One-Year Changes in Optic Nerve Head Parameters in Recovered COVID-19 Patients

The main purpose was to evaluate the changes in peripapillary retinal nerve fiber layer (RNFL) thickness and vessel density (VD) in post-COVID-19 patients during 12-month follow-up.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD One-Year Changes in Optic Nerve Head Parameters in Recovered COVID-19 Patients Barbara Burgos-Blasco, MD, PhD, FEBO, Noemi Güemes-Villahoz, MD, Beatriz Vidal-Villegas, MD, PhD, Jose M. Martinez-de-la-Casa, MD, PhD, Julian Garcia-Feijoo, MD, PhD, Juan Donate-Lopez, MD, PhD, Francisco J. Martin-Sanchez, MD, PhD, Juan J. Gonzalez-Armengol, MD, PhD, Carmen D. Mendez-Hernandez, MD, PhD Background: The main purpose was to evaluate the changes in peripapillary retinal nerve fiber layer (RNFL) thickness and vessel density (VD) in post–COVID-19 patients during 12-month follow-up. Methods: In this prospective study, patients with COVID-19 who were attended in the Hospital Clinico San Carlos (Madrid, Spain) were included. All patients underwent a complete ophthalmological examination, optic nerve head optical coherence tomography (OCT), and OCT angiography (OCTA) using the Cirrus HD-OCT 5,000 with AngioPlex OCTA 1, 3, and 12 months after laboratory-confirmed diagnosis. Sociodemographic data, medical history, disease severity, and laboratory workup were registered. Results: A total of 180 eyes of 90 patients with SARS-CoV-2 infection were included; the mean age was 55.5 ± 8.9 years, and 46 patients (51%) were females. The mean visual acuity was 0.76 ± 0.16, and no abnormalities attributable to SARS-CoV-2 were detected in the ocular or fundus examination. No differences in the OCT and OCTA data were found between severity groups in each visit (all P . 0.05). Overall, there was a decrease in RNFL global thickness (P , 0.001) from the first to the last visit, and an increase in VD and flux index was noted in some sectors at the 12-month examination. A significant correlation was detected at 12 months between vascularization parameters and RNFL thickness. Ophthalmology Department (BB-B, NG-V, BV-V, JMM-d-l-C, JG-F, JD-L, CDM-H), Instituto de investigación sanitaria del Hospital Clínico San Carlos (IsISSC), Hospital Clinico San Carlos, Madrid, Spain; Departamento de Inmunología (JMM-d-l-C, JG-F, CDM-H), Oftalmología y ORL, Facultad de Medicina, Instituto de Investigaciones Oftalmológicas Ramón Castroviejo, Universidad Complutense de Madrid, Spain; and Emergency Department (FJM-S, JJGA), Hospital Clínico San Carlos, Instituto de investigación sanitaria del Hospital Clínico San Carlos (IsISCC), Madrid, Spain. The authors report no conflicts of interest Address correspondence to Barbara Burgos-Blasco, MD, Ophthalmology Department, Hospital Clinico San Carlos, Calle del Profesor Martín Lagos, s/n. 28040 Madrid, Spain; E-mail: bburgos171@ hotmail.com 476 Conclusions: One year after SARS-CoV-2 infection, changes in peripapillary RNFL thickness and vascularization occur, possibly indicating a recovery in such parameters. Journal of Neuro-Ophthalmology 2022;42:476–482 doi: 10.1097/WNO.0000000000001626 © 2022 by North American Neuro-Ophthalmology Society S ince the outbreak of severe acute respiratory syndromecoronavirus-2 (SARS-CoV-2), responsible for coronavirus disease (COVID-19), in December 2019, it has quickly spread worldwide (1). Although COVID-19 main described symptoms were respiratory, there is now solid evidence that SARS-CoV-2 presents important vascular and neurological involvement (2). The eye has proven to be a useful window to evaluate microvascularization and the neurological system in multiple diseases. Optical coherence tomography (OCT) and OCT angiography (OCTA) are effective noninvasive tools to analyze the optic nerve, specifically the retinal nerve fiber layer (RNFL) thickness and the