Optic Disc Drusen in Patients With Ocular Hypertension: A Case Series and Review of the Literature

The identification of glaucomatous optic neuropathy in the setting of optic disc drusen (ODD) is a challenge, and the decision of whether to offer treatment in the form of intraocular pressure (IOP) reduction is controversial. Here, we present a series of patients with coexisting ocular hypertension and ODD to evaluate clinical features, treatment options, and progression of optic neuropathy. In addition, a review of the literature on ODD with elevated IOP is provided.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Optic Disc Drusen in Patients With Ocular Hypertension: A Case Series and Review of the Literature Darrell Kohli, MD, John J. Chen, MD, PhD, M. Tariq Bhatti, MD, Jodi M. Moore-Weiss, OD, Gavin W. Roddy, MD, PhD Background: The identification of glaucomatous optic neuropathy in the setting of optic disc drusen (ODD) is a challenge, and the decision of whether to offer treatment in the form of intraocular pressure (IOP) reduction is controversial. Here, we present a series of patients with coexisting ocular hypertension and ODD to evaluate clinical features, treatment options, and progression of optic neuropathy. In addition, a review of the literature on ODD with elevated IOP is provided. Methods: Six patients with ODD and a history of ocular hypertension are presented. Components of the examination and imaging modalities used to establish the diagnosis of ODD were recorded and a description of ocular hypertension history, glaucoma testing, and the potential treatment of IOP were also provided. Results: In this series, 4 of 6 patients with concurrent ocular hypertension and ODD showed progression of optic neuropathy as assessed by visual field or retinal nerve fiber layer thickness. Of the 2 patients who did not show evidence of progression, 1 was treated with IOP-lowering medications and 1 was observed off treatment. Of the 4 patients who showed evidence of progression, all 4 were initially treated with IOP-lowering medications and 2 ultimately went on to have trabeculectomy surgery. In the patients with progressive optic neuropathy, lowering the IOP seemed to halt the progression suggesting there was a pressure‐sensitive component. Conclusions: Distinguishing changes to the optic nerve, particularly the structural changes at the lamina cribrosa of true glaucomatous optic neuropathy in the setting of ODD, is a challenge. Careful consideration of risk factors including age, presenting features, progression indicators, and management goals is to be accounted for in the decision to offer treatment. We see the presence ODD in the patients with ocular hypertension as an additional risk for proDepartments of Ophthalmology (DK, JJC, MTB, JM-W, GWR) and Neurology (JJC, MTB), Mayo Clinic, Rochester, Minnesota. Supported by Mayo foundation (G. W. Roddy) and K08EY031758 (G. W. Roddy). J. J. Chen is a consultant to Roche and UCB. The authors report no conflicts of interest. Address correspondence to Gavin W. Roddy, MD, PhD, Department of Ophthalmology, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905; E-mail: [e-mail] 470 gressive changes to the nerve fiber layer and visual field that needs to be considered when determining whether to initiate therapy. Our data suggest that treatment of IOP in the patients with ocular hypertension with ODD and evidence of progression reduces the risk of further progression. Further work is needed to determine whether progression of optic neuropathy in the setting of coexisting ODD and ocular hypertension is related mechanistically to predominantly an ODD-type process, a glaucomatous process, or a combination thereof. Journal of Neuro-Ophthalmology 2022;42:470–475 doi: 10.1097/WNO.0000000000001647 © 2022 by North American Neuro-Ophthalmology Society O ptic disc drusen (ODD) are acellular deposits that likely occur because of impaired axonal transport and metabolism, although the exact pathogenesis has not been fully elucidated (1,2). ODD occur anterior to the lamina cribrosa and can be evident on the surface of the optic disc or deeper within the tissue, where imaging is necessary for diagnosis (2). In studies using histologic analysis in postmortem eyes, ODD have been reported in up to 2.4% of eyes (3,4), although ODD may be observed in up to 14.6% of normal-appearing eyes using enhanced-depth imaging (EDI) optical coherence tomography (OCT) of the optic disc (5). The presence of ODD can be benign or result in structural and functional