I am Dr. Tie-zhu Lin, from He Eye Specialist Hospital,Shenyang, China. I write to present the case of persistent macular oedema following Best vitelliform macular dystrophy(BVMD) undergoing anti-vascular endothelial growth factor(VEGF) treatment.

教學(xué)反思是概率統(tǒng)計思維型課堂教學(xué)模式中不可少的一個環(huán)節(jié)。教師通過反思教學(xué)過程可以總結(jié)經(jīng)驗教訓(xùn)，為學(xué)生知識建構(gòu)與思維發(fā)展尋找更快更好的途徑；學(xué)生通過反思課堂學(xué)習的過程，可以更好地總結(jié)本節(jié)課所學(xué)到的知識方法，理清知識架構(gòu)。思考過程中將新學(xué)的知識融入到舊的知識體系當中，回顧思維的過程，總結(jié)新的思維方法。

BVMD also called Best’s disease, is a hereditary disease due to mutation in the

gene located on chromosome 11

and has vastly variable phenotypic expression. During BVMD, a rare but severe complication known as choroidal neovascularization (CNV) can occur, which can rapidly decrease visual acuity

. Some studies reported that treatments such as intravitreal anti-VEGF agents and photodynamic therapy (PDT) have been effective on CNV associated with BVMD

. We report a case of a patient affected by CNV due to BVMD in the right eye (OD). We obtained the written informed consent from the patient, and this case study is in accordance with the tenets of the Declaration of Helsinki.

A 13-year-old Chinese girl presented with severe painless visual acuity reduction in her OD. During the first examination of the anterior segment and intraocular pressure (IOP) were within normal limits, best-corrected visual acuity (BCVA) was 20/200 OD and 20/32 in the left eye (OS). Fundus examination of the OD revealed a fibrous scarring in the macula (Figure 1A),a subretinal yellowish-grey lesion in the inferior part of the macula and subretinal flecks at the posterior pole was present on OS as showed in Figure 1B. Fundus autofluorescence(FAF) revealed hypofluorescence in the centre or macula with hyperfluorescent margin in the OD (Figure 1C) and punctuate hyperfluorescence in the fovea with hyperfluorescence in the inferior part of the macula in the OS (Figure 1D). Fluorescein angiography (FA) showed early hyperfluorescence with intense late leakage at the centre of the macula of the OD, indicating the presence of a subretinal neovascular membrane (Figure 1E). OS showed an area of mottled hyperfluorescence without leakage in the macula, indicating staining of vitelliform material around the foveal centre (Figure 1F). Indocyanine green angiography (ICGA) showed mild hyperfluorescence in the macula with hypofluorescence margin in the OD (Figure 1G), multiple punctuate hyperfluorescence in the macula of OS due to the staining of subretinal overlying vitelliform material(Figure 1H). Optical coherence tomography (OCT) revealed a sub-foveal protruding highly reflective lesion with subretinal fluid and intraretinal cystic oedema in the OD (Figure 1I), subfoveal optically empty space with sub-retinal highly reflective nodular lesion in the OS (Figure 1J). The Arden ratio in electrooculogram (EOG) was found to be abnormal in the OS(OD: 1.93, OS: 1.31). Genetic test confirmed heterozygous mutations [c.913T＞C(p.Phe305Leu)] in

gene.

The standard treatment for individuals with sub-foveal CNV is anti-VEGF agents. Some studies have reported that intravitreal bevacizumab/ranibizumab injections for CNV secondary to BVMD had positive outcomes with visual recovery and regression of the CNV in most cases, the age of cases in these studies were between 5 to 17y, and the follow-up time between 7 to 24mo

. However, currently no reports on the use of aflibercept have been published and long-term follow-up of these patients are unspecified. Some studies also treated this type of CNV with PDT, most cases had stable visual acuity,and the longest follow-up time was 33mo

. In the current case, macular edema was persistent with multiple intravitreal ranibizumab and aflibercept injections. Interestingly, the patient had steady BCVA, even during the 7mo observation time.The patient didn’t feel any change with or without treatment.Though previous studies reported positive outcomes with intravitreal anti-VEGF injections or PDT, but the follow-up time was not long enough to support that, and BVMD patients are usually very young, the expectation of life are decades.

DISCUSSION

Best

first identified Vitelliform macular dystrophy in 1905 and the age of onset is usually from 3 to 15y. A typical yellow yolk-like macular lesion may be present, usually bilateral, but in some cases unilateral. Slow visual deterioration is the usual course. EOG is usually abnormal with a reduced Arden ratio＜1.5, most often 1.0 and 1.3, but this value is not absolute, as the Arden ratio decreases with age. Splitting and elevation of outer retina and retinal pigment epithelial layer with dome-like hyporeflective or hyperreflective material and subretinal fluid,intraretinal cystoid could exist in CNV stage. Gene testing could confirm the mutations of genetic locus.

