Reduced choroidal peripapillary capillaries in thyroidassociated ophthalmopathy with early stage of dysthyroid optic neuropathy

INTRODUCTION

Thyroid-associated ophthalmopathy (TAO), also known as Graves’ ophthalmopathy, is an autoimmune disorder which has characteristic ocular manifestations,such as proptosis, eyelid retraction, eyelid lag and restrictive extraocular myopathy

. Among a series of TAO associated clinical findings, dysthyroid optic neuropathy (DON) is the most severe vision-threatening condition. The pathogenesis of DON is complicated, which is not fully understood by far.The most widely accepted theory is that DON is caused by the combined effects of mechanical, vascular and inflammatory process. Mostly, DON is secondary to a compartment syndrome in orbital apex, which is caused by enlargement of extraocular muscles and orbital fat resulting from orbital fibroblast deposition of hyaluronic acid

.

Our study demonstrated that a significant reduction of choroidal RPC observed in DON patients rather than normal and TAO without DON by using OCTA. RPC is a superficial capillary layer which comprise a unique vascular plexus. There have been reports demonstrating that RPC is necessary to metabolic demands of retinal ganglion cell (RGC) axons

.As the RGC axons are vulnerable to decease of blood flow, the structural changes to RPC network could lead to pathogenesis of RGC axonal loss

. There is evidence also showing an correlation between RPC loss and RNFL changes in chronic glaucoma

. The change of peripapillary microvasculature could not be efficiently detected by OCT

, which indicates that OCTA could be the most effective and easiest way to detect changes in retinal and/or choroidal microvasculature.Our data indicated a significant correlation between RPC reduction and VF defect. However, the decrease of choroidal RPC density could not be reversed 6mo after relieving optic nerve compression by either corticosteroid treatment or optic nerve decompression surgery though vision acuity significantly improved. However, longer term follow-up is required to further understand if the reduction of choroidal RPC could be recovered or permanently affected. Therefore, it is suggesting that choroidal RPC density could be clinically useful for early diagnose of DON.

There are around 4% to 8% TAO patients having DON

,of which the irreversible vision loss is largely caused by delayed diagnosis due to lack of efficient detecting method at early stage of TAO. It has been reported that the axonal changes of optic nerve are detected in patients with DON

.The compression caused by enlarged extraocular muscles and orbital fat may stretch the optic nerve and reduce the blood flow supply of retina. A report demonstrated that blood flow volume of superior ophthalmic vein decreased in DON eyes

.These findings suggest that the changes of optic nerve and hemodynamic state of the eye might be valuable for early diagnosis of DON.

There is no specific diagnosis guideline for DON due to various of clinical manifestations and limited detecting methods. Most clinicians diagnose DON by a combination of radiological findings and clinical manifestations. However, some patients may not present external signs, such as proptosis, because in some cases, DON only caused by congestion at the orbital apex

. The decline of visual acuity also sometimes lag behind other clinical presentations of DON, therefore, a number of tests should be run to evaluate the function of optic nerve for diagnosis of DON, including papillary exam, automated visual field (VF) and contrast sensitivity

.

圖畫書講讀，應(yīng)該建立在對圖畫書藝術(shù)的理解和把握的基礎(chǔ)上。兒童對圖畫書的喜愛，與圖畫書的內(nèi)容、形式、表達(dá)，與其圖畫文字的共同講述故事，與其獨(dú)有的藝術(shù)設(shè)計和效果，都有著密不可分的關(guān)系。圖畫書因此建立起不同于其他讀物的欣賞方式，兒童更有自己進(jìn)入圖畫書藝術(shù)世界的方法和途徑，有符合他們心理和趣味的審美體驗。教師進(jìn)行圖畫書的講讀活動，應(yīng)盡可能在認(rèn)識圖畫書藝術(shù)構(gòu)成和特點(diǎn)的基礎(chǔ)上進(jìn)行，幫助兒童積累或調(diào)動他們自己的閱讀經(jīng)驗，盡可能充分地、全方位地欣賞圖畫書作品，獲得愉悅并提升審美能力。

