Glaucoma

The Role of OCT When the Diagnosis of Glaucoma Is Uncertain Ocular imaging should be complementary and additive to the entire clinical evaluation. By Leon Nehmad, OD, MSW

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laucoma is a progressive optic neuropathy resulting in characteristic damage to the optic nerve and defects in the visual field.1 Because it can lead to irreversible vision loss, timely identification of glaucoma is crucial. Yet diagnosis is often uncertain. Early changes are apt to be subtle, and structural and functional defects commonly do not appear simultaneously.2,3 Neural damage often manifests before statistically significant visual field changes,4 so the ability to reliably detect it is crucial. Commonly cited characteristics of glaucomatous neuropathy include an increase in the cup-to-disc ratio, verticalization of the cup, notching of the neuroretinal rim, nerve fiber layer defects, vessel changes within the optic nerve head, and disc hemorrhage.5-7 There is often significant disagreement in assessing the optic nerve, even among experienced clinicians.8,9 A nerve with a large cup may be normal, while one with a small cup may be glaucomatous. A number of conditions including high myopia, tilted discs, or optic pits also affect the optic nerve, making it more difficult to identify glaucomatous optic neuropathy in their presence. REEVALUATING THE GOLD STANDARD The gold standard for assessing the optic nerve head for glaucomatous changes has traditionally been stereo disc photography.10 Photographic interpretation, however, is both qualitative and subjective. In recent years, imaging devices such as spectral-domain optical coherence tomography (OCT) have become more commonplace in the diagnosis and management of the disease.11 Guidelines from the American Optometric Association Clinical Practice Guidelines,12

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Figure 1. Optic nerve photographs (OD [A], OS [B]) and OCT of a patient (C) with asymmetric cup-to-disc ratios.

Glaucoma

Figure 2. OCT (A) and visual field (B) of a patient with glaucoma. The OCT map shows analysis of the optic nerve head, retinal nerve fiber layer, and ganglion cell complex.

right (2.55 mm²). It also confirmed that the rim area was exactly the same in each eye (1.41 mm²). The nerve fiber measurements were normal in all areas. On the basis of the findings, the differences in cupto-disc ratios were considered physiological, and the patient was monitored without treatment. It should be noted that although the disc size measurement does not require the use of OCT, its use enhances the precision and reliability. Recent research has advanced the role of OCT in the diagnosis of glaucoma by providing a more objective and accurate measurement of the optic nerve head. Chauhan and Burgoyne15 have identified the termination of Bruch membrane—the opening where axons pass in order to exit the eye—as marking the outer border of the neuroretinal rim. The Bruch membrane varies depending upon the clock hour of the disc. It is not always clinically visible, but it is consistently visible with OCT. Furthermore, Chauhan and Burgoyne and others have pointed out that the current method of acquiring and analyzing OCT scans based on the horizontal and vertical image axes generates inaccurate data. Nerve fibers connect to a foveal area whose location with respect to the disc is not located along a fixed horizontal and vertical axis, but variable depending upon the eye and individual. The authors call for a paradigm change; among other recommendations, they suggest evaluating the optic nerve head not by the cup-to-disc ratio but rather by rim width clock hours as defined by the Bruch membrane-foveal axis.9 They do not suggest that this should replace clinical observation but that it be integrated into the clinician’s optic nerve head evaluation to enhance detection of the disease.

American Academy of Ophthalmology Preferred Practice Patterns13 and World Glaucoma Association Consensus Statements14 all advocate the benefits of imaging as part of optic disc and retinal nerve fiber layer (RNFL) evaluation. OCT technology has advanced the ability to detect glaucoma, yet like any other instrument, it may mislead the clinician if it is not used judiciously. Figure 1A and B show the optic disc photos of a 40-year-old black woman who was referred for a glaucoma evaluation based on asymmetric cup-to disc ratios, left eye greater than right. Intraocular pressure was in the mid-teens, and there were no other reported risk factors. An OCT was performed (Figure 1C). The results confirmed the asymmetric cup-to-disc ratio, but also showed that the optic disc area was greater in the left eye (3.06 mm²) than the

ADDITIONAL MARKERS OF GLAUCOMATOUS DISEASE OCT has been integral in clinicians’ assessment of the optic disc and for revealing deeper structures that cannot be evaluated in the clinical examination, such as the lamina cribrosa. Recent evidence supports the notion that initial glaucomatous damage occurs at the lamina.16 Early changes show posterior deformation and thickening of laminar tissue, which deeper OCT imaging can now detect. If these changes can be identified early in the disease process, treatment interventions can be made to prevent disease progression. Although traditional imaging in glaucoma has emphasized measurement of the circumpapillary RNFL (cpRNFL), more recent innovations in OCT have expanded to include macular imaging.17 The fact

