The Value of Macular Optical Coherence Tomography in Watchful Waiting of Suprasellar Masses: A 2-Year Observational Study

A possible benefit of optical coherence tomography (OCT) in the approach to tumors involving the optic chiasm may be the ability to foresee visual deterioration. This study investigated the value of OCT in watchful waiting for compressive optic neuropathy as the primary management of suprasellar masses.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD The Value of Macular Optical Coherence Tomography in Watchful Waiting of Suprasellar Masses: A 2-Year Observational Study Øystein Kalsnes Jørstad, MD, Andreas Reidar Wigers, MD, Pål Bache Marthinsen, MD, Johan Arild Evang, MD, PhD, Morten Carstens Moe, MD, PhD Background: A possible benefit of optical coherence tomography (OCT) in the approach to tumors involving the optic chiasm may be the ability to foresee visual deterioration. This study investigated the value of OCT in watchful waiting for compressive optic neuropathy as the primary management of suprasellar masses. Methods: The research was conducted as a 2-year observational study of a patient cohort with conservatively managed mass lesions involving the optic chiasm on MRI. Threshold perimetry and macular OCT were performed at baseline and each follow-up examination. Univariate Cox regression was used to determine the effect of baseline and longitudinal covariates upon development of visual field (VF) loss compatible with chiasmal dysfunction. Results: Nineteen eyes of 19 patients were included. The optic chiasm–tumor relationship on baseline MRI was abutment in 6 cases and compression in 13 cases. Seven eyes developed VF loss. None of the baseline covariates were predictors of VF loss. The longitudinal decrease in mean macular ganglion cell complex (mGCC) thickness on OCT was 2.5 mm/yr for eyes that developed VF loss and 0.2 mm/yr for eyes that did not develop VF loss (P = 0.02). The hazard ratio for VF loss per 1-mm/yr decrease in mGCC thickness was 1.30 (95% confidence interval [CI] 1.04– 1.62; P = 0.02) for the inferior nasal quadrant and 1.45 (95% CI 1.02–2.07; P = 0.04) for the inferior temporal quadrant. Departement of Ophthalmology (ØKJ, ARW, MCM), Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine (ØKJ, MCM), Faculty of Medicine, University of Oslo, Oslo, Norway; The Integrative Pituitary Team (ØKJ, ARW, PBM, JAE), Oslo University Hospital, Oslo, Norway; Section of Neuroradiology (PBM), Oslo University Hospital, Oslo, Norway; and Section of Specialized Endocrinology (JAE), Oslo University Hospital, Oslo, Norway. Supported by Oslo University Hospital, Norway. The authors report no conflicts of interest. J. A. Evang and M. C. Moe are the Co-senior authors. Address correspondence to Øystein Kalsnes Jørstad, MD, Department of Ophthalmology, Oslo University Hospital, Postboks 4956 Nydalen, 0424 Oslo, Norway; E-mail: [e-mail] e516 Conclusions: OCT offers a valuable complement to perimetry in monitoring for compressive optic neuropathy. Longitudinal mGCC thinning can anticipate VF loss. Journal of Neuro-Ophthalmology 2021;41:e516–e522 doi: 10.1097/WNO.0000000000000993 © 2020 by North American Neuro-Ophthalmology Society A neuro-ophthalmic examination is an essential part of the multidisciplinary approach to tumors involving the optic chiasm (1). Notwithstanding lack of high-class evidence (Level I or II) to support specific recommendations, the traditional consensus is that perimetry represents the cornerstone of the ophthalmic assessment; the presence of visual field (VF) loss attributable to chiasmal compression is considered a strong indication for surgery of nonfunctioning pituitary adenomas (2–4). In recent years, optical coherence tomography (OCT) has become an important adjunctive test in the workup of suprasellar masses. As visual pathway compression eventually leads to descending atrophy of retinal ganglion cells and neighboring layers, the technology can provide structural evidence for optic neuropathy. The advancement of OCT imaging allows for evaluation of topographic macular changes, which, because of the retinotopic organization of the optic chiasm, predominantly occur in the nasal quadrants (5–11). As a result, OCT has brought about a new localizing sign in neuro-ophthalmology: binasal thinning of the inner macular layers in chiasmal compression. Intriguingly, several articles have demonstrated that OCT findings can even precede detectable functional deficits (9–11). There is an emerging consensus that OCT is beneficial both as a diagnostic and prognostic tool in the management of suprasellar masses; evidently, OCT can