Optical coherence tomography angiography (OCTA) is a noninvasive imaging facility which could be applied to measure the thickness of retinal nerve fiber layer (RNFL), macular and many other parameters of the eye. OCTA is a high-speed optical coherence tomography (OCT) that could characterize a map of blood flow and vessel network of different layer and area of the retina and choroid, which is achieved by comparing the captured signals between sequential scans taken at same crosssection. OCTA assists clinicians to non-invasively visualize and assess retinal and choroidal perfusion, while at the same time the assessment is trustworthy due to its reliable reproducibility,sensitivity and specificity

. With the emergence of OCTA,it is possible to study the correlation between microvascular perfusion changes and the development of DON.

Here we demonstrated that OCTA could detect early defects in density of radial peripapillary capillaries (RPC) around optic disc in DON, which was also significantly correlated with defect of VF and vision. The findings suggested that OCTA could be used to early diagnose DON in clinics.

SUBJECTS AND METHODS

Ethical Approval This was a retrospective cross-sectional study conducted at the Department of Ophthalmology in Shanghai General Hospital, China, from January 2019 to December 2020. The study protocol and ethics were approved by the Ethics Committee of Shanghai General Hospital (ref 2020KY206). The study was conducted complied with the tenets of the Declaration of Helsinki. Written informed consent was obtained from all participants.

李閨女又呸了一口：李六如，真是越來越不知道羞恥了。原先拆遷時，你想當(dāng)個先進(jìn)也就算了。如今，又勾結(jié)佟金鑫占了那點(diǎn)口糧田。你說，老少爺們今后怎么活？

Significant Reduction of Radial Peripapillary Capillaries in Dysthroid Optic Neuropathy Next, we further divided the patients of TAO into two subgroups, DON and non-DON,according to the criteria described in method section. DON had a significant reduction in both VF and the percentage of choroidal RPC, including whole and peripapillary, compared to both normal and TAO without DON (Figure 1). The percentage of whole choroidal RPC significantly reduced from 50.33%±0.3173% in normal to 49.16%±0.5463% in TAO without DON and further to 48.24%±0.4978% in DON(

=0.0041). The percentage of peripapillary choroidal RPC was also significant reduced from 53.24%±0.3914% in normal to 52.27%±0.5562% in TAO without DON, and further reduced to 51.50%±0.5399% in DON (

=0.03; Table 3). In agreement to the findings, the representative OCTA images also illustrated that the choroidal capillaries around optic disc were thinner in DON patients than that in normal and TAO without DON (Figure 2). There was no significant difference between DON, TAO without DON and normal controls in most tested parameters (Table 3). The above data suggested that change of choroidal RPC could be a specific sign in DON,and there was a possibility that the reduction of choroidal RPC in DON correlates with VF defect.

Patients diagnosed with TAO were based on Barley criteria

.Inclusion criteria for TAO participant were: 1) At least 18 years of age; 2) No history of radioactive iodine therapy or thyroidectomy. TAO participants were further divided into two groups, DON and non-DON. The diagnosis of DON was based on clinical findings

: 1) Decreased visual acuity compared to previous medical records; 2) Apparent VF defect mean deviation (MD) ＜-10 dB in Humphrey test; 3) Relative afferent pupillary defect; 4) Evidence of apical crowding in computed tomography or magnetic resonance imaging.

RTVue-XR Avanti system has been designed to minimize scanning time based on the SSADA algorithm. The system can also measure the variation of OCT signals among consecutive scans, therefore the motion of blood flow could be captured. In order to quantify and analyze the nerve fiber layer and macular circulation,

retinal angiogram images were processed and vessel density was calculated using the Avanti trend analysis software.

