As eye care providers, we seek to rule out ocular pathology, some of which can present in patients who completely lack any visual symptoms. These cases can be the most challenging from a clinical perspective because we are analyzing our clinical findings in the absence of visual complaints from the patient. When these findings relate to the optic nerve, even the experienced OD will want to pause to rule out sight and life-threatening conditions. Sometimes this can be a difficult and daunting task, as numerous types of optic nerve pathologies can present with a similar clinical appearance. This article will guide the differential diagnosis in non-glaucomatous optic neuropathy.

When patients present with unexplained optic atrophy, it is our responsibility to provide an explanation and if necessary, conduct a further investigation to determine the etiology. Patients may report having had a “stroke in the eye” (e.g. NAION or artery occlusion) or longstanding decreased vision from a past ocular injury or trauma (e.g. car accident or domestic violence). In these cases, the patient’s case history can serve as an excellent tool for determining the reason for the optic atrophy. Other times patients may present with 20/20 vision and are not aware of any optic nerve pathology, or maybe were told at their last eye exam that they were a suspect for glaucoma or even that nothing was wrong with their eyes. Unexplained optic atrophy is simply a finding, not a diagnosis, and in most cases will warrant a slightly different medical workup and investigation. Since the etiology of optic nerve pallor can range from benign to brain tumor, the stakes are potentially high when evaluating these patients. In cases where we’re unable to explain the presence of optic atrophy based on the patient’s history and exam findings, neuroimaging is often our next best step(1).

Degeneration of the axons within the optic nerve leads to optic atrophy, detected clinically by the presence of pallor of the neuroretinal rim. Optic atrophy leads to the recession and loss of the micro-capillary networks that supply the optic nerve. In certain cases, the optic nerve transitions from being normal and healthy with a pink hue to having a slightly yellow or pale appearance. This scenario is referred to as primary optic atrophy. The optic nerve can also appear pale and atrophic secondary to a prior history of disc edema (secondary optic atrophy). Unilateral optic nerve pallor results from pathology anterior to the optic chiasm (e.g. optic nerve glioma), while pathology affecting the optic chiasm or posteriorly along the optic tract can produce bilateral optic nerve pallor. Lesions located in the suprasellar region (e.g. pituitary adenoma) can produce optic disc pallor at the nasal and temporal disc margins and is referred to as “band or bowtie” atrophy.

Optic atrophy can be challenging to distinguish, especially when assessing the fundus through media opacities like a dense cataract or asteroid hyalosis. Many conditions can lead to a false appearance of nerve pallor or pseudopallor. After cataract surgery, an alteration in light filtration between the natural lens and the new lens implant occurs and can cause the temporal rim to appear lighter than the rest of the disc, known as pseudophakic pseudopallor. Many other physiological findings can also create the illusion of rim pallor or cupping, including highly myopic or tilted discs, scleral crescents, optic pits, peripapillary atrophy, large discs, and myelinated nerve fibers. To help to confirm ocular findings, it is sometimes helpful to review previous optometry/ophthalmology exam notes as well. These can help guide our diagnosis, however, we still need a system for reaching a clinical diagnosis when prior notes are not enough.

Table 1. Primary optic atrophy vs. secondary optic atrophy

Primary optic atrophy Secondary optic atrophy

(Prior history of optic disc edema)

Central/branch retinal artery occlusion Arteritic anterior ischemic optic neuropathy (giant cell arteritis)
Excessive pan-retinal photocoagulation Non- arteritic anterior ischemic optic neuropathy
Hereditary (Leber’s Optic Neuropathy, Dominant Optic Atrophy) Central retinal vein occlusion
Trauma Optic neuritis
Toxic/nutritional deficiency (e.g. chronic alcoholism, malnutrition)  

Papilledema

END-stage open angle glaucoma Hypotony
Compressive lesion to optic nerve/chiasm/tract (e.g. tumor/aneurysm) Graves’ disease
Congenital (e.g. Optic nerve hypoplasia)

 

What is glaucomatous optic neuropathy?

If we’re going to rule out the presence of non-glaucomatous optic neuropathy, first we need to know what glaucomatous optic neuropathy looks like. Classic glaucomatous optic neuropathy presents with vertical notching of the neuroretinal rim, absence of rim pallor, wedge defects of the peripapillary nerve fibers, and horizontally aligned visual field defects in patients typically older than 50 years of age. Visual acuity is usually preserved until late in the disease process, so expect vision better than 20/40. These patients tend to have elevated or asymmetric intraocular pressure, and/or systemic comorbidities that compromise ocular perfusion (e.g. diabetes, hypertension, or sleep apnea).

