Glaucoma is an overarching term used to describe a group of progressive optic neuropathies associated with acute or chronic destruction of the optic nerve and variable presence of increased intraocular pressure.
This disease entity is characterized by identification of progressive focal rim loss with corresponding visual field loss.
Classification of glaucoma
The two broad categories of primary glaucoma include open-angle glaucoma and angle-closure glaucoma. One systematic review of primary open-angle glaucoma diagnosis found that the risk of glaucoma is highest when clinical exam revealed increased cup-disc ratio, cup-disc ratio asymmetry, disc hemorrhage, or elevated intraocular pressure (IOP).
Risk factors for open-angle glaucoma and angle-closure glaucoma
Critical risk factors for glaucoma include older age, a family history of glaucoma, Black race, use of systemic or topical corticosteroids, and elevated IOP. Glaucoma can result secondarily from inflammation, tumors, corticosteroids, and other medications, as well as ocular conditions such as pigment dispersion syndrome or pseudoexfoliation syndrome.
A key factor in diagnosis of glaucoma is the presence of optic nerve “cupping” (i.e., disproportionately vertical neuroretinal rim loss with backward bowing of the lamina cribrosa) on ophthalmologic examination.1
While the presence of cupping has been tightly linked with the definition of glaucoma, there are non-glaucomatous causes of nerve loss that can have a similar appearance but require unique interventions. Thus, distinguishing between glaucoma and its masqueraders is an important clinical skill for eyecare providers to develop.
Overview of glaucoma masqueraders
Non-glaucomatous cupping
While many optic neuropathies cause pallor more often than cupping, there are some neuropathies that have significant cupping, referred to as non-glaucomatous cupping. The optic disc cupping that occurs in both glaucomatous and non-glaucomatous pathologies appears to be consistent with two principal processes: prelaminar and laminar thinning.
Prelaminar thinning occurs in all forms of retinal ganglion cell axon loss and results in an increased cup-to-disc ratio, although the cupping is typically shallow. Prelaminar thinning is frequently associated with non-specific etiologies that cause loss of retinal ganglion cells, including aging.2
In contrast, laminar thinning follows processes that damage the lamina cribrosa and peripapillary scleral connective tissue, presenting with a deeper form of cupping. Pathologies that contribute to laminar thinning are frequently associated with damage to the connective tissues of the optic nerve head (e.g., inflammation, autoimmunity, or ischemic etiologies). These insults yield heightened susceptibility to intraocular pressure-induced deformation.2
Thus, initial damages associated with inflammatory, ischemic, or genetic etiologies can incite a process that leads to changes in IOP that further damage tissues but are not necessarily glaucomatous. There are numerous diseases that can cause non-glaucomatous cupping, and some have been identified as primarily causing cupping in a pattern similar to glaucoma. Asymmetric, non-glaucomatous cupping has been reported in some cases of optic nerve ischemia,3 trauma,4,5 and inflammation.6
Compressive optic neuropathies
One of the most serious causes of non-glaucomatous cupping is optic nerve or chiasmal compression, particularly from pituitary adenoma or meningioma.5,6 Some authors describe cupping secondary to retinal diseases, including loss of the retinal nerve fiber layer, such as central retinal artery occlusion.5 Etiologies of compressive optic neuropathies, such as aneurysms and craniopharyngiomas, have been observed to demonstrate significantly larger cup-to-disc ratios when compared to control eyes.6
Distinguishing compressive optic neuropathies from glaucoma is largely dependent on the presence of clinical features that are not typical of glaucoma, including reduced visual acuity or color vision, pallor of the neuroretinal rim, or visual field defects that respect the vertical meridian. Glaucoma patients typically have sparing of the papillomacular bundle in the early stages of disease progression, which results in preserved central acuity and color vision.
The presence of papilledema, headache, and other signs of increased intracranial pressure can point to conditions associated with mass compression, such as Foster-Kennedy syndrome (FKS)—which is compression of the ipsilateral optic nerve by an intracranial mass.7 FKS has multiple subtypes but most frequently presents with unilateral visual loss, evidence of unilateral compressive optic atrophy in one eye and papilledema in the contralateral eye.
