18th Annual Glaucoma Report

Optic Neuropathies: Glaucomatous vs. Non-glaucomatous

While these conditions have overlapping clinical features, distinguishing one from the other is vital to chart the appropriate treatment and follow-up plan.

By Julie K. Hutchinson, O.D., Andrew S. Gurwood, O.D., and Marc D. Myers, O.D.

Goal Statement:

Glaucomatous optic neuropathy is the most commonly acquired optic neuropathy encountered in clinical practice. While it has clinical features that overlap with non-glaucomatous optic neuropathies—including the presence of vision loss, visual field (VF) loss and optic disc cupping—there are distinct differences. Thus, it is crucial for clinicians to determine the context of a discovered optic neuropathy so that they can consider an appropriate work-up that will lead to suitable intervention and follow-up.

Faculty/Editorial Board:

Julie K. Hutchinson, O.D., Andrew S. Gurwood, O.D., and Marc D. Myers, O.D.

Credit Statement:

This course is COPE-approved for 2 hours of CE credit. COPE ID is 35186-NO. Please check your state licensing board to see if this approval counts toward your CE requirement for relicensure.

Joint-Sponsorship Statement:

This continuing education course is joint-sponsored by the Pennsylvania College of Optometry.

Disclosure Statement:

Drs. Hutchinson, Gurwood and Myers have no relationships to disclose.

Glaucomatous optic neuropathy is the most commonly acquired optic neuropathy encountered in clinical practice.¹ While it has clinical features that overlap with non-glaucomatous optic neuropathies—including the presence of vision loss, visual field (VF) loss and optic disc cupping—there are distinct differences in conditions. Non-glaucomatous optic nerve disorders must be differentiated from their glaucomatous brethren because their underlying pathophysiological mechanisms are often part of systemic disease processes that have the potential to impact mortality.

Characteristic signs of irreversible retinal ganglion cell destruction include optic nerve cupping, optic disc sinking, optic disc pallor as well as focal and diffuse retinal nerve fiber layer (RNFL) loss. While these are commonly observed as part of the disease process in glaucoma, they are not exclusive signs of the disease. Other diseases or congenital conditions may exhibit these findings in either the absence of glaucoma or in tandem with it.

Thus, it is crucial for clinicians to determine the context of a discovered optic neuropathy so that they can consider an appropriate workup that will lead to suitable intervention and follow-up. Accurate and timely management of impending, worsening or developing conditions can only be instituted when the correct diagnosis is uncovered and the underlying causes are revealed.

Glaucomatous Optic Neuropathy

Glaucoma is traditionally defined as a progressive optic neuropathy with accompanying characteristic optic nerve and visual field changes.^1-8 It is classically diagnosed by the presence of a progressive optic nerve cupping with concurrent progressive VF loss.^1-8 Diagnosis is aided by the presence of risk factors such as elevated intraocular pressure (IOP), positive family history, predisposed race, advanced age and thin central corneal thickness.^1-8

There are three mechanistic theories to explain why glaucomatous optic neuropathy develops:^9-29

• The pressure-dependent bio-mechanical mechanism.^9-14 Here, "high" IOP causes the lamina cribrosa to physically deform and bow, which results in pinching of the axons and supportive tissues, leading to ganglion cell death and tissue remodeling.^30-32 "High" IOP also creates an environment of increased resistance to perfusion, which can produce axonal death by inducing poor axoplasmic and vascular flow.^30-32
• The vascular/autoregulatory mechanism.^20-26 This process is defined by vascular insufficiency or malfunctioning autoregulatory mechanisms at the level of the optic nerve.³³ Poor perfusion induces ganglion cell or supportive tissue death.^20-26 This mechanism most likely explains why glaucomatous processes are seen at "normal" IOPs.
• Linkage to genetic factors that coerce preprogrammed cell death (apoptosis).^27-30,34-39 The classic clinical finding seen in most glaucoma patients is a level of IOP inconsistent with the health of the optic nerve. While increased IOP has traditionally been associated with the disease process, the literature has lobbied that it be considered a single risk factor among several risk factors, rather than diagnostic for the disease.^40-41

Optic pits are depressions in the optic disc that result from herniation of neuroectoderm tissue during development. Although they may occur anywhere on the disc, they often are observed in the temporal quadrant and give the impression of a large disc.

