Peripapillary Vessel Density Measured by Optical Coherence Tomography Angiography in Idiopathic Intracranial Hypertension

Background: Although alterations in the peripapillary retinal nerve fiber layer (RNFL) in patients with idiopathic intracranial hypertension (IIH) have been characterized using optical coherence tomography (OCT), there are little data regarding the peripapillary vasculature in this patient population. Our aim was to evaluate findings of OCT angiography (OCT-A) in the peripapillary region in addition to the RNFL measurements on OCT in patients with IIH. Methods: Thirty-eight eyes of 19 patients with IIH and 42 eyes of 21 healthy controls were enrolled in our study. Papilledema was graded according to the Frisen scale. Peripapillary RNFL and vessel density were evaluated with OCT and OCT-A, respectively. Results: RNFL thickness was found to be increased with OCT, but this was statistically significant only in the inferior location in IIH patients when compared with the control group. There was a significant decrease in mean peripapillary vessel density measured with OCT-A in IIH patients with papilledema when compared with the control group (P < 0.05). Conclusions: In patients with IIH, there was a decrease in peripapillary vessel density measured by OCT-A, and this decrease may be a consequence of the swelling of axons in the peripapillary retina due to papilledema. However, autoregulatory vascular mechanisms may also play a role in decreased peripapillary vessel density.

Original Contribution Peripapillary Vessel Density Measured by Optical Coherence Tomography Angiography in Idiopathic Intracranial Hypertension Feyza Tüntaş Bilen, MD, Huban Atilla, MD Background: Although alterations in the peripapillary retinal nerve fiber layer (RNFL) in patients with idiopathic intracranial hypertension (IIH) have been characterized using optical coherence tomography (OCT), there are little data regarding the peripapillary vasculature in this patient population. Our aim was to evaluate findings of OCT angiography (OCT-A) in the peripapillary region in addition to the RNFL measurements on OCT in patients with IIH. Methods: Thirty-eight eyes of 19 patients with IIH and 42 eyes of 21 healthy controls were enrolled in our study. Papilledema was graded according to the Frisen scale. Peripapillary RNFL and vessel density were evaluated with OCT and OCT-A, respectively. Results: RNFL thickness was found to be increased with OCT, but this was statistically significant only in the inferior location in IIH patients when compared with the control group. There was a significant decrease in mean peripapillary vessel density measured with OCT-A in IIH patients with papilledema when compared with the control group (P , 0.05). Conclusions: In patients with IIH, there was a decrease in peripapillary vessel density measured by OCT-A, and this decrease may be a consequence of the swelling of axons in the peripapillary retina due to papilledema. However, autoregulatory vascular mechanisms may also play a role in decreased peripapillary vessel density. Journal of Neuro-Ophthalmology 2019;39:319-323 doi: 10.1097/WNO.0000000000000745 © 2018 by North American Neuro-Ophthalmology Society F luorescein angiography has been the primary method by which the vascular changes accompanying papilledema Ophthalmology Department, Ankara University Faculty of Medicine, Ankara, Turkey. The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www. jneuro-ophthalmology.com). Address correspondence to Feyza Tüntaş Bilen, MD, Ophthalmology Department, Ankara University Faculty of Medicine, Balkiraz Mahallesi Esenler Sokak 1/5, Dikimevi, Ankara, Turkey 06620; E-mail: [e-mail] Tüntaş Bilen and Atilla: J Neuro-Ophthalmol 2019; 39: 319-323 have been studied. These include capillary dilation in the peripapillary region, engorgement of the retinal venous system, and vascular leakage from the superficial vessels on the surface of the optic disc. Yet, quantitative data such as vessel density cannot be measured with fluorescein angiography. The purpose of our study was to assess the peripapillary vessel density using optical coherence tomography angiography (OCT-A) in a cohort of patients with idiopathic intracranial hypertension (IIH) including those with papilledema and others in whom papilledema had resolved. METHODS Our study was approved by the institutional review board of Ankara University School of Medicine and adhered to the tenets of the Declaration of Helsinki. Thirty-eight eyes of 19 patients with IIH who were evaluated at Ankara University Neuro-ophthalmology Department and 42 