Neuroimaging may be indicated in patients with clinical presentations atypical of glaucoma, such as visual field defects that do not correspond to nerve changes, disproportionate degrees of visual field loss when compared to the proportion of optic disc cupping, or signs of increased intracranial pressure (headache, nausea, vomiting, etc.).7
One paper reviewed 112 cases of non-glaucomatous neuropathy and found a mean cup-to-disk ratio of 0.35 +/- 0.15 in the affected eye vs. 0.31 +/- 0.14 in the unaffected fellow eyes, p<0.05.3 They concluded that while there was some cupping as compared to the fellow eye, most cases (number not specified) had pallor and a C/D ratio below 0.40.
Specific inclusion and exclusion criteria and variation of disease presentations may have led to other groups detecting contradicting findings, like when another study found an average C/D of 0.60 with compressive optic neuropathy from meningioma and C/D of 0.80 from aneurysm.7
Congenital and hereditary optic neuropathies
Morning glory syndrome is a congenital optic disc pathology characterized by an enlarged disc situated centrally within an excavated area.8 One study on 51 eyes of 44 patients demonstrated mean age of presentation as 8.8 years with most patients presenting with either vision loss, strabismus or leukocoria.9 Optical coherence tomography (OCT) serves as a helpful tool in the evaluation of this optic disc anomaly.9
Other congenital anomalies, such as optic disc pits present as unilateral, solitary, ovoid, gray-white excavations of the optic disc, with the most common manifestations in the inferotemporal quadrant of the nerve head. Optic disc pits may cause arcuate field defects or enlarged blind spots but visual acuity is not typically affected unless there is macular involvement.
Dystrophies such as Leber’s hereditary optic neuropathy or autosomal dominant optic atrophy are more often bilateral with earlier loss of color vision and visual acuity.5,10
Nutritional and toxic optic neuropathies
Nutritional optic neuropathies can be acquired or congenital and most commonly result from a disruption in the metabolism of group B vitamins (B12, B1, and B9) and, in less frequent cases, copper.11
Case reports documenting the effects of vitamin B12 deficiency are abundant. Patients may present with cupping ranging from cup-to-disk (C/D) ratios of 0.6 to 0.8 with temporal pallor (which can be an extremely subtle and subjective finding), as well as cecocentral scotomas.12
Nutritional optic neuropathy typically presents with subacute, bilateral, painless visual loss with central or centrocecal scotoma and preservation of the peripheral field with evidence of optic atrophy in later stages of disease.11
Toxic optic neuropathies may result after the use of medications such as ethambutol or linezolid or ingestion of toxic substances, such as methanol and ethylene glycol. One case report discussed methanol poisoning presenting with asymmetric cupping (0.50 and 0.90, although the discs were both pale.13
The clinical presentations of hereditary, toxic, and nutritional optic neuropathies are often distinguishable from glaucoma due to more frequent associations with loss of central vision, early changes in color vision, and bilateral manifestations that contrast with the typical features of early-stage glaucoma.
Inflammatory and ischemic conditions
Optic neuritis stereotypically results in painful subacute vision loss due to demyelination in the context of conditions, such as multiple sclerosis and neuromyelitis optica spectrum disorders.
A study by Zhang et al. reported four causes in which optic neuritis presented with diffuse optic disc cupping as well as associated disc pallor and excavation.14 In a study by Rebolleda et al. of 50 patients with a single episode of unilateral optic neuritis, OCT measured cup-to-disc ratios that were greater in affected eyes by an average of 0.12 when compared to control eyes.15
Non-glaucomatous cupping has been well-documented in cases of ischemic optic neuropathy with cupping occurring more often and to a greater degree in arteritic anterior ischemic optic neuropathy (AAION) than in non-arteritic ischemic optic neuropathy (NAION).
