Structural-visual functional relationships detected by optical coherence tomography in varying age-cohorts’patients with optic neuritis

INTRODUCTION

Optic neuritis (ON) is a variety of autoimmune-inflammatory demyelinating disease that exists as an isolated ON(ION) or an initial symptom of central neural system (CNS)demyelinating disease including multiple sclerosis (MS),neuromyelitis optica (NMO) or NMO spectrum disorders(NMOSD) and acute disseminated encephalomyelitis (ADEM),which is frequently involved in paediatric populations

.Most typical ON patients had a complete visual acuity (VA)recovery within 6mo after an episode of ON attack. The 89% pediatric ON and a little less of adult patients with ON had at least 20/40

. However, ON associated with MS,NMO or NMOSD and relapsing-remitting isolated syndrome would eventually cause blindness or disability after frequent relapsing-remitting of ON

. Previous studies demonstrated that 80% of the affected eyes from NMOSD patients and 38%of the eyes affected by MS experienced VA worse than 20/200 after an acute ON attack

. Whether the VA in the ON eyes recovered completely or not, their optic nerve microstructure always suffered irreversible impairments after an acute ON onset

. On the other hand, some ON patients exhibited rapid VA recovery to the baseline, others patients suffered permanent visual loss after frequently ON attacks and their final VA eventually associated with structural loss in the afferent optic pathway when it decreased below a certain threshold. The quantified optic nerve microstructure loss could be a potential biomarker to predict the visual function prognosis, even they could reflect on of the quality of life for MS and NMOSD patients

. Additionally, age was another crucial factor for VA recovery in ON affected eyes, due to neural repairing or regenerative ability declining with aging

. Until now,there are few studies about quantified assessment correlations between final VA and structural loss in varying age patients with ON. Therefore, this study was to quantificationally assess the relationships of final best-corrected VA (BCVA)and the optic nerve structural loss detected by optical coherent tomography (OCT) in varying age-cohorts of ON patients and analysed the thresholds of optic nerve loss to predict final VA.

SUBJECTS AND METHODS

This age-cohort study was conducted at the Chinese People’s Liberation Army General Hospital with approval of their Institutional Ethics Committee(NO.2017MBD-019). The study adhered to the tenets of the Helsinki Declaration. The written informed consents were obtained from all subjects or their guardians and were kept in Chinese People’s Liberation Army General Hospital and Beijng Children’s Hospital, Capital Medical University.

This was a retrospective, cross-sectional study.

Consecutive ON patients who had been diagnosed according to the criteria from the Optic Neuritis Treatment Trials (ONTT)

and had MRI images to excluded other CNS diseases from the Department of Ophthalmology Beijing Children’s Hospital, Capital Medical University and the Chinese Liberation Army General Hospital, from July 2014 to December 2019, were recruited as participants. The staff and their children from the two hospitals served as healthy controls(HCs). All ON patients were divided into 3 cohorts based on age: 0-18y, 19-40y and 41-70y.

Regardless of the useful parameters for predicting the vision prognosis drawn by this study, there are some limitations. This was a retrospective and cross-sectional study, and the biases of the participants recruited and the small size of the sample will weaken the reliability of the conclusions. In addition, the disease durations, the number of episodes of ON and the treatments were not well matched in the various cohorts, which also leads to bias in the outcomes. Moreover, the correlations of the structurefunction for ON eyes affected by gender, types of ON, population and races

, which were not considered in this study.

Participants who had a refractive error of more than ±6.00 spherical degree, ±2.00 cylindrical degree or an intraocular pressure value of more than 21 mm Hg were excluded. Participants with ocular diseases and surgery history,and with systemic nervous diseases caused by other than inflammation demyelination disorders identified by a senior neurologist were also excluded.

由于行星輪系具有傳動(dòng)比大、效率高、體積小、傳遞功率大、結(jié)構(gòu)緊湊等優(yōu)點(diǎn)，所以被越來越廣泛地應(yīng)用于冶金、汽車、機(jī)床、航空航天等多個(gè)領(lǐng)域，行星傳動(dòng)技術(shù)已成為世界各國機(jī)械傳動(dòng)發(fā)展的重點(diǎn)之一。

All the ON participants had their BCVA monocularly evaluated with the Snellen visual chart, and the BCVA values were converted to the logarithm values of the minimum angle of resolution (logMAR). Among them, the counting fingers (CF) and hand motion were identified as logMAR 1.85 and logMAR 2.00, respectively,with light perception and no light perception as logMAR 2.70 and logMAR 3.00, respectively

. The ON patients who were better than 0.1 with BCVA and whose age was more than 7 years also had visual field tests.

All the data were analysed by SPSS.19.0(IBM, USA), and graphic plots were performed using GraphPad Prism 5 (GraphPad Software, USA). The average measurements of OCT and BCVA were expressed by mean and standard deviation, whereas the average age of the participants was displayed by median and interquartile range(IQR). The comparisons of the age and gender in the various cohorts were tested by the Mann-Whitney

test and Pearson’s Chi-square test, respectively. The BCVA in the various agecohorts was analysed by analysis of variance (ANOVA). The OCT measurements in the various cohorts were tested by multivariate linear regression models and Bonferroni-Holm tests with eye gender (right eye or left eye) and ON episodes as covariant. The Pearson’s test for linear regression was performed to evaluate the correlations of the BCVA and the retinal structural alterations detected by OCT. The statistical significance was set when the

value was less than 0.05.