In diagnosing glaucoma, other clinical features that must be consistently detected with evidence of repeatability and reliability include spared central visual acuity in early-stage disease, spared central visual field with intact color vision in early-and moderate-stage disease, optic disc elongation with disc notching and evidence of RNFL atrophy or dropout providing the anatomic correlation for the non-vertical-respecting visual field loss. Also, an afferent pupillary defect (APD) may be present, depending on the relative asymmetry of optic nerve damage between the two eyes in glaucoma.

Glaucomatous VF defects traditionally correlate to the focal areas of optic nerve compromise. As the retinal ganglion cell axons undergo alterations, the regions of photo-receptors they subserve lose their connection with the visual pathway, creating the recognizable patterns
of functional deficit seen in glaucoma. Because the lamina cribrosa is anatomically weaker in its vertical regions, the nerve tissues that course those locations often succumb to the pathology during the beginning phases, creating pathognomonic patterns in synchrony with the distribution of the affected nerve fibers.^50-56 Early glaucomatous VF defects exhibit classic patterns of loss corresponding to the specific nerve bundles affected. In most cases, the earliest field defects are superior or inferior arcuate defects occurring secondary to loss of the optic nerve's corresponding portions. As a result, the corresponding VF defects present as relative, arcuate nasal scotomas (nasal step and Bjerrum scotoma).

With progressive optic disc damage, an arcuate defect will emerge in the affected eye having no respect for the virtual vertical field dividing line, permitting the loss to arc from the nasal field to the temporal blind spot.⁵⁶ The earliest field defects in glaucoma are small, shallow fluctuating scotomas due to highly variable retinal sensitivity, leading early field tests to be noisy and difficult to replicate. Eventually, the field loss becomes persistent in early and mid-level disease.

In most instances of open-angle glaucoma, bilateral, advancing disease inevitably presents as relative biarcuate defects. As the disease progresses, the field defects coalesce, creating a "tunnel" field in both eyes.⁵⁶ In glaucoma, because the ganglion cell axons lose function gradually as their injury progresses, the measurement of the loss can be variable until the end stage. This, along with peculiarities created by automated testing, creates a scenario where ganglion cells may be taxed in differing patterns, which gives the appearance of VF defects that seemingly come and go or change position from measurement to measurement.

Inflammatory Optic Neuropathy

Inflammatory optic neuropathy may be caused by a number of underlying conditions, including systemic infection, vaccination or autoimmune disease.⁵⁷ The most commonly associated cause of inflammatory optic neuropathy is demyelinating optic neuritis secondary to multiple sclerosis.^57,58 A complex cascade of inflammatory events begins peripherally in the body, induces the activation of T lymphocytes, and serves as the peripheral trigger.⁵⁹ The activated cells cross the blood-brain barrier and gain access to the central nervous system.⁵⁹ Antigens cause the activation of more inflammatory mediators, microglia, lymphocytes and cytokines.⁵⁹ The initial inflammatory cascade leads to phagocytosis of the myelin sheath.⁶⁰ As a result, fibrotic tissue is laid down in place of missing myelin; as this substitutive tissue lacks the saltatory conduction properties of myelin, the nerve impulse is interrupted.^59-60 As the disease progresses, further demyelination occurs, which exaggerates axonal damage and culminates in retinal ganglion cell death.⁶⁰