Exclusion criteria for all participants were: 1) Any retinal pathology and optic neuropathy, such as uveitis and diabetic retinopathy; 2) Any complication inducing VF loss, such as glaucoma or ocular tumor; 3) Any history of ocular trauma or intraocular surgery; 4) Vulnerable individuals or those who cannot conduct any test required in this study.

Humphrey Visual Field Test Humphrey Visual Field Analyzer II 750 (Carl Zeiss Meditec) was used to test VF for all participants, the data was calculated by Humphrey Swedish Interactive Threshold Algorithm (SITA) 30-2 test.The included results should meet the criteria that fixation loss was less than 20%, and both false-negative errors and falsepositive errors were less than 15%. All tests were performed without any inappropriate operation, such as eyelid artefacts,inattention, and fatigue effects. Any defects of VF caused by other diseases was excluded as described before.

通過本次研究可以看出,兇險性前置胎盤患者相對于普通前置胎盤患者來說,面臨的威脅更大,可能導(dǎo)致的不良妊娠結(jié)局與不良新生兒結(jié)局的概率更高。另外,在一般資料對比中我們可以看出,高齡產(chǎn)婦、孕次和產(chǎn)次較高的產(chǎn)婦其發(fā)生兇險型前置胎盤的可能性更大,因此,臨床上對于此類前置胎盤產(chǎn)婦要給予特別關(guān)注。

OCTA Image Acquisition and Processing The RTVue-XR Avanti could be used to visualize vascular structures of distinct layers of the retina and choroid. The scan was non-invasive and achieved by low-coherence interferometry. RTVue-XR Avanti used an 840 nm light source as the scan beam wavelength with an A-scan rate of 70 000 A-scan per second. Motion artefacts were minimized by dual orthogonal volumetric imaging of the retina. Each studied eye received four volumetric raster scans,which were composed of two horizontal priority (X-fast)and two vertical priority (Y-fast) scans. The scans provided consecutively information outside a 6×6 mm

field size of observed structures and assessed the details of retina in distinct layers.

Inclusion criteria for normal subjects were: 1) at least 18 years of age; 2) normal clinical appearance of the optic disc; 3) no RNFL loss; 4) no VF defect.

Measurement of Radial Peripapillary Capillaries, Macular Ganglion Cell Complex and Peripapillary RNFL The thickness of peripapillary RNFL and macular GCC were obtained using RNFL 4.5 scanning mode and analyzed by the GCC scan algorithm installed in the RTVue-XR Avanti. The RNFL thickness was measured around the optic disc with a circle of 4.5 mm diameter using RNFL mode, while the GCC scan was examined around the fovea with a square area of 6×6 mm

.GCC scan covers multiple layers of the retina, including the RNFL, the ganglion cell layer and the inner plexiform layer.The calculation of the scanned segmentations of the RNFL and GCC was analyzed by the SSADA algorithm. Furthermore,the SSADA algorithm can also measure and analyze separated areas of the retina including average, superior and inferior hemi-retinal RNFL and GCC.

Statistical Analysis All the data were calculated as mean and standard deviations and compared between groups. For the comparison between two groups, Student’s

test was used to compare the average values of all the measurements. Gender frequency comparison was analyzed by the Chi-square test.The correlation analysis was performed by univariate analysis with Pearson correlation test and multivariate analysis with ANOVA testing to determine the correlation between RPC and other parameters, such as visual acuity and MD and pattern standard deviation (PSD) of VF. Statistical significance was considered as

＜0.05. One-way ANOVA test with Tukey correction was applied for multiple comparison among groups with resultant significance level set at

＜0.01.

RESULTS

Demographic Data and Clinical Features Table 1 summarizes the clinical characteristics of each group. According to the inclusive and exclusive criteria, 34 eyes were included in normal group, while 64 eyes were included in TAO group.TAO was further divided into two groups, DON and TAO without DON, with 39 eyes in DON and 25 eyes in non-DON respectively. There was no statistically significant difference in DON, TAO without DON and normal controls, regarding to age and gender. The visual acuity of DON was significantlylower than the other two groups, though the CAS showed no difference between non-DON and DON.