Fig. 1. Primary open angle glaucoma in a 61-year-old male. Optic disc hemorrhage, peripapillary atrophy, RNFL wedge defects (shown superior temporal above), disc cupping and horizontally aligned VF defects are almost always pathognomonic for glaucoma.

 

Fig. 2. Primary open angle glaucoma, found in a 54-year-old male presenting for first eye exam. Visual field defects from glaucoma will always respect the horizontal meridian and are predictable based on optic nerve appearance.

 

Fig. 3. Normal tension glaucoma can also present with optic disc hemorrhage and centrocecal scotomas that respect the horizontal meridian. Some cases of compressive optic neuropathy or giant cell arteritis have also been shown to cause glaucomatous-like cupping. (6-8)

Non-glaucomatous optic neuropathies

When we’re unable to explain unilateral or bilateral optic nerve pallor, especially in younger patients (<50 years old), it is imperative that we rule out the presence of an intracranial mass lesion. Clinical findings that should raise suspicion include reduced visual acuity, afferent pupillary defect, and vertically aligned VF defects. The preferred imaging modality for these patients is a magnetic resonance image (MRI) of the brain and orbits (with and without contrast, with fat suppression). In cases where MRI is contraindicated (e.g. pacemaker, cochlear implant, vascular clips, retained metallic foreign body, prosthetic devices), a computed tomography scan of the brain and orbits is the next best approach.

Compressive optic neuropathy can be caused by a wide array of conditions, including thyroid eye disease, orbital/intracranial tumors, aneurysms, and orbital inflammation or infection. The literature varies as to what percentage of non-glaucomatous optic atrophy is attributed to compressive etiology, with ranges anywhere from 5%(3), 20%(4) to over 50%(5) of cases. One study showed that over 50% of non-glaucomatous optic neuropathy was caused by pathology of the pituitary gland (2), with classic bitemporal or junctional scotoma visual field patterns. Approximately 1/3 of tumors to the optic nerve are from optic nerve sheath meningiomas (ONM). ONM are the 2nd most common tumor to the optic nerve, after optic nerve gliomas.(11)

Fig. 4. Non-glaucomatous optic neuropathy in a 53-year-old male with bilateral optic disc pallor and “bowtie atrophy” seen on OCT. This case was due to chiasmal compression from a pituitary adenoma. Visual field defects (this patient’s shown below) from non-glaucomatous optic neuropathy will typically respect the vertical meridian, unlike primary open-angle glaucoma.

 

Fig. 5. Younger age (typically <50 years old), vertically aligned VF defect and optic atrophy are more indicative of a compressive lesion.

A detailed case history can help avoid unnecessary work up in some patients. A positive history for orbital/facial trauma can help explain non-glaucomatous optic neuropathy in some patients. As clinicians, we should not feel uncomfortable asking somewhat personal questions as a means to rule out sight and life-threatening pathology. It is important to remember that an intracranial mass lesion or history of blunt trauma can have similar clinical presentations and to convey this to the patient in our discussion with them.

Fig. 6. Traumatic optic neuropathy OS in an asymptomatic 47-year-old female that reported a history of domestic violence and injury to OS. Notice diffuse temporal pallor and nerve fiber loss superiorly OS. Viewing optic nerve photos side by side can be a useful way to assess suspected unilateral optic disc pallor.

 

Fig. 7. Red-free fundus photos can be useful in viewing RNFL dropout seen here superiorly. When assessing the rim tissue and associated nerve fiber layer, utilizing the red-free (green) filter on the slit lamp can help us better distinguish any abnormalities. This technique is also helpful for assessing flat/shallow cups that tend to be misleading.

Fig. 8. Secondary optic atrophy occurs when the optic nerve is first swollen. Shown here, a case of optic neuritis in a 42-year-old male demonstrating the progression of secondary optic atrophy from a swollen, edematous nerve in 2017 to having a pale, atrophic appearance in 2018.

Inherited optic neuropathy

When confronted with bilateral optic nerve pallor in a younger patient, we should consider the group of inherited optic neuropathies in our differential diagnosis, primarily Dominant Optic Atrophy (DOA) and Leber’s Hereditary Optic Neuropathy (LHON). Both of these conditions are attributed to a genetic mutation of the mitochondrial DNA. Inherited optic neuropathy typically presents in males within the first or second decade of life, causing optic atrophy and insidious loss in vision. DOA is a rare condition, with a prevalence of 1/100,000 in most populations(12), while LHON is slightly more common with a prevalence of 1/25,000. (13)

Patients with inherited optic neuropathy typically present with bilateral atrophy of the temporal neuroretinal rim, cecocentral/paracentral scotoma on visual field, blue/yellow color vision deficiency and rarely with blue-dot cerulean cataracts. DOA and LHON are both genetic disorders affecting mitochondrial function. Due to the high concentration of mitochondria within the retina, these conditions primarily cause damage to the retinal ganglion cells and their axons. These patients can also present with extra-ocular signs including hearing impairment/deafness, myopathy, cardiac arrhythmia, and peripheral neuropathy.(12,13) Numerous other genetic disorders also exist that can lead to optic atrophy, including Wolfram syndrome and Costeff syndrome. (12)

Treatment options for inherited optic neuropathy include genetic counseling, low vision evaluation, avoidance of alcohol/tobacco and medications that interfere with mitochondrial function (e.g. antivirals, antibiotics, statins). Various genetic and pharmacological interventions are currently being researched.