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March 2014  Advanced ocular care  37

Glaucoma

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Figure 3. OCT (A) and fundus photographs (B) of a patient with hypoplastic optic discs.

that approximately 50% of ganglion cells are located in the macular region18 underscores the importance of this addition. Scans now image the inner macular layers including the ganglion cell nuclei, inner plexiform layer, and RNFL. These are sometimes referred to as the ganglion cell complex (GCC). Using segmentation for a measurement referred to as the ganglion cell analysis, the RNFL portions can be removed to evaluate another part of the retina that can be difficult to assess via ophthalmoscopy. A number of recently published studies have supported the usefulness of including macular ganglion cell imaging as a supplement to traditional measurement of the cpRNFL.19-21 These have included findings that the GCC can be abnormal in preperimetric glaucoma. Some studies have shown its increased repeatability as compared to cpRNFL.22 This may be attrib38  Advanced ocular care  March 2014

“[Ganglion cell complex] abnormalities corresponding to defects found on a 10-2 visual field test support the notion that functional loss, like structural, is diffuse even early in the disease, and not limited to selective parts, such as the nasal-step region.” uted to the fact that cpRNFL measurements are more likely to be affected by individual variation in disc size and shape as well as in the peripapillary region. Other studies have shown that the GCC is comparable to the cpRNFL in detecting early glaucoma.23 In a recent study evaluating macular ganglion cell measurements using OCT units from two manufacturers, it was found that both showed similar diagnostic capability and that macular ganglion cell measurements were diagnostically comparable to those of the cpRNFL from each instrument.24 VISUAL FIELD DATA: COMPLEMENTARY INFORMATION Figure 2A shows the OCT of a 46-year-old woman with glaucoma. In the right eye, the average RNFL parameters in the upper right part of the printout are normal; the inferotemporal cpRNFL area, however, is abnormal. In the left eye, the average RNFL parameters are either normal or borderline, and both the superotemporal and inferotemporal cpRNFL are abnormal. In contrast, the GCC map is markedly abnormal in both eyes. The patient’s visual field (Figure 2B), consisting of a shallow nasal step in the right eye and a deep superior and inferior arcuate defect in the left, illustrates that this is a case in which the GCC map is more reflective of the visual field than the RNFL. The advanced capacity to image macular structure has afforded a better ability to correlate it with the central visual field. It has been shown that macular OCT measurements are able to identify visual field defects on a central 10-2 field that can be missed on the standard 24-2 pattern.25 Clinically, the central part of the visual field has not been considered to be significantly affected in early glaucoma; however, GCC abnormalities corresponding to defects found on a 10-2 visual field test support the notion that functional loss, like structural, is diffuse even early in

“Unlike other medical conditions that are defined by quantitative results, there is no fixed reference standard for what constitutes glaucoma.” the disease, and not limited to selective parts, such as the nasal-step region. In another association with perimetry, OCT data have recently been combined with that from visual fields to improve the detection and degree of damage in glaucoma. Medeiros and colleagues26 have developed a structure-function index by combining OCT and standard automated perimetry. The index is calculated from estimating the number of ganglion cells in patients based on OCT and standard automated perimetry findings. They found that the index performed better than structure or function alone in the detection of glaucoma and differentiating among different stages of disease severity. OCT IS NOT A STANDALONE TEST Despite advances in OCT imaging, the detection of glaucoma may be confounded by its misinterpretation. The term “red disease” has been used to describe false-positive results from printouts. Chong and others have identified several factors that may confound the diagnosis, including unrepresentative normative databases, poor-quality images, scan errors, segmentation errors, blink artifacts, myopia, and masquerading conditions.27-30 The term “green disease,”31 has also been used to identify false-negatives, where focal abnormal areas have been averaged out by measurements from surrounding normal tissues. This is illustrated in Figure 2A. The inferior average RNFL parameter is marked green in the right eye despite the abnormality shown by the red mark in the inferior temporal peripapillary area and temporal superior nasal inferior temporal graph. In a recent review article, Bussel and colleagues32 concluded that assessing cpRNFL on OCT is the strongest predictor of glaucoma, although optic disc and macular evaluations show promising results. They reported that the instrument’s diagnostic power is stronger in distinguishing normal individuals from more advanced glaucoma patients than between normal individuals and less advanced glaucoma patients. This underscores an important clinical point regarding the OCT: it should not be thought