據(jù)世界衛(wèi)生組織首份《全球糖尿病報告》顯示，全球糖尿病患者人數(shù)從1980年的1.08億增加到2014年的4.22億。目前我國確診的糖尿病患者已經(jīng)超過1億，居世界首位。據(jù)統(tǒng)計，糖尿病在我國的發(fā)病率已經(jīng)超過11.2%，處于糖尿病前期的人數(shù)占總?cè)丝诘?0.1%，我國約70%的糖尿病患者不知道自己已經(jīng)患上糖尿病。而接受治療的成人糖尿病患者中，血糖控制率不到40%。許多糖尿病患者服用了幾十年的降糖藥也沒有把血糖降下來，藥越吃越多，血糖卻越來越高，各種并發(fā)癥越來越嚴(yán)重。

Reduction of Radial Peripapillary Capillaries in Thyroid Associated Ophthalmopathy Compared to Normal Table 2 is an overview of a comparison in a series of parameters between TAO and normal subjects. When compared to normal participants, TAO showed significant reduction in the percentage of choroidal RPC, including whole and peripapillary area of choroidal RPC, as well as in MD of VF (Table 2). The percentage of whole choroidal RPC was 50.33%±0.3173%in normal controls, but reduced to 48.63%±0.3707% in TAO(

=0.0025). Similarly, significant reduction was seen in peripapillary choroidal RPC (51.83%±0.3896% in TAO

53.24%±0.3914% in normal controls,

=0.01; Table 2). While there was no statistical difference between the two groups in thickness of GCC and RNFL, disc area and percentage of focal loss volume (FLV) and global loss volume (GLV).

Study Participants A total number of 98 eyes from 50 subjects were enrolled according to the criteria of this study and imaged by RTVue-XR Avanti (Opto Vue, Inc, Fremnt, CA,USA) platform and analyzed with the split-spectrum amplitude decorrelation angiography (SSADA) algorithm. Each patient underwent a series of ophthalmological examinations, including slit-lamp clinical examination, best-corrected visual acuity test, ocular motility, severity of proptosis, VF test, clinical activity score (CAS)

and OCTA scanning of peripapillary RNFL, macular ganglion cell complex (GCC) and choroid RPC. There were 11 DON patients received intravenous corticosteroids treatment to relieve the clinical symptoms of optic nerve compression, while 5 of whom further received orbital decompression surgery due to the unresponsive to corticosteroids treatment. For the eyes received steroid therapy and surgery, the examinations were practiced both pre- and post- treatment/surgery. The comparison was made between pre-operation and 6-month after treatment/surgery.

Orbital imaging techniques, such as MRI and CT, play a vital role in diagnosing and following DON

. The muscle index is significantly greater in orbits with DON, and DON almost never occurs in patients when muscle index is less than 50%

.Orbital soft tissue imaging also help to diagnose DON, with up to 94% sensitivity and 91% specificity

. However, cost of these imaging detecting methods is high and some disable patients may find it difficult to take the scans. Therefore, there is still a demanding of a new technique which could detect subtle changes for early diagnose of DON.

Correlations Between Radial Peripapillary Capillaries and Visual Function Parameters To further investigate if the reduction of choroidal RPC accounts for any pathological changes in DON, we ran a series analysis to detect any correlations. Data showed that the whole percentage of choroidal RPC had a significant correlation with visual defect,especially defect in VF in DON (