Patients with optic neuritis typically present with ocular pain (exaggerated upon eye movement), noticeable changes in color vision in the affected eye and variable unilateral loss of vision, ranging from 20/30 to no light perception.^58,61-64 This is often accompanied by an APD, the magnitude of which depends on the degree of visual disability. Light disturbances in the field of vision known as phosphenes may also be reported during rapid eye movements (saccades). Dyschromatopsia as well as color desaturation and depressed contrast sensitivity are also often noted in these patients.^58,61,62

Affected eyes present with a depressed field having a variety patterns ranging from cecocentral scotomas to dense central scotomas.^61-66 As the eye naturally recovers over the course of the event, in most cases VF defects resolve as axonal damage becomes limited to localized nerve bundles.⁶⁵ Interestingly, patients often exhibit non-specific field deficits in the fellow, unaffected eye.⁶⁵

In patients presenting with acute optic neuritis, the optic nerve's clinical appearance ranges from normal to edematous (papillitis). Only one- third of patients manifest diffuse optic disc edema.⁶⁷ Disc hemorrhages are possible but less common in optic neuritis.⁶⁷ Segmental or diffuse optic disc pallor represents axonal infarction. Cases that present without the telltale optic disc signs are diagnosed based on the patient's history, demographics (young, typically female, white, age 20 to 40) and the constellation of clinical signs and symptoms. The nomenclature is often referred to as retrobulbar optic neuritis. Demylinating optic neuropathy is confirmed definitively through magnetic resonance imaging (MRI) and cerebrospinal fluid analysis.^1,67,68

Optic disc cupping and peripapillary tissue remodeling are plausible outcomes of demyelinating optic neuropathy.⁶⁸

The Optic Neuritis Treatment Trial (ONTT), a multicenter study of optic neuritis patients, delineated treatment options.^58,62,69 The study helped to point out that the previous treatment of oral steroids alone was contraindicated, recommending intravenous methylprednisone, administered over the course of three days followed by an 11-day course of oral prednisone.^58,62,69 The study also concluded that monitoring—while leading to increased recovery time—was essentially equivalent to the intervention arm of the study.^58,62,69

Compressive Optic Neuropathy

Compressive optic neuropathy results from mechanical mass effect secondary to tumors and non-neoplastic lesions (i.e., retrobulbar hemorrhage, aneurysm, mucocele, orbital apex syndrome), which impinge on intraorbital or intracranial structures of the visual pathway.^70-71 Intracranial tumors such as sphenoid wing meningioma, pituitary adenoma, craniopharyngioma, meningioma and masses secondary to metastases to the orbit or anterior intracranial cavity may cause unilateral or bilateral optic nerve compression. Optic nerve tumors, such as optic nerve sheath meningioma and optic nerve glioma, also may result in unilateral or bilateral optic nerve compromise.^70-71

Patients who develop compressive optic neuropathy have no specific demographic predilection to age or gender. In the case of traumatic orbital apex syndrome or traumatic retrobulbar hemorrhage, a provocative mechanical force will be uncovered in the history. In the case of space-occupying lesions (SOLs), history reveals a slowly progressive process with changes or fluctuations in visual acuity or missing visual field that occur over several months to years.^70-72 In cases where there is sudden expansion of an SOL, acute changes in field and acuity may occur as a result of novel vascular compression causing sudden infarction of the optic nerve.

NAION is caused by a lack of optic nerve perfusion or embolic disease that affects the arteries supplying the optic nerve. Fundoscopic examination in the acute phase of cases reveals mild to severe optic nerve swelling.