peripapillary plexus. These techniques allow for quantitative analysis and may reveal subclinical changes in the retina (3–5). Recent studies have assessed the peripapillary perfusion and RNFL thickness in recovered COVID-19 patients, reporting interesting findings. Previous reports from our group have revealed an increase in RNFL thickness after SARS-CoV-2 infection compared with healthy individuals and prior OCT examinations (6,7). Using OCTA, Savastano et al reported a lower peripapillary vessel density (VD) in post–COVID-19 patients one month after hospital discharge compared with healthy subjects (8). Our previous study could not detect differences in peripapillary vascularization of patients with COVID-19 compared with healthy individuals, probably because of the smaller sample Burgos-Blasco et al: J Neuro-Ophthalmol 2022; 42: 476-482 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution of the latter (9). In addition, no differences were found in peripapillary vascularization 1 and 3 months after SARSCoV-2 infection (9). Therefore, if an increase in RNFL thickness along with a decrease in vascularization does in fact occur, these could represent a long-term sequela of the virus. Notwithstanding, the results only show short-term changes, and the possible sequelae of the virus in peripapillary vascularization and RNFL remain to be investigated. In addition, as we do not have data on the acute phase of the infection for ethical and safety reasons, investigating how these parameters change with time could provide valuable information on possible events in the earlier phases of COVID-19. Given that our previous sample of patients with COVID-19 included a representative spectrum of the disease and differences in multiple parameters were able to be detected, we decided to follow-up these patients prospectively for 12 months. The main objective of this study was to investigate optic nerve changes in patients with COVID-19 during the first 12 months after SARS-CoV-2 infection using OCT and OCTA. METHODS In this prospective, observational study, patients with SARS-CoV-2 infection attended at the Hospital Clinico San Carlos Emergency Department in Madrid (Spain) were included. The study protocol was approved by the Hospital Clinico San Carlos Clinical Research Ethics Committee (20/356-E_COVID), and it was in adherence with the tenets of the Declaration of Helsinki. All participants gave informed consent before enrollment in the study. Patients from a previous study were followed for 12 months, additional examinations being performed at 3 and 12 months after SARS-CoV-2 infection (6,7,10,11). The inclusion criteria were the following: age younger than 65 years, laboratory-confirmed SARS-CoV-2 infection, blood test, chest x-ray, and ability to give written consent. The same exclusion criteria including ophthalmic diseases were applied. The patient’s age, sex, race, medical history (arterial hypertension, diabetes mellitus [DM], dyslipidemia [DL], or smoking), blood oxygen saturation, and laboratory tests results were recorded. Laboratory workup included the levels of hemoglobin (Hb), total lymphocytes, platelet count, ferritin, D-dimer, international normalized ratio, activated partial thromboplastin time, and fibrinogen. For each patient, the results of the blood test that represented the greatest severity were recorded. Patients were classified according to their clinical severity as mild, moderate, and severe, along with CURB-65 score, physical examination, respiratory assessment, or organ failure as in previous studies by our study group (6,7,10,11). In each visit, both OCT and OCTA examinations were performed. First, the Spectralis-OCT (Heidelberg EngiBurgos-Blasco et al: J Neuro-Ophthalmol 2022; 42: 476-482 neering, Heidelberg, Germany) was used to scan the optic nerve head and measure the