Sys-
temic hypertension, diabetes mellitus, and sleep apnea have
been associated with nonarteritic anterior ION, but in most
cases no direct underlying cause for vascular insufficiency is
found.3,4 Occasionally referred to as ‘‘common’’ or ‘‘idio-
pathic,’’ nonarteritic anterior ION tends to affect optic discs
Accepted for publication April 28, 2016.
From the Departments of Ophthalmology (Drs Patel and Margo),
Pathology and Molecular Biology (Dr Margo), Morsani College of
Medicine, University of South Florida, Tampa.
The authors have no relevant financial interest in the products or
companies described in this article.
Reprints: Curtis E. Margo, MD, MPH, Pathology/Dermatopathol-
ogy, Morsani College of Medicine, University of South Florida, MDC
Box 79, 12901 Bruce B. Downs Blvd, Tampa, FL 33612 (email:
cmargo@health.usf.edu).
162 Arch Pathol Lab Med—Vol 141, January 2017
with a small-diameter scleral canal and optic cup, the so-
called disc at risk.1,2
Based on conventional use of the term, ischemic optic
neuropathy refers to the acute stages of ischemic injury
before optic atrophy develops. Ischemic optic neuropathies
are common clinical conditions, with the incidence of
nonarteritic anterior ION between 2.3 and 10.3 per
100 000 population per year.5 The incidence of giant cell
arteritis varies geographically, ranging from 12 to 17 per
100 000 population that is older than 50 years per year.6
Despite the overall prevalence of ION clinically, eyes with
acute ION are rarely encountered in the pathology
laboratory, and then usually in the context of autopsy as
an incidental finding, or in specimens removed surgically for
other primary reasons.7
CLINICAL OVERVIEW
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 cortico-
steroids 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 Optic Neuropathy—Patel & Margo
Figure 1. Example of optic disc swelling in anterior ischemic optic neuropathy due to giant cell arteritis (ie, arteritic) (A) and optic disc swelling from
nonarteritic anterior ischemic optic neuropathy (B).
Figure 2. The optic nerve 36 hours after mycotic thrombosis of a branch of the ophthalmic artery. There is profound loss of cellularity from the optic
disc to several millimeters behind the lamina cribrosa. Inset, Higher magnification shows near absence of cells with scattered pyknotic nuclei
between remaining collagen septa (hematoxylin-eosin, original magnifications 312 and 3110 [inset]).
Figure 3. Cross-section of retrolaminar optic nerve with anterior ischemic optic neuropathy due to giant cell arteritis. The eye was obtained at
autopsy roughly 3 weeks after vision loss. Macrophages (gitter cells) are seen within necrotic axon bundles in the lower portion of the photograph
(hematoxylin-eosin, original magnification 3350).

PATHOPHYSIOLOGY Few cases of common or idiopathic nonarteritic anterior

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 ana-
tomic studies that demonstrate the short posterior ciliary
arteries are the main arterial supply to this region of the
optic nerve.13
Arch Pathol Lab Med—Vol 141, January 2017
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 tech-
Ischemic Optic Neuropathy—Patel & Margo 163
niques 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
ETIOLOGY
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-mediat-
ed 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
HISTOPATHOLOGY
Information on the pathology of ischemic optic neurop-
athies 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 macro-
phages appear after infarction is poorly characterized.
Coagulative necrosis is the defining feature of all forms of
ION.
164 Arch Pathol Lab Med—Vol 141, January 2017
Few microscopic studies have used techniques other than
basic histochemical stains. Investigations into the relation-
ship 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
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. Al-
though 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 immedi-
ate 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 charac-
terized 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
DIFFERENTIAL DIAGNOSIS
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 distinc-
tion from cavernous degeneration starts with gross
inspection of the cut surface of the eye. The colorless oil
Ischemic Optic Neuropathy—Patel & Margo

Figure 4. Retrolaminar optic nerve shows cavernous degeneration
involving about 90% of the cross-sectional area. This was an
unanticipated finding in an eye blind from glaucoma. Pial septa are
widely separated and filled with a faint mucinous material. Inset, The
substance stains weakly with Alcian blue (hematoxylin-eosin, original
magnification 312; Alcian blue, original magnification 3350 [inset]).
Arch Pathol Lab Med—Vol 141, January 2017
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 inconspicu-
ous. 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.
CONCLUSIONS
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 post-
inflammatory mediators and apoptosis play in the evolution
of ischemic injury.
Figure 5. Optic nerve at the level of the lamina cribrosa in an eye filled
with silicone oil shows numerous clear spaces. Macrophages wedged
between oval and round spaces have a foamy cytoplasm. Inset, A
membrane just anterior to the surface of the retina has a Swiss-cheese
appearance and contains foamy macrophages (hematoxylin-eosin,
original magnification 3350 and 3350 [inset]).
Figure 6. Hydropic degeneration of the optic nerve in an eye that
sustained a large corneal-scleral laceration. The eye was hypotonous
(without pressure) for a week before surgical removal. Myriad clear
spaces are present along axon bundles. Inset, High magnification shows
relatively uniform round and oval clear spaces (hematoxylin-eosin,
original magnifications 312 and 3110 [inset]).
Ischemic Optic Neuropathy—Patel & Margo 165
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166 Arch Pathol Lab Med—Vol 141, January 2017 Ischemic Optic Neuropathy—Patel & Margo