OPTOMETRY’S DISEASE MANAGEMENT AUTHORITY

Glaucoma

of as a monolithic test that has the same diagnostic value for all patients. Its clinical usefulness will depend upon the type of scan, particular data that are being evaluated, image acquisition, and disease stage of the patient. Figure 3A shows the OCT of a 68-year-old woman who was followed as a glaucoma suspect due to having maximum intraocular pressures in the low 20s mm Hg. The RNFL thickness map, thickness deviation, and temporal superior nasal inferior temporal curve show RNFL thinning superiorly greater than inferiorly in both eyes. The visual field (not shown) revealed mild superior arcuate defects in both eyes, which were stable for years without treatment. A close look at the optic nerve photographs (Figure 3B) shows tilted, hypoplastic discs with peripapillary atrophy and absence of characteristic glaucomatous cupping. The assessment was that the abnormal OCT and visual field defects were due to the hypoplastic discs rather than glaucoma. In this case, the OCT alone cannot distinguish between abnormalities due to glaucoma and anomalous discs; it can only show that the RNFL or disc is abnormal. CONCLUSION OCT has played an expanding and valuable role in glaucoma detection, and it adds to the diagnostic power in cases where the diagnosis is uncertain. It provides additional information that identifies and quantifies anatomical structures that cannot be detected during the clinical examination. By incorporating measurements into structure-function algorithms, it may be used to further enhance detection as well as more accurately assess the state of the disease. OCT has the potential to offer further benefit to the less trained practitioner who may not be as proficient in the area of glaucoma diagnostics.11 Yet, at this time, imaging alone cannot be used to establish the diagnosis. Unlike other medical conditions that are defined by quantitative results, there is no fixed reference standard for what constitutes glaucoma.33 Moreover, OCT does not identify important characteristics associated with glaucomatous optic neuropathy, such as disc hemorrhages. Factors such as measurement errors, nonrepresentative databases, and masquerading syndromes may be misleading to the assessment. To maximize its diagnostic potential, OCT needs to be employed with some understanding of its workings as well as knowledge of its capabilities and limitations. It is an important tool to be combined with patients’ risk factors, examination results, and 40  Advanced ocular care  March 2014