changes to the optic disc including slowly progressive visual field (VF) loss (1,2) and peripapillary retinal nerve fiber layer (pRNFL) or ganglion cell–inner plexiform layer (GCIPL) thinning (6,7). The VF, pRNFL, and GCIPL progression patterns may be similar to what is seen in glaucomatous optic neuropathy (GON) creating a diagnostic dilemma (2,6,8,9). In addition, ODD obscures the clinical assessment of the optic nerve cup, which is often seen as a “cupless disc” (10). Because the principal defining feature of GON is neuroretinal rim thinning and enlargement of the optic nerve cup, establishing a diagnosis of Kohli et al: J Neuro-Ophthalmol 2022; 42: 470-475 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution GON in the presence of ODD, which typically prevents a discrete designation of the cup and neuroretinal rim (2,8,11,12), is a diagnostic and therapeutic challenge where a diagnosis of GON could either be delayed or unnecessarily be made (13,14). There is currently no widely accepted treatment for ODD with progressive changes to the pRNFL or VF loss. Intraocular pressure (IOP)-lowering agents have been proposed as a therapeutic option (9,15,16). However, there is ongoing debate with data questioning the efficacy of IOP reduction for patients with ODD, particularly with an IOP within a normal range (15,17). To select a patient population with ODD and the leading risk factor for GON, elevated IOP, we present a case series of patients with coexisting ODD and ocular hypertension to determine whether treatment of IOP slowed progression of optic neuropathy as assessed by VF or OCT analysis. In addition, we present a review of the literature on ODD and IOP. METHODS Six consecutive cases evaluated at Mayo Clinic were retrospectively reviewed that had a documented history of ocular hypertension and ODD with baseline glaucoma testing that included Automated 24-2 Swedish Interactive Thresholding Algorithm (SITA), Cirrus pRNFL and GCIPL analysis, and optic disc photographs with at least one set of follow-up tests. Previous glaucoma testing from outside institutions were used when available. Ocular hypertension was defined as a current or past IOP measurement of .21 mm Hg. Each case is described briefly, emphasizing the characteristics of ODD and how their presence can interfere with GON diagnosis and monitoring. Information included IOP measurements from the visit where ODD were first suspected or identified, central corneal thickness (CCT), refraction, cup-to-disc ratio (CDR), and imaging studies obtained. Progression and management information was included. Articles from PubMed were identified using one or more of the following keywords: optic disc drusen, optic nerve head drusen, intraocular pressure, ocular hypertension, or glaucoma. Any study with 2 or more patients with ODD and a described association with IOP, ocular hypertension, or GON was included. RESULTS Patient Demographics Summary Two men and 4 women with an age range of 32–78 years were enrolled in the study. The mean follow-up was 40 months, with a range of 10–118 months. One of the 6 patients was observed without IOP-lowering medication, and the remaining 5 patients were treated with a combination of topical eye drop therapy, selective laser trabeculoplasty (SLT), Kohli et al: J Neuro-Ophthalmol 2022; 42: 470-475 or surgical intervention. Of the 10 eyes in the 5 treated patients, the average IOP reduction was 40.3% (Table 1). Case 1 A 41-year-old White man with a history of myopia treated with laser-assisted in situ keratomileusis (LASIK) was referred to the glaucoma service for ocular hypertension. Unmedicated Tmax was 29 mm Hg in the right eye and 26 mm Hg in the left eye. Post-LASIK CCT was 595 mm in the right eye and 583 mm in left eye. The patient had residual myopia, with 21.50 diopter sphere bilaterally, although the preoperative refractive error was unknown. CDRs were 0.2 in the right eye and 0.1 in the left eye. Structurally elevated optic discs without papilledema were noted bilaterally, and a tilted optic disc was also noted in the left eye. Baseline VF testing showed no deficits. OCT pRNFL analysis showed thinning superiorly in the right eye and diffuse thinning in the left eye, which had progressed compared with baseline testing 2 years before. GCIPL analysis showed no thinning in all sectors. B-scan ultrasonography revealed hyperechoic signal at both optic discs consistent with ODD. Given coexisting ocular hypertension, ODD, and progression by OCT pRNFL, treatment was recommended and