support a conclusion on whether compressive optic neuropathy is present or help clinicians counsel patients about expectations for visual Jørstad et al: J Neuro-Ophthalmol 2021; 41: e516-e522 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution recovery after surgical decompression (12–14). Other issues concerning the role of OCT in clinical decision-making remain undetermined. In particular, what relevance has OCT findings suggesting chiasmal compression in the absence of concurrent VF defects? This dilemma arises from a fundamental difference between perimetry and OCT; while the former presents a measure of the visual function, a clinically relevant treatment outcome, the latter merely provides structural biomarkers for compressive optic neuropathy. For glaucoma suspects, there is evidence that OCT findings can precede VF progression and predict conversion to glaucoma (15). Analogously, an additional benefit of OCT in the approach to compressive lesions may be the ability to foresee visual deterioration requiring surgical intervention. The aim of this study was to investigate the value of macular OCT in watchful waiting for compressive optic neuropathy as the primary management of suprasellar masses involving the optic chiasm. METHODS The research was conducted as a 2-year observational study of a patient cohort with conservatively managed mass lesions involving the optic chiasm. The study took place at Oslo University Hospital, at which an integrative pituitary team provides tertiary care for the patient group throughout Southeastern Norway. Since 2016, pituitary team patients referred for neuro-ophthalmological assessment have been included in a prospective quality-assurance registry approved by the institutional data protection officer. The participants in this study were selected from this registry. In agreement with the observational study design, a decision to convert from watchful waiting to neurosurgical intervention was made without regard to the study. The main inclusion criteria were untreated, nonfunctioning suprasellar mass lesions with MRI evidence of tumor-chiasmal abutment or compression but absence of VF abnormalities suggesting chiasmal dysfunction. Moreover, in accordance with the normative OCT database, only subjects aged 20–80 years and spherical equivalent refraction in the range of 26.0 to +3.0 diopters were included. Exclusion criteria were other ophthalmological or neurological disorders that could influence perimetry or OCT, for example, cataract, glaucoma, epiretinal fibrosis, or demyelinating disease. VF results with more than 3 false answers were also excluded. To avoid dependent data, one eye was randomized to enrollment if both eyes of a patient met the inclusion criteria. Baseline Perimetry Examination A trained ophthalmic nurse performed standard white-onwhite threshold perimetry using an Octopus 900 perimeter (Haag-Streit AG, Köniz, Switzerland). The central 30° field of vision was examined with the general (G) program, the Jørstad et al: J Neuro-Ophthalmol 2021; 41: e516-e522 tendency oriented perimetry test strategy, and fixation control activated. Two neuro-ophthalmologists independently confirmed whether included eyes had absence of VF loss compatible with chiasmal dysfunction. Baseline Optical Coherence Tomography Examination Spectral domain OCT images were obtained with a RS3000 OCT Advance (NIDEK CO, LTD, Gamag ori, Japan). The macular ganglion cell complex (mGCC) was examined with the 9 · 9 mm Macula Map program. Only scans with high signal strength index values ($7 out of 10) were accepted, and correct placement of the segmentation lines between the inner plexiform layer and the retinal nerve fiber layer was visually confirmed. The Macula Map program displays the mGCC thickness values in a circular grid with 4 inner and 4 outer sectors and a radius of 4.5 mm, that is, each macular quadrant consists of an outer and an inner sector. The measured mGCC values are compared with age-specific reference ranges; color codes indicate #5% or #1% probability of a normal mGCC value. Baseline OCT findings compatible with chiasmal compression were defined as sectorial mGCC thinning including at least one of the 4 nasal sectors. Baseline MRI Examination Cerebral MRI examination included #3-mm-thin, T1weighted sequences of the sellar region in the sagittal and coronal planes before and after gadolinium contrast enhancement (unless contraindicated). The maximum suprasellar tumor extension was measured on coronal images perpendicular to a reference line drawn between the upper surfaces of the horizontal segments of the internal carotid arteries