=0.5422), while such correlations were not observed in either normal (

=0.1529) or TAO without DON (

=0.07371; Table 4), which suggested that the reduction of choroidal RPC was a specific change in DON.Radial Peripapillary Capillaries Density Could not be Reversed by Medical or Surgical Decompression To investigate if the RPC density and other parameters would improve when DON is relieved, we compare all these observed clinical data before and after treatment. There were 11 DON eyes received intravenous methylprednisolone pulse therapy due to severe symptoms of optic nerve compression such as rapidly decline of vision acuity and defect of VF, but 5 of which did not respond well to corticosteroids treatment as the deterioration of vision and VF continued. Therefore,the 5 DON eyes further received orbital decompression surgery followed with symptoms of optic nerve compression significantly improved in all cases. After medical or surgical decompression, vision acuity and VF improved in all treated eyes, but there was no significant difference of choroidal RPCdensity between pre-treatment (whole 48.28%±1.147%) and post-treatment (whole 47.58%±1.144%; Table 5). The data demonstrated that both medical and surgical decompression could reverse defected visual function to a certain level, but the decline of choroidal RPC still remained.

DISCUSSION

In this study, we demonstrated that the percentage of choroidal RPC was significantly reduced in the patients of DON compared to both normal controls and the patients of TAO without DON. The reduction of choroidal RPC also correlated with defects of VF, which suggested the change of choroidal RPC could be an early sign of optic nerve damage. OCTA can be used to investigate vessel volume and density of multiple layers of the eye, which makes clinicians able to observe changes undetected by other investigating methods.

So far, there is no single protocol or guideline for diagnosing DON

, clinicians have to measure grades of clinicalsigns and symptoms of patients, and also run a series of tests, including CT or MRI scan, and VF test. Only with the combination of clinical findings and test results can DON be diagnosed. However, there are still a number of DON patients facing with delayed diagnosis due to unspecific clinical presentation

. For example, some patients with DON only caused by congestion at orbital apex without any sign of proptosis, and patients sometimes are lack of clinical manifestations of orbital inflammation, which could cause the delay use of radiology test as there is little sign of further investigations. Decreased visual acuity is also an unspecific symptom, though it is more often found in DON rather than thyroid eye diseases (TED) alone. It has been reported that there are about 47% of DON patients with visual acuity lower than 20/40, while the number is only 3% in TED patients

.Reduction of contrast sensitivity, colour vison change and an afferent pupillary defect are the other signs specific for DON,though all of these signs can be absent in some cases

.

VF test can accurately detect DON, according to studies, most of the DON eyes develop a central or paracentral scotoma during the progress of disease

. Visual evoked potential(VEP) can also assist to detect DON, and sometimes it is even more sensitive than VF test

. Therefore, the retinal function is one of the diagnostic factor for DON. Our data also suggested that there was a significant difference of VF defect between DON and non-DON.

大老李已經(jīng)五十多歲了，還從五十里外的西平老家來這里下井。他的背微駝，和我們常常見到的那種老實巴交的高個子男人一樣，整天不怎么言語。他的大女兒讀高中，兒子小學(xué)。大老李極疼他的孩子，他常常盯著一張皺巴巴的照片看，那是他們的全家福。他還買些紙筆書包的存著，說等到回家的時候給孩子帶回去。他說，現(xiàn)在農(nóng)村的孩子們除了讀書這條道再沒其他出路了?？磥硭菢O想把自己的孩子培養(yǎng)成大學(xué)生的。然而此刻，西山轟隆一聲，一縷灰煙過后，大老李兩腿一蹬，雙眼一閉，唉，都他媽的過去了。完蛋了，一切都完蛋了。

(一)釋義的內(nèi)容要能夠清楚地標(biāo)注出詞義中是借代意義的義項,而不應(yīng)該把借代意義混同為詞的普通一般的指稱意義。比如:

There were studies indicating that the macular microvascular densities were significantly reduced in TAO patients

. But our data presented no significant finding observed neither between normal and TAO, nor between normal and DON.One of the possible reasons of getting different result is that the acquisition area of GCC is different, we acquired 6×6 mm

OCTA images for GCC rather than 3×3 mm

acquired in other studies. Another possibility is that the different enrolled criteria of TAO may give biased readout. There was even one study reporting that microvascular density significantly increased in active TAO

. Taken these findings together, the GCC density varies during different stage of TAO, which indicates that the change of GCC density could not effectively monitor development of TAO.