Along with acuity changes, patients also may report changes in color vision and/or diplopia. Double vision results from interruption of any of the cranial nerves innervating the extraocular muscles (CN III, IV, VI). Compression may occur at the orbital apex, in the cavernous sinus or via mechanical restriction of the extraocular muscles (with or without proptosis) secondary to orbital tumor expansion or thyroid myopathy.^70,71

VF defects associated with compressive lesions vary depending on their location.^70,71 Retrobulbar optic nerve compression commonly produces central, cecocentral and paracentral defects. Compression in the optic chiasm region can produce junctional (the affected eye has a deep central scotoma with an afferent defect and the fellow eye has a temporal defect) and bitemporal hemianopsia. Optic tract lesions produce incongruous homonymous hemianopias.^66,70,71 In cases of unilateral or asymmetric optic nerve compression, an afferent defect may be noted. Orbital and eyelid signs may include proptosis, resistance to retropulsion, enophthalmos, ptosis or lid retraction.

The optic disc's appearance may vary greatly depending on the lesion's magnitude.^70,71 Note that early in the compressive disease process, the optic disc may appear normal. Other optic disc findings may include atrophic changes (most often due to chronic compression), optic disc edema and the presence of optociliary shunt vessels.^70,71

Optic disc cupping and tissue remodeling are a plausible outcome of compressive optic neuropathy.^73,74

Accurately diagnosing and promptly treating the underlying cause of the compression is vital to preserve the patient's vision and medical health. Surgical and medical treatments directed at managing the underlying etiology may result in recovery of acuity, fields and symptoms.^70,71

Anterior Ischemic Optic Neuropathy

Aside from glaucoma, anterior ischemic optic neuropathy (AION) is the most common cause of optic nerve-related permanent vision loss in adults.^75-79 The two forms of anterior ischemic optic neuropathy are non-arteritic (NAION) and arteritic (AAION). The main cause of AAION is infarction of the short posterior ciliary arteries due to giant cell arteritis (GCA), when large multinucleated monocytes infiltrate the small- and medium-sized arteries, causing obliteration of their lumen.^75-80 Some research suggests that transient hypoperfusion or non-perfusion of the optic nerve is the predominant cause of NAION, while atherosclerosis along with other systemic diseases like diabetes mellitus or hypertension are merely risk factors.^{33,75-79,107-108}

AION patients typically are more than 40 years of age, and the condition does not demonstrate a particular bias toward gender (slight predilection for males over females). Patients present with sudden unilateral visual acuity and/or visual field loss that occurred upon awakening. Patients may present with scalp or jaw pain, which may be interpreted by the patient as eye pain or may result in eye pain that is referred. Depending upon the anatomical involvement (cranial nerves III, IV, VI), diplopia is possible; however, global systemic neurologic symp toms are absent.^75-80

Key diagnostic signs include acuity that may range from normal to variably decreased, variably altered color vision, presence of a relative APD in the setting of no proptosis, no ptosis, normal ocular motilities, and normal corneal and facial sensation.^75-80

Fundoscopic examination in the acute phase of AION cases reveals mild to severe optic nerve swelling. Depending on the timing of the observation, the disc may appear hyperemic or pale, with sectorial findings in less severe cases and diffuse characteristics in a more severely damaged papilla. Retinal hemorrhages may be present at the optic disc margins with cotton-wool spots suggesting an arteritic etiology.^75-80 The uninvolved eye commonly presents with a "crowded" optic nerve head with an absent or small cup.^81,82 Medical history may include one or more vasculopathic risk factors such as hypertension, hypercholesterolemia, diabetes or smoking.^75-79

Optic disc cupping and tissue remodeling are a plausible outcome of ischemic optic neuropathy.^83-86

Acute management for any suspected ischemic optic neuropathy includes prompt laboratory and diagnostic studies (erythrocyte sedimentation rate, C-reactive protein, and platelets) to not only differentiate AAION from NAION, but to identify systemic etiologies that warrant immediate medical intervention.^75-80

The initial treatment for AAION includes high-dose (80mg to 100mg p.o. q.d.) prednisone or hospitalization to begin intravenous methyl-prednisolone followed by a course of oral prednisone.

