Persistent macular oedema following Best vitelliform macular dystrophy undergoing anti-VEGF treatment

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.

教学反思是概率统计思维型课堂教学模式中不可少的一个环节。教师通过反思教学过程可以总结经验教训，为学生知识建构与思维发展寻找更快更好的途径；学生通过反思课堂学习的过程，可以更好地总结本节课所学到的知识方法，理清知识架构。思考过程中将新学的知识融入到旧的知识体系当中，回顾思维的过程，总结新的思维方法。

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

.

阳台上摆满了大大小小的盆花，势如花店。细数它们的来处，不外乎如下几种：有从花卉市场买回来的，有从同事那里剪枝扦插的，还有花草分蘖后分盆栽种的。养花，应以易活好养为首选，太娇贵难侍弄的，养起来是一种心理负担。以不菲的价格买回来，还需要你对光照、湿度、土壤等各方面的生存条件把握得准准的，否则稍微不合心意，它就会叶枯花落。不但糟蹋了花苗，自己内心也会生出深深的失落。所以，多养些不开花的绿叶植物，一年四季阳台上都绿意葱茏，偶尔花香飘溢，会满心欢喜。

（2）洞脸部位锚杆锁口。在结束洞口开挖作业后，需要随即进行素喷混凝土作业，当厚度达到5cm后,应展开锚杆锁口处理。基于洞口部位的不同，需要用不同的方式。对于洞顶区域而言，锁口锚杆只需布设一排，而侧面区域则需有所改变，应再增设一排，两排之间保持0.5m距离。锚杆使用的是规格为Φ20mm的螺纹钢，入岩深度为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).

另外乡村教师中还存在着相当一部分的民办教师和代课教师，这些教师无论在工资待遇，还是进修学习，更是没有机会进一步深造，大部分靠自己的已有经验和传统教学，整体素质不高。乡村条件有限，很少有年轻教师愿意到乡村任教，因此乡村教师普遍年龄偏大。这部分教师一般教育观念传统，教育方法落后，很难吸收先进的教育理念，这部分教师对新课改的适应能力较差。再加上许多乡村优秀教师考调到其它重点学校或中心城市学校之后，部分年龄偏大但想走又没办法离开的教师，很多便自暴自弃，甚至不思进取只想混天度日，盼望早日退休。这些教师不但整体素质不高，教学质量不高，而且其思想还会影响学生学习积极主动性的提高。

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