eyes of 21 healthy volunteers were included. In addition to obtaining medical and family histories of all patients, medical records were reviewed with particular attention to opening pressure on lumbar puncture and neuroimaging reports. All patients and controls had a complete ophthalmic examination. Papilledema was assessed according to the Frisen Scale. Images from OCT and OCT-A (Optovue Inc, Fremont, CA) were recorded and fundus photographs were taken (Fig. 1). The 19 patients included in our study all had met the modified Dandy criteria (1). Seven patients were being treated with acetazolamide and 4 with topiramate. Four patients were on no medication for IIH because their disease, including papilledema, had resolved. Four newly diagnosed IIH cases had not been given medication when they were included in the study. Optic disc AngioVue and macula raster images were recorded with OCT-A. Retinal nerve fiber layer (RNFL) thickness was recorded for mean, superior, inferior, temporal, and nasal regions. The optic disc AngioVue images were recorded in 4.5 · 4.5 mm dimensions. The optic nerve head 319 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 1. A patient with IIH has Grade 3 papilledema (A). Results are shown for assessment of peripapillary RNFL thickness on OCT (B), and peripapillary vessel density on OCT-A (C). IIH, idiopathic intracranial hypertension; OCT, optical coherence tomography; OCT-A, optical coherence tomography angiography; RNFL, retinal nerve fiber layer. vessel density was calculated automatically for the 750-mm peripapillary region with AngioVue and was recorded as superior-temporal, superior-nasal, nasal, inferior-nasal, inferiortemporal, and temporal localizations, and as an average value. The statistical analysis was performed with SPSS 11.5 package program. Descriptive statistical data were shown as mean ± SD. The normal distribution of the data was examined by Kolmogorov-Smirnov and Shapiro-Wilk normality tests. The Student t test was used for the normally distributed groups, and the Mann-Whitney U test was used for the nonnormally distributed groups to assess whether there was a statistically significant difference between the groups. The Spearman correlation test was used for the measure of the strength of relationship between paired data. P values of ,0.05 were considered statistically significant. To reduce the effects of environmental or systemic factors on the statistical outcome, the right and left eyes of the subjects were evaluated independently. RESULTS Thirty-eight eyes of 19 patients with IIH and 42 eyes of 21 healthy volunteers were included in our study. The mean age was 35.7 ± 12 years for patients with IIH and 35.9 ± 9 years for the control group (P = 0.89). The mean study age at the time of diagnosis and the mean follow-up time were 31.9 ± 6 and 4.9 ± 6 years, respectively. The mean cerebrospinal fluid (CSF) pressure was 25.4 (10-38) mm H2O. Best-corrected visual acuity and Ishihara color vision test score was 20/20 and 13/13 plates for both groups, respectively. Ten patients had bilateral papilledema, 4 had unilateral papilledema, and in 5 patients, the papilledema had resolved. In the patients with papilledema, 15 had Grade 1, 4 had Grade 2, 3 had Grade 3, and 2 had Grade 4. Fourteen eyes had no papilledema. The RNFL thickness assessed by OCT was found to be thickened in all localizations in IIH cases, but this thickening was statistically significant only at the inferior location (P , 0.05) (Table 1). There was a significant decrease in mean peripapillary vessel density measured with OCT-A in patients 320 with IIH compared to the control group for left eyes (P = 0.08 and 0.05 for right and left eyes, respectively). Regarding peripapillary vessel density and grade of papilledema, there was a statistically significant negative correlation (P , 0.05 for right and left eyes). There was a negative correlation between mean RNFL thickness and mean peripapillary density, but this was not statistically significant (P = 0.72 and 0.18 for right and left eyes, respectively). There was no correlation between mean follow-up time and peripapillary vessel density (P = 0.06 and 0.87 for right and left eyes, respectively). Patients with and without papilledema within the IIH group were compared for RNFL thickness and peripapillary vessel density (Table 2). Although there was an increase in RNFL thickness in patients with papilledema compared to patients without papilledema, statistical significance was found only in the inferior localization for the right eye. Peripapillary vascular density decreased quantitatively in