within the cavernous sinuses (16). Furthermore, the relationship between the optic chiasm and tumor was determined (17). All MRI images were analyzed by the same neuroradiologist, who was blinded to the neuroophthalmic results. Ophthalmic Follow-up for the Event of Interest: Development of Visual Field Loss Compatible With Chiasmal Dysfunction The ophthalmic follow-up frequency was determined individually. In general, patients were initially examined every 3–6 months; in absence of progression, the examination interval was extended to once a year. Each assessment included perimetry and OCT after the same protocols as at baseline. The eye-tracing option ensured that the OCT position was identical with baseline. Follow-up perimetry results were evaluated for the event of interest: development of VF loss compatible with chiasmal dysfunction. VF abnormality was defined as square root of loss variance .2.5 dB or mean defect .2.0 dB, representing a local or global VF loss exceeding e517 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution the age-specific 95% reference range. In the case of VF abnormality, 2 neuro-ophthalmologists independently judged whether the pattern was compatible with chiasmal dysfunction, for example, a temporal VF defect with or without additional nasal field involvement (18). Perimetry was assessed independently from OCT, but as at least one of the 2 neuro-ophthalmologists had previously examined each patient, they were not formally blinded to mGCC findings. In the case of conflicting outcomes, the opinion of a third ophthalmologist was decisive. The follow-up OCT images were evaluated for longitudinal changes in the mGCC thickness. Commercial OCT solutions display mGCC thickness values in various ways. To present longitudinal data that are generally applicable, we determined the mGCC thickness change in each of the 4 macular quadrants by calculating the slope of the line of best fit for all consecutive examinations. Statistical Analyses The inter-rater reliability of the 2 neuro-ophthalmologists who primarily evaluated the perimetry results was determined by Cohen’s kappa coefficient. The Fisher exact test was used for categorical variables, and the Student’s t test was used for continuous variables. A univariate Cox regression model was used to analyze the effect of the following covariates upon the time of an event of interest: age (continuous), baseline OCT findings (categorical), suprasellar tumor extension (continuous), tumor-chiasmal compression (categorical), and per 1-mm/yr decrease in mGCC thickness for each macular quadrant (continuous). Statistical analyses were performed with IBM SPSS Statistics, Version 25.0 (IBM Corp, Armonk, NY). The statistical significance threshold was set at alpha = 0.05. As the Macula Map program simultaneously displays 4 nasal sectors, Bonferroni correction was applied to adjust for multiple comparisons, and the threshold for baseline sectorial mGCC thinning including at least one of the 4 nasal sectors was set at alpha = 0.01. Data are presented as mean (±SD) or median (range). RESULTS Nineteen eyes of 19 patients (12 women and 7 men) were included in the study. The mean age was 48.5 (±14.8) years. The mass lesion was an incidental finding in 17 cases (including neuroradiologic workup of headache in 10 cases), and pituitary dysfunction led to the discovery in 2 cases. The suggested MRI diagnosis was pituitary adenoma in 15 cases, Rathke’s cleft cyst in 3 cases, and epidermoid cyst in 1 case. The mean suprasellar tumor extension was 9.2 (±2.2) mm. The epidermoid cyst could not be accurately measured due to irregular surfaces. The relationship between the optic chiasm and tumor was abutment in 6 cases and compression in 13 cases. The position of the optic chiasm relative to the sella turcica was central in 13 cases, prefixed in 3 cases, e518 and postfixed in 3 cases. The tumor affected the optic pathway midline in 13 cases, to the right in 2 cases, and to the left in 3 cases. In accordance with the main inclusion criteria, all eyes had absence of baseline VF abnormalities suggesting chiasmal dysfunction. However, 3 of 19 eyes had baseline OCT findings compatible with chiasmal compression. Table 1 displays a summary of the baseline characteristics. In 2 years, 7 eyes (37%) developed VF loss compatible with chiasmal dysfunction. The pattern of VF loss was a temporal defect in 3 eyes, a temporal defect with additional nasal field involvement in 3 eyes, and central depression with discrete temporal predominance in 1 eye. Cohen’s kappa coefficient between the 2 neuroophthalmologists that primarily evaluated the perimetry