Optic Nerve Head Drusen: The Relationship Between Intraocular Pressure and Optic Nerve Structure and Function

To determine whether at the time of diagnosis, the intraocular pressure (IOP) in patients with optic nerve head drusen (ONHD) correlates with the perimetric mean deviation (PMD) and the mean retinal nerve fiber layer (RNFL) thickness on optical coherence tomography (OCT). This retrospective chart review included adults with ONHD from 2 academic medical centers. Inclusion criteria were age older than 18 years, definitive diagnosis of ONHD, measurement of IOP, and an automated visual field (VF) within 3 months of diagnosis. Exclusion criteria were unreliable VFs, use of IOP-lowering therapy, and visually significant ocular comorbidities. Data were collected from the initial visit. Age, IOP, method of diagnosis of ONHD, mean RNFL thickness, and PMD were recorded. Multiple and logistic regression models were used to control for potential confounders in statistical analyses. Chart review identified 623 patients, of which 146 patients met inclusion criteria. Mean age was 44.2 years (range: 19-82 years). Average PMD of 236 eyes was -5.22 dB (range, -31.2 to +1.21 dB). Mean IOP was 15.7 mm Hg (range: 6-24 mm Hg). Forty eyes (16.9%) underwent RNFL measurement using OCT; mean RNFL thickness was 79.9 μm (range: 43-117 μm). There was no statistically significant association between IOP and PMD (P = 0.13) or RNFL thickness (P = 0.65). Eyes with ocular hypertension tended to have less depressed PMD than those without (P= 0.031). Stratified analyses of visible and buried subgroups yielded similar results. Lowering IOP in patients with ONHD has been proposed as a means to prevent progression of optic neuropathy. Our study demonstrated that among predominately normotensive eyes, higher IOP was not associated with greater VF loss or thinner RNFL at the time of presentation. This suggests that lowering IOP may not be beneficial in preventing visual loss in normotensive eyes with ONHD.

Original Contribution Optic Nerve Head Drusen: The Relationship Between Intraocular Pressure and Optic Nerve Structure and Function Kaitlyn W. Nolan, MD, Michael S. Lee, MD, Rohan A. Jalalizadeh, MD, Kevin C. Firl, MS, Gregory P. Van Stavern, MD, Collin M. McClelland, MD Objective: To determine whether at the time of diagnosis, the intraocular pressure (IOP) in patients with optic nerve head drusen (ONHD) correlates with the perimetric mean deviation (PMD) and the mean retinal nerve fiber layer (RNFL) thickness on optical coherence tomography (OCT). Methods: This retrospective chart review included adults with ONHD from 2 academic medical centers. Inclusion criteria were age older than 18 years, definitive diagnosis of ONHD, measurement of IOP, and an automated visual field (VF) within 3 months of diagnosis. Exclusion criteria were unreliable VFs, use of IOP-lowering therapy, and visually significant ocular comorbidities. Data were collected from the initial visit. Age, IOP, method of diagnosis of ONHD, mean RNFL thickness, and PMD were recorded. Multiple and logistic regression models were used to control for potential confounders in statistical analyses. Results: Chart review identified 623 patients, of which 146 patients met inclusion criteria. Mean age was 44.2 years (range: 19-82 years). Average PMD of 236 eyes was 25.22 dB (range, 231.2 to +1.21 dB). Mean IOP was 15.7 mm Hg (range: 6-24 mm Hg). Forty eyes (16.9%) underwent RNFL measurement using OCT; mean RNFL thickness was 79.9 mm (range: 43-117 mm). There was no statistically significant association between IOP and PMD (P = 0.13) or RNFL thickness (P = 0.65). Eyes with ocular hypertension tended to have less depressed PMD than those without (P= 0.031). Stratified analyses of visible and buried subgroups yielded similar results. Conclusions: Lowering IOP in patients with ONHD has been proposed as a means to prevent progression of optic neuropathy. Our study demonstrated that among predominately normotensive eyes, higher IOP was not associated with greater VF loss or thinner RNFL at the time of presentation. This