cases with papilledema in all localizations for right and left eyes, except for inferior-nasal localization for right eyes (P = 0.17 and 0.03 for right and left eyes, respectively). Thickness of the RNFL was found to be quantitatively thicker in IIH patients with papilledema when compared to controls (Table 3). There was a statistically significant decrease in mean peripapillary vessel density measured with OCT-A in IIH patients with papilledema compared to the control group (P = 0.03 and 0.01 for the right and left eyes, respectively). There was no significant change in RNFL thickness or peripapillary vessel density between control subjects and IIH patients without papilledema (Table 4). Mean RNFL thickness (see Supplemental Digital Content, Figure E1, http://links.lww.com/WNO/A360) and mean peripapillary vessel density (see Supplemental Digital Content, Figure E2, http://links.lww.com/WNO/A361) were calculated for each group for right and left eyes. DISCUSSION In our study, we evaluated the peripapillary vasculature in patients with IIH to detect possible changes that may occur Tüntaş Bilen and Atilla: J Neuro-Ophthalmol 2019; 39: 319-323 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Comparison of RNFL thickness and peripapillary vessel density values between controls and patients with IIH Right Eyes RNFL thickness (mm) Mean Superior Nasal Inferior Temporal Peripapillary vessel density (%) Mean Superior temporal Superior nasal Nasal Inferior nasal Inferior temporal Temporal Left Eyes Control (n = 21) IIH (n = 19) P value Control (n = 21) IIH (n = 19) P value 103.00 126.71 81.95 126.47 77.09 111.94 131.78 93.05 144.00 78.63 0.37 0.62 0.96 0.05 0.77 102.76 127.04 79.42 126.76 78.00 112.05 135.26 89.26 141.36 82.21 0.33 0.28 0.87 0.03 0.92 62.60 64.12 62.09 60.92 64.43 64.57 62.43 60.94 61.45 58.89 59.96 63.17 62.79 60.95 0.08 0.08 0.07 0.33 0.31 0.26 0.19 62.27 65.19 61.73 59.87 63.79 67.69 60.75 60.56 61.77 60.74 58.87 62.12 63.24 59.90 0.05 0.006 0.58 0.38 0.20 0.002 0.40 IIH, idiopathic intracranial hypertension; RNFL, retinal nerve fiber layer. in this disease. We were able to find a significant decrease in mean peripapillary vessel density measured with OCT-A in IIH patients with papilledema compared to the control group. In IIH patients with regressed papilledema, peripapillary vessel density decreases to normal values. In addition, peripapillary vessel density was negatively correlated with the Frisen grade of papilledema. There are few published studies evaluating papilledema with OCT-A. Rougier et al (2) reported the vascular changes the optic nerve head of various types of optic disc edema during the acute phase. They included 13 patients with IIH, 12 had bilateral papilledema, and 1 had unilateral papilledema. They found that the radial peripapillary network was "unchanged." No mention is made of comparing the peripapillary vascular density in the patient with unilateral papilledema to the fellow eye. Fard et al (3) studied OCT-A results in a cohort of patients with various causes of optic disc swelling using both commercially available (Optovue) and customized OCT-A software programs. Using commercially available software, they found significantly TABLE 2. Comparison of RNFL thickness and peripapillary vessel density values between IIH cases with and without papilledema Right Eyes Left Eyes IIH Cases IIH Cases Without IIH Cases IIH Cases Without With Papilledema Papilledema With Papilledema Papilledema (n = 11) P value (n = 8) (n = 13) P value (n = 6) RNFL thickness (mm) Mean Superior Nasal Inferior Temporal Peripapillary vessel density (%) Mean Superior temporal Superior nasal Nasal Inferior nasal Inferior temporal Temporal 101.66 123.66 79.83 129.16 74.66 118.00 135.33 101.41 153.66 80.83 0.24 0.28 0.20 0.03 0.60 104.25 129.75 80.50 131.87 75.00 118.90 138.80 97.30 150.10 89.10 0.26 0.55 0.65 0.15 0.24 62.72 64.22 60.27 62.40 62.49 65.36 62.42 60.22 60.45 58.19 58.94 63.43 61.66 60.40 0.17 0.20 0.46 0.03 0.68 0.34 0.64 62.39 63.30 63.55 61.25 63.26 64.55 61.24 59.17 60.21 58.34 57.14 61.02 62.45 59.10 0.03 0.08 0.07 0.02 0.35 0.38 0.18 IIH, idiopathic intracranial hypertension; RNFL, retinal nerve fiber layer. Tüntaş Bilen and Atilla: J Neuro-Ophthalmol 2019; 39: 319-323 321 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 3. Comparison of RNFL thickness and peripapillary vessel density values between controls and IIH patients with papilledema Right Eyes RNFL thickness (mm) Mean Superior Nasal Inferior Temporal Peripapillary vessel density (%) Mean Superior temporal Superior nasal Nasal Inferior nasal Inferior temporal Temporal