Analysis of retinal vasculature changes in indirect traumatic optic neuropathy using optic coherence tomography angiography

INTRODUCTION

I ndirect traumatic optic neuropathy (ITON) refers to acute visual impairment due to optic nerve injury following remote forces applied to the head or face

. Common causes include vehicle and bicycle accidents, falling, or hits

, and ITON occurs in 2% to 5% of facial and 0.5% to 2% of head traumas

. Diagnostic characteristics of ITON include acutely decreased visual acuity (VA), change in color recognition,visual field defects, impaired visual evoked potentials (VEP)and relative afferent pupil defect (RAPD)

.

External concussive forces transmits shockwave to the optic nerve and causes indirect injuries

. A highly recognizable report by Gross

reported that the traumatic impact force may result in deformation of the ipsilateral orbital roof near the optic foramen, and such deformation could cause damage to the supporting vasculature and shear stress to the nerve

. The subsequent vascular ischemia-induced optic nerve swelling and compression due to optic canal are causes of insufficient blood supply to retinal ganglion cell (RGC)leading to irreversible degeneration of RGC axons at the time of injury or progress within ensuing weeks, and present with optic disc pallor

. This two-stage hypothesis is the basis for treatment of ITON with optic canal decompression

,among others such as steroid treatments and close observation with no interventions

. It is important to evaluate the degree of injury for trauma-induced indirect damages to the retina and optic nerve, therefore, it is necessary to adopt an appropriate examination method.

3.3.3学生对专业学习兴趣的提升由课后的问卷调查结果发现，PBL教学改革提高了学生对专业课的学习兴趣．在水文学教学改革开始前，S1班学生对地理学专业有了深入的认识，很多学生不再认为学习这种理论没有用，而是觉得地理学能够解决现实的问题，开始转变对专业的排斥心理，超过70%的学生决定报考地理专业研究生．

Axon degeneration has been demonstrated in rodent models as reported by several studies

. Thinning of RNFL at the ONH region has shown to be strongly correlated with impaired visual function and visual field loss in patients with compressive lesions, and suggest that damaging to the anterior pathways may occur before visual field loss

. A report showed that a significant thinning of macular GCC (the combination of RGC and IPL) was observed in the outer nasal, superior and inferior field in early traumatic optic neuropathy, which implied that RGC loss may participate in the development of traumatic optic neuropathy

. Hence, visual dysfunction might delay in up to 10% of patients, which is attributed to a deferred clinical diagnosis

. Concordantly, we found significant thinning of macular GCC in all assessed sectors, and all patients presented with decreased VA and impaired visual functions assessed by VEP, suggesting that changes in retinal thickness had already occurred before their first visit to clinic. Yet, an interesting finding from our OCTA result demonstrated a slight increase in RNFL thickness within 7d after injury and followed by significant decrease from 7 to 30d, with observation in fundoscopy examination, together suggested that acute edema at the ONH may have occurred immediately after injury and subsiding of RNFL swelling took place in the next few weeks.The OCTA also provides measurement of vessel density,which is evidential to the alteration of blood supply following traumatic impact to the optic nerve. To date, the discussion on vascular changes in optic neuropathies with OCTA has been scarce. Chan

showed that significant decrease in blood suppl and oxygenation to the retina was associated with choroidal thinning in chronic ITON patients. Although a different OCTA platform was used, our OCTA findings showed apparent attenuation in microvasculature densities at the RPC region of the ONH cube scan, as well as the perifovea sectors at the macular, suggesting possible impaired perfusion to the retina.

SUBJECTS AND METHODS

This is a retrospective observational study. Ethical approval and patient consent were obtained before surgery and the procedures adhered to the tenets of the 1964 Declaration of Helsinki. For patients of age below 18,consent was obtained from their parents or legal guardians.Protocols were approved by the Institutional Ethics Committee(2019KYPJ155, Medical Ethics Committee, Zhongshan Ophthalmic Center, Guangzhou, Guangdong Province, China).