subsequently initiated for this patient using aqueous suppression in both eyes. At 10-month follow-up, there was no further progression after treatment was initiated as assessed by OCT pRNFL, GCIPL, or VF in either eye (Table 1). Case 2 A 32-year-old White woman was evaluated for ocular hypertension. Baseline examination revealed an unmedicated IOP of 27 mm Hg in both eyes. CCT was 611 mm in the right eye and 608 mm in the left eye. The patient was myopic with 22.75 diopters of sphere bilaterally. Cup-todisk ratios were 0.1 in both eyes, and pseudopapilledema was seen bilaterally. Baseline VF analysis showed an early inferior arcuate defect on the right eye and no defects on the left eye. OCT pRNFL demonstrated a superior thinning bilaterally. GCIPL analysis showed mild thinning in the superior sector of the left eye. B-scan ultrasonography and EDI OCT analysis were obtained and revealed bilateral ODD. Given concurrent ocular hypertension and ODD but without evidence of progression and thicker than average corneas, the patient was offered treatment with a topical glaucoma medication vs observation with a recommendation to observe given thicker CCT and the patient’s apprehension to a commitment to treatment. Over 30 months of follow-up, no progression by VF or OCT pRNFL and GCIPL was noted. Case 3 An 83-year-old White man with a previous diagnosis of open-angle glaucoma with pretreatment maximum IOP of 471 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Patient demographics and management characteristics IOPmax CCT Most Recent IOP OAG Right—29 Left—26 595 583 14 16 IOP-lowering drops bilaterally 10 32 OHT OAG 25 25 12 9 30 83 611 608 543 553 Observation M Right—27 Left—27 Right—28 Left—28 54 4 F 78 PXE Right—34 Left—24 574 587 22 18 5 F 69 OAG Right—32 Left—35 520 518 10 13 6 F 44 PD Right—25 Left—25 613 600 18 15 Right—SLT x1 with 3 IOP-lowering drops. Left—SLT x1 and IOPlowering drops, followed by trabeculectomy Right—3 IOP-lowering medications and SLT. Left—1 IOP-lowering drop initiated later in course. Right—IOP-lowering drops and SLT, followed by trabeculectomy. Left—IOP-lowering drops and SLT, followed by trabeculectomy. IOP-lowering drops bilaterally Case Sex Age Diagnosis 1 M 41 2 F 3 Treatment Follow-up (mo) Progression Initial progression. No progression after final IOP-lowering treatment either eye No progression either eye Initial progression. No progression after final IOP-lowering treatment either eye 118 Initial progression. No progression after final IOP-lowering treatment either eye 21 Initial progression. No progression after final IOP-lowering treatment either eye 11 No progression either eye Age and sex are presented for each case in addition to diagnosis type, maximum IOP (IOPmax), central corneal thickness (CCT), treated IOP (most recent IOP), treatment, follow-up duration, and progression features. CCT, central corneal thickness; F, female; IOP, intraocular pressure; IOPmax, maximum intraocular pressure; M, male; OAG, open-angle glaucoma; OHT, ocular hypertension; PD, pigment dispersion glaucoma; PXE, pseudoexfoliation glaucoma; SLT, selective laser trabeculoplasty. 28 mm Hg bilaterally years before was referred for continued VF and pRNFL progression despite IOPlowering treatment. On presentation to our service, IOP was 14 mm Hg in the right eye and 15 mm Hg in the left eye on 4 topical glaucoma medications in each eye. The left eye also had a history of selective laser trabeculoplasty (SLT). CCT was 543 mm in the right eye and 553 mm in the left eye. The patient was pseudophakic with mild residual myopia bilaterally. CDRs were 0.2 in the right eye and 0.1 in the left eye. Tilting of the optic disc was noted on the left eye. VF testing was full on the right eye and the left eye revealed a dense inferior arcuate defect-threatening fixation that had been slowly progressive over time. OCT pRNFL demonstrated thinning superiorly in the right eye that was slowly progressive and diffuse thinning in the left eye that was near the floor. OCT GCIPL showed thinning superiorly and nasally in the right eye and diffuse thinning in the left eye. A B scan was obtained given minimal cupping and progression of optic neuropathy in a glaucomatous pattern, 472 which revealed ODD bilaterally. Given progression in both eyes, treatment was recommended. SLT was performed in the right eye, and a trabeculectomy with mitomycin C was performed in the left eye. After treatment, IOP in the right eye was low teens on glaucoma medications and high single digits in the left eye. No