suggests that lowering IOP may not be beneficial in preventing visual loss in normotensive eyes with ONHD. Journal of Neuro-Ophthalmology 2018;38:147-150 doi: 10.1097/WNO.0000000000000587 © 2017 by North American Neuro-Ophthalmology Society V The authors report no conflicts of interest. isual field (VF) defects have been reported to be present in 49%-85% of patients with optic nerve head drusen (ONHD) (1,2). Although rarely impairing visual acuity, ONHD often causes progressive VF loss. It has been proposed that lowering intraocular pressure (IOP) may be a protective treatment (3-5), similar to reducing the risk of progression in glaucomatous optic neuropathy (6). Brimonidine, an alpha-2 adrenergic agonist, has been used in patients with ONHD both for its IOP-lowering and neuroprotective effects. In animal models, brimonidine has demonstrated neuroprotection of retinal ganglion cells subjected to ischemic crush and compressive injury. However, there is little proof of neuroprotection in comparable human studies (7). There are scarce published data on the relationship between IOP and VF defects in ONHD. The purpose or our study was to determine whether, at the time of diagnosis, IOP in patients with ONHD correlated with perimetric mean deviation (PMD) and/or the mean retinal nerve fiber layer (RNFL) thickness as measured using optical coherence tomography (OCT). Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the full text and PDF versions of this article on the journal's Web site (www. jneuro-ophthalmology.com). METHODS Address correspondence to Collin M. McClelland, MD, Department of Ophthalmology and Visual Neurosciences, 420 Delaware Street, SE/MMC 493, Minneapolis, MN 55455; E-mail: [e-mail] Patients from 2 academic medical centers with a diagnosis of ONHD or pseudopapilledema were identified through Department of Ophthalmology and Visual Neurosciences (KWN, MSL, KCF, CMM), University of Minnesota School of Medicine, Minneapolis, Minnesota; and Department of Ophthalmology and Visual Sciences (RAJ, GPVS), Washington University School of Medicine, St. Louis, Missouri. Nolan et al: J Neuro-Ophthalmol 2018; 38: 147-150 147 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution billing records from January 1, 2005, to January 1, 2016. Inclusion criteria were age older than 18 years, confirmed diagnosis of ONHD, an IOP reading at presentation, and an automated VF (either Humphrey or Octopus) within 3 months of diagnosis. Exclusion criteria were unreliable VFs, use of IOP-lowering therapy, and ocular comorbidities that could alter VF results. VFs were considered unreliable if they had greater than 33% false positives, false negatives, or fixation losses. Mean RNFL data were not available for all patients, but were collected if tested within 3 months of ONHD diagnosis. All data were obtained from either Cirrus or Spectralis OCT systems. IOP measurements were obtained using applanation, Tono-Pen, or ICare tonometry. The diagnosis of ONHD was established by B-scan ultrasound, computed tomography, fundus autofluorescence, enhanced-depth imaging OCT (EDI-OCT), and/or visualization of drusen on clinical examination or fundus photographs. The location of drusen (buried or surface) was noted. Our primary objective was to determine whether IOP correlated with PMD. Secondary objectives included correlation of IOP with RNFL thickness and correlation of ocular hypertension (IOP $ 22 mm Hg) and with the presence of VF defects (defined as PMD worse than 23.0 dB). Before analysis, PMD values were transformed logarithmically to normalize their distribution. Initial statistical analysis of continuous and binary outcome variables was performed using simple linear regression and Fisher exact tests. To control for potential confounders including age, sex, history of transient visual obscurations, history of glaucoma, left vs. right eye, and diagnostic modality, multiple linear regression and logistic regression were used. Statistical significance was assigned to results with a P value less than or equal to 0.05. All statistical analyses were