1941年4月4日，熊式辉向蒋介石进言:“领袖只宜以思想领导干部，功名利禄，只能奔走一般中下之士，凡为革命奋斗冒险犯难而不辞者，皆思想上信仰力之驱使，故把握正确的思想路线是第一要务。”㊾实则亦是针对蒋以功名利禄笼络干部的做法提出的改进意见。

All statistical calculation and analysis were performed with IBM SPSS Statistics 24 software (IBM Corp., Armonk, NY, USA) and GraphPad Prism 8 (GraphPad Software, San Diego CA, USA). Alteration in retinal thickness and vasculature density were calculated as percentage of measurements in ITON eyes as compared to the contralateral unaffected eye. For continuous variables, data were presented as mean±standard deviation (SD) unless otherwise stated;parametric (

-tests or ANOVA) or non-parametric tests (Mann-Whitney

or Kruskal Wallis) for comparisons between groups(pairwise where appropriate); Pearson’s correlation analysis was performed to reveal time-dependent changes in parameters where appropriate. Statistical significance was calculated for two-tail significance and was defined with

-value of less than 0.05.

2006年首届香山论坛举办时，仅有来自14个国家的24名外国代表与会。而在第八届论坛上，来自74个国家和国际组织的400余名代表不远万里齐聚北京，共商打造新型安全伙伴关系之道。北京香山论坛之所以能在短短十几年内异军突起，是因为秉持平等、开放、包容、互鉴精神，求同存异、聚同化异，倡“和”而不倡“斗”，推动构建人类命运共同体。

All patients had comprehensive systemic and ophthalmic examination. ITON was diagnosed according to patients’traumatic history and ophthalmic examination, including symptoms: 1) a close head injury with no direct force trauma made to the optic nerve; 2) decrease of VA; 3) positive of RAPD; 4) abnormal VEP with normal fundus examination.

All subjects were examined under one OCTA system (AngioVue; Optovue Inc., Fremont, CA, USA), which scanned at speed of 70 000 A-scans per second, and wavelength of 840 nm. For each eye of all patients, 4.5×4.5 mm

cube angio scan was centered at the optic nerve head (ONH), and 3.0×3.0 mm

cube angio scan was centered at the fovea for macular region.

“由于健康需求的迫切性和多样化，我国特殊食品市场潜力巨大。”中国营养保健食品协会秘书长刘学聪说，随着中国居民生活水平和健康意识增强，人们的观念正在从吃得饱、满足基本生理需要，向均衡营养摄入、利于身体健康的方向转变；从有病治病向无病预防、提高健康质量转变，这些都将促进特殊食品产业迅猛发展。

Vessel density was defined as the proportion (in percentage)of perfused vascular area in the whole selected region in en face views. OCTA output data from the 4.5×4.5 mm

ONH scan included readings for vessel densities of whole ONH image (onh-wiVD), inside-disc and peripapillary sectors.The 3.0×3.0 mm

macular scan included readings for vessel densities of whole macular image (m-wiVD), fovea, parafovea and peri-fovea sectors. OCTA also provided automated measurements of retinal thickness parameters, which included retinal nerve fiber layer (RNFL) at the ONH and a complexed layer (GCC) at the macular B-scans. The latter is the combination of RNFL, RGC, and inner plexiform layers (IPL).Representative images of OCTA performed on both eyes of the same patient was shown in Figure 1. At very early stage of the disease (day 4 from injury), retina thickness and vessel density did not change greatly in the ITON eye as compared to the unaffected fellow eye. After approximately 3mo from injury,retina thickness and vessel density decreased significantly in the ITON eye, suggesting progression of RGC over time.