Left Eyes P value Control (n = 21) IIH With papilledema (n = 11) 118.00 135.33 101.41 153.66 80.83 0.08 0.68 0.42 0.02 0.89 102.76 127.04 79.42 126.76 78.00 118.90 138.80 97.30 150.10 89.10 0.14 0.36 0.62 0.01 0.31 60.22 60.45 58.19 58.94 61.66 61.60 60.40 0.03 0.03 0.06 0.07 0.47 0.16 0.19 62.27 65.19 61.73 59.87 63.79 67.69 60.75 59.17 60.21 58.34 57.14 61.02 62.45 59.10 0.01 ,0.01 0.12 0.03 0.11 ,0.01 0.17 Control (n = 21) IIH With papilledema (n = 13) 103.00 126.71 81.95 126.47 77.09 62.60 64.12 62.09 60.92 64.43 64.57 62.43 P value IIH, idiopathic intracranial hypertension; RNFL, retinal nerve fiber layer. lower peripapillary vessel density in 22 patients (44 eyes) with IIH and papilledema (Frisen Grade 1 or 2 in 17 eyes; Grade 3 or 4 in 27 eyes). By contrast, when the customized software was used, there were no significant differences in peripapillary density values in patients with IIH vs healthy controls. The customized software excluded contributions from major retinal vessels, which obscure vessels of lesser caliber. Further research is required to better understand the observation made by Ford et al using the customized software. A number of factors may contribute to altered peripapillary vessel density in patients with papilledema. Previously, it has been reported that there is an increase in cerebral blood volume and a decrease in blood flow in patients with IIH (4-6). Decrease in cerebral blood flow in IIH may be due to increased cerebral vascular resistance, deterioration of TABLE 4. Comparison of RNFL thickness and peripapillary vessel density values between controls and IIH patients without papilledema Right Eyes RNFL thickness (mm) Mean Superior Nasal Inferior Temporal Peripapillary vessel density (%) Mean Superior temporal Superior nasal Nasal Inferior nasal Inferior temporal Temporal Left Eyes P value Control (n = 21) IIH Without Papilledema (n = 8) P value 101.66 123.66 79.83 129.16 74.66 0.65 0.58 0.68 0.69 0.45 102.76 127.04 79.42 126.76 78.00 104.25 129.75 80.50 131.87 75.00 0.72 0.67 0.83 0.43 0.31 62.72 64.22 60.27 62.40 62.49 65.36 62.42 0.91 0.95 0.47 0.26 0.27 0.77 0.99 62.27 65.19 61.73 59.87 63.79 67.69 60.75 62.39 63.30 63.55 61.25 63.26 64.55 61.24 0.89 0.18 0.37 0.31 0.67 0.16 0.71 Control (n = 21) IIH Without Papilledema (n = 6) 103.00 126.71 81.95 126.47 77.09 62.60 64.12 62.09 60.92 64.43 64.57 62.43 IIH, idiopathic intracranial hypertension; RNFL, retinal nerve fiber layer. 322 Tüntaş Bilen and Atilla: J Neuro-Ophthalmol 2019; 39: 319-323 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution cerebral blood flow autoregulation, or decrease in tissue vascular density due to brain edema (7). The central retinal artery and ophthalmic artery pass through the subarachnoid space and can be affected by intracranial pressure. It has been shown that color Doppler imaging flow velocity parameters are reduced in the ophthalmic, short posterior ciliary and central retinal arteries in patients with IIH (8,9). Querfurth et al (10) demonstrated that, with a mild to moderate increase in CSF pressures, there was a decrease in the ophthalmic and central retinal artery systolic flow, whereas with higher CSF pressures, there was a relative increase in these flow parameters. The authors concluded that the causes of decreased flow in mild to moderate CSF pressures were: increased flow resistance, axonal swelling in the optic disc, and focal vascular dilatation. We found reduced peripapillary vessel density, particularly in patients with Frisen Grade 2 papilledema. It is possible that these vascular autoregulatory mechanisms might result in decreased peripapillary vascular density. Mechanical factors also must be considered. When CSF pressure increases, axoplasmic flow slows and this may cause compression of the capillary network (11). In addition, compared with healthy controls, there was a decrease in peripapillary vessel density in some locations in IIH patients without papilledema. Although not statistically significant, this result suggests that the decrease in peripapillary vessel density may be related to autoregulatory mechanisms, apart from stasis of axoplasmic flow. It has been shown that the peripapillary vessel density decreases in cases with optic neuropathy (12). Similarly, peripapillary vessels may regress as a result of subclinical nerve fiber atrophy in patients with IIH. We did find a negative correlation between mean RNFL thickness and peripapillary vessel density, but it was not statistically significant. This may, in part, be due to the small number of patients included in our study and the lower grade of