Despite the efforts of modern medicine, glaucoma remains the leading cause of irreversible blindness worldwide.1 Effective measures to control disease through reduction of intraocular pressure (IOP) exist, but early diagnosis and prompt initiation of therapy are paramount to help prevent disease-related vision loss and its associated burdens.
The best clinical approach to early diagnosis of glaucoma is an evolving topic. Technological advances in computerized imaging of the optic nerve, retinal nerve fiber layer, and ganglion cells can now provide enhanced structural detection of early disease. Traditional techniques of optic nerve head (ONH) imaging such as stereophotography also remain relevant and provide complementary information in suspicious optic nerves. Selective functional testing of the visual field can also allow clinicians a method to detect early functional loss prior to that of standard perimetry. In this article, we will review current best practices for early detection of this blinding disease.
Thorough structural assessment of the optic nerve is paramount for the appropriate diagnosis of glaucoma. Because of the redundancy of ganglion cells and the retinal nerve fiber layer (RNFL), optic nerve changes can often be seen well in advance of functional defects. In fact, 20% to 50% of the RNFL may be lost prior to the appearance of visual field defects on standard automated perimetry (SAP).2 Therefore, identification of suspicious structural glaucomatous change is critical to initiating further structural and functional assessments. A number of methods are currently available for optic nerve assessment.
Stereoscopic Optic Disc Photography
Despite recent advancements in computerized optic nerve imaging, clinical optic disc exam and stereo photographs still remain a useful measure for detection of glaucomatous disease. Characteristic findings include diffuse or focal thinning of the neuroretinal rim, especially at the inferior and superior poles, resulting in an increased vertical cup-to-disc ratio. Other suspicious findings include cup–disc asymmetry as well as rim notching, disc hemorrhages, parapapillary atrophy, and RNFL wedge defects, which are more readily visible with red-free photography.3 Negative findings such as lack of pallor or drusen may also be helpful in distinguishing glaucoma from other optic neuropathies. In the Ocular Hypertension Treatment Study (OHTS), 65% of patients who went on to develop glaucoma were diagnosed based on ONH changes.4 While optic disc photography may help identify and document these types of findings, the numerous physiologic variants of optic disc architecture and lack of a standardized control group makes diagnosis based solely on optic nerve examination difficult. Despite this limitation, photos will always remain clinically relevant and allow for comparison with future exams or photos. In contrast, the constant evolution of computerized imaging can make comparisons of tests across major upgrades or between manufacturers difficult at best.
Computer-Based Quantitative Imaging
In addition to clinical examination and photography of the optic nerve, quantitative imaging of the disc, RNFL, and ganglion cell layer can provide additional data to clinicians for early diagnosis. One major advantage of these techniques is the objective quantification of optic disc parameters and RNFL with the ability to compare metrics against normative databases to help distinguish early disease from healthy eyes. Three commonly available types of imaging are scanning laser polarimetry, computerized scanning laser ophthalmoscopy (CSLO), and optical coherence tomography (OCT). While the former 2 were more commonly utilized in the past, major advancements in imaging speed and resolution as well as improved normative databases and versatility have helped propel OCT to the lead in diagnostic glaucoma imaging today.
Commercially available spectral-domain OCT (SD-OCT) instruments can provide clinicians with high-resolution images of optic nerve head parameters, accurately measuring RNFL thickness as well as ganglion cell layer or macular thickness in areas with the highest concentration of ganglion cells.3 Studies have proven the diagnostic accuracy of these SD-OCT parameters in distinguishing suspect eyes from those with well-defined glaucomatous visual field loss.5,6 Even in eyes without visual field defects, SD-OCT parameters are able to reliably identify preperimetric disease.7 The most common pattern of RNFL loss occurs at the inferior/inferotemporal and superior/superotemporal locations of the optic nerve. Macular thickness is also preferentially thinned in glaucomatous eyes at the inferior, inferotemporal, and superotemporal locations compared to healthy eyes. Of the optic disc parameters, global and inferior rim area as well as vertical cup-to-disc ratio are most likely to identify disease.