There is no one perfect test for diagnosing GCA. The laboratory work-up includes complete blood count with differential and platelets, liver function studies, erythrocyte sedimentation rate and C-reactive protein. Suspicious results are followed up with temporal artery biopsy (TAB), while management is immediately initiated.^75,76,78,79

While the TAB is not foolproof (false positives and false negatives occur), the constellation of signs and symptoms dictate the treatment protocols. Occult GCA is subtler, because its eye problems occur in the absence of systemic signs and symptoms. Expert evaluation by neurology or neuro-ophthalmology is critical.

When there is no suspicion of GCA, the initial treatment of NAION should focus on medical management of potential vasculo-pathic etiologies. The main goal of therapy is to control the suspected disease process and to ultimately protect the unaffected eye and reduce the risk of cerebrovascular accident and myocardial infarction.^75-79

In cases of AAION, recovery of visual acuity and/or visual field is rare.^75-80 There are reports describing NAION patients who recover some visual acuity and some visual field; however, the recovery is often small and not approaching the pre-loss function.⁷⁵

In both AAION and NAION, the disease's natural course over several months brings about resolution of the disc swelling, eventual resultant disc pallor with the potential for papillary disc and tissue remodeling that results in what appears to be disc cupping.^75-79

Infiltrative Optic Neuropathy

Infiltrative optic neuropathy can result from systemic infection, systemic lupus erythematosus, blood-borne cancers and metastatic disease; however, it is most commonly found in association with sarcoidosis.^87-97

While neuroimaging may be used to confirm the presence of inflammation or an SOL, it is not specific in cases of infiltrative optic neu-ropathy. Infiltration can be difficult to confirm without biopsy and the ability to directly observe the histological characteristics of the pathological cells.^87-92

The sequence of events that occurs in optic nerve infiltration varies. Generally, it is believed that the bloodstream carries pathologic cells to the meninges via the perivascular and subarachnoid space.⁹³ Once present in meningeal tissue, these cells have the capability to invade the cranial nerves.^89,93 Infiltration of optic nerve tissue along with accompanying impairment to its blood supply lead to infarction and loss of axons.⁹³

The demographics of infiltrative neuropathy varies widely by age, race, gender and is subject to the particular demographics of underlying disease.^87-97 Clinically, these patients often experience a reduction in visual acuity, color vision and contrast sensitivity that is typically painless, unilateral or asymmetric and variable in its nadir.^87-97 An APD is often present.^88,91,94 Associated ocular inflammation (iritis, vitritis, pars planitis, intermediate uveitis) can be present depending on the etiology.⁹⁴ The optic disc is often diffusely edematous.^87-97

In cases producing granulomatous infiltration, such as sarcoidosis, the optic nerve may accumulate numerous discrete granulomata, creating
a cauliflower-like appearance.^88,94 However, because infiltrative events may occur anywhere along the length of the optic nerve, it is not always possible to distinguish infiltrative etiology based on disc observation alone.

Optociliary shunts may develop at the optic disc to serve as a second drainage route in cases where infiltrative, compressive or neoplasmic compression reduces ocular vascular egress.⁸⁸ The presence of optociliary shunts predicts a poor visual outcome and definitively suggests a pathological process independent of glaucoma.⁸⁸

The pattern of VF defects seen in these cases is variable, ranging from diffuse, non-specific defects to amaurosis.^89,91,94 Visual field improvement is possible in some cases with timely therapeutic intervention.^89,91

Congenital Optic Disc Anomalies

Congenital optic nerve anomalies can appear pseudo-glaucomatous. Congenital anomalies that may mimic glaucomatous disease include megalopapillae, tilted discs and optic pit. Each of these entities has distinguishing characteristics that allow differentiation from glauco-matous nerves.

Megalopapilla is similar to its glaucomatous disc counterpart in that it is defined as having a disc volume greater than 2.5mm² with increased cupping.^98,99 Two variants of megalopapillae exist:⁹⁹

• Type 1, which is bilateral with large round or oval cupping where the rim tissue obeys the ISNT rule but may appear paler than the average healthy nerve.
• Type 2, which is unilateral with a displaced round cup.