An observational case series conducted by Danesh-Meyer et al. of 92 eyes with AAION and 113 eyes with NAION and found evidence of optic nerve cupping in 92% of the AAION eyes compared to 2% of the NAION eyes.2 An assessment of cupping by the minimum rim width at Bruch’s membrane opening (MRW-BMO) is a metric that has demonstrated utility for distinguishing glaucoma from non-glaucomatous ischemic optic neuropathies.
Infectious and traumatic optic neuropathies
Syphilis is a more common infectious etiology of non-glaucomatous cupping outside of the Western world and has been documented in various case reports to manifest with symmetric optic nerve cupping, thinning of the retinal nerve fiber layer, and in one reported case, loss of macular thickness.16
Traumatic optic neuropathies have also been reported but are limited to case reports with examination revealing asymmetric cupping, color deficits and nerve pallor dependent on the extent of injury.
Testing sensitivity as a determinant
While cases describing sensitive or specific features for non-glaucomatous cupping are often presented in curated case series, one carefully designed study sought to determine expert detection of the classic signs of glaucomatous versus non-glaucomatous atrophy using stereophotographs.5
Established academic attendings inaccurately ascribed glaucomatous nerve loss to 44% of cases of non-glaucomatous rim loss (compression, dominant hereditary optic atrophy, and retrobulbar neuritis). They concluded that cupping extending to the margin of the disc (present in ¾ of cases) was the most specific sign for glaucoma, while pallor of the neuroretinal rim (present in ⅔ of cases) was most specific for non-glaucomatous neuropathy.
One of the reasons why it is so difficult to distinguish glaucomatous from non-glaucomatous cupping may be due to the severity of the disease. For instance, in a series of Leber's hereditary optic neuropathy, while all nerves were pale, the C/D ratio only ranged from 0.70 to 0.90.10
In a case series of arteritic anterior ischemic optic neuropathy, cupping was present in 92% with an average C/D 0.85, and it becomes increasingly difficult to identify pallor when there is less remaining rim tissue left to evaluate.3
While more modern testing has been suggested to better distinguish glaucoma from non-glaucomatous rim loss, the datasets are still relatively small and highly specific. For instance, one study published in 2022 selected patients with chiasmal compression (cases that had more horizontal nerve loss) to compare to glaucoma using OCT.14
While cases of glaucoma had more thinning of the inferotemporal, superonasal, and inferonasal rim, both groups had similar findings in the superotemporal and nasal rim, thus revealing significant overlap between the two groups. In a series relying on classification based on Heidelberg retinal tomography, 73% of cases of Leber’s were classified as having glaucoma.10
Should I pursue further workup?
Overall, deciding when to pursue further workup to rule out non-glaucomatous cupping remains ambiguous.
One study suggested that the following signs suggest the need for further workup:6
- Age under 50 years
- Pallor worse than cupping
- Vision worse than 20/40
- Visual field loss respecting the vertical midline, each having a specificity between 77 to 93%
Serving as a reminder of the variation of disease presentation, 10% of their glaucoma group had pallor worse than cupping (versus 46% of the nong-laucomatous cupping). The presence of signs that are atypical for early glaucoma, such as afferent pupillary defect, decreased color vision, and visual field loss that does not correspond to the area of rim thinning, is another indication for workup.
While the yield of neuroimaging in detecting alternative explanations of cupping may be low, it may still be useful. In a small series of only 29 patients with normal tension glaucoma, imaging revealed that 7% had central nervous system (CNS) tumors that were deemed not to affect the visual field, so there can be some benefit, even in terms of incidental findings that may require further evaluation.6
Conclusion
There are many etiologies of non-glaucomatous cupping and certainly, some cases of cupping that may be secondary to glaucoma and another etiology. With overlapping findings, the distinctions can not always be definitive.
It is important to evaluate for glaucomatous risk factors such as older age and family history in addition to evaluating the optic nerve color, pupillary response, central vision, and color vision.
Correlating the visual field loss to the nerve fiber layer defect and looking for typical glaucomatous patterns of structural and functional damage can be helpful as well.