sound clinical judgment to optimize its effectiveness in the diagnosis of glaucoma.  n The author thanks Joseph J. Pizzimenti, OD, for his assistance with the images for this article. Leon Nehmad, OD, MSW, is an associate professor at Nova Southeastern University, College of Optometry, Ft. Lauderdale, Florida. Dr. Nehmad may be reached at [email protected]. 1. Gupta N, Weinreb RN. New definitions of glaucoma. Curr Opin Ophthalmol. 1997; 8: 38-41. 2. Keltner JL, Johnson CA, Anderson DR, et al. The association between glaucomatous visual fields and optic nerve head features in the Ocular Hypertension Treatment Study. Ophthalmology. 2006;113:1603-1612. 3. Garway-Heath DF. Early diagnosis in glaucoma. Prog Brain Res. 2008;173:47-57. 4. Sommer A, Katz J, Quigley HA, et al. Clinically detectable nerve fiber atrophy precedes the onset of glaucomatous field loss. Arch Ophthalmol. 1991;109:77-83. 5. Fingeret M, Medeiros FA, Susanna R, Jr., Weinreb RN. Five rules to evaluate the optic disc and retinal nerve fiber layer for glaucoma. Optometry. 2005;76:661-668. 6. Jonas JB, Budde WM, Panda-Jonas S. Ophthalmoscopic evaluation of the optic nerve head. Surv Ophthalmol. 1999;43:293-320. 7. Quigley HA. Glaucoma. Lancet 2011; 377: 1367-1377. 8. Abrams LS, Scott IU, Spaeth GL, et al. Agreement among optometrists, ophthalmologists, and residents in evaluating the optic disc for glaucoma. Ophthalmology. 1994;101:1662-1667. 9. Burgoyne CF. The death of the cup to disc ratio in glaucoma - SDOCT paradigm change and its clinical implications. Presented at Optometric Glaucoma Society, 12th Annual Scientific Meeting; October 22, 2013; Seattle, WA. 10. Morgan JE, Sheen NJ, North RV, et al. Discrimination of glaucomatous optic neuropathy by digital stereoscopic analysis. Ophthalmology. 2005;112:855-862. 11. Schuman JS. Detection and diagnosis of glaucoma: ocular imaging. Invest Ophthalmol Vis Sci. 2012;53:2488-2490. 12. American Optometric Association Clinical Practice Guidelines. Care of the Patient with Open Angle Glaucoma (CPG9), revised 2010. www.aoa.org/optometrists/tools-and-resources/clinical-care-publications/clinical-practice-guidelines. Accessed February 10, 2014. 13. Primary Open-Angle Glaucoma Suspect PPP-2010. AAO PPP Glaucoma Panel, Hoskins Center for Quality Eye Care. http://one. aao.org/preferred-practice-pattern/primary-openangle-glaucoma-suspect-ppp--october-20. Accessed February 10, 2014. 14. Weinreb RN, Greve El, eds. Glaucoma diagnosis: structure and function. Gilsum, NH: Kugler Publications; 2003. 15. Chauhan BC, Burgoyne CF. From clinical examination of the optic disc to clinical assessment of the optic nerve head: a paradigm change. Am J Ophthalmol. 2013;156:218-227.e212. 16. Strouthidis NG, Grimm J, Williams GA, Cull GA, Wilson DJ, Burgoyne CF. A comparison of optic nerve head morphology viewed by spectral domain optical coherence tomography and by serial histology. Invest Ophthalmol Vis Sci. 2010;51:1464-1474. 17. Shin HY, Park HY, Jung KI, Park CK. Comparative study of macular ganglion cell-inner plexiform layer and peripapillary retinal nerve fiber layer measurement: structure-function analysis. Invest Ophthalmol Vis Sci. 2013;54:7344-7353. 18. Curcio CA, Allen KA. Topography of ganglion cells in human retina. J Comp Neurol. 1990;300:5-25. 19. Sung MS, Yoon JH, Park SW. Diagnostic validity of macular ganglion cell-inner plexiform layer thickness deviation map algorithm using Cirrus HD-OCT in preperimetric and early glaucoma [published online ahead of print November 14, 2013]. J Glaucoma. 2013. doi: 10.1097/IJG.0000000000000028 20. Tan O, Li G, Lu AT, Varma R, Huang D. Mapping of macular substructures with optical coherence tomography for glaucoma diagnosis. Ophthalmology. 2008;115:949-956. 21. Arintawati P, Sone T, Akita T, et al. The applicability of ganglion cell complex parameters determined from SD-OCT images to detect glaucomatous eyes. J Glaucoma. 2013;22:713-718. 22. Tan O, Chopra V, Lu AT, et al. Detection of macular ganglion cell loss in glaucoma by Fourier-domain optical coherence tomography. Ophthalmology. 2009;116:2305-2314.e2301-2302. 23. Yoon MH, Park SJ, Kim CY, et al. Glaucoma diagnostic value of the total macular thickness and ganglion cell-inner plexiform layer thickness according to optic disc area. Br J Ophthalmol. 2014;98(3):315-2124 24. Francoz M, Fenolland JR, Giraud JM, et al. Reproducibility of macular ganglion cell-inner plexiform layer thickness measurement with cirrus HD-OCT in normal, hypertensive and glaucomatous eyes. Br J Ophthalmol. 2014;98(3):322-328. 25. Hood DC, Slobodnick A, Raza AS, et al. Early glaucoma involves both deep local, and shallow widespread, retinal nerve fiber damage of the macular region. Invest Ophthalmol Vis Sci. 2014;55(2):632-649 26. Medeiros FA, Lisboa R, Weinreb RN, et al. A combined index of structure and function for staging glaucomatous damage. Arch Ophthalmol. 2012;130:1107-1116. 27. Chong GT, Lee RK. Glaucoma versus red disease: imaging and glaucoma diagnosis. Curr Opin Ophthalmol. 2012;23:79-88. 28. Asrani S, Edghill B, Gupta Y, Meerhoff G. Optical coherence tomography errors in glaucoma. J Glaucoma. 2010;19:237-242. 29. Leal-Fonseca M, Rebolleda G, Oblanca N, et al. A comparison of false positives in retinal nerve fiber layer, optic nerve head and macular ganglion cell-inner plexiform layer from two spectral-domain optical coherence tomography devices. Graefes Arch Clin Exp Ophthalmol. 2014;252(2):321-330. 30. Rao HL, Addepalli UK, Yadav RK, et al. Effect of scan quality on diagnostic accuracy of spectral domain optical coherence tomography in glaucoma. Am J Ophthalmol. 2014;157(3):719-727.e1. 31. Asrani S. OCT and glaucoma: artifact alert. Review of Ophthalmology. 2013. www.revophth.com/content/d/glaucoma_ management/c/39451/. Accessed February 10, 2014. 32. Bussel, II, Wollstein G, Schuman JS. OCT for glaucoma diagnosis, screening and detection of glaucoma progression [published online ahead of print December 19, 2013]. Br J Ophthalmol. 2013. doi: 10.1136/bjophthalmol-2013-304326. 33. Medeiros FA. How should diagnostic tests be evaluated in glaucoma? Br J Ophthalmol. 2007;91:273-274.