A total of 73 patients who were diagnosed of monocular ITON in Zhongshan Ophthalmic Center (ZOC)from August 2016 to May 2020 were recruited in this study.The inclusion criteria were as follows: 1) diagnosed of ITON;2) no history of other ophthalmic conditions or ocular surgeries apart from optic canal decompression. Patient details on age, gender,cause of injuries and time of visit after injury were recorded.

RESULTS

1.1.3 试验用虾 2018年4月从距武汉农业气象试验基地30 min车程的虾苗养殖基地购入平均质量3～5 g的虾苗，每个网箱虾苗投放数量均为20尾。

Thickness of RNFL and GCC were compared between ITON eyes and the unaffected fellow eyes(Table 2). Pair-wised statistical analysis revealed that RNFL was significantly thinner in ITON eyes for most of ONH sectors (all

<0.05) except for temporal quadrant. Meanwhile,for the macular region and quadrants, thinning of GCC was significant in ITON eyes for all sectors (all

<0.05) except the fovea.

Time-dependent correlation analysis on retinal thinning was performed with the inter-eye difference of retinal thickness between ITON and unaffected eyes. Data were acquired at different post-injury timepoints, at which the patients were examined with OCTA: within 7d, 8 to 30d, 31 to 90d, and 91 to 365d. Correlation analysis findings revealed that the change in retinal thickness, of both radial papillary capillary (RPC)and macular, were inversely time-dependent,

thinning of retina at the RPC and macular had been worsening with time after injury (all

<0.05; Table 3). It was noteworthy that the thinning of retina was most significant during 31 to 90d and became stabilized after 3mo from injury.

ITON is the commonest type of optic nerve injury related to orbital trauma. It often causes severe vision loss in patients who suffers from craniofacial trauma, which remotely induces indirect injuries to the optic nerve. With the advancement of neuroimaging in clinical practice, detailed ophthalmic examination are routinely necessitated by the requirement of indication for treatment. In the current study, we are the first to in-depth assess changes of retinal vasculature in ITON patients using the OCTA.

随着社会经济的不断发展，人们对于能源的需求也呈现出不断上升的趋势，在我国电力市场供应中发电厂具有非常重要的位置。在发电厂的运行以及发展过程中，还需要提高发电厂的发电效率以及能源利用率，才能够更好地降低能源损耗，而通过小真空泵技改能够更好地促进发电厂能源效率的提升。

Again, time-dependent correlation analysis on vessel density attenuation was performed with the inter-eye difference of vessel densities between ITON and unaffected eyes. The findings revealed that the change in vessel densities, of both RPC and macular, were inversely time-dependent,

vessel density attenuation had been worsening with time after injury(all

<0.05; Table 5). Similar to that of retina thickness, the decrease of vessel density was most significant during 31 to 90d and became stabilized after 3mo from injury.

A total of 73 patients diagnosed with monocular ITON were recruited in this study. Patient and clinical information were listed in Table 1.

Recruited patients were categorized according to their preoperative vision: no light perception (NLP), light precepted (LP), hand movement (HM),finger count (FC), VA between 0.01 and 0.08, and VA between 0.1 and 0.3. For each group, time-dependent correlation analysis was performed for retinal layer thinning and vascular alteration. For NLP patients, retina thinning, and vessel density changes were time-dependent for all measured parameters and sectors. For non-NLP patients (

LP, HM, FC, 0.01-0.08, and 0.1-0.3), preserved vision was not associated with time-dependent alteration in retina thickness and vascular attenuation (Table 6).

本文采用相关性分析对研究假设H1、假设H1a～假设H1d、假设H3a～假设H3c进行检验，采用线性回归模型拟合方法对研究假设H2进行检验。为满足假设检验需求设置如下变量：全国两化融合发展水平DLIII、企业两化融合发展水平EDLIII、重点行业两化融合发展水平SDLIII、第二产业两化融合发展水平SIDLIII、上市公司市场总价值EMV、产业全要素生产率TFPI，第二产业的投入产出比IOR、人均增加值AVPC和全要素生产率TFPSI。

Changes in vessel density and retinal layer thickness were analyzed for correlation with clinical parameters such as patient age, gender, and cause of injuries. For all these parameters, alterations in retinal vasculature parameters were not statistical significantly correlated.