results was 0.88, indicating very good inter-rater agreement (19). The median follow-up time until development of VF loss was 5 (3–17) months, and the median number of neuro-ophthalmic examinations was 3 (2–5). One patient was lost to follow-up after 13 months. Figure 1 displays a typical case from the study. Baseline Covariates Because the 3 eyes with baseline OCT findings did not develop VF loss, this covariate was not included in the analyses. Mean suprasellar tumor extension was 10.0 mm for eyes that developed VF loss and 8.6 mm for eyes that did not develop VF loss (P = 0.22). Chiasmal compression was evident for all 7 eyes that developed VF loss and for 6 of 12 eyes that did not develop VF loss (P = 0.04). In univariate Cox regression, neither age (hazard ratio [HR] per 1-year increase: 1.06; 95% confidence interval [CI] 0.99–1.13; P = 0.08), nor suprasellar tumor extension (HR per 1 mm increase: 1.21; 95% CI 0.87–1.69; P = 0.27), nor chiasmal compression (HR: 0.02; 95% CI 0.00–12.58; P = 0.24) was a significant predictors for developing VF loss. Longitudinal Covariates Table 2 shows the univariate Cox regression results for the longitudinal covariates. The mean decrease in mGCC thickness was 2.5 mm/yr for eyes that developed VF loss and 0.2 mm/yr for eyes that did not develop VF loss (P = 0.02). With one exception (case 13), all eyes that developed VF loss displayed a longitudinal decrease in mean mGCC thickness (Fig. 2). In the univariate Cox regression model, the HR for developing VF loss per 1-mm/yr decrease in mGCC thickness for each macular quadrant was 1.30 (95% CI 1.04– 1.62; P = 0.02) for the inferior nasal quadrant and 1.45 (95% CI 1.02–2.07; P = 0.04) for the inferior temporal quadrant. Moreover, there was a nonsignificant trend for the superior nasal quadrant: HR 1.16 (95% CI 1.00–1.35; Jørstad et al: J Neuro-Ophthalmol 2021; 41: e516-e522 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. A summary of baseline characteristics in relation to development of visual field loss in watchful waiting for suprasellar masses Case 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Age, Sex Suggested MRI Diagnosis 52, female Adenoma 31, female Rathke’s cyst 30, female Adenoma 63, female Adenoma 26, female Adenoma 43, male Epidermoid cyst 60, female Adenoma 60, male Adenoma 40, female Adenoma 38, female Rathke’s cyst 49, male Adenoma 75, male Adenoma 60, female Adenoma 48, female Adenoma 53, male Adenoma 64, male Adenoma 21, female Rathke’s cyst 63, female Adenoma 46, male Adenoma Optic Chiasm– Suprasellar Development Continued Observation Tumor Tumor Baseline OCT of Visual or Surgery After Relationship Extension (mm) Findings Field Loss End of Study Compression Compression Compression Abutment Abutment Abutment Compression Compression Compression Compression Compression Compression Compression Compression Abutment Compression Compression Abutment Abutment 11 7 9 7 6 — 12 12 8 13 11 10 10 7 8 12 7 7 8 No No No Yes No No No No No No No No No No Yes No No No Yes No Yes No No No No Yes Yes No No No Yes Yes Yes No Yes No No No Observation Observation Observation Observation Observation Observation — Observation Lost to follow-up Observation Observation Surgery Surgery Surgery Observation Observation Observation Observation Observation Despite absence of suggestive visual field abnormalities at baseline, OCT displayed nasal thinning of the macular ganglion cell complex in 3 eyes. In case 6, the suprasellar tumor extension could not be accurately measured due to irregular surfaces. In case 7, the adenoma spontaneously regressed, and surgery was unnecessary. OCT, optical coherence tomography. FIG. 1. Contrast-enhanced, T1-weighted MRI, threshold perimetry (top), and macular ganglion cell complex (mGCC) thickness values (bottom) of a 48-year-old woman with an incidentally discovered pituitary adenoma; the right eye was included in the study. MRI showed suprasellar extension of the tumor and compression of the optic chiasm. A. At baseline, there were only subtle, nonspecific perimetric findings with global indices within age-specific 95% reference ranges. Likewise, the mGCC thickness values were within normal ranges. Based on normal perimetry and mGCC findings, the decision was to pursue a watchful waiting strategy. B. After 5 months, mild central visual field (VF) loss with discrete upper temporal predominance developed. During this period, mGCC thinning progressed in the inferior nasal quadrant, superior nasal quadrant, and inferior temporal quadrant. The patient underwent trans-sphenoidal surgery shortly afterward, and the VF defect fully recovered