While all OCT parameters can help detect disease, some metrics have demonstrated improved diagnostic accuracy in early or preperimetric disease. In one study by Lisboa et al, RNFL thickness parameters performed significantly better than ONH and macular thickness measurements at disease identification.7 Average RNFL thickness was found to be the single best parameter for early detection, followed by inferior hemifield and inferior quadrant RNFL thickness. Of the macular parameters studied, the average ganglion cell layer thickness performed the best. More recent studies of macular OCT parameters found the minimum ganglion cell inner plexiform layer thickness to be the most sensitive for glaucoma diagnosis.8 In another study by Sung et al, RNFL thickness was shown to be superior to ONH parameters on OCT at glaucoma discrimination, particularly in those with early disease.6 In separate studies, a faster rate of RNFL loss over time has also been shown to be strongly predictive of future visual field loss.9,10
Recently, OCT angiography (OCTA) has been employed as another aid in early glaucoma diagnosis. Initial studies have found a significant decrease in macular vessel density in early glaucoma compared to healthy eyes with a similar ability to detect disease when compared to ganglion cell complex and RNFL measurements.11,12 Eyes with primary open-angle glaucoma also had significantly faster rates of vascular density loss compared to suspect or healthy eyes.13 Further study of this novel imaging technique is still needed to better define the role of OCTA in the diagnosis of early glaucoma.
Despite the utility of OCT in monitoring for the early onset of disease, the inherent variability of measurements and potential for artifact must always be kept in mind when analyzing test results.14 For most OCT machines, a change of approximately 4-5 microns or more is likely clinically significant.15 Clinicians must ensure scan reliability before interpretation by verification of suitable signal strength as well as absence of artifact from a variety of sources including media opacities, cataracts, high myopia, and scan decentration. The normal age-related RNFL decline of approximately 1 micron per year must also be kept in mind because age is not adjusted for in most normative databases.15 Verification of any significant change or abnormal result with a repeat scan is always prudent to ensuring an accurate diagnosis.
Standard automated perimetry (SAP) using a white-on-white stimulus remains the gold standard for the diagnosis and management of glaucoma today.3 Careful analysis of visual fields for early nasal step and arcuate depressions can help confirm an early diagnosis of disease in patients with corresponding optic nerve or RNFL defects. In patients with focal notching of the ONH rim or suspicion of paracentral field loss such as in normal tension glaucoma, changing from a 24-2 to 10-2 testing strategy can help reveal focal central defects that may be missed on the mere 12 points tested in the central 10 degrees using a 24-2 test pattern. In a study by DeMoraes et al, 10-2 testing revealed abnormalities in 35% of glaucoma suspects and 40% of ocular hypertensive patients who had normal 24-2 examinations.16 Increasing test frequency early in the evaluation of glaucoma suspects may also be helpful in quickly moving patients through the learning curve and establishing a baseline to detect early defects sooner. Before starting treatment based on VF changes, a repeat examination should always be performed for confirmation.
While structural and functional testing are critical to detection of early glaucoma, clinicians must always interpret results in the context of patients’ risk factors. Increased age and a family history of glaucoma in a first-degree relative are 2 important risk factors to be assessed. Race or ethnicity should also be considered because disease prevalence is 3 times to 5 times higher in African Americans and Hispanics compared to non-Hispanic whites.17,18 Elevated IOP alone lacks specificity and sensitivity for diagnosis, yet a thorough assessment of IOP in combination with other metrics such as corneal pachymetry are a vital part of the diagnostic workup. Lower central corneal thickness has been shown to be an independent risk factor in addition to the fact that applanation tonometry readings may be artifactually lower in eyes with thinner corneas.19 Corneal hysteresis (CH) has also been shown to be a similar but unique assessment of corneal biomechanics that can also predict risk for glaucoma. In a recent study by Susanna et al, lower baseline CH measurements were significantly associated with the development of VF defects over time.20 Finally, a careful slit lamp examination is foundational in the assessment of patients and should include careful gonioscopy and surveillance for secondary causes of glaucoma.
Diagnosis in the Future
Missing from our current preferred practice patterns for the diagnosis and management of glaucoma is a direct measure of ganglion cell death, the key pathological process of this disease. However, this may change in future with the recent development of techniques to image apoptosis, or programmed cell death. Detection of apoptosing retina cells, also known as DARC imaging, utilizes a fluorescently labeled annexin V to visualize individual retinal cells undergoing apoptosis in a minimally invasive manner.21,22 The technique is currently being utilized in clinical trials to assess the neuroprotective abilities of therapies but may someday allow even earlier detection of glaucoma in suspect patients. From a much broader point of view, magnetic resonance neuroimaging methods may also detect structural, functional, and metabolic changes within the visual pathway as well as other parts of the brain in patients with glaucoma.23 With further study, these objective measures may help distinguish suspicious yet healthy eyes from eyes with early disease in the future.
In the end, the best approach to early diagnosis is likely a combination of novel and traditional techniques in patients at highest risk for glaucoma. Clinicians should utilize all available data on structure and function within the context of a patient’s age, vision, risk factors, and other clinical exam findings to appropriately detect disease and initiate timely treatment. GP
- Tham YC, Li X, Wong TY, Quigley HA, Aung T, Cheng CY. Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis. Ophthalmology. 2014;121(11):2081-2090.