DISCUSSION

Vasculature perfusion in retina was presented as percentage of vessel densities per en face views.Vessel densities of the RPC and the macular for ITON eyes and the unaffected fellow eyes were listed in Table 4. Pairwised statistical analysis revealed that RPC vessel density was significantly lower in ITON eyes for all RPC regions and quadrants (all

<0.05). Meanwhile, for macular regions and quadrants, vessel density was significantly lower in ITON eyes for whole image, perifovea, superior, inferior and nasal quadrants (all

<0.05).

Optical coherence tomography (OCT) was one of the biggest advances in ophthalmic imaging. Based on this technology,optical coherence tomography angiography (OCTA) was established in mid-2000’s, offers non-invasive, depth-resolved images to access retinal and choroidal vasculature and layering details

. It has been proven to show many important clinical findings in neovascularization, impaired perfusion, macular telangiectasia, and capillary remodeling

. Also, OCTA is currently applied for diagnosing and evaluating a wide variety of ophthalmic conditions, including age-related macular degeneration

, glaucoma

and diabetic retinopathy

,and some optic neuropathies

. The underlying etiology in ITON remains unclear and may be multifactorial, and vascular insufficiency might be a vital causal factor as in other optic neuropathies

. The emergence of OCTA provides the feasibility to explore the pathology and microvascular perfusion with the development of traumatic optic neuropathy.In this study, we have collected OCTA data from serial followup from ITON patients and performed in-depth analysis in order to clarify the time-course retinal vessel layer changes in ITON patients.

It has been suggested by several studies that the retrograde degeneration of post-traumatic retinal vasculature is a time-dependent progress, and takes at least six weeks to complete

. In concordance, we found that decrease in retinal layer thickness and vasculature were most significant within the first three months after injury. For OCTA examinations taken in follow-up timepoints after three months, alterations in retinal layer thickness and vasculature reached plateau with less progressive worsening.

In our study, when comparing preoperative macula retinal thickness and vessel densities between ITON and the good fellow eyes, GCC thinning was significant in all segments except the fovea, and vessel attenuation was significant in all segments except the fovea and temporal. Traumatic ischemia-induced optic nerve swelling and compression from optic canal are causes of insufficient blood supply in RGC,and degeneration of RGC axons starts from chiasma RNFL at the ONH in the earlier stage of the disease and extendsperipherally towards the macula at the temporal over time.Gradual axonal loss and progressive macula GCC thinning in ITON has been reported in some case studies

, and in our cohort, we anticipated that further RGC axon degeneration progressed and reached the macula. Therefore, although we may not have observed significant GCC thinning or macular vessel attenuation at the fovea in early-stage data, analysis of long-term data demonstrates time-dependent significance in decrease of macular GCC thickness and vasculature density at the fovea.

Moreover, we investigated the association between the alteration in retinal thickness and vasculature and preserved vision acuity in ITON patients. Some patients had better preserved eyesight at their visit while some had poor vision such as NLP.However, we found that the prognostic association between time-dependent retinal vasculature alteration and the patients’post-injury eyesight was weak. For patients who had mild vision impairment (VA between 0.1 and 0.3), they usually had delayed hospital visit,

at least 30d after injury, and OCTA findings suggested that they had worse retinal thickness and vessel density. This observation added evidence to that postinjury retinal degeneration was time-dependent, however the immediate effect of injury or the onset of the disease was not often reflected on the patients’ vision loss.