A systematic approach to unexplained optic nerve pallor

1) Establish a thorough case history and timeline for loss of vision (acute vs. chronic). While not always reliable, the patient’s age, systemic risk factors, and sequence of events can often help steer our clinical judgment and determine the differential diagnosis. Does the patient’s medical history suggest possible etiology? (e.g.history of optic neuritis/MS, NAION, drug/alcohol toxicity, pituitary pathology, papilledema, trauma, or high-risk medication?)

It is important to ask ourselves “was this nerve ever swollen or edematous at some point in the past?” Are there any concomitant neurological symptoms occurring (e.g. new headaches, numbness/tingling of extremities, slurred speech, or dizziness). Requesting/reviewing prior eye exam records can also be useful in establishing a timeline of vision loss.

2) Conduct a thorough, dilated eye exam. Be sure to perform visual field testing, as the pattern can help refine the differential diagnosis. Does the field respect vertical vs. horizontal meridians? Do both eyes have visual field defects, or is only one eye abnormal? Does the pattern localize anywhere specific? If possible, OCT scans can be helpful as well to confirm neuroretinal rim loss or ganglion cell thinning. 

3) If you are still unable to explain optic nerve pallor, proceed with ordering cranial/orbital neuroimaging to rule out compressive etiology. MRI of orbits/brain with and without contrast, with fat suppression or CT scan if MRI is contraindicated.

4) Consider further serologic testing only as necessary per your history/examination. Unless the patient is at high risk for disease, general screening evaluations are typically not recommended1. (e.g. if syphilis, sarcoid or lyme are highly prevalent with a particular demographic)

5) Repeat the visual field to establish stability of vision loss over time.

6) In children and young adults with unexplained, bilateral optic atrophy, consider referring for molecular genetic testing, visual evoked potentials, or pattern ERG testing, to rule out variants of Dominant Optic Atrophy or Leber’s Hereditary Optic Neuropathy.

7) If you still come up short in explaining the patient’s optic atrophy, collaborating/co-managing with a primary care physician, neurologist and/or neuro-ophthalmologist is a great next step. This is especially true with cases that appear progressive and/or non-isolated.

Table 2. How to differentiate true glaucoma (POAG) vs. non-glaucomatous optic neuropathy

Glaucoma (primary open-angle) Non-glaucomatous optic neuropathy
Older age (>50 y/o) Younger age (<50 y/o)
Visual acuity typically preserved

(better than 20/40)

Decreased visual acuity (worse than 20/40)
Gradual/painless loss of vision Variable – Can be sudden vs. gradual (+/- pain)
VF defects respect horizontal meridian2

Central fixation typically spared until late stage

(Normal tension glaucoma can have paracentral VF defect)

Variable VF findings

Central vs. peripheral defect

More likely to respect vertical meridian2

(some fields may also respect horizontal meridian, i.e., optic neuritis, trauma, or NAION)

Optic nerve appearance correlates well with VF defect

(VF can be BETTER than optic nerve appearance but never worse)

Poor correlation between VF and optic nerve.

 

Elevated IOP Normal IOP
Increased cupping/excavation

C/d Asymmetry between eyes

Vertical elongation of cup

(+) disc hemorrhage

Increased cupping/excavation6-8

C/D Asymmetry between eyes

(-) disc hemorrhage unless concomitant disc edema

(+) Collateral vessels

Rim tissue pink/healthy

Focal notching/rim erosion (very useful if present)

Rim tissue pale/atrophic (diffuse vs. segmental)

 

Superior/Inferior RNFL thinning on OCT Temporal/Nasal RNFL thinning on OCT more common9,10

 

Given the variable nature of vision loss from non-glaucomatous optic neuropathy, the history may not be the most reliable, and the clinician may need to rely more on objective exam findings to help steer the diagnosis.