peripapillary RNFL thickness. The software calculates RNFL thickness because of automated segmentation. RNFL measurements were registered globally and in the 6 quadrants (superior temporal, temporal, inferior temporal, superior nasal, nasal, and inferior nasal). Second, peripapillary vascularization was investigated with the Cirrus HD-OCT 5000 with AngioPlex OCTA (Zeiss, Dublin, CA). A scan area of 4.5 · 4.5 mm area centered on the optic nerve head was performed, with which the device’s software automatically quantifies VD and flux index (FI). Both variables are calculated for the global and quadrant peripapillary regions (superior, temporal, inferior, and nasal) in an annulus with an inner diameter of 2 mm and outer diameter of 4.5 mm. VD is the total area of perfused radial peripapillary capillary vasculature per unit area, and FI is the total area of perfused vasculature per unit area in a specific region. A single experienced physician performed all examinations. Only images with a signal strength level above the recommended level and good image quality were included. Visual acuity was also measured, and a decimal scale was used. The IBM SPSS software (version 21.0; IBM Corp, Somers, NY) was used for the statistical analysis. Statistical significance was set at P , 0.05. Data are presented as mean ± SD or as frequencies. Comorbidities were considered as binary variables without further characterization. The Kolmogorov–Smirnov test was used to confirm the normal distribution of the quantitative data, with variables being normally distributed. Demographic and clinical variables were compared using the analysis of variance (ANOVA) with Bonferroni correction and the x2 to determine whether there were differences between groups. OCTA data from the first and one-year visit were compared among each other and according to the severity group (mild-stage, moderate-stage, and severe-stage disease) using the paired samples Student t test. To study the relationship between variables, Pearson correlation was used. RESULTS The study population comprised 180 eyes of 90 patients with laboratory-confirmed SARS-CoV-2 infection. The mean age was 55.5 ± 8.9 years, and 46 patients (51%) were females. Demographic medical history and clinical characteristics of the study group are represented in Table 1. The mean visual acuity was 0.76 ± 0.16, and no abnormalities attributable to SARS-CoV-2 were detected in the ophthalmologic examination. The results on RNFL thickness and vascularization, along with their differences between visits are depicted in Table 2 (for clarity, only the first and last visit are shown). No 477 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Clinical characteristics of recovered COVID-19 patients divided by disease severity Characteristic Total (n = 90) Mild-stage Disease (n = 31) Age (years) Sex (females) Race (Caucasian/ Hispanic/Black) 55.5 ± 8.9 53.3 ± 9.4 46 (51%) 19 (61%) 60 (61%)/29 24 (77%)/7 (32%)/1 (1%) (23%)/0 AHT (yes) DM (yes) DL (yes) Smoking (yes) Hemoglobin (mg/dL) Total lymphocytes (/ml) Platelet count (/ml) Ferritin (ng/mL) 26 (29%) 8 (9%) 25 (28%) 17 (19%) 14.2 ± 1.3 D-dimer (ng/mL) INR (ratio) APTT (ratio) Fibrinogen (mg/dL) Moderate- Severe-stage P (Mild and stage Disease Disease (n = 36) Moderate) (n = 23) P (Moderate P (Mild and and Severe) Severe) 59.3 ± 6.1 17 (47%) 19 (53%)/17 (47%)/0 0.684* 0.067† 0.457† 0.0001* 0.694† 0.091† 0.0001* 0.105† 0.004† 7 (23%) 2 (6%) 6 (31%) 4 (13%) 14.3 ± 1.2 52.5 ± 10.1 10 (43%) 17 (74%)/5 (22%)/1 (4%) 6 (26%) 2 (9%) 4 (17%) 4 (17%) 14.1 ± 1.7 13 (36%) 4 (11%) 15 (42%) 9 (25%) 14.2 ± 1.1 0.677† 0.633† 0.797† 0.769† 0.596* 0.260† 0.675† 0.006† 0.143† 0.770* 0.089† 0.350† 0.005† 0.058† 0.718* 1.1 ± 0.5 1.5 ± 0.6 1.2 ± 0.4 1.2 ± 0.4 0.006* 0.0001* 0.0001* 246.0 ± 96.4 804.5 ± 857.0 1920.5 ± 6673.3 1.1 ± 0.1 1.0 ± 0.1 739.9 ± 180.5 256.4 ± 100.0 384.3 ± 450.8 723.8 ± 603.6 1.1 ± 0.1 1.0 ± 0.1 637.4 ± 167.5 240.4 ± 110.0241.4 ± 83.8 0.443* 0.952* 0.363* 900.0 ± 965.61085.9 ± 908.4 777.8 ± 510.63681.1 ± 10,322.5 1.1 ± 0.1 1.2 ± 0.2 1.0 ± 0.1 1.0 ± 0.1 748.8 ± 153.0811.3 ± 173.3 0.001* 0.928* 0.0001* 0.625* 0.059* 0.026* 0.0001* 0.641* 0.001* 0.056* 0.604* 0.052* 0.0001* 0.904* 0.0001* All above measurements are represented by mean ± SD and frequency. Statistical significant differences are shown in bold values. *ANOVA test and Bonferroni correction. † 2 x test. AHT, arterial hypertension; APTT, activated partial thromboplastin time; DL, dyslipidemia; DM, diabetes mellitus; INR, international normalized ratio. differences in the OCT and OCTA data were found between severity groups in each visit using the ANOVA (all P . 0.05, not shown). Overall, there was a decrease in RNFL global thickness (P , 0.001) from the first to the last visit. In addition, a statistically significant increase in VD and FI was noted in some sectors at the 12-month examination. In addition, a significant correlation was detected at 12 months between peripapillary VD and RNFL (P , 0.001; Fig. 1), as well as between peripapillary FI and RNFL thickness (P = 0.003; Fig. 2). No correlation was noted between VD, FI, or RNFL thickness at the 12-month visit and SARS-CoV-2 parameters, which included clinical parameters, disease severity, and blood test (all P . 0.05, not shown). Regarding patients’ medical history data, DM was associated with VD and RNFL (as in previous study, not shown) (9). CONCLUSIONS Although knowledge on SARS-CoV-2 is increasing, the sequelae are yet to be thoroughly investigated. Our study provides valuable insight into the changes in peripapillary RNFL thickness and vascularization during the first 12 478 months after SARS-CoV-2 infection. One year after COVID-19 diagnosis, there is a decrease in RNFL thickness and an increase in peripapillary VD compared with 1 month after diagnosis. Multiple studies from our group and other investigators have shown that patients with COVID-19 present increased peripapillary RNFL thickness, compared with healthy controls and with previous examinations (6,7,12). Although some have found no differences in RNFL thickness, it is mostly due to smaller samples of patients with COVID-19 (13). The decrease at 12-month visit supports this increase in the acute phases further because it could imply a recovery of possible involvement during the earlier phases of the disease. As for OCTA, a decrease in retinal VD has been described in patients with COVID-19, microvascular endothelial injury and cytokine release playing a key role (14,15). Oxygen saturation and hemoglobin abnormalities in patients with COVID-19, especially in severe forms of the disease, might lead to a vascularization deficiency which could affect the peripapillary vascularization. Evidence suggests that peripapillary VD is decreased in post– COVID-19 patients, with a lower radial peripapillary Burgos-Blasco et al: J Neuro-Ophthalmol 2022; 42: 476-482 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Burgos-Blasco et al: J Neuro-Ophthalmol 2022; 42: 476-482 1 Month Parameter RNFL global thickness (mm) External region VD (%) External region FI (ratio) Superior VD (%) Superior FI (ratio) Nasal VD (%) Nasal FI (ratio) Inferior VD (%) Inferior FI (ratio) Temporal VD (%) Temporal FI (ratio) 12 Months Total (n = 90) Mild-stage Disease (n = 31) Moderatestage Disease (n = 23) Severestage Disease (n = 36) 101.67 ± 1.42 99.98 ± 10.28 99.50 ± 7.15 100.47 ± 13.64 44.86 ± 1.81 0.44 ± 0.03 44.85 ± 1.53 0.44 ± 0.03 45.16 ± 1.42 0.44 ± 0.03 45.16 ± 1.15 0.45 ± 0.03 43.56 ± 2.26 0.42 ± 0.03 45.58 ± 2.51 0.45 ± 0.03 44.83 ± 3.31 0.43 ± 0.03 45.37 ± 2.94 0.45 ± 0.03 43.04 ± 1.89 0.42 ± 0.03 45.84 ± 2.90 0.44 ± 0.03 45.29 ± 2.28 0.43 ± 0.02 45.19 ± 2.61 0.44 ± 0.03 43.62 ± 1.96 0.43 ± 0.03 45.96 ± 2.51 0.46 ± 0.03 45.16 ± 2.46 0.44 ± 0.04 45.81 ± 3.15 0.45 ± 0.04 43.12 ± 1.79 0.43 ± 0.03 46.05 ± 2.64 0.46 ± 0.03 45.09 ± 2.14 0.44 ± 0.02 46.14 ± 3.08 0.45 ± 0.03 Total (n = 90) Mild-stage Disease (n = 31) Moderatestage Disease (n = 23) Severestage Disease (n = 36) 101.15 ± 10.47 100.42 ± 7.81 101.21 ± 13.62 44.93 ± 1.49 0.44 ± 0.03 45.06 ± 1.17 0.44 ± 0.03 43.24 ± 2.04 0.42 ± 0.03 45.78 ± 2.62 0.45 ± 0.04 45.14 ± 2.84 0.43 ± 0.03 45.43 ± 2.68 0.44 ± 0.03 42.58 ± 2.44 0.43 ± 0.03 45.85 ± 2.41 0.45 ± 0.05 45.20 ± 3.06 0.43 ± 0.03 45.74 ± 2.59 0.44 ± 0.04 P, Total P, Mild-stage P, Moderatestage P, Severestage 100.00 ± 9.66 ,0.001 0.053 0.353 ,0.001 45.23 ± 1.74 0.45 ± 0.03 45.11 ± 1.39 0.44 ± 0.03 0.377 0.002 0.030 0.334 0.690 0.063 0.528 0.515 44.02 ± 223 0.44 ± 0.03 45.74 ± 2.44 0.46 ± 0.04 45.49 ± 3.03 0.43 ± 0.03 45.58 ± 3.11 0.46 ± 0.04 43.74 ± 1.82 0.43 ± 0.03 46.04 ± 2.49 0.45 ± 0.04 44.96 ± 2.24 0.43 ± 0.02 45.70 ± 3.29 0.45 ± 0.04 0.031 0.036 0.229 0.138 0.716 0.135 0.700 0.537 0.206 0.308 0.774 0.395 0.113 0.017 0.841 0.661 0.077 0.048 0.130 0.617 0.986 0.055 0.592 0.376 0.005 0.007 0.272 0.240 0.608 0.478 0.994 0.696 Original Contribution Two-tailed paired t test. All above measurements are represented by mean ± SD. Statistically significant differences are shown in bold values. FI, flux index; RNFL, retinal nerve fiber layer; VD, vessel density. 479 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. TABLE 2. One-month and 12-month optic nerve parameters comparison according to disease severity Original Contribution FIG. 1. Correlation between peripapillary vessel density (VD) and retinal nerve fiber layer (RNFL) thickness at 12 months. capillary plexus (RPCP) perfusion density. Interestingly, a linear correlation between RNFL thickness and RPCP perfusion density and FI was found in this study, linking both variables and suggesting that a similar pathophysiology is involved in the changes of these parameters (8). On the contrary, no relationships between treatment and severity parameters with OCT and OCTA parameters at 12 months were noted. After the acute phase, many patients continue with some symptoms, mainly fatigue and dyspnea, and chest image FIG. 2. Correlation between peripapillary flux index (FI) and retinal nerve fiber layer (RNFL) thickness at 12 months. 480 Burgos-Blasco et al: J Neuro-Ophthalmol 2022; 42: 476-482 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution abnormalities may persist. Microvascular angiopathy has proven a key role in organ dysfunction even after acute phases of the disease (16). Hence, investigation of the microvascular changes over time, including the recovery phase, is highly relevant. However, published prospective analysis only covers the first 6 months, and the microvascular long-term changes have not yet been reported. As for ophthalmological studies and possible persistent alterations, they have not been extensively investigated. Our previous study, reveal a lack of differences in peripapillary VD at 1 and 3 months, suggesting that if a decrease did occur, it was stable in that time frame. The analysis by Bilbao-Malavé et al in 17 patients yielded a significantly thinner RNFL at 6 months compared with baseline, although there was still a significant increase compared with controls. On the contrary, microvascular alterations persisted after 6 months similar to baseline examination, with lower foveal VD and a greater avascular foveal zone (17). In view of the present findings, peripapillary vascularization does seem to decrease after COVID-19 but may recover between 6 and 12 months after diagnosis, similar to RNFL changes. Therefore, changes in optic nerve head parameters may return to baseline at 12 months, suggesting a probable lack of sequelae in this regard. This could give valuable insight into the