The major limitation in this observational study was the inconsistency of follow-up timeframe among patients, which was due to several reasons: 1) varied lag-time between injury and initial hospital visit due to different severity of injuries;2) loss of follow-up after few months following optic canal decompression surgeries, whether they benefited vision recovery, especially for non-local patients who lived in rural regions. Due to the limited time of following-up after surgery(mean 83.32d), it is unclear whether surgical intervention is helpful for chronic recovery of microvasculature perfusion over a long-term period, it would be interesting to include patients for longer observation.

In conclusion, OCTA is a useful ophthalmic examination tool for routine diagnostic and treatment indication, where it provides depth resolved images for evaluating retinal vascular changes in ITON eyes by assessing thickness of the RNFL and macular GCC. In present study, OCTA revealed that time-dependent retina thinning and vascular attenuation are physiological features of ITON due to insufficient retinal blood supply.

ACKNOWLEDGEMENTS

Supported by the High-level Hospital Construction Project (No.303010406); Natural Science Foundation of Guangdong Province, China (No.2019A1515010361).

我说的是心里话，在这辆老掉牙的古典列车上，看到穿着维多利亚时代服装的老妇人蹒跚走动，本身就有种梦幻般的感觉。

None;

None;

None;

None;

None;

None;

None;

None;

None.

1 Singman EL, Daphalapurkar N, White H, Nguyen TD, Panghat L,Chang J, McCulley T. Indirect traumatic optic neuropathy.

2016;3:2.

2 Lee V, Ford RL, Xing W, Bunce C, Foot B. Surveillance of traumatic optic neuropathy in the UK.

2010;24(2):240-250.

3 Anderson RL, Panje WR, Gross CE. Optic nerve blindness following blunt forehead trauma.

1982;89(5):445-455.

4 Warner N, Eggenberger E. Traumatic optic neuropathy: a review of the current literature.

2010;21(6):459-462.

5 Sarkies N. Traumatic optic neuropathy.

2004;18(11):1122-1125.

6 Gross CE, DeKock JR, Panje WR, Hershkowitz N, Newman J. Evidence for orbital deformation that may contribute to monocular blindness following minor frontal head trauma.

1981;55(6):963-966.

7 Lee AG. Traumatic optic neuropathy.

2000;107(5):814.

8 Tong J, Kedar S, Ghate D, Gu L. Indirect traumatic optic neuropathy induced by primary blast: a fluid-structure interaction study.

2019. Epub ahead of print.

9 Steinsapir KD, Goldberg RA. Traumatic optic neuropathy: an evolving understanding.

2011;151(6):928-933.e2.

10 Wu N, Yin ZQ, Wang Y. Traumatic optic neuropathy therapy: an update of clinical and experimental studies.

2008;36(5):883-889.

11 Crompton MR. Visual lesions in closed head injury.

1970;93(4):785-792.

12 Jang SY. Traumatic optic neuropathy.

2018;14(1):1-5.

13 Yu-Wai-Man P. Traumatic optic neuropathy-clinical features and management issues.

2015;5(1):3-8.

14 Spaide RF, Fujimoto JG, Waheed NK, Sadda SR, Staurenghi G.Optical coherence tomography angiography.

2018;64:1-55.

15 Spaide RF, Klancnik JM Jr, Cooney MJ. Retinal vascular layers imaged by fluorescein angiography and optical coherence tomography angiography.

2015;133(1):45-50.

16 Jia Y, Tan O, Tokayer J, Potsaid B, Wang Y, Liu JJ, Kraus MF, Subhash H, Fujimoto JG, Hornegger J, Huang D. Split-spectrum amplitudedecorrelation angiography with optical coherence tomography.

2012;20(4):4710-4725.

17 Kashani AH, Chen CL, Gahm JK, Zheng F, Richter GM, Rosenfeld PJ, Shi Y, Wang RK. Optical coherence tomography angiography: a comprehensive review of current methods and clinical applications.

2017;60:66-100.