further progression was observed 54 months from intervention. Case 4 A 78-year-old White woman with pseudoexfoliation syndrome with an IOP of 34 mm Hg in the right eye and 14 mm Hg in the left eye was referred to our department for concerns of persistently elevated IOP. CCT was 574 mm in the right eye and 587 mm in the left eye. Mild hyperopia was noted bilaterally, and pseudoexfoliation of the anterior lens capsule was noted in the right eye. The CDR was 0.1 bilaterally. Structurally elevated discs without papilledema were observed bilaterally. Buried ODD were suspected and Kohli et al: J Neuro-Ophthalmol 2022; 42: 470-475 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution subsequently confirmed on OCT. Baseline visual fields demonstrated inferior arcuate defects with unreliable testing. OCT pRNFL revealed thinning superiorly and inferiorly in both eyes. GCIPL analysis demonstrated diffuse thinning in the right eye and thinning of the superotemporal sector in the left eye. Given ODD and ocular hypertension with IOP in the 30s in the right eye and with the additional risk factor of pseudoexfoliation, treatment was initiated with a prostaglandin and was shortly followed by aqueous suppression and SLT in the right eye. Subsequent OCT pRNFL testing showed progression so a third drop was added for further IOP reduction. Since then, testing has been stable with over 77 months of additional follow-up. The left eye eventually showed IOP elevation of 24 and progression by OCT pRNFL, so a prostaglandin analog was added. Since that time, OCT pRNFL has remained stable for an additional 77 months of follow-up. The patient was followed with testing for a total of 118 months. Case 5 A 69-year-old White woman was referred with a diagnosis of open-angle glaucoma with IOP in the mid-30s bilaterally, progression by OCT pRNFL in both eyes, and progression by VF in the left locally. On presentation to our service, IOP was 32 mm Hg in the right eye and 35 mm Hg in the left eye, and the patient was intolerant to all topical medications. CCT was 520 mm in the right eye and 518 mm in the left eye. The patient was mildly hyperopic bilaterally. The CDR was 0.1 bilaterally. VF testing showed no notable defects in the right eye and a superior arcuate and dense inferior arcuate-threatening fixation in the left eye. OCT pRNFL had thinning inferiorly on the right eye and diffuse thinning on the left eye and progression on locally obtained studies was observed. GCIPL analysis was within normal limits in the right eye and showed thinning of the superior and temporal sectors in the left eye. Because the VF and OCT pRNFL were out of proportion to the degree of cupping, a B scan was obtained that revealed bilateral ODD. Given IOP in the 30s bilaterally and progression by OCT pRNFL and VF, treatment was recommended. The patient was completely drop intolerant and initially underwent SLT in both eyes without significant response and ultimately went on to require trabeculectomy bilaterally. After trabeculectomy, IOP has been low teens bilaterally without further evidence of progression over 21-month follow-up. Case 6 A 44-year-old White woman with a history of ocular hypertension and pigment dispersion syndrome was referred to our service for further evaluation. On presentation, examination revealed diffuse iris transillumination defects bilaterally consistent with the previous diagnosis of pigment dispersion syndrome. IOP was 25 mm Hg bilaterally, Kohli et al: J Neuro-Ophthalmol 2022; 42: 470-475 unmedicated. CCT was 613 mm in the right eye and 600 mm in the left eye. Myopia was present with 211.0 and 29.25 diopters in the right eye and left eye, respectively. The CDR was 0.0 bilaterally. VF analysis showed no defects in either eye. OCT pRNLF revealed thinning inferiorly in both eyes. GCIPL analysis showed diffuse thinning bilaterally. With crowding of the optic discs noted, a B scan and EDI OCT were obtained and revealed ODD bilaterally. Given concurrent ocular hypertension and ODD with the additional risk factor of pigment dispersion syndrome in a young myopic patient, treatment was recommended. After initiation of treatment with a prostaglandin analog, IOP was lowered 25%, and no progression has been noted with over 11-months follow-up. DISCUSSION ODD is a condition that causes progressive VF loss in some patients, and there is no currently accepted treatment strategy to reduce the risk of further progression. Identification of risk factors may allow for novel treatment strategies in hopes of reducing