- Harwerth RS, Quigley HA. Visual field defects and retinal ganglion cell losses in patients with glaucoma. Arch Ophthalmol. 2006;124(6):853-859.
- Prum BE Jr., Lim MC, Mansberger SL, et al. Primary open-angle glaucoma suspect preferred practice pattern guidelines. Ophthalmology. 2016;123(1):P112-P151.
- Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120(6):701-713.
- Mwanza JC, Oakley JD, Budenz DL, Anderson DR; Cirrus Optical Coherence Tomography Normative Database Study. Ability of cirrus HD-OCT optic nerve head parameters to discriminate normal from glaucomatous eyes. Ophthalmology. 2011;118(2):241-248.
- Sung KR, Na JH, Lee Y. Glaucoma diagnostic capabilities of optic nerve head parameters as determined by Cirrus HD optical coherence tomography. J Glaucoma. 2012;21(7):498-504.
- Lisboa R, Paranhos A Jr., Weinreb RN, Zangwill LM, Leite MT, Medeiros FA. Comparison of different spectral domain OCT scanning protocols for diagnosing preperimetric glaucoma. Invest Ophthalmol Vis Sci. 2013;54(5):3417-3425.
- Jeoung JW, Choi YJ, Park KH, Kim DM. Macular ganglion cell imaging study: glaucoma diagnostic accuracy of spectral-domain optical coherence tomography. Invest Ophthalmol Vis Sci. 2013;54(7):4422-4429.
- Yu M, Lin C, Weinreb RN, Lai G, Chiu V, Leung CK. Risk of visual field progression in glaucoma patients with progressive retinal nerve fiber layer thinning: a 5-year prospective study. Ophthalmology. 2016;123(6):1201-1210.
- Miki A, Medeiros FA, Weinreb RN, et al. Rates of retinal nerve fiber layer thinning in glaucoma suspect eyes. Ophthalmology. 2014;121(7):1350-1358.
- Hou H, Moghimi S, Zangwill LM, et al. Macula vessel density and thickness in early primary open angle glaucoma. Am J Ophthalmol. 2018. [Epub ahead of print]
- Chen HS, Liu CH, Wu WC, Tseng HJ, Lee YS. Optical coherence tomography angiography of the superficial microvasculature in the macular and peripapillary areas in glaucomatous and healthy eyes. Invest Ophthalmol Vis Sci. 2017;58(9):3637-3645.
- Shoji T, Zangwill LM, Akagi T, et al. Progressive macula vessel density loss in primary open-angle glaucoma: a longitudinal study. Am J Ophthalmol. 2017;182:107-117.
- Seibold LK, Mandava N, Kahook MY. Comparison of retinal nerve fiber layer thickness in normal eyes using time-domain and spectral-domain optical coherence tomography. Am J Ophthalmol. 2010;150(6):807-814.
- Tatham AJ, Medeiros FA. Detecting structural progression in glaucoma with optical coherence tomography. Ophthalmology. 2017;124(12S):S57-S65.
- De Moraes CG, Hood DC, Thenappan A, et al. 24-2 visual fields miss central defects shown on 10-2 tests in glaucoma suspects, ocular hypertensives, and early glaucoma. Ophthalmology. 2017;124(10):1449-1456.
- Varma R, Ying-Lai M, Francis BA, et al. Prevalence of open-angle glaucoma and ocular hypertension in Latinos: the Los Angeles Latino Eye Study. Ophthalmology. 2004;111(8):1439-1448.
- Tielsch JM, Sommer A, Katz J, Royall RM, Quigley HA, Javitt J. Racial variations in the prevalence of primary open-angle glaucoma. The Baltimore Eye Survey. JAMA. 1991;266(3):369-374.
- Gordon MO, Beiser JA, Brandt JD, et al. The Ocular Hypertension Treatment Study: baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120(6):714-720.
- Susanna CN, Diniz-Filho A, Daga FB, et al. A prospective longitudinal study to investigate corneal hysteresis as a risk factor for predicting development of glaucoma. Am J Ophthalmol. 2018;187:148-152.
- Cordeiro MF, Normando EM, Cardoso MJ, et al. Real-time imaging of single neuronal cell apoptosis in patients with glaucoma. Brain. 2017;140(6):1757-1767.
- Cordeiro MF, Migdal C, Bloom P, Fitzke FW, Moss SE. Imaging apoptosis in the eye. Eye (Lond). 2011;25(5):545-553.
- Nuzzi R, Dallorto L, Rolle T. Changes of visual pathway and brain connectivity in glaucoma: a systematic review. Front Neurosci. 2018;12:363.