performed using SAS 9.4 (SAS Institute, Cary, NC). TABLE 1. Demographics and clinical findings of patients with ONHD Total eyes Total patients 236 146 n (% of eyes) Male Ocular hypertension History of TVO Buried drusen Visible drusen 77 (32.6) 8 (3.39) 24 (10.2) 74 (31.4) 162 (68.6) Mean (range) Age, yrs IOP, mm Hg RNFL thickness, mm PMD, dB 44.2 (19 to 82) 15.7 (6 to 24) 79.9 (43 to 117) 25.22 (231.2 to 1.21) IOP, intraocular pressure; ONHD, optic nerve head drusen; PMD, perimetric mean deviation; RNFL, retinal nerve fiber layer; TVO, transient visual obscurations. no association was found in the buried or visible drusen subgroups between IOP and RNFL thicknesses (P = 0.50, P = 0.87, respectively). Eyes with ocular hypertension were less likely to have VF defects than those with normal IOP (odds ratio: 0.20; 95% confidence interval: 0.037-1.07), although this did not reach statistical significance (P = 0.061). Also, this association was not significant in the visible drusen subgroup (P = 0.064), nor the buried drusen subgroup (P = 0.79). Interestingly, eyes with ocular hypertension had significantly less depressed PMD than those without hypertension among all eyes (P = 0.038) and those with visible drusen (P= 0.035). This association was not found in the buried drusen subgroup (P = 0.65). Greater RNFL thickness was significantly associated with less depressed PMD among the buried drusen subgroup (P = 0.037), visible drusen subgroup (P = 0.0001), and all eyes (P , 0.0001). RESULTS DISCUSSION Eight hundred eleven eyes of 623 patients were identified as having ONHD or pseudopapilledema. Of these, 236 eyes of 146 patients met inclusion criteria. The mean age was 44.2 years (range, 19-82 years); the average PMD was 25.22 dB (range: 31.2 to +1.21 dB); and the mean IOP was 15.7 mm Hg (range: 6-24 mm Hg) (Table 1). Of the 236 eyes, 8 had ocular hypertension (3.39%), and 40 (17%) had RNFL OCT measurement data available. There was no significant association between PMD and IOP (see Supplemental Digital Content, Figure E1, http://links.lww.com/WNO/A276). This also was true for subgroup analyses of eyes with buried and visible ONHD (Table 2). A comparison of RNFL thickness and IOP showed almost no linear trend for the group at large (see Supplemental Digital Content, Figure E2, http://links.lww.com/WNO/A277), and analyses found no significant association (P = 0.65). Likewise, Once the diagnosis of ONHD has been established, clinicians must counsel their patients on prognosis and management, despite the lack of good evidence to guide them. Up to 87% of individuals with ONHD either have VF defects at diagnosis or will develop them (2). Factors associated with higher rates of VF defects in patients with ONHD include superficial drusen (8), thinner RNFL (8,9), and increasing age (10). One study of 23 untreated eyes with ONHD, followed over a mean of 9.7 years, showed an average interval loss of 20.78 dB on automated VF testing (Humphrey) and only 3 eyes demonstrated more than a 3 dB decrease (11). In addition, Abegao Pinto et al (12) determined that individuals with ONHD (like those with glaucoma) have low blood flow velocities through the arterioles surrounding around the optic disc. Furthermore, the pattern of central retinal artery 148 Nolan et al: J Neuro-Ophthalmol 2018; 38: 147-150 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 2. Comparison of patients with visible vs. buried ONHD Visible ONHD Buried ONHD Total eyes 162 n (% of eyes) 74 n (% of eyes) Male Ocular hypertension History of TVO 54 (33.3) 5 (3.09) 12 (7.41) Mean (range) 23 (31.1) 3 (4.05) 12 (16.2) Mean (range) Age, yrs IOP, mm Hg RNFL thickness, mm Mean deviation, dB 47.6 (19 to 82) 15.7 (6 to 24) 76.6 (43 to 117) 26.07 (231.2 to 1.21) 36.5 (19 to 80) 15.7 (9 to 24) 85.9 (58 to 111) 23.36 (217.6 to 0.97) IOP, intraocular pressure; ONHD, optic nerve head drusen; RNFL, retinal nerve fiber layer; TVO, transient visual obscurations. velocity correlated with the extent of VF loss, a feature not seen in patients with glaucoma. In theory, lowering IOP could improve optic nerve head