Our data demonstrated that the density of choroidal RPC,both whole and peripapillary area, was significantly decreased in DON compared to normal eyes and TAO without DON.The decrease of vessel density in the peripapillary area in eye with DON had also been shown by one previous study

. The reduction of choroidal RPC has been found to be correlated with defects of VF. Therefore, the change of choroidal RPC could be an early sign of optic nerve damage. Furthermore,our study found that the reduction of RPC density could not be reversed by medical or surgical decompression. So far, the most widely accepted mechanism is that DON is secondary to a compartment syndrome in orbital apex, and the changes of vessels in orbit may also be related to DON. The decreased blood flow in the active stage of orbitopathy, while the reversed or even absent blood flow in many advanced cases can even induce the optic nerve vasculature which further develops ischemia. Medical and surgical decompression could decrease the direct optic nerve compression in DON, however,might not benefit to restore the vasculature

.

還記得那是去年十月的最后一天中午，我們準(zhǔn)時來到了“神秘”的校長室。校長室里寬敞明亮，一塵不染，陳校長已經(jīng)在那里微笑地看著我們。在聽完我們簡單的自我介紹后，陳校長笑著說：“我非常高興能接受你們的采訪，你們有什么問題嗎？”望著陳校長那慈祥的笑容，我們緊張的情緒一掃而空，緊接著就開始了關(guān)于校慶三十周年的專訪。

疫情對生豬生產(chǎn)產(chǎn)生了一定影響，春節(jié)前豬價或出現(xiàn)一波上漲。主要是由于部分地區(qū)仔豬無法調(diào)運(yùn)。目前很多自繁自養(yǎng)和公司+農(nóng)戶企業(yè)生豬育肥需要跨市、跨省調(diào)運(yùn)仔豬，由于仔豬無法調(diào)運(yùn)，特別是9月中旬之后，導(dǎo)致繁育場壓欄嚴(yán)重、仔豬死亡率較高，而育肥場無豬可育，因此將會影響4個月以后的生豬供應(yīng)，或?qū)?dǎo)致某個時期豬價較快上漲，2019年二季度豬價淡季不淡。

There are limitations in our study. First, the observation period is not very long. Longer follow-up could help to get more comprehensive understanding of the role of choroidal RPC in the development of DON. Second, the sample size of treated eyes is also small, more samples would make the conclusion stronger. Last, the diameter of analyzed area by OCTA seems to make some biases in making conclusions, which requires further investigations in future study.

In conclusion, there are advantages of using OCTA in diagnosis of DON. It improves our understanding of pathogenic relationships between optic disc circulation and VF defect. It is also non-invasive and easy to operate, which can be accepted by a wide range of patients. Therefore, choroidal RPC scan by OCTA could be an effective way to investigate and monitor DON, it is also possible to help in early diagnosis of DON.

ACKNOWLEDGEMENTS

Authors’ contributions: Cheng JW designed the study,wrote the manuscript and collected data; Wu JH wrote the manuscript, collected and analyzed data; Luo LY, Zhou H, Wu Y, Zhang J, Cheng JW performed OCTA and collected data.All authors have read and approved the manuscript.

Fe0-PRB技術(shù)在含鈾廢水處理方面得到了研究與應(yīng)用，但也存在許多缺陷與不足，制約了該技術(shù)的進(jìn)一步發(fā)展和實際應(yīng)用的推廣.因此，對這些問題的研究與改進(jìn)，將會成為Fe0-PRB技術(shù)在含鈾廢水處理方面的研發(fā)重點(diǎn).

Supported by the National Natural Science Foundation of China (No.81170874; No.81900868).

Conflicts of Interest: Wu JH, None; Luo LY, None; Zhou H,None; Wu Y, None; Zhang J, None; Cheng JW, None.

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