The patient was given intravitreal ranibizumab (0.05 mg/0.05 mL)in the OD following detailed informed consent was obtained from the family (Figure 2A). Post-injection period was uneventful and at 1mo follow-up, BCVA in the OD was maintained at 20/200. OCT revealed subretinal/intraretinal fluid was absorbed completely (Figure 2B). The retina of the OD kept dry at 2mo follow-up (Figure 2C). The patients didn’t come back at 3mo follow-up due to COVID-19 prevalence. CNV of the OD was reactive at 4mo follow-up, but BCVA didn’t change (Figure 2D). Though three more monthly intravitreal ranibizumab (0.05 mg/0.05 mL) were administered, CNV was still active, BCVA was always kept at 20/200 (Figure 2E-2G). Then ranibizumab was switched to aflibercept due to poor response.The patient got monthly intravitreal aflibercept (2 mg/0.05 mL)for two injections, but mild leakage was continuous observed on OCT. OD BCVA was maintained at 20/200 (Figure 2H-2I).The observation was poor response to anti-VEGF treatment and stable vision acuity. OD BCVA remained at 20/200 during the next 7mo follow-up, and OCT showed persistent macular oedema (Figure 2J-2O). During 16mo follow-up, BCVA was maintained at 20/32 in the OS, and the morphology on OCT and fundus examination did not change much.

Though PDT therapy could make CNV lesion stable, but previous studies didn’t find any visual acuity improvement from that

. In the current case, BCVA is stable during followup, so we didn’t choose this option.

In conclusion, our case shows persistent macular oedema secondary CNV to BVMD after anti-VEGF treatment. The patient kept stable BCVA during the 16mo follow-up. We suggest close observation for this kind of disease.

Intravitreal therapies targeting VEGF have revolutionised treatment of ocular neovascular diseases as VEGF is implicated in a wide variety of pathophysiologic processes and therefore the ocular and systemic safety of anti-VEGF agents is of importance. The primary ocular adverse event detected in clinical trials regarding anti-VEGF drugs was a low frequency of ocular inflammation and systemic adverse events such as slightly elevated risk of stroke. The sporadic adverse events included retinal detachments, retinal tears, elevated intraocular pressure, ischemia, transient global amnesia, sixth nerve palsy,

. We do not know if long term anti-VEGF treatment could influence children physical development either. Currently, the long term use of anti-VEGF treatment lacks sufficient evidence

.

陽臺上擺滿了大大小小的盆花，勢如花店。細數(shù)它們的來處，不外乎如下幾種：有從花卉市場買回來的，有從同事那里剪枝扦插的，還有花草分蘗后分盆栽種的。養(yǎng)花，應(yīng)以易活好養(yǎng)為首選，太嬌貴難侍弄的，養(yǎng)起來是一種心理負擔。以不菲的價格買回來，還需要你對光照、濕度、土壤等各方面的生存條件把握得準準的，否則稍微不合心意，它就會葉枯花落。不但糟蹋了花苗，自己內(nèi)心也會生出深深的失落。所以，多養(yǎng)些不開花的綠葉植物，一年四季陽臺上都綠意蔥蘢，偶爾花香飄溢，會滿心歡喜。

（2）洞臉部位錨桿鎖口。在結(jié)束洞口開挖作業(yè)后，需要隨即進行素噴混凝土作業(yè)，當厚度達到5cm后,應(yīng)展開錨桿鎖口處理?；诙纯诓课坏牟煌枰貌煌姆绞?。對于洞頂區(qū)域而言，鎖口錨桿只需布設(shè)一排，而側(cè)面區(qū)域則需有所改變，應(yīng)再增設(shè)一排，兩排之間保持0.5m距離。錨桿使用的是規(guī)格為Φ20mm的螺紋鋼，入巖深度為5m。

Intravitreal anti-VEGF agents are also widely used in other CNV diseases and macular edema (ME). Many studies reported poor response or resistance to some anti-VEGF agent in the real word and switched agents. In Protocol T, persistent DME was in 65.6% patients with bevacizumab, 31.6% patients with aflibercept,and 41.5% patients with ranibizumab through 24wk

. To the best of our known, this is the first case reporting CNV secondary BVMD resistant to intravitreal anti-VEGF treatment.

Supported by Natural Science Foundation of Liaoning Province, China (No.2020-MS-360); Shenyang Science and Technology Bureau (No.20-205-4-063).