VF progression. Nonmodifiable risk factors including ODD height and volume, measured by delineation on EDI OCT and B scan, have been associated with VF abnormalities (11,18,19). Modifiable risk factors amendable to treatment, including IOP, with topical medications, laser, or surgical intervention, have been controversial and were the subject of a recent Point Counter-Point in the Journal of NeuroOphthalmology (20). Rationale for treating progressive VF loss with IOP-lowering medications in ODD is largely secondary to the difficulty in excluding a coexisting GON or the possibility of a shared pathophysiological mechanism between ODD and GON. In this article, we present a cohort of patients with coexisting ODD and ocular hypertension. In our series of 6 patients, 2 patients showed no progression in either eye and 4 patients showed progression in both eyes. Five patients were ultimately treated with IOP-lowering treatment. Of the 4 patients who showed evidence of progression in the setting of ocular hypertension, no further progression was observed after the final IOP-lowering treatment (i.e., the time at which the target IOP was reached). This series of patients is presented to highlight the coexistence of ocular hypertension with ODD and suggests that treatment of ocular hypertension in a patient with ODD is a reasonable therapeutic option to reduce the risk of progression by VF or OCT pRNFL. Relatively few reports are available in the medical literature studying patients with concurrent ODD and ocular hypertension. Descriptions of this rare patient population are mostly limited to the level of individual case reports (21) or series (13,14). Larger studies have also included a cohort of patients with coexisting ocular hypertension and ODD on subgroup analysis (15,17). One series in the 1980s described 5 patients 473 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution with coexisting pigment dispersion syndrome and ODD. Although not all patients had elevated IOP, treatment of IOP in the setting of progression of VF deficits and/or optic disc changes was recommended (14). Another series of 2 patients detailed treatment of ocular hypertension in the setting of ODD with topical medications and/or laser intervention, which discussed the utility of using OCT pRNFL to help analyze progression when cup features are obscured by ODD (13). A larger study including 13 patients with coexisting ODD and ocular hypertension found that VF loss was more likely in eyes with ODD and coexisting ocular hypertension (15). Another report found a higher incidence of a positive family history of glaucoma in patients with ODD, although specific IOP or progression data were not presented (22). In the absence of ocular hypertension, IOP reduction as a treatment for ODD is also particularly controversial. In a retrospective study of 36 patients with ODD that did not include patients with ocular hypertension, higher IOP was associated with greater VF and pRNFL loss (9). Furthermore, in a study of 34 patients with ODD, IOP reduction with topical aqueous suppression was associated with decreased progression by VF and pRNFL thickness (16). On the contrary, in 1 study of 47 eyes, IOP was not associated with progression of VF deficits in patients with ODD, although patients with ocular hypertension were excluded from the study (18). In addition, in a retrospective chart review that included 146 patients but excluded patients on IOP-lowering therapy, higher IOP was not associated with greater rates of progression by VF testing or OCT pRNFL. Of note, the 8 eyes with ocular hypertension included in this study did not have worse perimetric mean deviation as assessed by VF testing (17). Shared pathophysiological mechanisms may contribute to both ODD and GON. Therefore, IOP-related stresses whether related to mechanical, metabolic, or vascular stress may contribute to progression of ODD. Ocular perfusion pressure (OPP) describes perfusion of the retina as a difference in pressure between the central retinal artery and central retinal vein. Because IOP and central retinal venous pressure are similar and because the mean brachial artery blood pressure is similar to the central retinal artery pressure, OPP is generally estimated as a function of mean arterial pressure and IOP (23). Diminished OPP may be a shared pathophysiological mechanism with GON (24,25) and ODD (26,27). Alternatively, elevated retinal ganglion cell susceptibility to damage by increased mechanical stress and impairing axonal transport at a given IOP is a potential mechanism of GON (28–30). ODD are suspected to arise from impaired axonal transport and metabolism of the retinal ganglion cells (1,2). Therefore, impairment of axonal transport and mechanical stress may be an additional shared pathophysiological mechanism. Although different conditions, both ODD and GON may both show a pressure-dependent loss of retinal ganglion cells by shared mechanisms and may, therefore, respond to IOP-lowering treatment in a similar fashion. 