postoperatively. N, nasal; T, temporal. Jørstad et al: J Neuro-Ophthalmol 2021; 41: e516-e522 e519 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 2. The effect of longitudinal optical coherence tomography covariates upon development of visual field loss in watchful waiting for suprasellar masses Univariate Cox Regression Hazard Ratio (95% Confidence Interval) Longitudinal OCT Covariates mGCC mGCC mGCC mGCC thickness thickness thickness thickness inferior nasal quadrant (per 1-mm/yr decrease) superior nasal quadrant (per 1-mm/yr decrease) inferior temporal quadrant (per 1-mm/yr decrease) superior temporal quadrant (per 1-mm/yr decrease) 1.30 1.16 1.45 1.25 (1.04–1.62) (1.00–1.35) (1.02–2.07) (0.82–1.90) P 0.02 0.06 0.04 0.29 Progressive mGCC thinning in the inferior macular quadrants increased the risk of visual field loss. mGCC, macular ganglion cell complex; OCT, optical coherence tomography. P = 0.06). For the superior temporal quadrant, longitudinal mGCC changes were not significantly associated with development of VF loss. DISCUSSION Previous studies of chiasmal compression have shown that macular OCT findings can occur without measurable functional deficits (9–11). What is more, a recent paper by Monteiro demonstrated how consecutive OCT examinations in a case of a conservatively managed pituitary adenoma were able to detect progression before perimetry (20). The present study extends this work and supports the hypothesis that longitudinal mGCC thinning can predict VF loss when watchful waiting is chosen for tumors affecting the optic chiasm. A dilemma about clinical decision-making in incidentally discovered pituitary adenomas lies at their natural history, which remains poorly understood. Still, evidence suggests that tumor growth and visual complications are more common for larger lesions, and careful observation for signs of progression is crucial for conservative management of such cases (21,22). In this regard, the present study shows that OCT has the potential to serve as a valuable tool for monitoring development of early compressive optic neuropathy below the detection threshold for perimetry. Recognizing the topography of longitudinal mGCC changes proves particularly important. In agreement with the textbook example of an upper temporal VF defect in chiasmal compression, progressive mGCC thinning in the inferior nasal quadrant was associated with an increased risk of developing VF loss. There was only a trend toward corresponding findings for the superior nasal quadrant. FIG. 2. Noncontrast, T1-weighted MRI, threshold perimetry (top), and macular ganglion cell complex (mGCC) thickness values (bottom) of a 60-year-old woman with a pituitary adenoma discovered during an evaluation for secondary hypothyroidism; the right eye was included in the study. MRI showed suprasellar extension of the tumor and compression of the optic chiasm. A. Perimetry at baseline displayed subtle, nonspecific findings with global indices within age-specific 95% reference ranges. Likewise, the mGCC thickness values were within normal ranges. Based on normal perimetry and mGCC findings, the decision was to pursue a watchful waiting strategy. B. After 4 months, upper temporal visual field loss (VF) developed. There was, however, no corresponding mGCC thinning, and the mean mGCC thickness was practically unchanged. Follow-up MRI revealed a relatively fast-growing tumor, which may explain why perimetric findings preceded structural deterioration in this particular case. The patient underwent trans-sphenoidal surgery shortly afterward, and the VF defect fully recovered postoperatively. N, nasal; T, temporal. e520 Jørstad et al: J Neuro-Ophthalmol 2021; 41: e516-e522 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution However, it must be taken into account that all eyes were undergoing watchful waiting and findings therefore reflect early progression. In that regard, preference for the inferior macula might be explained by the fact that all mass lesions compressed the visual pathway from below. There was also a significant HR for the inferior temporal quadrant, indicating descending optic atrophy across the vertical meridian. The variability in tumor configuration and sellar region anatomy at baseline may have been a contributing factor to this observation. Moreover, OCT has led to a more nuanced understanding of axonal injury patterns in chiasmal syndromes, and even in the absence of detectable nasal VF defects, OCT may reveal temporal mGCC thinning (6,23). There are 2 main mechanisms of visual loss in chiasmal compression (24). First, a conduction block can arise at the level of the optic