perfusion pressure and provide clinicians a viable treatment option for ONHD. The Ocular Hypertension Treatment Study found that treating ocular hypertension (lowering IOP by 22.5%) reduced the risk of progression of VF defects from 9.5% to 4.4% in 5 years (6). In a cross-sectional study of 103 eyes with ONHD, Grippo et al (5) found that VF loss was present in 90% of hypertensive eyes and 66.7% of normotensive eyes, independent of age, sex, and visibility of ONHD. They recommended that individuals with ONHD and elevated IOP undergo close monitoring and receive IOP-lowering therapy to prevent progression of VF loss. Others have made similar recommendations (3,4). In addition, the finding of RNFL thinning using OCT has been used as an indication of glaucoma, despite the fact that drusen alone can cause loss of RNFL (13,14). Our study showed no clinically significant correlation between IOP and PMD or RNFL thickness (P = 0.13 and 0.65, respectively) in patients with ONHD at the time of diagnosis. In contrast to the study by Grippo et al (5), we did not find ocular hypertension to be associated with a PMD worse than 23.0 dB (P = 0.071). However, in our patient cohort, we had fewer individuals with ocular hypertension (3.39%) compared with that of Grippo et al (21.4%), making a comparison of the 2 studies problematic. We did find a significant correlation between the presence of ocular hypertension and less depressed PMD among all eyes and the visible ONHD subgroup (P = 0.038 and 0.035 respectively). There were only 5 patients with ocular hypertension and visible drusen, so our results should be interpreted with caution. We acknowledge a number of limitations to our study. First, we did not measure central corneal thickness (CCT) because pachymetry is not routinely obtained in patients with ONHD. Interestingly, one study of 37 eyes with visible ONHD found a statistically higher average CCT in drusen eyes (581.32 mm) as compared to healthy controls (556.23 mm), suggesting that measured IOP in our study Nolan et al: J Neuro-Ophthalmol 2018; 38: 147-150 eyes as a group may be slightly higher than actual IOP (15). Second, the use of PMD ,23.0 dB as the sole criterion to determine whether or not a VF is abnormal was seen arbitrarily. Third, our results were limited to eyes with OCT data (n = 40 total eyes, n = 2 ocular hypertensive eyes) and using RNFL thickness alone as a measure of optic nerve health. Casado et al (16) demonstrated that measurement of the retinal ganglion cell layer rather than RNFL thickness may be a more accurate marker of optic nerve damage in patients with ONHD. Fourth, our report was retrospective and, therefore, subject to ascertainment bias, lack of consistent data collection and testing, and referral bias. In addition, there was only 1 set of IOPs and VFs per patient. Finally, VF data were included from both the Octopus and the Humphrey automated VF systems. Although a consistent method of automated perimetry would have been ideal, the PMD between these 2 perimeters has been reliably compared (17,18). Despite these limitations, we believe our results are valid and indicate that lowering IOP in normotensive eyes may not be beneficial in preventing vision loss in patients with ONHD. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: K. W. Nolan, M. S. Lee, R. A. Jalalizadeh, G. P. Van Stavern, and C. M. McClelland; b. Acquisition of data: K. W. Nolan, M. S. Lee, R. A. Jalalizadeh, G. P. Van Stavern, and C. M. McClelland; c. Analysis and interpretation of data: K. C. Firl, K. W. Nolan, C. M. McClelland, M. S. Lee, and G. P. Van Stavern. Category 2: a. Drafting the manuscript: K. W. Nolan, C. M. McClelland, and K. C. Firl; b. Revising it for intellectual content: C. M. McClelland, M. S. Lee, G. P. Van Stavern, and R. A. Jalalizadeh. Category 3: a. Final approval of the completed manuscript: K. W. Nolan, M. S. Lee, R. A. Jalalizadeh, G. P. Van Stavern, C. M. McClelland, and K. C. Firl. REFERENCES 1. Lorentzen SE. Drusen of the optic disk. A clinical and genetic study. 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