What distinguishes megalopapilla from optic discs that incur cupping from glaucomatous optic neuropathy is that megalopapilla discs display a normal visual field (some may exhibit an enlarged blind spot), have a normal rim area, have a normal cup volume and have a normal RNFL, as measured by scanning laser technology.^99,100 It should be noted that skewed findings can result from interpretation of scanning laser topography, as the Moorfields regression analysis on the Heidelberg Retinal Tomograph is calibrated to discs ranging from 1.2mm² to 2.8mm².⁹⁹

Glaucoma traditionally is defined as a progressive optic neuropathy with accompanying characteristic optic nerve and VF changes. It is classically diagnosed by the presence of a progressive optic nerve cupping with concurrent progressive VF loss.

Tilted optic discs, colobomatous discs and discs exhibiting conus from axial myopia can also mimic glaucomatous discs. Scanning laser ophthalmoscopyoptical coherence tomography (OCT) has shown tilted discs to have thicker-than-average temporal nerve fiber layer tissue.^101,102 Interestingly, there is no actual rotation of the disc in tilted disc cases—the name is a misnomer. The tilted nature appears secondary to abnormal scleral canal morphology where there is an absence of fibers inferiorly and an excess of fibers superiorly.¹⁰³

Additionally, due to the optic disc's counterclockwise rotation, the superior nerve fiber layer tissue's peak thickness appears to be dislocated temporally.^101-102 Helpful clues to discriminate myopic conus discs from glaucomatous discs include high myopia and increased axial length (detectable on A-scan echography).¹⁰⁴

Optic disc colobomas also can mimic glaucomatous optic neuropathy. They appear as enlarged, excavated discs with reduced nerve fiber volume in the vertical pole where the coloboma is present.¹⁰⁰ A distinguishing characteristic of disc coloboma that can help differentiate it from a glaucomatous disc is that there may be other colobomas present in the iris or lens. Involvement of neighboring tissues (including the choroid or retina) and the presence of microphthalmia are also indicators of coloboma.¹⁰⁰

Disc cupping with a concomitant presentation of macular retinoschisis or serous macular retinal detachment is inconsistent with glaucomatous disease.¹⁰⁵ Records indicating the presence of this anomaly from birth should provide definitive proof that the unusual appearance is not secondary to glaucomatous processes.

Optic pits are depressions in the optic disc that result from herniation of neuroectoderm tissue during development.¹⁰⁰ They may occur anywhere on the disc but are often observed in the optic disc's temporal quadrant and give the impression of a large disc.¹⁰⁰

Optic pits are associated with variable visual field defects. Associated paracentral arcuate deficits can mimic those seen in glaucoma.¹⁰⁰ Optic pits increase the risk of vision loss from complications, which include macular schisis or serous retinal detachment.^100,106

They can be differentiated from the glaucomatous cupping process by their location, depth, lack of change over time, and associated complications that are inconsistent with glaucomatous disease, such as retinoschisis and serous macular detachment.

It is imperative to note that the presence of an optic disc anomaly does not preclude the development of glaucomatous disease. Reliable and repeatable changes detected in diagnostic testing may indicate the development of an optic neuropathy.

Differentiating non-glaucomatous optic nerve disorders from glaucomatous disease can save significant time and money that would have been spent managing a condition that is neither there nor developing. It can also save many lives. In cases where optic disc changes evolve secondary to non-glaucomatous pro cesses, pathophysiological mechanisms may be budding, producing consequences that are systemic with the potential to impact other organ systems or mortality.

Dr. Hutchinson practices in St. Louis and is an adjunct faculty member at the University of Missouri-St. Louis College of Optometry. Dr. Gurwood is a professor at Salus University in Elkins Park, Pa. Dr. Myers is the senior staff optometrist at the Coatesville VA Medical Center in Pennsylvania.

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