papilledema in our patients with IIH. We recognize several limitations of our study. The patients with IIH were a heterogenous group. Some were newly diagnosed and had not yet received treatment, whereas others were being followed up with or without medication. To reduce potential environmental and genetic factors, right and left eyes were evaluated separately, which could have reduced the statistical power of the study. Optovue has 2-mm scan depth with 2-mm axial resolution (13). The radial peripapillary capillary lies within a depth of 150 mm (14). Theoretically, in severe papilledema, increased thickness of the RNFL could alter the OCT-A results. In our study, none of the patients had severe papilledema. Wang et al (15) studied the relationship between peripapillary flow parameters and myopia, and showed that myopic eyes had decreased peripapillary retinal perfusion compared with emmetropic eyes (15). Given these findings, the fact that our patients' refraction and axial length values were not recorded is another limitation of our study. Tüntaş Bilen and Atilla: J Neuro-Ophthalmol 2019; 39: 319-323 In conclusion, we were able to demonstrate a decrease in peripapillary vessel density with OCT-A in patients with papilledema from IIH, yet many questions remain. Future improvements in OCT-A technology may affect our findings, and the underlying mechanisms for our results remain to be elucidated. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: F. T. Bilen and H. Atilla; b. Acquisition of data: F. T. Bilen and H. Atilla; c. Analysis and interpretation of data: F. T. Bilen and H. Atilla. Category 2: a. Drafting the manuscript: F. T. Bilen and H. Atilla; b. Revising it for intellectual content: F. T. Bilen and H. Atilla. Category 3: a. Final approval of the completed manuscript: F. T. Bilen and H. Atilla. REFERENCES 1. Hayreh SS. Pathogenesis of optic disc edema in raised intracranial pressure. Prog Retin Eye Res. 2016;50:108-144. 2. Rougier MB, Le Goff M, Korobelnik JF. Optical coherence tomography angiography at the acute phase of optic disc edema. Eye Vis (Lond). 2018;5:15. 3. Fard MA, Jalili J, Sahraiyan A, Khojasteh H, Hejazi M, Ritch R, Subramanian PS. Optical coherence tomography angiography in optic disc swelling. Am J Ophthalmol. 2018;191:116-123. 4. Mathew NT, Meyer JS, Ott EO. Increased cerebral blood volume in benign intracranial hypertension. Neurology. 1975;25:64664-64669. 5. Raichle ME, Grubb RL Jr, Phelps ME, Gado MH, Caronna JJ. Cerebral hemodynamics and metabolism in pseudotumor cerebri. Ann Neurol. 1978;4:104-111. 6. Grubb RL Jr, Raichle ME, Phelps ME, Ratcheson RA. Effects of increased intracranial pressure on cerebral blood volume, blood flow, and oxygen utilization in monkeys. J Neurosurg. 1975;43:385-398. 7. Bakar M, Tamgac F, Alper E, Zarifoglu M, Bora I, Turan F, Ogul E. 99Tcm-HMPAO brain SPET in patients with pseudotumour cerebri. Nucl Med Commun. 1996;17:696-700. 8. Guthoff RF, Berger RW, Winkler P, Helmke K, Chumbley LC. Doppler ultrasonography of malignant melanomas of the uvea. Arch Ophthalmol. 1991;109:537-541. 9. Mittra RA, Sergott RC, Flaharty PM, Lieb WE, Savino PJ, Bosley TM, Hedges TR Jr. Optic nerve decompression improves hemodynamic parameters in papilledema. Ophthalmology. 1993;100:987-997. 10. Querfurth HW, Lagreze WD, Hedges TR, Heggerick PA. Flow velocity and pulsatility of the ocular circulation in chronic intracranial hypertension. Acta Neurol Scand. 2002;105:431-440. 11. Hayreh SS, Zimmerman MB. Non-arteritic anterior ischemic optic neuropathy: role of systemic corticosteroid therapy. Graefes Arch Clin Exp Ophthalmol. 2008;246:1029-1046. 12. Hata M, Oishi A, Muraoka Y, Miyamoto K, Kawai K, Yokota S, Fujimoto M, Miyata M, Yoshimura N. Structural and functional analyses in nonarteritic anterior ischemic optic neuropathy: optical coherence tomography angiography study. J Neuroophthalmol. 2016;37:140-148. 13. Khadamy J. Optical coherence tomography angiography (OCTA) in ophthalmology; technology, pros, cons and commercial prototypes. JOJ Ophthalmol. 2017;6:555598. 14. Mo S, Phillips E, Krawitz BD, Garg R, Salim S, Geyman LS, Efstathiadis E, Carroll J, Rosen RB, Chui TY. Visualization of radial peripapillary capillaries using optical coherence tomography angiography: the effect of image averaging. PLoS One. 2017;12:e0169385. 15. Wang X, Kong X, Jiang C, Li M, Yu J, Sun X. Is the peripapillary retinal perfusion related to myopia in healthy eyes? A prospective comparative study. BMJ Open. 2016;6:e010791. 323 Copyright © North American Neuro-Ophthalmology Society. 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