Patients with non-glaucomatous optic neuropathy can still have 20/20 visual acuity, as long as the papillomacular bundle nerve fibers are still intact. Always perform visual field testing on these patients to refine the differential diagnosis. We know that the magnitude of vision loss is best determined with the assessment of peripheral vision vs. visual acuity alone. (5)

Obtaining optical coherence tomography can also be useful in detecting non-glaucomatous optic neuropathy. Patients with non-glaucomatous optic neuropathy tend to have RNFL thinning more nasal and temporally, (9,10) while primary open-angle glaucoma will classically show vertical quadrant thinning superiorly and inferiorly.

Optic nerve pallor is simply a clinical finding and not a diagnosis. Atrophy of the optic nerve can present a challenge for both new and seasoned optometrists alike. If we are unable to definitively determine the reason for our patient’s atrophic optic nerve(s), it is imperative that we refer our patient to another medical professional whom we can further collaborate with.

Next time you are confronted with optic atrophy, don’t lose your cool. You are equipped with a strong skill set and knowledge base. It’s just a matter of opening up the clinical toolbox and taking a thorough, comprehensive approach in providing a diagnosis and explanation that makes sense for your patient.


References

1.  Lee, AG, et al. “The Diagnostic Yield of the Evaluation for Isolated Unexplained Optic Atrophy.” Ophthalmology., U.S. National Library of Medicine, May 2005, www.ncbi.nlm.nih.gov/pubmed/158780532.

2.  Greenfield, David S, and et al. “The Cupped Disc: Who Needs Neuroimaging?” Ophthalmology, Elsevier, 25 Aug. 2003, www.sciencedirect.com/science/article/pii/S0161642098910314?via%

3.  Osaguona, Vivian B., and Valentina W. Okeigbemen. “Nonglaucomatous Optic Atrophy in Benin City.” Annals of African Medicine, 19 Feb. 2015, www.annalsafrmed.org/article.asp?issn=1596-3519;year=2015;volume=14;issue=2;spage=109;epage=113;aulast=Osaguona

4.  Mbekeani, Joyce N., et al. “Etiology of Optic Atrophy: a Prospective Observational Study from Saudi Arabia.” Annals of Saudi Medicine, Jan. 2017, www.annsaudimed.net/index.php/vol37/vol37iss3/4447.html

5.  DeWitt, C A, et al. “Visual Function in Patients with Optic Nerve Pallor (Optic Atrophy).” Journal of the National Medical Association., U.S. National Library of Medicine, May 2003, www.ncbi.nlm.nih.gov/pubmed/12793796

6.  Bianchi-Marzoli, Stefania, et al. “Quantitative Analysis of Optic Disc Cupping in Compressive Optic Neuropathy.” Ophthalmology, Elsevier, 27 Sept. 2013, www.sciencedirect.com/science/article/pii/S0161642095310032?via%3Dihub

7.  Sebag, J, et al. “Optic Disc Cupping in Arteritic Anterior Ischemic Optic Neuropathy Resembles Glaucomatous Cupping.” Ophthalmology., U.S. National Library of Medicine, Mar. 1986, www.ncbi.nlm.nih.gov/pubmed/3703503

8.  Danesh-Meyer, H V, et al. “The Prevalence of Cupping in End-Stage Arteritic and Nonarteritic Anterior Ischemic Optic Neuropathy.” Ophthalmology., U.S. National Library of Medicine, Mar. 2001, www.ncbi.nlm.nih.gov/pubmed/11237915

9.  Gupta, PK, et al. “Differentiating Glaucomatous from Non-Glaucomatous Optic Nerve Cupping by Optical Coherence Tomography.” National Center for Biotechnology Information, U.S. National Library of Medicine, 26 Jan. 2011, www.ncbi.nlm.nih.gov/pubmed/?term=differentiating%2Bglaucomatous%2Bfrom%2Bnon-glaucomatous%2Boptic%2Bnerve%2Bcupping

10.  Danesh-Meyer, H V, et al. “Differentiation of Compressive from Glaucomatous Optic Neuropathy with Spectral-Domain Optical Coherence Tomography.” Ophthalmology., U.S. National Library of Medicine, Aug. 2014, www.ncbi.nlm.nih.gov/pubmed/24725827

11. Shapey, J. et al.Diagnosis, and management of optic nerve sheath meningiomas Journal of Clinical Neuroscience, Volume 20, Issue 8, 1045 – 1056

12. Lenaers, G., Hamel, C., Delettre, C., Amati-Bonneau, P., Procaccio, V., Bonneau, D. Milea, D. (2012). Dominant optic atrophy. Orphanet Journal of Rare Diseases, 7, 46. http://doi.org/10.1186/1750-1172-7-46

13. Piotrowska, A, et al. “Leber Hereditary Optic Neuropathy – Historical Report in Comparison with the Current Knowledge.” Gene, Elsevier, 26 Sept. 2014, www.sciencedirect.com/science/article/pii/S0378111914011020?via%3Dihub