chiasm. A conduction block is potentially reversible, and visual function may completely recover after treatment. Second, compression can cause retrograde degeneration and permanent loss of retinal ganglion cells and their axons. It should be emphasized that while perimetry detects visual loss irrespective of the underlying mechanism, OCT only determines whether retrograde degeneration is present. Furthermore, a conduction block can develop rapidly, whereas retrograde degeneration is a time-dependent phenomenon (25). Because structural changes can occur below the sensory threshold, one might conclude that OCT will consistently recognize progression before perimetry. However, this requires retrograde degeneration to precede detectable blocking of nerve conduction, which is not always the case. Instead, discordance between longitudinal perimetry and OCT measurements in chiasmal compression could possibly work both ways, depending on the tumor growth rate. Admittedly, as most lesions are slow-growing pituitary adenomas, longitudinal mGCC thinning generally anticipates measurable functional loss. Nonetheless, one eye (Case 13) in this study developed VF defects compatible with chiasmal dysfunction without concurrent OCT findings (Fig. 2). Remarkably, in this case, follow-up MRI demonstrated increasing chiasmal compression and dislocation in only 6 months, suggesting a rather fast-growing tumor. The predictive value of OCT notwithstanding, perimetric progression might precede structural deterioration. Therefore, OCT should not replace perimetry but serve as a complementary tool in monitoring for compressive optic neuropathy. This study has some important limitations. First, the sample size is relatively small. Although there were significant findings among the longitudinal covariates, the study may lack statistical power to identify baseline predictors of VF loss. Nevertheless, baseline characteristics are cross-sectional in nature and might not provide a direct measure of progression; it seems plausible that VF loss is better predicted by longitudinal OCT parameters. Second, because the follow-up frequency was determined according to clinical practice and development of VF loss typically Jørstad et al: J Neuro-Ophthalmol 2021; 41: e516-e522 resulted in neurosurgery, the number of neuro-ophthalmic examinations per patient was limited. For this reason, the study could not require reproducibility of findings across consecutive tests, making the perimetry and OCT results susceptible to test–retest variation. Third, in addition to assumption of proportional hazards, the Cox regression analyses were based on the premise that the longitudinal mGCC changes were linear, that is, constant over time. Finally, as Horton and Costello have previously discussed in this journal, several ambiguities surround the relationship between structure and function in chiasmal compression (26,27). For instance, although progressive mGCC thinning increased the risk of developing VF loss in our study, the visual function may nevertheless recover after tumour decompression. Needless to say, OCT findings may pose a clinical decision-making dilemma, particularly in the absence of concurrent visual loss. Progressive mGCC thinning during watchful waiting for suprasellar masses requires particular vigilance, but even then, there is lack of evidence that a treatment decision based on structural surrogates corresponds to an improved visual outcome. This is an important topic for future studies. In conclusion, macular OCT offers a valuable complement to perimetry in monitoring for compressive optic neuropathy. If watchful waiting is the chosen approach to suprasellar masses, our study provides proof of concept that a more rapid mGCC thinning indicates an increased risk of developing VF loss. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: Ø. K. Jørstad, A. R. Wigers, P. B. Marthinsen, J. A. Evang, and M. C. Moe; b. Acquisition of data: Ø. K. Jørstad, A. R. Wigers, and P. B. Marthinsen; c. Analysis and interpretation of data: Ø. K. Jørstad, A. R. Wigers, P. B. Marthinsen, J. A. Evang, and M. C. Moe. Category 2: a. Drafting the manuscript: Ø. K. Jørstad; b. Revising it for intellectual content: Ø. K. Jørstad, A. R. Wigers, P. B. Marthinsen, J. A. Evang, and M. C. Moe. Category 3: a. Final approval of the completed manuscript: Ø. K. Jørstad, A. R. Wigers, P. B. Marthinsen, J. A. Evang, and M. C. Moe. ACKNOWLEDGMENTS The authors thank Geir Aksel Qvale for programming the mGCC algorithms and NIDEK for providing insights into the OCT normative database. REFERENCES 1. 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