behavior of other vascular plexus in the body. Mediated inflammatory responses could be partly responsible for these findings. The fact that perfusion has improved and the RNFL thickness decreased after 1 year could be related to the initial inflammatory process of the disease. In animal models, retinal invasion of the virus caused inflammation in the early phases and could result in optic nerve edema (18). The central nervous system can react quickly and intensely to virus with neurotropic virus–like SARS-CoV-2 causing intense brain parenchyma inflammation (19). On the other hand, angiotensinconverting enzyme 2 is the main receptor for SARS-CoV2 and has been reported to be present in most organs, including neural tissue and the retina. Therefore, direct viral invasion could be another possible mechanism (20). Some limitations of this study should be acknowledged. First, no control group was included given that it is still difficult to recruit, and the main objective of the study was to evaluate the variations in patients with COVID-19. Second, follow-up of patients with COVID-19 did not include the acute phase of the disease because of ethical and public health reasons, and the 6-month visit had to be canceled because of a COVID-19 wave at that moment. We present a smaller sample of patients as a consequence of loss to follow-up of a proportion of patients. In addition, not many patients with the most severe forms of the disease could be recruited in most cases because they remained hospitalized, symptomatic, isolated, or had died. Patients older than 65 years were not included because of a higher incidence of ophthalmic disease and because they represent Burgos-Blasco et al: J Neuro-Ophthalmol 2022; 42: 476-482 population at risk that should avoid going to hospitals unless they require emergency care during this critical situation. Although differences in RNFL and vascularization parameters may seem small and could be questioned because of repeatability, the results and tendencies are consistent. Notwithstanding, this is one of the largest and with longer follow-up of patients with COVID-19 in the literature. In conclusion, our results reveal that although changes in peripapillary RNFL thickness and vascularization occur, significant recovery can be expected at 12 months after SARS-CoV-2 infection. Further investigations are mandatory to deepen our knowledge in possible sequels of COVID-19. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: B. Burgos-Blasco, N. GüemesVillahoz, B. Vidal-Villegas, J. Donate-Lopez, F. J. Martin-Sanchez, and J. J. Gonzalez-Armengol; b. Acquisition of data: B. BurgosBlasco, N. Güemes-Villahoz, and B. Vidal-Villegas; c. Analysis and interpretation of data: J. M. Martinez-de-la-Casa, J. Garcia-Feijoo, and C. D. Mendez-Hernandez. Category 2: a. Drafting the manuscript: B. Burgos-Blasco, N. Güemes-Villahoz, and B. Vidal-Villegas. b. Revising the manuscript for intellectual content: C. D. Mendez-Hernandez, J. M. Martinez-de-la-Casa, and J. Garcia-Feijoo. Category 3: a. Final approval of the completed manuscript: B. Burgos-Blasco, N. Güemes-Villahoz, B. Vidal-Villegas, J. M. Martinez-de-la-Casa, Julian Garcia-Feijoo, Juan Donate-Lopez, Francisco Javier Martin-Sanchez, Juan Jorge Gonzalez-Armengol, and Carmen Dora MendezHernandez. ACKNOWLEDGMENTS The authors thank the patients who participated in this study. The authors are also grateful to the investigators of COVID-19_URG-HCSC Register: Juan González del Castillo, Adrián Valls Carbó, Enrique del Toro, Eduardo Cardassay, Gabriel Cozar López, María del Mar Suárez-Cadenas, Pablo Jerez Fernández, Beatriz Angós, Cristina Díaz del Arco, Esther Rodríguez Adrada, María Teresa Montalvo Moraleda, Carolina Espejo Paeres, Amanda López Picado, Carmen Martínez Valero, Juande D. 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