Both ON patients and HCs had a peripapillary retinal nerve fibre layer(pRNFL) and inner macular segmented layers assessment with Spectralis-OCT (Heidelberg Engineering Corporation,Heidelberg, Germany) and Microsoft 6.0.9 Nisite (Heidelberg Engineering Corporation, Heidelberg, Germany) according to standard operational protocols on the same day as the other ophthalmological examinations

. All the participants underwent OCT examinations in room light conditions and they did not have pupil dilation before the OCT performances.The pRNFL assessment used a 3.4 mm circle A-scanning centre on an optic disc. To better visualise retinal structure and precisely measure in repeated examinations multiple times[Automatic Real-Time (ART)=100] and eye-track models were performed. The global pRNFL thicknesses were assessed. The B-scanning model was used to measure the macular segmented layers and automatically calculate the total volumes of each layer within the outer circle zone (6-mm diameter circle) mapped by the Early Treatment Diabetic Retinopathy Study (ETDRS) by Microsoft 6.0.9 Nisite, which mainly comprised the macular retinal nerve fibre layer (mRNFL), macular retinal ganglion cells layer (mRGCL), macular inner plexiform layer (mIPL)and macular inner nuclear layer (mINL). The OCT images obtained with a signal strength less than 15 were discarded according to OSCAR-IB quality control criteria

. Two experienced technicians who were blind to the participants’clinical information performed all the OCT examinations.

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RESULTS

Among the 300 patients (487 eyes) with ON who were recruited and underwent assessment in this study, 130 ON patients (200 eyes) who met the included criteria participated in the study. The 130 ON patients were grouped into three cohorts based on age (Figure 1). In the age-cohorts, the gender and age compositions were strictly matched to their HC cohorts. Most of the included patients with ON suffered more than one episodes of ON attacks and the average episodes of ON onset and other clinical and demographic features are shown in Table 1. The final BCVA in 0-18y cohort (logMAR:0.16±0.39) was best followed by the 41-70 (logMAR:1.14±1.22) and 19-40y (logMAR: 1.19±1.08) cohorts (Figure 2A).As for the ON episodes, both the 19-40 and the 41-70y cohorts were more frequent than those of the 0-18y cohort (Figure 2B).In contrast to the global pRNFL thicknesses in the HCs, all the ON patients exhibited severe thinning in the pRNFL after the ON attacks (all

=0.000). The eyes from 19-40y cohort lost the most, approximately 54.5 μm; then, the 41-70y cohort lost by 50.1 μm, followed by the 0-18y cohort with 34.7 μm(Table 2). In comparisons within the ON patients, the global pRNFL thicknesses of the 0-18y cohort were reduced less than that of both the 19-40 and the 41-70y cohorts (

=0.02, 0.01);there were no significant differences between the latter agecohorts (

=1.000; Figure 3).

The neural structural impairments that emerged from noninfectious inflammatory demyelination or astrocytopathy and subsequent neuro-degeneration were not independent of the corresponding functional injuries. The cerebral lesion patterns measured by MRI were associated with the disability progression in MS and NMO

. However, it was impossible to evaluate their correlations accurately due to the limitations of the measurement technique. However, optic nerve can be precisely quantified by OCT with a 3.5 μm axial resolution

, and the visual function can be evaluated readily and quantitatively. Previous studies demonstrated that optic nerve alterations correlated to final visual acuity in ON patients;furthermore, they reflect the cerebral structural alterations inMS patients

. However, few of them considered the age influence. In this study, we studied structural-final visual functional relationships in varying age-cohort ON patients and outcomes revealed that paediatric ON patients had the best prognosis and young adult ON patients exhibited perfectly linear correlations of final vision and structural loss. The pRNFL and the mRGCL could be potential structural markers to predict the vision prognosis for varying-age ON patients. Paediatric ON had much better final visual acuity and less episodes of ON onsets than the adult ON. Consistent with that finding, the paediatric ON cohorts had a better prognosis with excellent visual recovery and a lower risk of recurrence, even though they presented severely vision decreasing at the initial onset of ON

.

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DISCUSSION

Final BCVA in the ON affected eyes from all the age-cohorts of the patients was related positively to the pRNFL thicknesses and the volumes of mRNFL, mRGCL, and mIPL (Figure 4).Of those, the linear relationships of the pRFNL thicknesses and the mRGCL volumes to the final BCVA were much stronger in varying age cohorts, when the pRNFL thicknesses were reduced to the thresholds of 57.2-67.5 μm or 0.691-0.737 mm

in mRGCL volumes, respectively, and 19-40y cohort had the strongest correlations. The thresholds of pRNFL and mRGCL loss after ON attacks to predict the variety of final visual loss,ranging from normal to CF, were listed in Table 3. When the pRNFL thicknesses and the mRGCL volumes decreased to 57.2-67.5 μm and 0.691-0.790 mm

, respectively, the ON patients suffered irreversible visual loss and dropped close to 36.7-48.3 μm and 0.495-0.613 mm

, respectively, predicting of blindness in law.