474 Although ocular hypertension is a significant risk factor for GON, not all patients with ocular hypertension will develop VF or structural changes consistent with GON over time. While lowering IOP medically or surgically in patients with ocular hypertension decreases the risk of progression into GON, there is a subset of patients in whom ocular hypertension seems to never result in GON (31,32). It is possible that a similar phenomenon may be observed in patients with concurrent ODD and ocular hypertension where some patients may benefit from IOP reduction while others are more resistant to progressive optic disc changes consistent with ODD or GON, which was seen in our case series. Furthermore, many patients with GON will have no history of IOP higher than the upper limit of normal (21 mm Hg). These patients have a diagnosis of normal or low-tension glaucoma (LTG). In some populations, LTG is the most common type of open-angle glaucoma (33). Therefore, it is possible that patients with progressive ODD without elevated IOP are progressing by an LTG-type mechanism. In this case, the hypothesis would be that it is a predominantly GON-driven process, whether high-tension or LTG, that drives the progression seen in ODD that is simply masked at the neuroretinal rim by the presence of ODD. There are limitations to this study inherent to the retrospective and descriptive nature of a case series. First, although one of the larger case series available in the medical literature on the subject (13–15), our study was also limited by a relatively small sample size. Second, in some of the cases, a limited number of serial glaucoma tests were available limiting the detection of progression and potential treatment effects over a long period of time. However, the primary goal of this case series was to present characteristics in this relatively rare subset of patients with simultaneously coexisting ODD and ocular hypertension where glaucoma monitoring and management is challenging rather than providing evidence supporting a definitive cause–effect relationship. Establishing a concurrent diagnosis of ODD and GON is both challenging and controversial (13,15). With current diagnostic modalities, it may not be possible to distinguish with certainty progressive ODD vs progressive GON in the setting of ODD. Cupping in the setting of ODD has been suggested as a rare occurrence (14) but this may be dependent on the location of the ODD. Further work is needed to elucidate the mechanisms of optic neuropathy progression in patients with ODD. Because IOP seems to be a risk factor, particularly in patients with ocular hypertension, it needs to be determined whether a potential shared mechanism between ODD and GON exists or whether a predominantly GON process is occurring and the definitive diagnosis is masked by the appearance of the optic disc. Our case series of 6 patients with coexisting ODD and ocular hypertension with two-thirds showing progression that was halted with IOP-lowering interventions suggests there is a GON-like mechanism in some of these patients. Although progression inferences are limited given the duration of follow-up for some cases, 2 patients Kohli et al: J Neuro-Ophthalmol 2022; 42: 470-475 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution did not show progression despite being ocular hypertensive, which suggests that the process is multifactorial and not all patients require treatment. In the setting of progressive optic neuropathy, treatment of IOP, particularly for patients with ocular hypertension, is a reasonable therapeutic option. Although determining the origin of optic neuropathy in patients with ocular hypertension with ODD can be a challenge, we believe having a low threshold for initiating IOPlowering treatment is warranted at this time. STATEMENT OF AUTHORSHIP Conception and design: D. Kohli, G. Roddy; Acquisition of data: D. Kohli; Analysis and interpretation of data: D. Kohli, G. Roddy. Drafting the manuscript: D. 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