18 Choi W, Moult EM, Waheed NK, Adhi M, Lee B, Lu CD, de Carlo TE, Jayaraman V, Rosenfeld PJ, Duker JS, Fujimoto JG. Ultrahighspeed, swept-source optical coherence tomography angiography in nonexudative age-related macular degeneration with geographic atrophy.

2015;122(12):2532-2544.

19 Coscas GJ, Lupidi M, Coscas F, Cagini C, Souied EH. Optical coherence tomography angiography versus traditional multimodal imaging in assessing the activity of exudative age-related macular degeneration.

2015;35(11):2219-2228.

20 Akagi T, Iida Y, Nakanishi H, Terada N, Morooka S, Yamada H,Hasegawa T, Yokota S, Yoshikawa M, Yoshimura N. Microvascular density in glaucomatous eyes with hemifield visual field defects: an optical coherence tomography angiography study.

2016;168:237-249.

21 Chen CL, Zhang A, Bojikian KD, Wen JC, Zhang Q, Xin C,Mudumbai RC, Johnstone MA, Chen PP, Wang RK. Peripapillary retinal nerve fiber layer vascular microcirculation in glaucoma using optical coherence tomography-based microangiography.

2016;57(9):OCT475-OCT485.

22 Al-Sheikh M, Akil H, Pfau M, Sadda SR. Swept-source OCT angiography imaging of the foveal avascular zone and macular capillary network density in diabetic retinopathy.

2016;57(8):3907-3913.

23 Couturier A, Mané V, Bonnin S, Erginay A, Massin P, Gaudric A,Tadayoni R. Capillary plexus anomalies in diabetic retinopathy on optical coherence tomography angiography.

2015;35(11):2384-2391.

24 Zhang T, Xiao W, Ye H, Chen R, Mao Y, Yang H. Peripapillary and macular vessel density in dysthyroid optic neuropathy: an optical coherence tomography angiography study.

2019;60(6):1863-1869.

25 Augstburger E, Zéboulon P, Keilani C, Baudouin C, Labbé A. Retinal and choroidal microvasculature in nonarteritic anterior ischemic optic neuropathy: an optical coherence tomography angiography study.

2018;59(2):870-877.

26 Munemasa Y, Kitaoka Y. Autophagy in axonal degeneration in glaucomatous optic neuropathy.

2015;47:1-18.

27 Bernardo-Colón A, Vest V, Cooper ML, Naguib SA, Calkins DJ, Rex TS. Progression and pathology of traumatic optic neuropathy from repeated primary blast exposure.

2019;13:719.

28 Micieli JA, Newman NJ, Biousse V. The role of optical coherence tomography in the evaluation of compressive optic neuropathies.

2019;32(1):115-123.

29 Danesh-Meyer HV, Carroll SC, Foroozan R, Savino PJ, Fan J, Jiang Y, Vander Hoorn S. Relationship between retinal nerve fiber layer and visual field sensitivity as measured by optical coherence tomography in chiasmal compression.

2006;47(11):4827-4835.

30 Lee JY, Cho K, Park KA, Oh SY. Analysis of retinal layer thicknesses and their clinical correlation in patients with traumatic optic neuropathy.

2016;11(6):e0157388.

31 Chan JW, Hills NK, Bakall B, Fernandez B. Indirect traumatic optic neuropathy in mild chronic traumatic brain injury.

2019;60(6):2005-2011.

32 Li J, Shi W, Li M, Wang Z, He H, Xian J, Lv B, Yan F. Timedependent diffusion tensor changes of optic nerve in patients with indirect traumatic optic neuropathy.

2014;55(7):855-863.

33 Medeiros FA, Moura FC, Vessani RM, Susanna R Jr. Axonal loss after traumatic optic neuropathy documented by optical coherence tomography.

2003;135(3):406-408.

34 Vessani RM, Cunha LP, Monteiro ML. Progressive macular thinning after indirect traumatic optic neuropathy documented by optical coherence tomography.

2007;91(5):697-698.