All participants underwent slit-lamp microscope and indirect-ophthalmoscopy examinations by two senior ophthalmologists.

Previous studies verified that the risk of ON relapsing and developing to MS became higher with the increased age of the ON presentation. To some extent, this outcome was similar to the opinion of fewer frequencies of ON in younger patients

. Additionally, the gender predilection of the paediatric ON was equal with the 26:22 of the ratio of female to male, whereas the female frequencies were much higher in the adult ON, with an approximate 3-2:1 ratio of female to male, which was compatible with the distinct features of paediatric as compared to adult ON

. These distinguishing characteristics between paediatric and adult ON could attribute to their distinct pathogenesis. Paediatric ON usually occurs as a post-infection of a virus, a vaccination or ADEM and itsdemyelination processes were stimulated by the virus, which is considered as a distinct entity from adult ON. Both paediatric ON and ADEM are typically a monophasic process with the same age of presentation and a better prognosis than that of MS, NMO and NMOSD

.

In conclusion, in this study, paediatric ON patients had the best prognosis and young adult ON patients exhibited perfectly linear correlations of final vision and structural loss. The final BCVA exhibited irreversible loss when the pRNFL thicknesses were reduced to 57.2-67.5 μm or mRGCL volumes dropped to 0.691-0.737 mm

, respectively and would be threatened by blindness when the pRNFL thicknesses dropped 36.7-48.3 μm or the mRGCL volumes dropped to 0.495-0.613 mm

. These structural biomarkers could be potential cues to guide the treatment programme for ON patients.

Patients diagnosed with ON without ON recurrence within 6mo and their OCT images should met the OSCAR-IB which is the international quality control criteria for retinal OCT

and images quality were good enough to perform retinal segmented analysis and correctly centred in circular scans. The HCs participants whose BCVA was equal to or better than 0.8 (40/50).

As revealed by this study, due to the number and functional decline of the neural stem cells, the retinal structure impairment of ON worsens with increased age

. The pRNFL thicknesses and mRGCL volumes lost less in the paediatric ON, followed by the 19-40y, and more than with the 40y of adult ON. Aside from the distinct pathogenesis between paediatric and adult ON, this could be explained by the much stronger neural repairing and regenerating capability to preserve retinal microstructures and restore visual function in the youth, as compared to older populations. Moreover, the pRNFL and mRGCL thinning was also associated with the final visual acuity in varying age-cohorts of ON, which were in accordance with previous studies

. Final visual acuity was related linearly and negatively to the pRNFL thicknesses and mRGCL volumes in varying age ON patients when they were reduced to the thresholds of 57.2-67.5 μm and 0.691-0.790 mm

in pRNFL thicknesses and mRGCL volumes, respectively. When pRNFL thicknesses or the mRGCL volumes were reduced close to 36.7-48.3 μm and 0.495-0.613 mm

in both eyes after frequent ON attacks, it warned doctors to prevent next ON attack as possible as they can. Otherwise, the patients would be likely to become a blind. Additionally, linear interdependency was strongest in young adult ON patients and the possible reasons could be the more suitable repair and regeneration of the optic nerve to the demyelinating injury in young adult ON patients, rather than strong repairs in paediatric ON and under repairs in aged ON patients

.

We acknowledge Ms. Li-Rong Tian, Ru Zhang and Hui-Hui Zhu’s supporting for OCT images and data collection who are from the Department of Ophthalmology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, China.

Conception and design: Peng CX,Shi W, and Li L. Analysis and interpretation: Peng CX and Cai SY. Data collection: Zhang HT, Zuo HX, Li SY, Zheng PP and Xu QG. Obtained funding: Wei SH. Overall responsibility: Shi W, Zhang HT, Peng CX and Li L.

在鐵路污工梁人行道設(shè)計(jì)標(biāo)準(zhǔn)中，采用U型螺栓等預(yù)埋件連接的角鋼支架成為寬0.50～1.55m人行道的主導(dǎo)方法，這些連接件成為承受托架動(dòng)靜載荷的關(guān)鍵著力點(diǎn)[1]。由于螺栓連接方式及受力狀態(tài)比較復(fù)雜，加之在運(yùn)營過程中外界環(huán)境和列車振動(dòng)的影響以及在日常維修不當(dāng)，在人行道寬度較大的橋梁中逐漸出現(xiàn)螺栓彎曲和折斷的病害，然而這些關(guān)鍵連接件一旦出現(xiàn)問題，可能造成托架脫落導(dǎo)致的人身傷害。

Supported by the National High Technology Research and Development Program of China (863 Programme, No.2015AA020511); Clinical Support Foundation of PLA General Hospital, China (No.2016FC-TSYS-I016).

湖泊面積大，岸線長，以高郵湖為例，760.67 km2的水域面積，僅僅依靠湖泊管理人員的眼觀腳量，不僅成本高、難度大，而且也很難準(zhǔn)確掌握湖泊流域的綜合情況。

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