另外鄉(xiāng)村教師中還存在著相當一部分的民辦教師和代課教師，這些教師無論在工資待遇，還是進修學(xué)習，更是沒有機會進一步深造，大部分靠自己的已有經(jīng)驗和傳統(tǒng)教學(xué)，整體素質(zhì)不高。鄉(xiāng)村條件有限，很少有年輕教師愿意到鄉(xiāng)村任教，因此鄉(xiāng)村教師普遍年齡偏大。這部分教師一般教育觀念傳統(tǒng)，教育方法落后，很難吸收先進的教育理念，這部分教師對新課改的適應(yīng)能力較差。再加上許多鄉(xiāng)村優(yōu)秀教師考調(diào)到其它重點學(xué)?；蛑行某鞘袑W(xué)校之后，部分年齡偏大但想走又沒辦法離開的教師，很多便自暴自棄，甚至不思進取只想混天度日，盼望早日退休。這些教師不但整體素質(zhì)不高，教學(xué)質(zhì)量不高，而且其思想還會影響學(xué)生學(xué)習積極主動性的提高。

None;

None;

None;

None.

1 Petrukhin K, Koisti MJ, Bakall B, Li W, Xie G, Marknell T, Sandgren O, Forsman K, Holmgren G, Andreasson S, Vujic M, Bergen AA,Mcgarty-Dugan V, Figueroa D, Austin CP, Metzker ML, Caskey CT,Wadelius C. Identification of the gene responsible for Best macular dystrophy.

1998;19(3):241-247.2 Miller SA, Bresnick GH, Chandra SR. Choroidal neovascular

membrane in Best’s vitelliform macular dystrophy.

1976;82(2):252-255.

3 Mohler CW, Fine SL. Long-term evaluation of patients with Best’s vitelliform dystrophy.

1981;88(7):688-692.

4 Leu J, Schrage NF, Degenring RF. Choroidal neovascularisation secondary to Best’s disease in a 13-year-old boy treated by intravitreal bevacizumab.

2007;245(11):1723-1725.

5 Cennamo G, Cesarano I, Vecchio EC, Reibaldi M, de Crecchio G. Functional and anatomic changes in bilateral choroidal neovascularization associated with vitelliform macular dystrophy after intravitreal bevacizumab.

2012;28(6):643-646.

6 Frennesson CI, Wadelius C, Nilsson SEG. Best vitelliform macular dystrophy in a Swedish family: genetic analysis and a seven-year follow-up of photodynamic treatment of a young boy with choroidal neovascularization.

2014;92(3):238-242.

7 Elbany S, Kodjikian L, Boucher S, Loria O, Burillon C, Mathis T.Neovascularized best disease in child: contribution of optical coherence tomography angiography.

2019;50(9):597-601.

8 Chhablani J, Jalali S. Intravitreal bevacizumab for choroidal neovascularization secondary to best vitelliform macular dystrophy in a 6-year-old child.

2012;22(4):677-679.

9 Ozdek S, Ozmen MC, Tufan HA, Gurelik G, Hasanreisoglu B.Photodynamic therapy for best disease complicated by choroidal neovascularization in children.

2012;49(4):216-221.

10 Murro V, Mucciolo DP, Giorgio D, Sodi A, Passerini I, Cipollini F,Virgili G, Giansanti F. Optical coherence tomography angiography cyclic remodeling of CNV in patients affected by Best macular dystrophy.

2020;41(5):440-447.

11 Andrade RE, Farah ME, Costa RA. Photodynamic therapy with verteporfin for subfoveal choroidal neovascularization in best disease.

2003;136(6):1179-1181.

12 Best F. II. über eine heredit?re maculaaffektion.

1905;13(3):199-212.

13 Bressler NM, Beaulieu WT, Glassman AR, Blinder KJ, Bressler SB, Jampol LM, Melia M, Wells JA 3rd, Diabetic Retinopathy Clinical Research Network 3rd. Persistent macular thickening following intravitreous aflibercept, bevacizumab, or ranibizumab for central-involved diabetic macular edema with vision impairment: a secondary analysis of a randomized clinical trial.

2018;136(3):257-269.

14 Tolentino M. Systemic and ocular safety of intravitreal anti-VEGF therapies for ocular neovascular disease.

2011;56(2):95-113.

15 Nowak MS, Jurowski P, Grzybowski A, Go? R, Pastuszka M, Kapica A, ?migielski J. A prospective study on different methods for the treatment of choroidal neovascularization. The efficacy of verteporfin photodynamic therapy, intravitreal bevacizumab and transpupillary thermotherapy in patients with neovascular age-related macular degeneration.

2012;18(6):CR374-CR380.